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Use of type 4 phosphodiesterase inhibitors in myocardial diseases |
The invention relates to the use of type 4 phosphodiesterase inhibitors to treat myocardial diseases. |
1. Use of a) compounds of formula I disclosed in EP 0763534 in which B is an aromatic heterocycle having 1 to 4 N, O and/or S atoms, bonded via N or C, which can be unsubstituted or mono-, di- or trisubstituted by HaI, A and/or OA, and can also be fused to a benzene or pyridine ring, Q is absent or is alkylene having 1-6 C atoms, X is CH2, S or O, R1 and R2 in each case independently of one another are H or A, R3 and R4 in each case independently of one another are —OH, OR5, —S—R5, —SO—R5, —SO2—R5, HaI, methylenedioxy, —NO2, —NH2, —NHR5 or —NR5R6, R5 and R6 in each case independently of one another are A, cycloalkyl having 3-7 C atoms, methylenecycloalkyl having 4-8 C atoms or alkenyl having 2-8 C atoms, A is alkyl having 1 to 10 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms and HaI is F, Cl, Br or I and their stereoisomers and physiologically acceptable, salts and solvates; b) compounds of formula I disclosed in WO 99/65880 in which B is a phenyl ring which is unsubstituted or mono- or polysubstituted by R3, Q is absent or is alkylene having 1-4 C atoms, R1,R2 each independently of one another are —OR4, —S—R4, —SO—R4, —SO2—R4 or HaI, R1 and R2 together are also —O—CH2—O—, R3 is R4, HaI, OH, OR4, OPh, NO2, NHR4, N(R4)2, NHCOR4, NHSO2R4 or NHCOOR4, R4 is A, cycloalkyl having 3-7 C atoms, alkylenecycloalkyl having 5-10 C atoms or alkenyl having 2-8 C atoms, A is alkyl having 1 to 10 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms and HaI is F, Cl, Br or I, and their physiologically acceptable salts and solvates; c) compounds of formula I disclosed in WO 00/26201 in which R1, R2 in each case independently of one another are —OH, OR5, —S—R5, —SO—R5, —SO2—R5 or HaI, R1 and R2 together are also —O—CH2—O—, R3 is NH2, NHA, NAA′ or a saturated heterocycle having 1 to 4 N, O and/or S atoms which can be unsubstituted or mono-, di- or tri-substituted by HaI, A and/or OA, Q is absent or is branched or unbranched alkylene having 1-10 C atoms, R5 is A, cycloalkyl having 3-7 C atoms, alkylenecycloalkyl having 4-8 C atoms or alkenyl having 2-8 C atoms, A, A′ in each case independently of one another are alkyl which has 1 to 10 C atoms and which can be substituted by 1 to 5 F and/or Cl atoms and HaI is F, Cl, Br or I, and the physiologically acceptable salts and solvates thereof; d) compounds of formula I disclosed in WO 98/06704 in which B is A, OA, NH2, NHA, NAA′ or an unsaturated heterocycle which has 1 to 4 N, O and/or S atoms and which can be unsubstituted or mono-, di- or trisubstituted by HaI, A and/or OA, Q is absent or is alkylene having 1-6 C atoms, R1, R2 in each case independently of one another are —OH, OR5, —S—R5, —SO—R5, —SO2—R5, HaI, —NO2, —NH2, —NHR5 or —NRR6, R1 and R2 together are also —O—CH2—O—, R3, R4 in each case independently of one another are H or A, R5, R6 in each case independently of one another are A, cycloalkyl having 3-7 C atoms, methylenecycloalkyl having 4-8 C atoms or alkenyl having 2-8 C atoms, A, A′ in each case independently of one another are alkyl which has 1 to 10 C atoms and which can be substituted by 1 to 5 F and/or Cl atoms and HaI is F, Cl, Br or I, and the stereoisomers and physiologically acceptable salts and solvates thereof; e) compounds disclosed in WO 00/59890 1-(4-ureidobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-nicotinoylaminobenzoyl)-3-(3-propoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-trifluoroacetamidobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-ethoxycarbonylaminobenzoyl)-3-(3-propoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-isopropoxycarbonylaminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-propoxycarbonylaminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-nicotinoylaminobenzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1,4,5,6-tetrahydropyridazine, 1-(4-ethoxycarbonylaminobenzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1,4,5,6-tetrahydropyridazine and 1-(4-acetamidobenzoyl)-3-(3,4-dimethoxyphenyl)-4-ethyl-1,4,5,6-tetrahydropyridazine, and their physiologically acceptable salts and solvates; f) compounds of formula I disclosed in DE 19604388 in which R1, R2 in each case independently of one another are H or A, R3, R4 in each case independently of one another are —OH, OA, —S-A, —SO-A, —SO2-A, HaI, methylenedioxy, —NO2, —NH2, —NHA or —NAA′, A, A′ in each case independently of one another are alkyl having 1 to 10 C-atoms, and which can be substituted by 1 to 5 F and/or Cl atoms, cycloalkyl having 3-7 C atoms or methylenecycloalkyl having 4-8 C atoms, B is —Y—R5 oder —O—Y—R5, Q is absent or is alkylene having 1-4 C atoms, Y is absent or is alkylene having 1-10 C atoms, X is CH2or S, R5 is NH2, NHA, NAA′ or is a saturated 3-8 membered heterocycle having at least one N atom, and wherein other CH2 groups optionally may be replaced by NH, NA, S or O, which can be unsubstituted or monosubstituted by A or OH, HaI is F, Cl, Br oder I and the stereoisomers and physiologically acceptable salts and solvates thereof; g) compounds of formula I disclosed in DE 19932315 in which R1, R2 in each case independently of one another are H, OH, OA, SA, SOA, SO2A, F, Cl or A′2N—(CH2)n—O—, R1 and R2 together are also —O—CH2—O—, R3, R4 in each case independently of one another are H, A, HaI, OH, OA, NO2, NHA, NA2, CN, COOH, COOA, NHCOA, NHSO2A or NHCOOA, R5, R6 in each case independently of one another are H or alkyl having 1 to 6 C atoms, A is alkyl having 1 to 10 C atoms, which can be substituted by 1 to 5 F and/or Cl atoms, is cycloalkyl having 3-7 C atoms, alkylenecycloalkyl having 5-10 C atoms or alkenyl having 2-8 C atoms, A′ is alkyl having 1, 2, 3, 4, 5 or 6 C atoms, n is 1, 2, 3 or 4, HaI is F, Cl, Br or I, and their physiologically acceptable salts and solvates; h) compounds of formula I disclosed in EP 0723962 in which R1 and R2 in each case independently of one another are H or A, R3 and R4 in each case independently of one another are —OH, —OR10, —S—R10, —SO—R10, —SO2R10, HaI, methylenedioxy, —NO2, —NH2, —NHR10 or —NR10R11, R5 is a phenyl radical which is unsubstituted or mono- or disubstituted by R6 and/or R7, Q is absent or is alkylene having 1-6 C atoms, R6 and R7 in each case independently of one another are —NH2, —NR8R9, —NHR10, —NR10R11, —NO2, HaI, —CN, —OA, —COOH or —COOA, R8 and R9 in each case independently of one another are H, acyl having 1-8 C atoms which can be substituted by 1-5 F and/or Cl atoms, —COOA, —S-A, —SO-A, —SO2A, —CONH2, —CONHA, —CONA2, —CO—COOH, —CO—COOA, —CO—CONH2, —CO—CONHA or —CO—CONA2, A is alkyl having 1 to 6 C atoms which can be substituted by 1-5 F and/or Cl atoms, R10 and R11 in each case independently of one another are A, cycloalkyl having 3-7 C atoms, methylenecycloalkyl having 4-8 C atoms or alkenyl having 2-8 C-atoms and HaI is F, Cl, Br or I, and their physiologically acceptable salts and solvates; i) compounds of formula I disclosed in EP 0738715 in which R1 and R2 in each case independently of one another are H or A, R3 and R4 in each case independently of one another are —OH, —OR10, —S—R10, —SO—R10, —SO2R10, HaI, methylenedioxy, —NO2, —NH2, —NHR10 or —NR10R11, R5 is a phenyl radical which is unsubstituted or mono- or disubstituted by R6 and/or R7, Q is absent or is alkylene having 1-6 C atoms, R6 and R7 in each case independently of one another are —NH2, —NR8R9, —NHR10, —NR10R11, —NO2, HaI, —CN, —OA, —COOH or —COOA, R8 and R9 in each case independently of one another are H, acyl having 1-8 C atoms which can be substituted by 1-5 F and/or Cl atoms, —COOA, —SO-A, —SO2A, —CONH2, —CONHA, —CONA2, —CO—COOH, —CO—COOA, —CO—CONH2, —CO—CONHA or —CO—CONA2, A is alkyl having 1 to 6 C atoms which can be substituted by 1-5 F and/or Cl atoms, R10 and R11 in each case independently of one another are A, cycloalkyl having 3-7 C atoms, methylenecycloalkyl having 4-8 C atoms or alkenyl having 2-8 C-atoms and HaI is F, Cl, Br or I, and their physiologically acceptable salts and solvates; for preparing a medicament for treating myocardial diseases. 2. Use according to claim 1 of a) compounds disclosed in EP 0763534: 2-(3-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(2-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(3-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(2-nicotinoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-methoxy-4-trifluoromethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-methoxy-4-difluoromethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-methoxy-4-fluoromethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-difluoromethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-trifluoromethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-fluoromethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-methoxy-4-ethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-hydroxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(4-methylsulfonylphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(4-methyleneoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(3-nicotinoylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminophenethyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminophenethyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 3-(4-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(3-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(2-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(3-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(2-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-methoxy-4-trifluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-methoxy-4-difluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-difluoromethoxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-trifluoromethoxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-fluoromethoxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-methoxy-4-ethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-ethoxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-ethoxy-4-methoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-hydroxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(4-methysulfonylphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(4-methyleneoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-cyclopentyloxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(3-nicotinoylaminobenzyl)-5-(3-cyclopentyloxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminophenethyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminophenethyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(3-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(2-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(3-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(2-nicotinoylaminobenzyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-methoxy-4-trifluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-methoxy-4-difluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-methoxy-4-fluoromethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-difluoromethoxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-trifluoromethoxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-fluoromethoxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-methoxy-4-ethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-ethoxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-hydroxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(4-methylsulfonylphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(4-methyleneoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminobenzyl)-5-(3-cyclopentyloxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(3-nicotinoylaminobenzyl)-5-(3-cyclopentyloxy-4-methoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminophenethyl)-5-(3,4-dimethoxyphenyl)-3,6-dihydro-1,3,4-oxadiazin-2-one, 3-(4-nicotinoylaminophenethyl)-5-(3,4-dimethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-oxadiazin-2-one, 2-(3-nicotinoylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-isonicotinoylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pyrazinecarbonylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-(isoxazole-5-carbonylamino)benzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-nicotinoylaminobenzyl)-6-(3,4,-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, hydrochloride, and their stereoisomers and physiologically acceptable, salts and solvates; b) compounds disclosed in WO 99/65880 N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-4-methoxybenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-4-methylbenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)benzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-3,4-dichlorobenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-4-trifluoromethylbenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-3-chlorobenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-4-fluorobenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-4-butoxybenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-4-pentoxybenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-4-ethoxybenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-3,4-dimethoxybenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-3-methylbenzoyl-3-carboxamide, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-3-methoxybenzoyl-3-carboxamide, and their physiologically acceptable salts and solvates; c) compounds disclosed in WO 00/26201 3-dimethylaminopropyl{4-[3-(3-ethoxy-4-methoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, N-methylpiperidin-4-yl-{4-[3-(3-ethoxy-4-methoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, 3-dimethylaminopropyl{4-[3-(3-isopropoxy-4-methoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, 3-dimethylaminopropyl{3-[3-(3-ethoxy-4-methoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, 3-dimethylaminopropyl{3-[3-(3-cyclopentyloxy-4-methoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, N-methylpiperidin-4-yl-{3[3-(3-cyclopentyloxy-4-methoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, 3-dimethylaminopropyl{3-[3-(3-propyloxy-4-methoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, 3-dimethylaminopropyl{4-[3-(3,4-diethoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, N-methylpiperidin-4-yl-{4-[3-(3,4-diethoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, 3-dimethylaminopropyl{3-[3-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate 3-dimethylaminopropyl{4-[3-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydropyridazin-1-ylcarbonyl]phenyl}carbamate, and the physiologically acceptable salts and solvates thereof; d) compounds disclosed in WO 98/06704 1-(4-nicotinoylaminobenzoyl)-3-(3,4-dimethoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(3-nicotinoylaminobenzoyl)-3-(3,4-dimethoxy-phenyl)-1,4,5,6-tetrahydropyridazine hydrochloride, 1-(2-nicotinoylaminobenzoyl)-3-(3,4-dimethoxy-phenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-nicotinoylaminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(3-nicotinoylaminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-nicotinoylaminobenzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(3-nicotinoylaminobenzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-nicotinoylaminobenzoyl)-3-(3,4-methylene-dioxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-nicotinoylaminobenzoyl)-3-(3-methoxy-4-methylsulfonylphenyl)-1,4,5,6-tetrahydro-pyridazine, 1-(4-nicotinoylaminobenzoyl)-3-(3-trifluoro-methoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, 1-(4-ethoxy-carbonylaminobenzoyl)-3-(3,4-dimethoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(3-ethoxycarbonylaminobenzoyl)-3-(3,4-dimethoxy-phenyl)-1,4,5,6-tetrahydropyridazine, 1-(2-ethoxycarbonylaminobenzoyl)-3-(3,4-dimethoxy-phenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-ethoxycarbonylaminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(3-ethoxycarbonylaminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-ethoxycarbonylaminobenzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, 1-(3-ethoxycarbonylaminobenzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, 1-(4-ethoxycarbonylaminobenzoyl)-3-(3,4-methylene-dioxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-ethoxycarbonylaminobenzoyl)-3-(3-methoxy-4-methylsulfonylphenyl)-1,4,5,6-tetrahydro-pyridazine, 1-(4-ethoxycarbonylaminobenzoyl)-3-(3-trifluoro-methoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, and the stereoisomers and physiologically acceptable salts and solvates thereof; e) compounds disclosed in EP 0723962 3-(4-ethoxycarbonylaminobenzyl)-5-(3-ethoxy-4-methoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, 3-(4-ethoxycarbonylaminobenzyl)-5-(3-cyclopentyloxy-4-methoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, and their physiologically acceptable salts and solvates; f) compounds disclosed in EP 0738715 2-(4-butyrylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-acetamidobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-trifluoroacetamidobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methylsulfonamidobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-propionylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-tert-butylcarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-isobutyrylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxycarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pivalylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-cyclopentylcarbamoylbenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ethoxycarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxalylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ureidobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentanoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-hexanoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropiridazin-3-one, 2-(4-pentafluoropropionylaminobenzyl)-6-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-acetamidobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-trifluoroacetamidobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methylsulfonamidobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-propionylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-tert-butylcarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-butyrylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-isobutyrylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxycarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pivalylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-cyclopentylcarbamoylbenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ethoxycarbonylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxalylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ureidobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentanoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-hexanoylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentafluoropropionylaminobenzyl)-6-(3,4-dimethoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-acetamidobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-trifluoroacetamidobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methylsulfonamidobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-propionylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-butyrylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-isobutyrylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxycarbonylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pivalylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-cyclopentylcarbamoylbenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ethoxycarbonylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4, 5-tetrahydropyridazin-3-one; 2-(4-methoxalylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ureidobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentanoylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-hexanoylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentafluoropropionylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-acetamidobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-trifluoroacetamidobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methylsulfonamidobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-propionylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-tert-butylcarbonylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-butyrylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-isobutyrylaminobenzyl)-6(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxycarbonylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pivalylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-cyclopentylcarbamoylbenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ethoxycarbonylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxalylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ureidobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentanoylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-hexanoylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentafluoropropionylaminobenzyl)-6-(3-cyclopentyloxy-4-methoxyphenyl)-5-ethyl-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-acetamidobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-trifluoroacetamidobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methylsulfonamidobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-propionylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-butyrylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-isobutyrylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxycarbonylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pivalylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-cyclopentylcarbamoylbenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ethoxycarbonylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-methoxalylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-ureidobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentanoylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-hexanoylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, 2-(4-pentafluoropropionylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, and their physiologically acceptable salts and solvates; for preparing a medicament for treating myocardial diseases. 3. Use according to claim 1 of compounds selected from 3-(4-nicotinoylaminobenzyl)-5-(3-ethoxy-4-methoxyphenyl)-3,6-dihydro-1,3,4-thiadiazin-2-one, N-(3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazin-1-ylcarbonyl)phenyl)-4-methoxybenzoyl-3-carboxamide, 1-(4-nicotinoylaminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 1-(4-ethoxycarbonylaminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridazine, 2-(4-ethoxycarbonylaminobenzyl)-6-(3-ethoxy-4-methoxyphenyl)-2,3,4,5-tetrahydropyridazin-3-one, and their physiologically acceptable salts and solvates; for preparing a medicament for treating myocardial diseases. 4. Use according to claim 1 for preparing a medicament for treating myocardial diseases, where said myocardial diseases show inflammatory and immunological characteristics. 5. Use according to claim 1 for preparing a medicament for treating coronary artery disease, reversible or irreversible myocardial ischemia/reperfusion injury, acute or chronic heart failure and restenosis, including instent-restenosis and stent-in-stent-restenosis. |
Substrate processing method and substrate processing apparatus |
In a substrate processing apparatus, a control electrode (131) separates a process space (11C) including a substrate to be processed and a plasma formation space (11B) not including the substrate. The control electrode includes a conductive member formed in a processing vessel and having a plurality of apertures (131a) for passing plasma. A surface of the control electrode is covered by an aluminum oxide or a conductive nitride. In the substrate processing apparatus, a gas containing He and N2 is supplied into the processing vessel. In the plasma formation space, there is formed plasma under a condition in which atomic state nitrogen N* are excited. The atomic state nitrogen N* are used to nitride a surface of the substrate. |
1. A method of processing a substrate by using a substrate processing apparatus which has such a construction that a process space, in which a substrate to be processed is contained, is separated from plasma formation space, in which the substrate to be processed is not contained, by a control electrode in a processing vessel, characterized by the steps of: supplying a gas containing He and N2 to said processing vessel; forming plasma in said plasma formation space under a condition such that there is caused excitation of atomic state nitrogen N* in said plasma; and nitriding a surface of the substrate to be processed by said atomic state nitrogen N* in said process space. 2. The substrate processing method as claimed in claim 1, characterized in that said step of forming plasma is conducted such that an intermediate excitation state of the energy of 23 to 25 eV is realized. 3. The substrate processing method as claimed in claim 1, characterized in that said step of forming plasma comprises the step of supplying a microwave to said plasma formation space. 4. The substrate processing method as claimed in claim 3, characterized in that said step of supplying microwave is conducted by driving a radial line slot antenna. 5. The substrate processing method as claimed in claim 1, characterized in that said step of forming plasma comprises the step of forming an induction magnetic field in said plasma formation space. 6. The substrate processing method as claimed in claim 5, characterized in that said step of forming an induction magnetic field comprises the step of driving an induction coil wound around said processing vessel by a high frequency electric power. 7. The substrate processing method as claimed in claim 1, characterized in the said control electrode is grounded during said step of exciting plasma. 8. The substrate processing method as claimed in claim 1, characterized in that a negative potential is supplied to said control electrode in said step of forming plasma. 9. The substrate processing method as claimed in claim 1, wherein said gas supplied to said processing vessel further contains O2. 10. A substrate processing apparatus, comprising: a processing vessel defined by an outer wall and having a stage for holding a substrate to be processed thereon; an evacuation system coupled to said processing vessel; a plasma gas supplying part supplying a plasma excitation gas and a process gas into said processing vessel; a microwave window provided on said processing vessel so as to face said substrate to be processed; and a control electrode provided between said substrate to be processed on said stage and said plasma gas supplying part so as to face said substrate to be procesed, and separating a plasma excitation space containing said microwave window and a process space containing said substrate to be processed, said control electrode comprising a conductive member having a plurality of apertures for passing plasma formed in said processing vessel therethrough, and a surface of said control electrode being covered by any of aluminum oxide or electrically conductive nitride. 11. The substrate processing apparatus as claimed in claim 10, characterized in that said control electrode has a lattice-shaped form and is grounded. 12. The substrate processing apparatus as claimed in claim 10, characterized in that said control electro has a form of a lattice-like shape and said substrate processing apparatus comprises a negative voltage source connected to said control electrode. 13. The substrate processing apparatus as claimed in claim 10, characterized in that an inner wall of said processing vessel is covered with an insulation film in said plasma excitation space. 14. The substrate processing apparatus as claimed in claim 10, characterized by further comprising a microwave antenna coupled to said microwave window at an outer side of said processing vessel. 15. A substrate processing apparatus, characterized by: a processing vessel defined by a wall of quartz glass and having a stage for holding a substrate to be processed; an evacuation system coupled to said processing vessel; a plasma gas supplying part supplying a plasma excitation gas and a process gas to said processing vessel; a control electrode provided so as to face said substrate to be processed on said stage and dividing an interior of said processing vessel into a process space containing said substrate to be processed and a plasma excitation space; and an induction coil provided outside said quartz glass wall in correspondence to said plasma excitation space, said control electrode comprising a conductive member having a plurality of apertures passing therethrough plasma formed in said processing vessel, and a surface of said control electrode being covered with any of aluminum oxide or electrically conductive nitride. 16. The substrate processing apparatus as claimed in claim 15, characterized in that said quartz glass wall defines a dome-like space. 17. The substrate processing apparatus as claimed in claim 15, characterized in that said control electrode is grounded. 18. The substrate processing apparatus as claimed in claim 15, characterized in that said control gate is connected to a negative voltage source. |
<SOH> BACKGROUND ART <EOH>FIG. 1 shows the schematic construction of a conventional induction-coupled plasma processing apparatus 1 . Referring to FIG. 1 , the plasma processing apparatus 1 includes a processing vessel 2 of a quartz dome evacuated by an evacuation line 2 A, and there is provided a stage 3 in a process space 2 B defined by the processing vessel 2 such that the stage 2 is rotated by a rotating mechanism 3 A. Further, a substrate 4 is held on the stage 3 . Further, an inert gas such as Ar and a process gas such as oxygen or nitrogen are supplied to the process space 2 B via a process gas supply line 2 C. Further, there is provided a coil 5 around the top part of the processing vessel 2 at the outside thereof, and high-density plasma 2 D is inducted at the top part of the process space 2 B by driving the coil 5 by a d.c. power source. In the plasma processing apparatus 1 of FIG. 1 , the radicals of the process gas formed with the high-density plasma 2 D reach the surface of the substrate 4 and the substrate processing such as oxidation or nitridation is achieved. In such a conventional induction-coupled plasma processing apparatus 1 , on the other hand, there exists a drawback in that the high-density plasma 2 D is localized at the top part of the processing vessel and there appears an extremely non-uniform distribution in the radicals that are formed with the plasma. Particularly, the non-uniformity of the radical concentration in the radial direction of the substrate is not resolved even when the stage 3 is rotated by the rotating mechanism 3 A. Thus, in the conventional induction-coupled plasma processing apparatus 1 , the plasma processing apparatus was designed such that the substrate 4 is separated from the region in which the high-density plasma 2 D is formed with a large distance for realizing as uniform radical concentration distribution as possible at the surface of the substrate 4 . As a result of such a construction, on the other hand, the overall size of the substrate processing apparatus 1 is increased inevitably. Further, the amount of the radicals reaching the substrate 4 is reduced. These problems become particularly serious in the technology of current trend of processing a large-diameter substrate. On the other hand, there is a proposal of a microwave plasma processing apparatus that uses high-density plasma induced, not by an induction magnetic field but by a microwave electric field. For example, there is proposed a plasma processing apparatus that uses a planar antenna (radial line slot antenna) having a large number of slots arranged so as to produce a uniform microwave, for emitting a microwave into a processing vessel. In this apparatus, the microwave electric field thus induced is used to excite plasma by causing ionization in the gas in the vacuum vessel. Reference should be made to Japanese Laid-Open Patent Application 9-63793. By using the microwave plasma excited according to such a process, it becomes possible to realize a high-plasma density over a wide area right underneath the antenna, and uniform plasma processing becomes possible with short time period. Further, the microwave plasma thus excited has an advantageous feature of low electron temperature as a result of excitation of the plasma by using a microwave, and it becomes possible to avoid the problem of damages or metal contamination caused in the substrate. Further, it becomes possible to excite uniform plasma over a substrate of large area, and thus, the plasma processing apparatus can easily handle the fabrication of semiconductor devices on a large-diameter semiconductor wafer or fabrication of large flat panel display devices. FIG. 2 shows the construction of a microwave plasma processing apparatus 10 that uses such a radial line slot antenna as proposed before by the inventor of the present invention. Referring to FIG. 2 , the microwave plasma processing apparatus 10 includes a processing chamber 11 evacuated at a plurality of evacuation ports 11 a , and there is provided a stage 13 inside the processing chamber 11 for supporting a substrate 12 to be processed. In order to achieve uniform evacuation of the processing chamber 11 , there is provided a ring-shaped space 11 A around the stage 13 , and the processing chamber 11 is evacuated uniformly via the space 11 A and further via the evacuation ports 11 a by arranging the evacuation ports 11 a communicating with the space 11 A in axial symmetry with respect to the substrate. On the processing chamber 11 , there is provided a plate-like shower plate 14 formed of a low-loss dielectric such as Al 2 O 3 or SiO 2 as a part of the outer wall of the processing chamber 11 at a location facing the substrate 12 held on the stage 13 , wherein the shower plate 14 is provided via a seal ring not illustrated and includes a number of apertures 14 A. Further, a cover plate 15 also of a low-loss dielectric such as Al 2 O 3 or SiO 2 is provided at the outer side of the shower plate 14 via another seal ring not illustrated. The shower plate 14 is provided with a gas passage 14 B at a top surface thereof, and each of the apertures 14 A are provided so as to communicate with the gas passage 14 B. Further, there is provided a gas supply passage 14 C in the interior of the shower plate 14 in communication with a gas supply port lip provided at an outer wall of the processing vessel 11 . Thus, the plasma-excitation gas such as Ar or Kr supplied to the gas supply port 11 p is forwarded to the apertures 11 A via the supply passage 14 C and further via the passage 14 B and is released to the process space 11 B right underneath the shower plate 14 inside the processing vessel 11 from the foregoing apertures 14 A. On the processing vessel 11 , there is further provided a radial line slot antenna 20 at the outer side of the cover plate 15 with a separation of 4-5 mm from the cover plate 15 . The radial line slot antenna 20 is connected to an external microwave source (not illustrated) via a coaxial waveguide 21 and causes excitation of the plasma-excitation gas released into the process space 11 B by the microwave from the microwave source. It should be noted that the cover plate 15 and the radiation surface of the radial line slot antenna are contacted closely, and there is provided a cooling block 19 on the antenna 20 for cooling the antenna. The cooling block 19 includes a cooling water passage 19 A. The radial line slot antenna 20 is formed of a flat, disk-shaped antenna body 17 connected to an outer waveguide tube 21 A of the coaxial waveguide 21 and a radiation plate 16 provided at the opening of the antenna body 17 , wherein the radiation plate 16 is formed with a number of slots and a retardation plate of a dielectric plate having a constant thickness is interposed between the antenna body 17 and the radiation plate 16 . In the radial line slot antenna 20 having such a construction, the microwave fed thereto from the coaxial waveguide 21 propagates along a path between the disk-shaped antenna body 17 and the radiation plate 16 in the radial direction, wherein the microwave thus propagating undergoes compression of wavelength as a result of the existence of the retardation plate 18 . Thus, by forming the slots concentrically in correspondence to the wavelength of the microwave thus propagating in the radial direction, and by forming the slots so as to form a perpendicular angle with each other, it becomes possible to emit a plane wave having a circular polarization from the radial line slot antenna 20 in the direction substantially perpendicular to the radiation plate 16 . By using such a radial line slot antenna 20 , there is formed uniform high-density plasma in the process space 11 B right underneath the shower plate 14 . The high-density plasma thus formed has a feature of low electron temperature and the occurrence of damages in the substrate 12 to be processed is avoided. Further, there occurs no metal contamination caused by sputtering of the chamber wall of the processing vessel 11 . Thus, by supplying a process gas, such as an O 2 gas, an NH 3 gas, or a mixed gas of an N 2 gas and an H 2 gas, to the gas inlet port 11 p of the substrate processing apparatus 10 of FIG. 2 in addition to the plasma-excitation gas such as Ar or Kr, there is caused an excitation of active species such as atomic state oxygen O* or hydrogen nitride radicals NH* in the process space 11 B by the high-density plasma, and it becomes possible to conduct oxidation processing, nitridation processing or oxynitridation processing on the surface of the substrate 12 . Further, there is proposed a substrate processing apparatus 10 A shown in FIG. 3 having a construction similar to the substrate processing apparatus 10 of FIG. 2 except that there is provided a lower shower plate 31 at the lower side of the shower plate 14 . The lower shower plate 31 is provided with a process gas passage 31 A communicating with a process gas inlet port 11 r formed at the surface of the processing vessel 1 and a large number of process gas inlet nozzle openings 31 B are formed in communication with the process gas passage 31 A. Further, the lower shower plate 31 is provided with large apertures for passing the process gas radicals formed in the space 11 B. Thus, in the substrate processing apparatus 10 A of FIG. 3 , there is defined another process space 11 C underneath the lower shower plate 31 . By forming the lower shower plate 31 by a conductive material such as a stainless steel having a passivation surface by aluminum oxide (Al 2 O 3 ) in such an apparatus, it becomes possible to block the penetration of microwave to the process space 11 C. Thereby, the excitation of plasma is limited in the process space 11 B right underneath the upper shower plate 14 , and the radicals Kr* of Kr or Ar* of Ar penetrate into the process space 11 C through the large apertures formed in the shower plate 31 after excitation in the space 11 B. The radicals Kr* or Ar* thus penetrated into the process space 11 C cause activation of the process gas released from the nozzle apertures 31 B, and the processing of the substrate 12 is achieved by the process gas radicals thus activated. In the substrate processing apparatus 10 A of FIG. 3 , it should be noted that the microwave is expelled from the process space 11 C by forming the lower shower plate 31 by a conductive material, and the damaging of the substrate by microwave is avoided. In the substrate processing apparatus 10 A of FIG. 3 , it is also possible to conduct a plasma CVD process by introducing a CVD source gas from the lower shower plate 31 . Further, it is possible to conduct a dry etching process by introducing a dry etching gas from the lower shower plate 31 and applying a high-frequency bias to the stage 13 . Thus, in the substrate processing apparatus of FIG. 2 of FIG. 3 , Kr radicals (Kr*) of intermediate excitation state having an energy of about 10 eV are excited at the time of conducting an oxidation processing, by introducing a Kr gas and an oxygen gas into the process space 11 B. The Kr radicals thus excited cause efficient excitation of atomic state oxygen O* according to the reaction in-line-formulae description="In-line Formulae" end="lead"? O 2 →O*+O*, in-line-formulae description="In-line Formulae" end="tail"? while the atomic state oxygen O* thus excited cause the desired oxidation of the surface of the substrate 12 . In the case of conducting a nitridation processing of the substrate 12 , a Kr gas and an ammonia gas, or a Kr gas and a nitrogen gas and a hydrogen gas are introduced. In this case, the excited Kr radicals (Kr*) or Ar radicals (Ar*) cause the excitation of hydrogen nitride radicals NH* according to the reaction in-line-formulae description="In-line Formulae" end="lead"? NH 3 →NH*+2H*+ e − , in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? or in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? N 2 +H 2 →NH*+NH*, in-line-formulae description="In-line Formulae" end="tail"? wherein the hydrogen nitride radicals thus excited cause the desired nitridation processing of the substrate of the surface 12 . Meanwhile, there are cases in which it is preferable to use atomic state nitrogen (N*), free from hydrogen and having a strong nitriding power, at the time of the nitridation processing of the substrate. The atomic state nitrogen N* are formed according to the reaction in-line-formulae description="In-line Formulae" end="lead"? N 2 →N*+N*, in-line-formulae description="In-line Formulae" end="tail"? wherein it should be noted that such a reaction requires the energy of 23-25 eV. This means that it is not possible to excite the atomic state nitrogen N* according to the foregoing reaction, as long as Kr or Ar plasma is used. As noted previously, the energy of the Kr radicals or Ar radicals obtained by the Kr or Ar plasma is merely in the order of 10 eV. Thus, even when there is made an attempt to supply a nitrogen gas in the substrate processing apparatus of FIG. 2 or FIG. 3 in place of the Kr gas or the Ar gas, merely the reaction in-line-formulae description="In-line Formulae" end="lead"? N 2 →N 2 + +e − , in-line-formulae description="In-line Formulae" end="tail"? is obtained, and there is caused no desired atomic state oxygen N*. FIG. 4 shows the relationship between the state density of the Kr plasma and the excitation energy of the atomic state nitrogen N*, hydrogen nitride radicals NH* and nitrogen atoms N 2 + . Referring to FIG. 4 , it can be seen that the state density of the Kr plasma is large at the low energy side, while the state density shows a rapid decrease with increase of the energy. Such a plasma cannot achieve efficient excitation of the desired nitrogen radicals. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a diagram showing the construction of a conventional induction coupled plasma processing apparatus; FIG. 2 is a diagram showing the construction of a previously proposed microwave substrate processing apparatus; FIG. 3 is a diagram showing the construction of another previously proposed microwave substrate processing apparatus; FIG. 4 is a diagram explaining the characteristics of plasma excitation in the microwave substrate processing apparatus of FIG. 2 or FIG. 3 ; FIG. 5 is a diagram showing the construction of a microwave substrate processing apparatus according to a first embodiment of the present invention; FIG. 6 is a diagram showing a part of the microwave substrate processing apparatus of FIG. 5 ; FIG. 7 is a diagram showing the characteristics of plasma excitation in the microwave substrate processing apparatus of FIG. 5 ; FIG. 8 is a diagram showing a modification of the microwave plasma processing apparatus of FIG. 5 ; FIG. 9 is a diagram showing the construction of a microwave plasma processing apparatus according to a second embodiment of the present invention; and FIG. 10 is a diagram showing the construction of an induction coupled plasma processing apparatus according to a third embodiment of the present invention. detailed-description description="Detailed Description" end="lead"? |
Immunogenic compositions comprising an antigen and a purified m protein from respiratory syncytial virus |
Methods and compositions for enhancing an immune response to an antigen in a host are provided. Immunogenic composition comprising an antigen and an amount of purified M protein from respiratory syncytial virus are provided in a pre-selected amount to provide an enhanced immune response to said antigen in a host having a pre-existing respiratory syncytial virus M-specific immune response. The antigen can be an antigen from Respiratory syncytial virus. |
1. An immunogenic composition comprising an antigen and an amount of purified M protein from respiratory syncytial virus or at least one immunoeffective fragment thereof, wherein the amount of said M protein or immunoeffective fragment is provided in a pre-selected amount to provide an enhanced immune response to said antigen in a host having a pre-existing respiratory syncytial virus M-specific immune response. 2. The immunogenic composition of claim 1 wherein said antigen is from a pathogen. 3. The immunogenic composition of claim 1 formulated as a vaccine. 4. The immunogenic composition of claim 1 wherein said antigen or at least one immunogenic fragment thereof, is a protein antigen selected from the group consisting of, a viral antigen, a bacterial antigen, a respiratory syncytial virus antigen, a respiratory syncytial virus G antigen substantially free from respiratory syncytial virus F antigen, respiratory syncytial virus F antigen substantially free from respiratory syncytial virus G antigen, or a respiratory syncytial virus M22 antigen. 5. The immunogenic composition of claim 1 wherein said pre-existing respiratory syncytial virus M-specific immune response is a T-cell immune response. 6. The immunogenic composition of claim 1 wherein the amount of purified M protein is about 0.1 μg to about 1,000 μg per dose. 7. The immunogenic composition of claim 6 wherein the amount of purified M protein is about 1 μg to about 100 μg per dose. 8. The immunogenic composition of claim 7 wherein the amount of purified M protein is about 1 μg to about 50 μg per dose. 9. The immunogenic composition of claim 1 wherein the purified M protein is greater than 50% pure as measured by SDS-PAGE analysis or in an M-specific ELISA assay. 10. The immunogenic composition of claim 9 wherein the purity is greater that 70%. 11. The immunogenic composition of claim 10 wherein the purity is greater that 90%. 12. A method of making a immunogenic composition comprising providing an antigen and an amount of purified M protein from from respiratory syncytial virus or at least one immunoeffective fragment thereof, wherein the amount of said M protein or immunoeffective fragment is provided in a pre-selected amount to provide an enhanced immune response to said antigen in a host having a pre-existing respiratory syncytial virus M-specific immune response. 13. The method of claim 12 further formulated with a pharmaceutically acceptable carrier to provide a vaccine. 14. A method of immunizing a host comprising administering the immunogenic composition of claim 1 to said host. 15. A method of enhancing an immune response to an antigen in a host having a pre-existing immune response to respiratory syncytial virus M protein comprising the steps of: i) purifying M protein of respiratory syncytial virus; ii) mixing a pre-selected amount of said purified M protein with a different antigen; iii) formulating said mixture as a vaccine; and iv) administering said vaccine to a host. 16. The immunogenic composition of claim 1 wherein the antigen is encoded by a nucleic acid vector comprising an antigen encoding portion and a promoter to effect expression of the antigen encoding portion in the host. 17. The use of a pre-selected amount of purified M from respiratory syncytial virus or immunoeffective fragments thereof, to enhance the immune response to an antigen in a host having a pre-existing respiratory syncytial virus M-specific immune response. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Adjuvants have been used for many years to improve the host immune response to antigens of interest in vaccines, especially subunit or component vaccines comprised of recombinant proteins. Adjuvants are immunomodulators that are typically non-covalently linked to antigens and are formulated to enhance the host immune response. Examples include aluminum hydroxide and aluminum phosphate (collectively commonly referred to as alum). While little or no systemic toxicity is observed with alum, its use is associated with local reactions such as erythema, subcutaneous nodules, contact hypersensitivity and granulomatous inflammation. Such local reactions may be of particular concern in the context of frequent, e.g., annual immunizations. Adjuvants enhance the immunogenicity of an immunogen but are not necessarily immunogenic themselves. Adjuvants have been identified that enhance the immune response to antigens delivered parenterally. Some of these adjuvants are toxic, however, and can cause undesirable side-effects making them unsuitable for use in humans and many animals. Indeed, only aluminum hydroxide and aluminum phosphate (collectively commonly referred to as alum) are routinely used as adjuvants in human and veterinary vaccines. To efficiently induce humoral immune responses (HIR) and cell-mediated immunity (CMI), immunogens (antigens) are often emulsified in adjuvants. Many adjuvants are toxic, inducing granulomas, acute and chronic inflammations (Freund's complete adjuvant, FCA), cytolysis (saponins and pluronic polymers) and pyrogenicity, arthritis and anterior uveitis (LPS and MDP). Although FCA is a potent adjuvant and widely used in research, it is not licensed for use in human or veterinary vaccines because of its toxicity. Human Respiratory Syncytial Virus (RSV) is a major cause of respiratory tract infections. Globally, 65 million infections occur every year resulting in 160,000 deaths (ref. 1; a list of references appears at the end of the disclosure and each of the references in the list is incorporated herein by reference thereto.) In the USA alone 100,000 children, may require hospitalization for pneumonia and bronchiolitis caused by RSV in a single year (refs. 2). Providing inpatient and ambulatory care for children with RSV infections costs in excess of $340 million annually in the USA. RSV is a major cause of serious lower respiratory illness in elderly and immunocompromised adults (refs. 3). Outbreaks in nursing or retirement homes are well documented (ref. 3) and a significant proportion of disease involving the lower respiratory tract in outbreaks were associated with mortality. Approximately 7% of hospitalized community acquired pneumonias have been attributed to RSV (ref. 4). Mortality due to RSV may exceed that due to influenza by 60 to 80% (ref. 5) The annual costs attributed to hospitalizations for RSV pneumonia in the elderly in the USA has been conservatively estimated at between $150 to $680 million (ref. 6). An RSV vaccine could therefore play an important role in lessening morbidity and mortality in the elderly and decreasing health care costs. RSV is an enveloped RNA virus of the family paramyxoviridae and of the genus pneumovirus. The structure and composition of RSV has been elucidated and is described in detail in the textbook “Fields Virology”, Fields, B.N. Raven Press, N.Y. (1996), pp 1313-1351 “Respiratory Syncytial Virus” by Collins, P., McIntosh, K., and Chanock, R. M. (ref. 7). Cross neutralization studies have shown that RSV isolates can be classified into two major antigenic groups, designated A and B. (ref. 8) The G glycoprotein shows the greatest divergence between groups showing 53% amino acid homology between RSV A and B. (ref. 9) The two major protective antigens of RSV are the envelope fusion (F) and the attachment (G) glycoproteins (ref. 10). The F protein is synthesized as an about 68 kDa precursor molecule (Fo) which is proteolytically cleaved into disulfide-linked F1 (about 48 kDa) and F2 (about 20 kDa) polypeptide fragments (ref. 11). The G protein (about 33 kDa) is heavily O-glycosylated giving rise to a glycoprotein of apparent molecular weight of about 90 kDa (ref. 12). Two broad subtypes of RSV have been defined A and B (ref. 13). The major antigenic differences between these subtypes are found in the G glycoprotein while the F glycoprotein is more conserved (refs. 14). Antibodies directed against the F protein or against the G protein can neutralize the virus. Antibodies to the F protein block the spread of the virus between cells. In addition to the antibody response generated by the F and G glycoproteins, human cytotoxic T cells produced by RSV infection have been shown to recognize the RSV F protein, matrix protein (M), 22 k protein (M22) nucleoprotein (N), small hydrophobic protein (SH), and the nonstructural protein (lb.) (ref 15). The human RSV M gene coding for the matrix protein has been sequenced (ref 18). It would be desirable to enhance the immune response to an antigen, in particular an RSV antigen to provide a more efficacious vaccine. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides methods and compositions of enhancing the response to vaccines. Accordingly, in one aspect of the present invention there is provided an immunogenic composition comprising an antigen and an amount of purified M protein from respiratory syncytial virus or at least one immunogenic fragment thereof, wherein the amount of said M protein or immunogenic fragment is provided in a pre-selected amount to provide an enhanced immune response to said antigen in a host having a pre-existing respiratory syncytial virus M-specific immune response. In accordance with another aspect of the present invention, there is provided a method of making a immunogenic composition comprising providing an antigen and an amount of purified M protein from from respiratory syncytial virus or at least one immunogenic fragment thereof, wherein the amount of said M protein or immunogenic fragment is provided in a pre-selected amount to provide an enhanced immune response to said antigen in a host having a pre-existing respiratory syncytial virus M-specific immune response. In a further aspect of the present invention there is provided the use of a pre-selected amount of purified M from respiratory syncytial virus or immunogenic fragments thereof, to enhance the immune response to an antigen in a host having a pre-existing respiratory syncytial virus M-specific immune response. The hosts protected against disease caused by RSV include humans and the invention includes methods of immunization and protection of hosts against disease caused by infection by RSV by administering the immunogenic and preparations and vaccines as provided herein to susceptible hosts. The hosts may be elderly humans or other humans previously exposed to RSV M protein and immunologically primed to respond to the immunization. |
System and method for an auction of multiple types of items |
An improved system and method for a computer-implemented auction in which multiple types of items are auctioned together without imposing a particular division of supply or demand among the individual types of items. In some embodiments the auction of the present invention provides a means or method for establishing prices for the types of items, wherein the prices maintain a relationship. In other embodiments, the present invention provides a means or method for implying prices from price parameters in the bids received form bidders, based on a relation among the prices for the types of items. Market clearing may be defined by the condition that the aggregate quantity bid for all types of items is less than or equal to the available quantity of all types of items. The division among the types of items within is thus determined flexibly, based on the bids at the associated prices. In other embodiments, market clearing is defined by the condition that the quantity bid for one selected type of item is less than or equal to the available quantity of the selected type of item. The quantities of the other types of items are thus determined flexibly, based on the bids at the associated prices. |
1. A computer system for conducting an auction of a plurality of types of items among a plurality of bidders, wherein bids are received and an allocation of the items among the bidders is determined by the computer system based on the bids, comprising: establishing means for establishing prices for the plurality of types of items, wherein the prices maintain a relationship, receiving means for receiving bids associated with the established prices, and processing means for processing the received bids to determine an allocation of the items among the bidders consistent with the bids in the event that an allocation consistent with the bids is possible, otherwise enabling the establishing means to alter the prices established for the plurality of types of items. 2. A system as recited in claim 1 which further comprises means for constraining the changes in a bid from a given bidder as the established prices are altered by considering, in the processing means, only bids which satisfy a constraint enforced by the means for constraining. 3. A system as recited in claim 2 wherein the constraining means includes summation means for calculating a sum of quantity parameters for a group of types of items. 4. A system as recited in claim 3 wherein the constraining means includes comparing means for comparing the calculated sum with a previous calculated sum for the same group of types of items. 5. A system as recited in claim 1 wherein each received bid comprises a quantity parameter for at least one of the types of items in the auction. 6. A system as recited in claim 5 wherein the establishing means establishes a price for a first type of item and then determines prices for each other type of item based on the price for the first type of item. 7. A system as recited in claim 6 wherein the establishing means determines prices from a predetermined schedule. 8. A system as recited in claim 7 wherein the establishing means includes interpolation means for interpolating prices among prices on the predetermined schedule. 9. A system as recited in claim 6 wherein the processing means includes summation means for calculating a sum of the quantity parameters for the first type of item. 10. A system as recited in claim 9 wherein the processing means includes comparing means for comparing the calculated sum with an available quantity parameter. 11. A system as recited in claim 1 wherein the plurality of types of items are contracts for provision of a commodity covering different time periods, wherein the time periods of at least some of the contracts have at least some overlap. 12. A system as recited in claim 5 wherein the plurality of types of items are contracts for provision of a commodity covering different time periods, wherein the time periods of at least some of the contracts have at least some overlap. 13. A system as recited in claim 12 wherein the processing means includes summation means for calculating a sum of the quantity parameters for the overlapping contracts. 14. A system as recited in claim 13 wherein the processing means includes comparing means for comparing the calculated sum with an available quantity parameter. 15. A system as recited in claim 1 wherein the relationship of the prices established by the establishing means is determined by a schedule. 16. A system as recited in claim 1 wherein the relationship of the prices established by the establishing means is determined by an algorithm. 17. A computer implemented method for conducting an auction of a plurality of types of items among a plurality of bidders, wherein bids are received and an allocation of the items among the bidders is determined based on the bids, comprising: establishing prices for the plurality of types of items, wherein the prices maintain a relationship, receiving bids associated with the established prices, and processing the received bids to determine an allocation of the items among the bidders consistent with the bids in the event that an allocation consistent with the bids is possible, otherwise altering the established prices for the plurality of types of items. 18. A method as recited in claim 17 which further comprises constraining the changes in a bid from a given bidder as the established prices are altered by considering, in the processing, only bids which satisfy a constraint. 19. A method as recited in claim 18 wherein the constraining includes calculating a sum of quantity parameters for a group of types of items. 20. A method as recited in claim 19 wherein the constraining includes comparing the calculated sum with a previous calculated sum for the same group of types of items. 21. A method as recited in claim 17 wherein each received bid comprises a quantity parameter for at least one of the types of items in the auction. 22. A method as recited in claim 21 wherein a price is established for a first type of item and then prices for each other type of item are determined based on the price for the first type of item. 23. A method as recited in claim 22 wherein the determined prices are determined from a predetermined schedule. 24. A method as recited in claim 23 wherein establishing prices includes interpolating prices among prices included in the predetermined schedule. 25. A method as recited in claim 22 wherein processing the received bids includes calculating a sum of the quantity parameters for the first type of item. 26. A method as recited in claim 25 wherein processing the received bids includes comparing the calculated sum with an available quantity parameter. 27. A method as recited in claim 17 wherein the plurality of types of items are contracts for provision of a commodity covering different time periods, wherein the time periods of at least some of the contracts have at least some overlap. 28. A method as recited in claim 21 wherein the plurality of types of items are contracts for provision of a commodity covering different time periods, wherein the time periods of at least some of the contracts have at least some overlap. 29. A method as recited in claim 28 wherein processing the received bids includes calculating a sum of the quantity parameters for the overlapping contracts. 30. A method as recited in claim 29 wherein processing the received bids includes comparing the calculated sum with an available quantity parameter. 31. A method as recited in claim 17 wherein the relationship of the prices is based on a schedule. 32. A method as recited in claim 17 wherein the relationship of the prices is based on an algorithm. 33. A computer system for conducting an auction of a plurality of types of items among a plurality of bidders, wherein bids are received and an allocation of the items among the bidders is determined based on the bids, comprising: receiving means for receiving bids comprising a quantity parameter for at least one of the types of items in the auction and a price parameter, and processing means for processing the received bids to determine an allocation of the items among the bidders that is consistent with the bids in the event that an allocation consistent with the bids is possible, wherein the processing means includes implying means for implying prices from price parameters in the received bids based on a fixed relation among the prices of the plurality of types of items. 34. A system as recited in claim 33 which includes means for inviting additional bids in the event that an allocation of items consistent with the received bids is not possible, and means for applying the additional bids to the processing means for processing the additional bids to determine an allocation of the items among the bidders consistent with the additional bids in the event that an allocation consistent with the additional bids is possible. 35. A computer system as recited in claim 34 which further comprises means for constraining the additional bids from a given bidder by limiting the processing to only additional bids which satisfy a constraint. 36. A system as recited in claim 35 wherein the constraining means includes summation means for calculating a sum of quantity parameters for a group of types of items. 37. A system as recited in claim, 36 wherein the constraining means includes comparing means for comparing the calculated sum with a previous calculated sum for the same group of types of items. 38. A system as recited in claim 33 wherein the plurality of types of items are contracts for provision of a commodity covering different time periods, wherein the time periods for at least some of the contracts have at least some overlap. 39. A system as recited in claim 35 wherein the processing means includes summation means for calculating a sum of the quantity parameters for at least some of the overlapping contracts. 40. A system as recited in claim 39 wherein the processing means includes comparing means for comparing the calculated sum with an available quantity parameter. 41. A system as recited in claim 33 wherein the fixed relation of the implying means is based on a schedule. 42. A system as recited in claim 33 wherein the fixed relation of the implying means is based on an algorithm. 43. A computer implemented method for conducting an auction of a plurality of types of items among a plurality of bidders, wherein bids are received and an allocation of the items among the bidders is determined based on the bids, comprising: receiving bids comprising a quantity parameter for at least one of the types of items in the auction and a price parameter, and processing the received bids to determine an allocation of the items among the bidders consistent with the bids in the event that an allocation consistent with the bids is possible, wherein the processing includes implying prices from price parameters in the received bids based on a fixed relation among the prices of the plurality of types of items. 44. A method as recited in claim 43 which includes inviting additional bids in the event that an allocation of items consistent with the received bids is not possible, and processing the additional bids to determine an allocation of the items among the bidders consistent with the additional bids in the event that an allocation consistent with the additional bids is possible. 45. A method as recited in claim 44 which further comprises constraining the additional bids from a given bidder by considering, in the processing, only additional bids which satisfy a constraint. 46. A method as recited in claim 45 wherein the constraining includes calculating a sum of quantity parameters for a group of types of items. 47. A method as recited in claim 46 wherein the constraining includes comparing the calculated sum with a previous calculated sum for the same group of types of items. 48. A method as recited in claim 43 wherein the plurality of types of items are contracts for provision of a commodity covering different time periods, wherein the time periods for at least some of the contracts have at least some overlap. 49. A method as recited in claim 48 wherein the processing includes calculating a sum of the quantity parameters for at least some of the overlapping contracts. 50. A method as recited in claim 49 wherein the processing includes comparing the calculated sum with an available quantity parameter. 51. A method as recited in claim 43 wherein the fixed relation of the processing is determined by a schedule. 52. A method as recited in claim 43 wherein the fixed relation of the processing is determined by an algorithm. 53. A computer system for conducting an auction of at least one type of item among a plurality of bidders in a plurality of rounds, wherein bids are received and an allocation of the items among the bidders is determined by the computer system based on the bids, comprising: establishing means for establishing starting prices and ending prices for each type of item in a plurality of rounds, receiving means for receiving bids, wherein a bid comprises a quantity for at least one type of item and a price parameter signifying a percentage of the distance from the established starting prices to the established ending prices, and processing means for processing the received bids to determine an allocation of the items among the bidders consistent with the bids in the event that an allocation consistent with the bids is possible, otherwise enabling the establishing means to alter the prices established for at least one type of item. 54. A system as recited in claim 53 where the establishing means includes means to maintain a relation among the established prices. 55. A system as recited in claim 54 wherein the means to maintain a relation among the established prices employs a schedule of prices. 56. A system as recited in claim 54 wherein the means to maintain a relation among the established prices employs an algorithm. 57. A system as recited in claim 53 which further comprises means for constraining the changes in a bid from a given bidder as the established prices are altered by considering, in the processing means, only bids which satisfy a constraint enforced by the means for constraining. 58. A system as recited in claim 58 wherein the constraining means includes summation means for calculating a sum of quantities bid for a group of types of items. 59. A system as recited in claim 59 wherein the constraining means includes comparing means for comparing the calculated sum with a previous calculated sum for the same group of types of items. 60. A computer implemented method for conducting an auction of at least one type of item among a plurality of bidders in a plurality of rounds, wherein bids are received and an allocation of the items among the bidders is determined based on the bids, comprising: establishing starting prices and ending prices for each type of item in a plurality of rounds, receiving bids, wherein a bid comprises a quantity for at least one type of item and a price parameter signifying a percentage of the distance from the established starting prices to the established ending prices, and processing the received bids to determine an allocation of the items among the bidders consistent with the bids in the event that an allocation consistent with the bids is possible, otherwise altering the established prices for at least one type of item. 61. A method as recited in claim 61 where the establishing includes maintaining a relation among the established prices. 62. A method as recited in claim 62 wherein the relation among the established prices is determined by a schedule. 63. A method as recited in claim 62 wherein the relation among the established prices is determined by an algorithm. 64. A method as recited in claim 61 which further comprises constraining the changes in a bid from a given bidder as the established prices are altered by considering, in the processing, only bids which satisfy a constraint. 65. A method as recited in claim 65 wherein the constraining includes calculating a sum of quantities bid for a group of types of items. 66. A method as recited in claim 66 wherein the constraining includes comparing the calculated sum with a previous calculated sum for the same group of types of items. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Sellers and buyers of commodities, financial securities, and other goods and services are increasingly turning to auctions to assist in the sale or purchase of a wide range of items. Auctions are useful for selling a unique item (e.g., a painting), a single type of item available in multiple units (e.g., 10 tons of gold), and multiple types of items available in multiple units (e.g., 10 tons of gold and 20 tons of silver). And just as auctions are useful for efficiently selling items at maximum price, they are also useful for efficiently procuring items at minimum cost. Auction formats in the art tend generally to be of the sealed-bid or ascending-bid variety. In standard sealed-bid auctions, bidders—in one single bidding round—simultaneously and independently submit bids to the auctioneer, who then determines the auction outcome. In standard ascending-bid auctions, bidders—in a dynamic bidding process—submit bids in real time until no more bids are forthcoming. Sealed-bid auction formats offer the advantage of speed of the auction process. Ascending-bid auction formats offer the advantage that there is feedback among participants' bids, which tends to result in more aggressive bidding and in more efficient auction outcomes. When auction systems and methods in the art are used to sell (or buy) multiple types of items, the auctioneer generally specifies an available supply (or demand) for each type of item. For example, the auctioneer announces a supply of 10 tons of gold and 20 tons of silver, and then solicits bids, in a sealed-bid or ascending-bid procedure, in order to obtain market-clearing prices for each of the two types of commodities. However, consider a situation where the types of items are related, for example, contracts for provision of a commodity covering different time periods. For example, a government may wish to sell three types of financial securities: 3-month Treasury bills; 6-month Treasury bills; and 12-month Treasury bills. The government's only constraint may be that it needs to sell $50 billion worth of new debt securities at this auction, since this is the quantity of old debt securities that are maturing in the current calendar quarter. However, the government may have no preference as to how the required $50 billion is divided among 3-month bills, 6-month bills, and 12-month bills, respectively, and the government may simply wish to “let the market decide” the division among the various durations Auction systems and methods in the art provide effective ways for the government to sell bonds with a fixed division among the various durations. However, new and better systems and methods can be devised for “letting the market decide” the division among the various durations. The same problem also occurs in real life in the sale of contracts for electricity and all kinds of other commodities, as well as in the procurement of related items. In several preferred embodiments, the present invention provides a system and method for the government in the above example to simply auction $50 billion of Treasury bills at the lowest possible cost (relative to the market's yield curve), without imposing a particular division among the various durations. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention is an improved system and method for a computer-implemented auction, particularly for a computer-implemented auction in which multiple types of items are auctioned together. In several embodiments, the present invention provides a system and method to conduct an auction of a group of related types of items, without imposing a particular division of supply or demand among the individual types of items within the group. In other embodiments, the present invention provides a system and method to conduct an auction of a group of related types of items, without imposing a particular division of supply or demand on some of the individual types of items within the group. Instead, in some embodiments, the present invention provides a means or method for establishing prices for the types of items within a group, wherein the prices maintain a relationship. In other embodiments, the present invention provides a means or method for implying prices from price parameters in the bids received from bidders, based on a relation among the prices for the types of items within a group. In some embodiments, market clearing is defined by the condition that the aggregate quantity bid for all types of items within a group is less than or equal to the available quantity of all types of items within the group. The division among the types of items within the group is thus determined flexibly, based on the bids at the associated prices. In other embodiments, market clearing is defined by the condition that the quantity bid for one selected type of item within a group is less than or equal to the available quantity of the selected type of item. The quantities of the other types of items within the group are thus determined flexibly, based on the bids at the associated prices. In a first preferred embodiment, the present invention is: A computer implemented method for conducting an auction of a plurality of types of items among a plurality of bidders, wherein bids are received and an allocation of the items among the bidders is determined based on the bids, comprising: establishing prices for the plurality of types of items, wherein the prices maintain a relationship, receiving bids associated with the established prices, and processing the received bids to determine an allocation of the items among the bidders consistent with the bids in the event that an allocation consistent with the bids is possible, otherwise altering the established prices for the plurality of types of items. In a second preferred embodiment, the present invention is a computer system for conducting an auction according to the method of the first preferred embodiment. The system includes an establishing means, a receiving means, and a processing means. In both the first and second preferred embodiments, the relationship or relation among the prices may involve a schedule or algorithm. In the event that the relationship or relation is based on a schedule, determining prices may involve looking up and possibly interpolating numbers that are contained in a table. Alternatively the relationship or relation may be represented as an algorithm or a formula that provides a relationship among the prices. The data table may reflect a market beyond the auction (for example, it may reflect price differentials in a separate commodities market or exchange) and the data table may change during the course of the auction (for example, if price differentials change in the separate commodities market or exchange, or if a significant news event occurs during the course of the auction). Similarly, the data set to which the algorithm or formula are applied may reflect a market beyond the auction and the data set may change during the course of the auction. In a third preferred embodiment, the present invention is: A computer implemented method for conducting an auction of a plurality of types of items among a plurality of bidders, wherein bids are received and an allocation of the items among the bidders is determined based on the bids, comprising: receiving bids comprising a quantity parameter for at least one of the types of items in the auction and a price parameter, and processing the received bids to determine an allocation of the items among the bidders consistent with the bids in the event that an allocation consistent with the bids is possible, wherein the processing includes implying prices from price parameters in the received bids based on a fixed relation among the prices of the plurality of types of items. In a fourth preferred embodiment, the present invention is a computer system for conducting an auction according to the method of the third preferred embodiment. The system includes a receiving means and a processing means. In both the third and fourth preferred embodiments, the “price parameters” in the received bids that are used for “implying prices” could be prices for one or more selected types of items. (For example, the price parameter could be an actual price for 3-month Treasury bills, and the prices for 6-month and 12-month Treasury bills could be implied, based on a fixed relation among the prices.) The “price parameters” could also be neutral parameters or indicators (e.g., in the nature of an index) of a price. Indeed, in a fifth preferred embodiment, bids include price parameters that may be a particularly useful form of neutral parameter. For example, an auctioneer may announce a starting price vector of (4.00, 4.50, 4.75) and an ending price vector of (8.00, 8.50, 8.75). If a bidder enters a price parameter of 25%, this may signify that the bidder is indicating a price which is 25% of the distance from the starting price to the ending price, i.e., an implied price vector of (5.00, 5.50, 5.75). In the fifth preferred embodiment, the present invention is: A computer implemented method for conducting an auction of at least one type of item among a plurality of bidders in a plurality of rounds, wherein bids are received and an allocation of the items among the bidders is determined based on the bids, comprising: establishing starting prices and ending prices for each type of item in a plurality of rounds, receiving bids, wherein a bid comprises a quantity for at least one type of item and a price parameter signifying a percentage of the distance from the established starting prices to the established ending prices, and processing the received bids to determine an allocation of the items among the bidders consistent with the bids in the event that an allocation consistent with the bids is possible, otherwise altering the established prices for at least one type of item. In a sixth preferred embodiment, the present invention is a computer system for conducting an auction according to the method of the fifth preferred embodiment. The system includes an establishing means, a receiving means, and a processing means. Various preferred embodiments of the present invention resolve a number of important limitations to the systems and methods for computer-implemented auctions in the art. Thus, the present invention offers the further technical effect of improving computer-implemented auctions, making them operate more efficiently. The present invention improves the ability of bidders to readily participate in the auction and to express their needs and preferences. The present invention improves the ability of the auctioneer to sell at higher prices the items being sold in the auction or to obtain at lower cost the items being procured in the auction. The present invention improves the efficiency of the auction process by enabling the auction to operate in shorter time, expending less computer time, fewer communications resources, and less bidder and auctioneer time. Finally, the present invention improves the allocative efficiency of the auction process by better allocating items to bidders who value them the highest (or, in a procurement auction, to bidders who can provide them at lowest cost). Certain constraints are desirable in order for the present invention to operate optimally and to reach an economically efficient outcome. In many auctions, it is desirable to impose constraints on bidders that require them to bid significantly on items early in the auction in order for them to be allowed to bid on items later in the auction. Otherwise, one may find oneself in a situation where bidders refrain from submitting serious bids until near the very end of the auction, defeating the purpose of a dynamic auction. One exemplary constraint is an activity rule which constrains a bidder not to increase his quantity, summed over all of the types of items within a group, from one round to the next. Another exemplary constraint is a more stringent activity rule which constrains a bidder not to increase his quantity, individually on each of the individual types of items, from one bid or one round to the next. A third exemplary constraint is a reduction rule which constrains a bidder not to decrease his quantity, for any single type of item, beyond the point where the sum of the quantities bid for this type of item by all bidders equals the sum of the quantities being auctioned. (If, in a given round, two or more bidders simultaneously attempt to decrease their quantities, for any single type of item, having the effect of reducing bids beyond the point where the sum of the quantities bid for this type of item by all bidders equals the sum of the quantities being auctioned, the auction procedure will resolve this discrepancy. For example, the auctioneer may honor these attempts to decrease in order of time priority, or may ration these simultaneous attempts to decrease in proportion to the attempted reductions.) The present invention includes treating the case of auctioning a set of items which includes two (or more) items that are neither identical nor perfect substitutes to one another. Henceforth, this will be described for short as a situation with “multiple types of items,” or simply “heterogeneous items” or “heterogeneous objects.” Often, but not always, the heterogeneous items auctioned together will bear some relationship to one another: for example, they may be securities issued by the same entity but with different durations to maturity; or contracts for the same goods or services but with different durations. One particularly salient use for the present invention is as follows. A national government or a private corporation may wish to simultaneously sell 3-month, 6-month and 12-month bonds or notes. More generally, these may be contracts for provision of any commodity; the contracts are for the same commodity, but covering different but possibly overlapping time periods. For the government's or corporation's purposes, the allocation of sales among the 3-month, 6-month and 12-month bonds or notes may not be critical; the main issue is that the total quantity of the bonds or notes of the three durations add up to the desired dollar figure. Meanwhile, the current “yield curve” on financial markets may have 6-month bonds or notes yielding interest rates 0.50% higher than 3-month bonds or notes, and the current “yield curve” on financial markets may have 12-month bonds or notes yielding interest rates 0.25% higher than 6-month bonds or notes. Under these circumstances, the government or corporation may utilize the present invention by beginning the auction with an (interest rate) vector of (6.00%, 6.50%, 6.75%) for the three respective durations. If the aggregate quantity of the bonds or notes desired by all the bidders at these interest rates is greater than the quantity of bonds or notes that the government or corporation wishes to sell, the government or corporation might then continue the auction by announcing a new vector of (5.99%, 6.49%, 6.74%) for the three respective durations. If the aggregate quantity of the bonds or notes desired by all the bidders at these interest rates is still greater than the quantity of bonds or notes that the government or corporation wishes to sell, the government or corporation might then continue the auction by announcing a new vector of (5.98%, 6.48%, 6.73%) for the three respective durations. The auction continues in this way, with the government or corporation always following the yield curve in setting. the relative interest rates for the various durations. Meanwhile, bidders are held to the exemplary activity rule which constrains a bidder not to increase his quantity, summed over the m types of items, from one round to the next. That is, the bidder is allowed to change the mix of 3-month, 6-month and 12-month bonds or notes that he demands, but his total quantity demanded of bonds or notes may not be increased as the interest rate goes down. A second use for the present invention is as follows. An electric utility may wish to sell contracts to provide a given quantity of electricity for 3-month, 6-month and 12-month durations. For the electric utility's purposes, the allocation of sales among the 3-month, 6-month and 12-month contracts may not be critical; the main issue may be that the total quantity of the contracts add up to a desired amount of electricity. Meanwhile, current energy prices may imply that a 6-month contract should be priced at $2 per-unit higher than a 3-month contract, and that a 12-month contract should be priced at $1 per unit higher than a 6-month contract. Under these circumstances, the electric utility may utilize the present invention by beginning the auction with a price vector of ($10.50, $12.50, $13.50) for the three respective durations. If the aggregate quantity of contracts desired by all the bidders at these prices is greater than the quantity of contracts that the electric utility wishes to sell, the electric utility might then continue the auction by announcing a new price vector of ($10.60, $12.60, $13.60) for the three respective durations. If the aggregate quantity of contracts desired by all the bidders at these prices is still greater than the quantity of contracts that the electric utility wishes to sell, the electric utility might then continue the auction by announcing a new price vector of ($10.70, $12.70, $13.70) for the three respective durations. The auction continues in this way, with the electric utility always following the implied price differential in setting the relative prices for the various durations. Meanwhile, bidders are held to the exemplary activity rule which constrains a bidder not to increase his quantity, summed over the types of items within a group, from one round to the next. That is, the bidder is allowed to change the mix of 3-month, 6-month and 12-month contracts that he demands, but his total quantity demanded of contracts may not be increased as the price goes up. In addition, the present invention may also be used to auction two or more groups of types of items. For example, the previous electric utility example could be complicated by the presence of two groups of electricity contracts: base and peak. (Base-load quantity is produced all of the time while peak-load quantity is only produced at times of peak demand.) Within each group, there might be three durations of contracts. Thus, in total, there could be six contracts for sale: 3-month, 6-month and 12-month base contracts; and 3-month, 6-month and 12-month peak contracts. To continue the example, current energy prices may imply that a 6-month base contract should be priced at $2 per unit higher than a 3-month base contract, and that a 12-month base contract should be priced at $1 per unit higher than a 6-month base contract. Meanwhile, current energy prices may imply that a 6-month peak contract should be priced at $3 per unit higher than a 3-month peak contract, and that a 12-month peak contract should be priced at $2 per unit higher than a 6-month peak contract. Under these circumstances, the electric utility may utilize the present invention by beginning the auction with a price vector of ($10.50, $12.50, $13.50) for the three respective base durations and a price vector of ($26.50, $29.50, $31.50) for the three respective peak durations. If the aggregate quantity of base contracts desired by all the bidders at these prices is slightly greater than the quantity of base contracts that the electric utility wishes to sell, but the aggregate quantity of peak contracts desired by all the bidders at these prices is much greater than the quantity of peak contracts that the electric utility wishes to sell, the electric utility might then continue the auction by announcing a new price vector of ($10.60, $12.60, $13.60) for the three respective base durations and a price vector of ($29.20, $32.20, $34.20) for the three respective peak durations. If the aggregate quantity of base contracts desired by all the bidders at these prices is still slightly greater than the quantity of base contracts that the electric utility wishes to sell, and the aggregate quantity of peak contracts desired by all the bidders at these prices is still somewhat greater than the quantity of peak contracts that the electric utility wishes to sell, the electric utility might then continue the auction by announcing a new price vector of ($10.60, $12.60, $13.60) for the three respective base durations and a price vector of ($29.40, $32.40, $34.40) for the three respective peak durations. The auction continues in this way, with the electric utility always following the implied price differential in setting the relative prices for the various durations within a group. (However, between groups, the prices may go up at very different rates.) Meanwhile, bidders are held to the exemplary activity rule which constrains a bidder not to increase his quantity, summed over the types of items within a group, from one round to the next. That is, the bidder is allowed to change the mix of 3-month, 6-month and 12-month base contracts that he demands, but his total quantity demanded of base contracts may not be increased as the price goes up. Similarly, the bidder is allowed to change the mix of 3-month, 6-month and 12-month peak contracts that he demands, but his total quantity demanded of peak contracts may not be increased as the price goes up. However, in this exemplary embodiment, the bidder is not allowed to substitute any quantity between the base group and the peak group. In many of the preferred embodiments, the auction with two or more groups of types of items ends at the first moment in time that the aggregate quantity of items bid for by all the bidders within each group is less than or equal to the quantity of items being auctioned within each group. An auction in accordance with an embodiment of the present invention could also allow various improvements to the bidding rules. In the previous example of base contracts and peak contracts, it may be the case that even if the price of only one group goes up, a bidder may be permitted to reduce his demands in both product groups. For example, if the base price vector is held constant and the peak price vector goes up, a bidder may be permitted to reduce his quantity bid on both base and peak products. The reason for allowing this is that the base and peak product may be complements (loosely speaking, products that are useful together, such as left shoes and right shoes), so an increased price for one product could reduce a bidder's demand for both. Throughout this document, the terms “objects”, “items”, “units” and “goods” are used essentially interchangeably. The inventive system and method may be used both for tangible objects, such as real or personal property, and intangible items, such as telecommunications licenses or electric power. The inventive system and method may be used in auctions where the auctioneer is a seller, buyer or broker, the bidders are buyers, sellers or brokers, and for auction-like activities which cannot be interpreted as selling or buying. The inventive system and method may be used for items including, but not restricted to, the following: public-sector bonds, bills, notes, stocks, and other securities or derivatives; private-sector bonds, bills, notes, stocks, and other securities or derivatives; communication licenses and spectrum rights; clearing, relocation or other rights concerning encumbrances of spectrum licenses; electric power and other commodity items; rights for terminal, entry, exit or transmission capacities or other rights in gas pipeline systems; airport landing rights; emission allowances and pollution permits; and other goods, services, objects, items or other property, tangible or intangible. It may also be used for option contracts on any of the above. It may be used in initial public offerings, secondary offerings, and in secondary or resale markets. The present invention is useful for “reverse auctions” conducted by or for buyers to acquire various kinds of items or resources, “standard auctions” conducted by sellers in which items are offered for sale, and “exchanges” in which both buyers and sellers place bids. Although terms such as “items or quantities demanded” (by a bidder) and “demand curve” (of a bidder) are used to describe the present invention, the terms “items or quantities offered” (by a bidder) and “supply curve” (of a bidder) are equally applicable. In some cases, this is made explicit by the use of both terms, or by the use of the terms “items or quantities transacted” (by a bidder) and “transaction curve” (of a bidder). The term “items or quantities transacted” includes both “items or quantities demanded” and “items or quantities offered”. The term “bid” includes both offers to sell and offers to buy. The term “transaction curve” includes both “demand curve” and “supply curve”. Moreover, any references to “items or quantities being offered” includes both “items or quantities being sold” by the auctioneer, in the case this is a standard auction for selling items, as well as “items or quantities being bought or procured” by the auctioneer, in the case this is a reverse auction for buying items or procuring items. Moreover, while standard auctions to sell typically involve ascending prices and reverse auctions to buy typically involve descending prices, the present invention may utilize prices that ascend and/or descend. While an auction method following this description could be conducted manually, computerized implementation of the auction method on an auction system allows the auction to be conducted with all bidding information taken into account, while carefully controlling the degree to which the information itself is disclosed to the participants. In one embodiment, all bidding information is displayed to the bidders. In another embodiment, no bidding information is displayed to the bidders; only the results of the auction are displayed. A number of intermediate embodiments are also possible, in which some but not all bidding information is displayed to the bidders. For example, in one preferred embodiment, the auctioneer discloses only the aggregate quantity bid for each type of item in each round, as opposed to disclosing each individual bid. Computerized implementation of the auction also allows the auction to be conducted swiftly and reliably, even if bidders are not located on-site. The auctioneer can receive large numbers of bids, determine the auction outcome, and transmit the results to bidders with minimal labor and in a very short span of time. In particular, sophisticated dynamic auction methods become feasible with a computer implementation; it becomes practical to operate iterative auction procedures in which there may be ten or more auction rounds, yet bidders can participate from different parts of the globe and the entire process can conclude in a single day. The present invention comprises a computer that receives bids in a static or dynamic bidding process and assigns the items to bidders, and a method for receiving bids in a static or dynamic bidding process and assigning the items to bidders. In one embodiment, the invention comprises a Bidding Information Processor (BIP), a plurality of Bidding Terminals (BT's) communicatively coupled to the BIP, and an Auctioneer's Terminal (AT) communicatively coupled to the BIP. Bidders at the BT's enter bids in multiple rounds, and may observe displayed auction information. The BIP, BT's and AT communicate and process information in order to conduct an auction. The network used, if any, can be any system capable of providing the necessary communication to/from a Bidding Information Processor (BIP), a Bidding Terminal (BT), and an Auctioneer's Terminal (AT). The network may be a local or wide area network such as, for example, Ethernet, token ring, the Internet, the World Wide Web, the information superhighway, an intranet or a virtual private network, or alternatively a telephone system, either private or public, a facsimile system, an electronic mail system, or a wireless communications system, or combinations of the foregoing. The following patents and published applications are related to the present invention: Ausubel, Lawrence M., U.S. Pat. No. 5,905,975, May 1999. Ausubel, Lawrence M., U.S. Pat. No. 6,021,398, Feb. 2000. Ausubel, Lawrence M., U.S. Pat. No. 6,026,383, Feb. 2000. Ausubel, Lawrence M., Application No. 00304195.1 at the European Patent Office, May 2000. 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Method and system for multiple hosts anycast routing |
Conventional anycast networks provide a service which allows a sender to access the nearest of a group of receivers sharing a common anycast address. In contrast thereto, multicast networks establish data communications between a sender and all receivers confined by a group having the same multicast address. Thus, the networks providing both anycast and multicast routing only allow for accesses by a sender to one receiver being specified according to the employed anycast protocol or to a plurality of receivers forming a multicast group. In order to provide accesses by a sender to a specified number of nearest receivers, the present invention provides a method and a system for multiple hosts anycast routing in a network. An indicator specifying the number of nearest receivers to be set up for data communications with a sender is included in an anycast address or associated thereto as an extension. On the basis of the indicator, a corresponding number of anycast members of an anycast group identified by the anycast address are contacted/allocated for data communications with the sender. |
1. A method for multiple hosts anycast routing in a network, the method comprising: communicating sender data from a sender addressed to an anycast group including anycast members, said sender data including an anycast address for addressing said anycast group and a first indicator specifying a first number of said anycast members within said anycast group for data communications with said sender, and determining a number of nearest of said anycast members within said anycast group as hosts for data communications with said sender, said number of nearest anycast members being defined by said first indicator. 2. The method according to claim 1, comprising: communicating further sender data from said sender addressed to said anycast group including said anycast members, said further sender data further including a second indicator specifying a second number of said anycast members within said anycast group, said second number being indicative of already determined nearest of said anycast members within said anycast group, and determining said number of nearest of said anycast members within said anycast group, said number of nearest anycast members being defined by said first and said second indicator. 3. A method for multiple hosts anycast routing in an anycast capable network, the method comprising: associating a first indicator with an anycast address identifying an anycast group having anycast members in a network, said first indicator specifying a first number of anycast members within said anycast group, communicating at least said anycast address and said first indicator in said network to said anycast group, and determining a number of nearest of said anycast members within said anycast group as hosts for data communications in said network, said number of nearest anycast members being defined by said first indicator. 4. The method according to claim 3, comprising: associating a second indicator with said anycast address, said indicator specifying a second number of said anycast members within said anycast group, said second number being indicative of already determined nearest of said anycast members within said anycast group, communicating at least said anycast address, said first indicator and said second indicator in said network to said anycast group and determining said number of nearest of said anycast members within said anycast group, said number of nearest anycast members being defined by said first and said second indicator. 5. The method according to claim 2, wherein said number of nearest anycast members to be determined is defined by the difference between said first number and said second number. 6. The method according to claim 1, wherein said first and/or said second indicator is included in said anycast address. 7. The method according to claim 1, wherein said anycast address is extended by said first and/or said second indicator. 8. The method according to claim 1, wherein an anycast address prefix is included in said anycast address, said anycast address prefix identifying a topological region in said network confining said anycast group, said anycast address prefix including said first and/or said second indicator or being extended by said first and/or said second indicator. 9. The method according to claim 1, wherein said anycast address and said first and/or said second indicator are communicated by communicating an Internet Protocol data packet header including said anycast address. 10. The method according to claim 9, wherein said first and/or said second indicator is included in said Internet Protocol data packet header as a part or an extension of said anycast address, or said Internet Protocol data packet header is extended by said first and/or said second indicator by means of an options field for Internet Protocol data packet headers. 11. The method according to claim 1, wherein said number of nearest anycast members is determined by utilizing a measure of distance of a routing protocol for said network and/or determined by utilizing a measure of distance specified by said sender. 12. The method according to claim 1, wherein said anycast address and said first and/or said second indicator are communicated in said network between domains thereof via routers to network domains having at least one of said anycast members. 13. The method according to claim 12, wherein an ordering of said routers is defined such that said anycast address and said first and/or said second indicator are communicated to the nearest network domains, the nearest network domains being specified according to a measure of distance of a routing protocol for said network and/or according to a measure of distance specified by said sender. 14. The method according to claim 1, wherein said number of anycast members is contacted sequentially. 15. (Cancel) 16. The method according to claim 1, wherein said first indicator is modified according to a number of already determined nearest anycast members such that said modified indicator specifies a number of said anycast members still to be determined as receivers. 17. The method according to claim 16, wherein said first indicator is decreased by the value of said second indicator. 18. The method according to claim 1, wherein said second indicator is decreased to a value corresponding to a number of 0 and said first indicator is decreased correspondingly to the decrease of the second indicator and said determining of said number of nearest of said anycast members within said anycast group is performed in dependence of said decreased first indicator if said second indicator has a value corresponding to a number of 0. 19. The method according to claim 1, wherein said anycast address and said first and/or said second indicator are communicated to at least two network domains including at least one of said anycast members by multiplying said anycast address and said first indicator, and communicating said multiplied anycast address and said first and/or said second indicator to anycast members. 20. The method according to claim 1, wherein said first number specified by said first indicator is decreased corresponding to a number of said anycast members in a network domain to which said anycast address and said first indicator are communicated. 21. The method according to claim 1, wherein said communicating is performed according to the strict routing mechanism or the loose routing mechanism as defined in for the Internet Protocol. 22. The method according to claim 1, wherein said first and said second indicator are communicated together. 23. A system for multiple hosts anycast routing, comprising: a network a sender, and a group of receivers being identified by an anycast address, wherein data communications between said sender and a number of nearest of said receivers are established on the basis of a first indicator provided by said sender specifying said number of receivers. 24. The system according to claim 23, wherein data communications between said sender and said number of nearest of said receivers are further established on the basis of a second indicator provided by said sender specifying a number of receivers already determined for data communications with said sender. 25-28. (Cancel) 29. The method according to claim 4, wherein said number of nearest anycast members to be determined is defined by the difference between said first number and said second number. 30. The method according to claim 3, wherein said first and/or said second indicator is included in said anycast address. 31. The method according to claim 3, wherein said anycast address is extended by said first and/or said second indicator. 32. The method according to claim 3, wherein an anycast address prefix is included in said anycast address, said anycast address prefix identifying a topological region in said network confining said anycast group, said anycast address prefix including said first and/or said second indicator or being extended by said first and/or said second indicator. 33. The method according to claim 3, wherein said number of nearest anycast members is determined by utilizing a measure of distance of a routing protocol for said network and/or determined by utilizing a measure of distance specified by said sender. 34. The method according to claim 3, wherein said first indicator is modified according to a number of already determined nearest anycast members such that said modified indicator specifies a number of said anycast members still to be determined as receivers. 35. The method according to claim 34, wherein said first indicator is decreased by the value of said second indicator. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Technical Field The present invention relates to a method and a system for establishing data communications between a sender and receivers, the number thereof being defined by the sender, wherein the receivers are not individually addressed by the sender, but selected from a group of receivers being addressed from the sender by means of a common address. 2. Background of the Invention An anycast network is a network providing a service which allows a sender to access the nearest of a group of receivers having a common address. The common address, in particular, the same anycast address for the group of receivers enables a sender to identify a plurality of receivers by providing only one address, namely an anycast address, instead of individually addressing each receiver. In contrast to a multicast system, wherein data communications are performed between a sender and all receivers sharing a common address, i.e. the same multicast address, data communications in an anycast network are performed between a sender and a particular receiver of a group of receivers sharing the same anycast address. In the context, data communications include any kind of data, such as alphanumerical, graphic, multimedia, audio, video, voice data, information, signals etc. which can be exchanged between systems, devices, network components etc. (e.g. computers, end user devices, hosts, servers, routers, modes). In particular, data communications in an anycast network are performed between a sender and the nearest receiver of the group of receivers sharing the same anycast address. In this respect, the nearest receiver in relation to a sender is defined according to a measure of a distance employed by a routing protocol or routing system used for data communications in a respective network. Since the routing protocol or routing system of a network which identifies the nearest receiver for accesses by a sender, the sender does not need to care about how to select the closest destination, i.e. the nearest receiver. Usually, receivers in an anycast group are so-called replicas being able to support a same network service for requesting sender. Examples for such replicas are mirrored web servers. For accessing a desired network service, among a group of receivers sharing the same anycast address, i.e. anycast receivers, each thereof providing the desired network service, the nearest receiver is determined and respective data communications are performed between the nearest receiver and the requesting sender. Thus, accessing the nearest receiver enhances the network performance perceived by the requesting sender, saves network capacities such as network's bandwidth, and provides the desired network service. In FIG. 1 , the basic principle of an anycast network is illustrated. Both, members M 1 and M 2 are members of the same anycast group and share the same respective anycast address. In line with the measure of a distance employed for routing of data in the network, the distances between requesting senders S 1 and S 2 and all members of the anycast group are computed. Since the distance 2 calculated for the sender S 1 in relation to the anycast group members is the smallest distance, data communications will be performed between the sender S 1 and the member M 1 acting as a receiver for the sender S 1 . In this manner, it is possible for example to direct Internet Protocol (IP) datagrams from the sender S 1 towards the member M 1 . Accordingly, data communications are established between the sender S 2 and the member M 2 being a nearest receiver with respect to the sender S 2 , for example to direct IP datagrams from the sender S 2 towards the member M 2 . Anycast Addresses According to the Internet Protocol version 6 (IPv6), special anycast addresses have been specified in addition to unicast addresses for individually addressing single receivers and multicast addresses for addressing all receivers sharing the same multicast address. Anycast addresses are allocated from the address space employed for unicast addresses, using any of the formats defined for unicast addresses. As a result, anycast addresses cannot be syntactically distinguished from unicast addresses. An anycast address identifies a set of interfaces which typically belong to different nodes of a network. Data, e.g. a data packet, communicated from a sender to an anycast address is delivered to one of the interfaces identified by the respective anycast address, in particular, to the nearest interface according to the measure of a distance employed for the network routing protocol or system. In case, a unicast address is assigned to more than one interface, thus turning the unicast address into a respective anycast address, the nodes of the network to which the address is assigned must be explicitly configured to interpret the address as an anycast address. According to the IPv6, an anycast address must not be assigned to a host, but may be assigned to an IPv6 router, only. Usually, for any assigned anycast address, an address prefix P is utilized which identifies a topological region in which all interfaces belonging to an anycast address reside. In the region identified by the address prefix P, each member of the respective anycast group is advertised as separate entry in a network routing protocol or system. Outside the region identified by the address prefix P, the anycast address may be aggregated into the routing advertisement for the address prefix P. Anycast Host Registration In order to join an anycast group, a host instructs its first hop router, i.e. the closest router in relation to the host for data communications via a network, to advertise the anycast address of the anycast group on its behalf. This can be achieved by adding a new message type to either the Internet Group Management Protocol (IGMP) or the Neighbor Discovery Protocol. Then, the first hop router advertises the anycast address according to an anycast routing protocol employed for the domain including the host. Anycast Routing Each anycast group is confined to a particular topological region with which it shares a common address prefix. Within the topological region identified by the shared address prefix, each member of the anycast group is advertised as a separate entry in the employed unicast routing protocol or system. The principle of anycast routing within a topological region identified by an address prefix shared by an anycast group is illustrated in FIG. 2 . As can be derived from the table in FIG. 2 , there are multiple paths to the anycast address. In case, multiple paths exist to a destination address prefix, a routing table look up of the router will return multiple next hops. The selection of the next hop router to be used for data communications, e.g. a particular data packet, depends on the implemented routing protocol or system. Further, the path selected for data communications can also be effected by the type of data communications to be performed. For example in case of the Internet Protocol standard, the Type Of Service (TOS) field in the IP header of a data packet can be used to define a data communications path. Thus, a TOS designation of a data packet would help the router to chose an appropriate communication path for the given data packet. The selection of an appropriate path is accomplished on the basis on a determination of the distances to the destination defined by the address prefix according to a measure of distance of the respective routing protocol or system. In case of the Internet Protocol standard, for example, the OSPF knows the distance related to the corresponding matrix as identified in the TOS field of a data packet to the destination, i.e. the hop count. As a result, for an anycast routing it is possible to select the nearest next hop on the basis of the employed matrix. In this respect, it is not necessary to analyze the whole IP address of a given data packet. In FIG. 2 , this in indicated by the destination address Mx wherein only the prefix “M” is analyzed. For an anycast routing outside the topological region identified by the shared address prefix, the anycast address may be aggregerated into the routing advertisement for the shared address prefix. This principle is illustrated in FIG. 3 . The destination address Ax in FIG. 3 denotes that only the shared address prefix is utilized in order to determine that data communications are to be routed to the corresponding domain. Since the anycast address for the anycast group shares the address prefix with network domain A, network domain B cannot aggregerate the anycast address in its address prefix. Therefore, network domain B should advertise the anycast address as a separate entry covering both anycast members A 4 and A 5 . This is indicated in FIG. 3 by the destination address Ax being based on the address prefix for domain A and destination address Ax′ containing the complete anycast address. The routing for data communications within the network domains A and B is performed as described before with reference to FIG. 2 . Strict and Loose Routing According to the Internet Protocol version 4 (IPv4) and the Internet Protocol version 6 (IPv6), the following options for routing data communications from a source (e.g. sender, requesting system) to a destination (e.g. receiver, accessed system) have been defined as part of the IP data packet header: Strict Routing This option defines a complete data communications path from a source to a destination by means of a sequence of IP addresses. Data to be communicated between the source and the destination is required to exactly follow the defined path. Loose Routing This option specifies a number of routers and an order thereof. Data to be communicated from a source to a destination is required to traverse the specified routers in the specified order, but is allowed to be communicated via other routers on its way from the source to the destination. Problems Existing solutions for networks being capable of anycast routing are restricted to the selection of a single nearest receiver for data communications with an accessing sender. In case a sender intends to access more than one receiver, existing anycast networks do no provide such a service. A situation for which accesses to more than one receiver are desired is, for example, a network user wanting to access a number of nearest network servers in order to negotiate for the best network service conditions. A further example is a network user wishing to contact a number of nearest restaurants by accessing the network servers thereof in order to check e.g. meals, prices, available seats, etc. or wishing to access a number of nearest emergency service providers in order to ensure that at least one is able to assist (note for the latter examples, sufficient information for the accessing user is only provided in case there is a geographical relationship between the restaurants and the emergency service providers and the corresponding servers). In conventional networks, accesses to more than one receiver can be accomplished by accessing a number of receivers by individually addressing the same on the basis of a unicast routing or by accessing a group of receivers by commonly addressing the same on the basis of a shared multicasting address. Such a multiple unicast routing requires that an accessing user must know each individual network address of the desired receivers and individually perform accesses thereto. This is a time consuming procedure which cannot lead to the desired information for a user in a case, for example, he/she is not provided the respective network addresses and/or information concerning distances to the accessed servers. With respect to the above given example concerning a negotiation for the best network service conditions by accessing a number of nearest servers, such a multiple unicast routing is also not appropriate since no information indicative of distances to receivers is provided and/or available. Accesses on the basis of a multicast routing can result in a number of contacted receivers being too high in view of the demands and desired information of a requesting sender/user. Further, with multicast routing it is not possible to access a desired number of receivers and, in particular, a desired number of nearest receivers, since all receivers being a member of the respective multicasting group are addressed together. Furthermore, a second attempt, e.g. by a multiple unicast routing, to access/contact receivers, the number thereof being higher compared to the number of receivers specified in a preceding, first attempt, would unnecessarily return the results from the first attempt again. This repetition of data communications with respect to the result of the first attempt unnecessarily utilizes network resources in case the requesting network user is not interested in being provided the first attempt results again. |
<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>The approach underlying the present invention to obtain the above object is to extend principles employed in existing anycast networks for accessing a single nearest client in order to allow for a multiple anycast routing to a specified number of nearest receivers. In principle, this is achieved by associating data communications from a sender directed to a network by means of an anycast routing to data which indicate the number of nearest receivers. In particular, such data which will be referred to as a first indicator in the following, specifies the number of nearest receivers being anycast members of an anycast group identified by an anycast address given by the sender (left) to be contacted by and/or allocated for the sender for data communications, such as requests, accesses, data transmissions, etc. According to the present invention, a method for multiple hosts anycast routing in a network is provided wherein sender data is communicated from a sender to an anycast group including anycast members. For communicating the sender data to the anycast group, the sender data includes an anycast address for addressing the anycast group. In order to specify a number of the anycast members for data communications with the sender, the sender data further includes a first indicator being indicative of the desired, first number of anycast members. On the basis of the sender data, a number of nearest anycast members is determined as hosts with respect to the sender for data communications. In particular, the number of nearest anycast members being determined is defined by the first indicator. This solution provides for data communications between a sender and a number of receivers without addressing the same separately, but addressing a plurality of possible receivers by a single address being common for all receivers and selecting a desired number therefrom by means of a data being simply amended to the single common address. A further benefit is that it can be employed for any network, even for networks not providing known anycast routing services. After having performed the above described method it may be possible that a further multiple host anycast routing should be performed wherein the number of anycast members to be determined is varied compared to the number of anycast members previously specified. In order to avoid that anycast members already determined in the previous multiple host anycast routing are contacted again a second indicator can be used. The second indicator specifies the number of anycast members previously determined in the preceding multiple host anycast routing. Then, the number of nearest anycast members can be determined on the basis of the first and the second indicator. In case the first indicator specifies a number of anycast members then the second indicator does, the number of nearest anycast members indicated by the second indicator (in the following: second number of anycast members) are skipped and not contacted, while a number of anycast member is determined for data communications with the sender up to a number obtained by a comparison of the number of anycast members specified by the first indicator (in the following: first number) and the second number. In particular, the number of nearest anycast members to be determined corresponds to the difference between the first number and the second number. In case the first number corresponds to the second number, no further anycast members have to be determined. The same applies for the case wherein the first number is smaller than the second number. In order to provide for a method according to the invention for multiple hosts anycast routing to be employed in a network providing a known anycast routing, a first indicator specifying a first number of anycast members to be contacted/allocated for data communications is associated to an anycast address. By means of the anycast address, an anycast group having anycast members is identified in the network. To establish the desired data communications, at least the anycast address and the first indicator is communicated in the network to the anycast group. The anycast group is identified by the anycast address, while the number of anycast members to be contacted/allocated for data communications is selected according to the first indicator. In particular, the first indicator defines the number of nearest anycast members and according to the first indicator, the specified number of nearest anycast members is determined as hosts for data communications in the network. Comparable to the embodiment of the above described method for multiple hosts anycast routing in a network, this method for multiple hosts anycast routing in an anycast capable network can employ a second indicator specifying a number of anycast members (in the following: second number) already determined for data communications in the network, e.g. on the basis of a previously performed multiple hosts anycast routing in a (anycast capable) network. For providing the first and/or the second indicator, it is possible to include the indicator(s) in the anycast address or to extend the same by the first and/or the second indicator. Preferably, the anycast address is included an anycast address prefix which identifies a topological region in the network, the topological region confining the anycast group. Here it is possible, that the anycast address prefix includes the first and/or the second indicator or is extended by the same. In a case of a network being operated according to an Internet Protocol standard (e.g. IPv4 or IPv6) the anycast address and the indicator can be communicated by a transmission of an Internet Protocol data packet header which includes at least the anycast address. For communicating the first and/or the second indicator, the Internet Protocol data packet header can be included the first and/or the second indicator as a part of or an extension for the anycast address. With respect to the options mechanisms defined for the Internet Protocols, the first and/or the second indicator can be provided by extending the Internet Protocol data packet header by an options field and, in particular, a so-called multiple anycasting options field including the first and/or the second indicator. It is preferred, that the property “nearest” of anycast members is determined according to a measure of distance of the respective routing protocol employed for the network. In particular, “nearest” may be understood as the shortest distance between a sender and anycast members. Additionally or as an option, “nearest” may be specified according to a distance metric requested by the sender. Usually, the distance metric requested by the sender, e.g. in the TOS field of an IP header, indicates a smaller distance metrics or nearest distance, respectively. In case the network comprises domains at least some of which including at least of the anycast members, the anycast address and the first and/or the second indicator can be communicated via network routers to and/or between domains having anycast members. Since it is assumed that a nearest network domain will also include anycast members being nearer compared to anycast members of more distant domains, it is preferred that the ordering of routers for network domain communications is set up such that the anycast address and the first and/or the second indicator are communicated to nearest network domains. The nearest network domains may specified according to a measure of distance of a routing protocol for the network and/or according to a (e.g. smallest) distance metric requested by the sender, e.g. in the TOS field. In order to provide for a fast multiple anycasting, the number of anycast members can be contacted sequentially, in particular for a small number specified by the first and/or the second indicator. Within a network domain, multiple anycast routing and, in particular, a communication of the anycast address and the first and/or the second indicator can be accomplished on the basis of data identifying each of the anycast members. Such an identifying data can be, for example, provided by means of separate entries for anycast members in a routing table according to the employed routing protocol. With respect to the anycast routing performed for a network domain, the first indicator can be updated by decreasing the same according to a number of anycast members comprised by a network domain being identified by means of the anycast address and receiving the first indicator. Further, the anycast routing can be enhanced by multiplying the anycast address and the first and/or the second indicator and communicating the multiplied anycast addresses and indicators to network domains and/or anycast members. Here, it is preferred to communicate the multiplied data simultaneously to the further network domain and/or anycast members. In order to precisely select the specified number of anycast members, while determining the number of anycast members, the indicator is modified according to a number of already determined/contacted/allocated nearest anycast members such that the modified indicator being communicated in the network specifies a number of anycast members still to be determined as receivers. This embodiment avoids a utilization of further data beside the indicator to provide information how many receivers are already obtained and how many are still to be selected. According to an Internet Protocol standard, the communication in the network can be performed by using the strict routing mechanism or the loose routing mechanism. Preferably, the first and the second indicator are communicated together and, advantageously in the same manner, e.g. both indicators being included in the anycast address or extending the same. Further, the present invention provides a system for multiple hosts anycast routing and an anycast routing capable network which are preferred to be operated according to the method according to the invention as set forth above. Moreover, the present invention provides a computer program product being adapted to carry out the method steps according to the invention and embodiments thereof as set forth above. |
Enhanced data storage and retrieval devices and systems and methods for utilizing the same |
The invention relates generally to store information on magnetic or optical storage media by using one or more novel approaches alone or in combination. These novel approaches are capable of using at least one code which may comprise more than two values (FIG. 4d, 43). A first series of approaches for the storage of information applies generally to optical recording and reproducing system (FIGS. 7-10, optical media 66), while a second series of approaches applies generally to electric or magnetic recording and reproducing systems (FIG. 1-2, magnetic medium 1), Each series of approaches is capable of storing information data in one or more codes (FIG. 4d, 42a, 42b, 42c, 42d) and the use of at least one higher order code which is different from the traditional binary code of “0” and “1”. |
1. A method for storing data comprising: storing at least one magnetic field strength; utilizing said at least one stored magnetic field strength to cause an amount of splitting or shifting of at least one frequency in at least one material; determining the amount of shifting or splitting in said at least one material; and assigning a data value to said amount of splitting or shifting. 2. The method of claim 1, wherein said determining comprises a means for interrogating said at least one material with electromagnetic energy to determine said amount of shifting or splitting. 3. The method of claim 1, wherein said at least one material comprises at least one magnetic material. 4. The method of claim 3, wherein said at least one material comprises at least one material contiguous to at least one magnetic material. 5. The method of claim 1, wherein said method for storing data comprises a base-2 data storage system. 6. The method of claim 1, wherein said method for storing data comprises, comprises greater than a base-2 data storage system. 7. The method of claim 1, wherein said splitting or shifting comprises at least one Zeeman effect. 8. A method for reading data comprising: creating at least one magnetic field strength; utilizing at least one magnetic field strength to cause an amount of splitting or shifting of at least one frequency and at least one material; determining the amount of shifting or splitting in said at least one material; and assigning a data value to said amount of splitting or shifting. 9. A data storage apparatus comprising: means for storing at least one magnetic field strength; means for utilizing said at least one stored magnetic field strength to cause an amount of splitting or shifting of at least one frequency in said at least one material; means for determining the amount of shifting or splitting in said at least one material; and means for assigning a data value to said amount of shifting or splitting. 10. A method for storing information optically comprising: an optical source; a means for achieving different optical intensity; a means for recording said different optical intensity; and a means for reading said different recorded intensities. 11. A method for storing information optically comprising: an optical source; a means for achieving different optical wavelengths; a means for recording said different optical wavelengths; and a means for reading said different recorded optical wavelengths. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Data storage devices have been becoming smaller in size (as well as faster) due to, for example, the continued improvement in the ability to store more information in smaller spaces. For example, over the past twenty years the ability to place more data on magnetic storage media such as magnetized hard-disk drives and/or floppy disks, as well as on optical media (e.g., compact disks “CD's” and more recently, Digital Versatile Disk “DVD's”) has been increasing at a phenomenal pace. The impressive increase in the ability to store more data in smaller areas has been one of the main driving forces for rendering computers, and other electronic devices with reasonably sized memories, accessible to a typical home or small business consumer. Further, the high operating speeds of microprocessors have required stored data in computers to be rapidly accessible (e.g., both the rate at which information is delivered to a microprocessor as well as the amount of time it takes between the time that a microprocessor requests a file and when the first piece of data begins to flow from the file to the microprocessor are important). Magnetic memory has undergone many recent improvements and has been utilized extensively in data storage/retrieval devices because magnetic memory currently provides the least expensive alternative for the fast writing and reading capabilities for data. However, the various currently utilized magnetic technologies face a variety of technical challenges and appear to be headed for a stopping point. Specifically, these various approaches for the storage and/or retrieval of information may no longer be capable of meeting the growing demands of the industry, without experiencing significant technical enhancements. For applications where speed has historically been less important, various optical technologies have been growing in popularity. Many technical advances have been made in the recording and/or retrieval of information by optical means. In systems which use compact disks (“CD's”), compact disk read-only memory (“CD-ROM's”) and/or Direct Video Disks (“DVD's”), the storage and/or retrieval of information has also been of great interest. For example, the first CD's manufactured were CD-ROM's that are currently capable of storing about 650 MB of data. This equates to about 74 minutes of play-time for music that has been recorded in a typical recording mode. In particular, the standard current approach for utilizing CD-ROM's, includes the use of a solid state interrogating laser (or in some cases more than one laser) which has a wavelength of about 780 nanometers (0.78 μm). The standard CD-ROM is about 12 cm in total diameter and has a thickness of about 1.2 mm. The standard CD-ROM has information recorded on plateaus (“bumps”) and valleys (“pits”) that spiral from the inside of the disk toward the outside of the disk. The digital data stored in the tracks that comprise the spirals must be separated by enough space (e.g., tracks are typically separated radially by about 1.6 μm) so that when the data is read with an interrogating solid state laser, crosstalk from adjacent tracks does not occur (i.e., recorded information is received from only one track at a time). Accordingly, the placement of more information onto a typical CD has been limited by the required size (e.g., length and width) of the plateaus (“bumps”) and valleys (“pits”). The size of the plateaus and valleys (e.g., typically not less than 830 nanometers in length) has been a function of various factors, including the wavelength of the laser utilized to read the information from the CD. Various attempts have been made to increase the memory capacity of current CD's, including the stacking of a plurality of disks one on top of the other so as to provide more memory space, as well as other attempts to miniaturize the digitized information stored in the tracks. The most recent significant improvements in this type of optical storage/retrieval technology have been the creation of the DVD, which is known as the “Direct Video Disk” or the “Digital Versatile Disk”. The first commercial products of DVD's entered the marketplace in late 1997. The DVD technology is similar to the technology in CD's, except that, for example, the wavelength of lasers utilized to read information from DVD's is smaller than that used for CD's, namely, about 635 nanometers or 650 nanometers, compared to about 780 nanometers for CD's. The size of the plateaus (“bumps”) that make up the DVD are about 320 nanometers wide, a minimum of about 400 nanometers long and about 120 nanometers thick. About 740 nanometers separate one track from the next, compared to the about 1600 nanometer separation of tracks in CD's. A standard DVD is physically about the same size as a CD, but has a memory capacity that is about seven times greater than that of CD's. In particular, the memory capacity of a one-sided, one-track, DVD is now about 4.7 GB. However, recent improvements in DVD have allowed digital information to be placed on both sides of a single track, as well as both sides of a double track. In this regard, a first interrogating laser reads the digitized data on a first side of a first track (i.e., in the form of bits arranged in a spiral track that begin in the innermost portion of the DVD and spirals outward). Then, information can be retrieved from the opposite side of the first track in a similar manner from a second laser; however, the spiral track of information typically begins on the outermost portion of the disk and spirals inward toward the center. Accordingly, when dual-track, dual-sided DVD disks are used, the current amount of memory that can be achieved is about 17 GB. Another optical data storage technique which shows promise is known as holographic memory. The potential for high storage capacity and high storage retrieval rates using the holographic technique is tremendous. In particular, for example, recent work in a system known as Holographic Data Storage System (“HDSS”), has shown that data can be accessed in 100 microseconds or less, which is several orders of magnitude faster than the millisecond retrieval of data in typical magnetic-disk drives. Briefly, in this technology, an optical-interference pattern is created within a desired photosensitive material (e.g., a crystal or a polymer). The optical interference pattern is imprinted as a result of physical changes in such materials. The interference pattern is created by the interaction between an object beam and a reference beam, both of which typically originate from a single light source (e.g., a laser), but are split into two different pathways by a beam splitter. Specifically, the object beam is incident on a target object that contains data, and modifies the object beam, while the reference beam, taking a separate path which leaves it unmodified, interferes with the object beam at the holographic storage medium. When the two beams meet at the holographic storage means, the interference pattern which results from their interaction is stored on or in the holographic storage means. The holographic storage means is later interrogated by a reading or reference beam, which upon interacting with the holographically stored interference pattern, can then recreate the holographic image containing the data originally stored in the object beam. While the holographic optical technique shows great promise for the future, current industrial emphasis is being placed primarily on improving existing digital optical and magnetic storage/retrieval systems so that more information can be stored in smaller spaces, and retrieval times can be decreased without significantly changing the basic methodology and hardware for the storing and retrieving of information. With regard to placing more data onto magnetic recording media, effects such as the paramagnetic effect (e.g., magnetic crosstalk between magnetic domains comprising bits) are already beginning to cause problems. Experts have postulated that in coming years, magnetic storage technologies could reach a limit imposed by the superparamagnetic effect (“SPE”). The physical phenomenon known as SPE can occur in a magnetic data storage system when the magnetic spins of electrons in the domains which comprise a bit (e.g., in current technology typically either a “0” or a “1”) become unstable due to, for example, the environmental thermal energy surrounding the bits. Instability of bits occurs when smaller and smaller numbers of domains or atoms are used to comprise a bit and the ability for the domains or atoms to maintain their given spin directions (e.g., corresponding to, for example, a “0” or a “1”) becomes difficult. Non-maintenance of spin directions results in a “flipping” of spins back and forth and thus changing “0's” to “1's” and “1's” to “0's”, etc. Such changing or flipping of spins will result in a corruption of the data or information that the “0's” and “1's” represent. Accordingly, in order for smaller numbers of atoms to be used to form a bit and in order for the bit to be viable, techniques and/or materials for preventing the superparamagnetic effect need to be developed to overcome the deficiencies of the prior art. Another potential problem in recording information magnetically is that the write head which is used to align magnetic domains in the magnetic storage media may be limited in the ability to impart a required field strength over the entire domain area comprising a bit to cause the magnetic domains to behave as though they have been exposed to a substantially uniform field. In such cases, it is possible that differently oriented domains within a bit (e.g., differently oriented due to being subjected to different magnetic field strengths within a single writing head due to, for example, non-uniformity of the magnetic flux lines emanating from the write head and/or differently oriented because some domains require more energy than other domains to align due to, for example, their location within a bit) may have a higher tendency to become corrupted, as well as adding to signal/noise ratio problems. One attempt for miniaturizing domains involves the use of so-called “hard” magnetic materials. The use of hard magnetic materials is desirable when compared to “soft” magnetic materials because hard magnetic materials are more likely to maintain their magnetic spin directions when domains comprising the hard magnetic materials are closely spaced. In this regard, various rare-earth and transition elements have been found to be magnetically stable and are thus termed “hard”. Such magnetically stable materials are known to have a higher coercivity, which is typically represented by “H c ”. Stated in an over simplified manner, the higher the H c value, the greater the resistance of the material to outside influences, such as outside magnetic fields (e.g., the harder it is for material to lose its imprinted spin direction due to an increase in temperature and/or the influence of other magnetic fields, etc.). However, one drawback for utilizing “hard” magnetic materials is that hard magnetic materials are more difficult to magnetize than soft magnetic materials (e.g., in some cases, depending on the particular materials chosen, much more difficult to magnetize). This makes it more difficult to record data initially in hard magnetic materials. There are various known approaches for solving the problem of encoding data into hard magnetic materials which approaches utilize a laser in conjunction with an appropriate magnetic write head. These various approaches have been referred to generally as the “magneto-optical” approach. These magneto-optical approaches effectively reduce the H c value of the magnetic domains by causing the domains to be locally heated just prior to being subjected to the magnetic write head. Thus, the coercivity (H c ) of the domains is effectively reduced and when such effective reduction in H c has occurred, a somewhat standard write head, or in some cases a very different write head, can be used to alter favorably the magnetic domains. In other words, the use of a laser, which provides thermal energy to the domains of the hard magnetic material, causes the hard magnetic material to behave in a manner which is similar to a somewhat softer and thus easier to magnetize magnetic material. Each of the known approaches for utilizing the magneto-optic techniques involves the use of at least one laser and/or at least one laser focusing system. However, one of the common problems facing these magneto-optical approaches is that the lasers that are utilized to soften the hard magnetic material prior to subjecting the hard magnetic material to a magnetic field is that the lasers typically generate excess amounts of heat that can flow to neighboring bits or tracks (e.g., thermal energy is caused to migrate to undesirable neighboring tracks or areas resulting in a potential corruption of stored information). Accordingly, various laser applications and/or storage solutions have been devised to minimize the transfer of heat from the laser to neighboring tracks, and thus minimize the loss of recorded information. However, to date this thermal transfer of laser energy still presents problems to varying degrees in all the prior art approaches. One interesting technique for the reading of data in connection with one optical-magnetic system is the use of an effect known as the “Kerr effect”, and more particularly, the “magneto-optical Kerr effect”. Briefly, current uses of the magneto-optical Kerr effect involve incident polarized light being reflected from the surface of a magnetic domain in different ways, depending on the orientation of the magnetic domains (e.g., depending on electron spin directions). The changes in the reflected polarized light are made, by algorithms, to correspond to different digitized data. Specifically, when the incident polarized light encounters different magnetic field orientations (e.g., north or south domains comprising a bit which are ordered to represent either a “0” or a “1”) the polarization state of the reflected light is changed. Another approach to the digital storage of information that shows future promise is known as atomic resolution storage (“ARS”). This approach, similar to holographic techniques, is capable of storing tremendous amounts of information in a small amount of space. In this technique, generally, very small electron probes, which are used to generate electron beams, are formed into an array. The electron probes have tips that are roughly the size of atoms. The electron beams from the electron probes are made to be incident upon a storage medium so that the incident beams cause some sort of physical change in the storage medium (i.e., the medium comprising the computer memory). One example of such a storage medium is a material that is capable of containing at least two stable phases at ambient operating conditions so that an incident electron beam emitted from an electron probe changes the storage material from one phase to the other. In this technique, encoded bits of information are represented by the change in phase of the phase-change storage material. This technique, similar to the magneto-optical technique discussed above, also suffers from the problem of heat flowing between data spots created by the incident electron beams when the spots or bits are initially recorded. Accordingly, one of the challenges faced by this relatively new technology includes reducing the flow of heat between data spots which are created by the array of electron beam generators. The retrieval of stored information is also a challenge. In this regard, as bits become smaller and include lesser numbers of magnetic domains per bit and/or the domains are oriented differently, (e.g., domains are aligned perpendicular to the substrate containing at least one magnetic surface thereon instead of being parallel to the substrate surface) such bits are capable of being packed more tightly together. Assuming that the bits are not corrupted by their tight packing and/or smaller numbers of magnetic domains and/or non-uniform alignment within a bit, then reading of these tighter packed domains comprising the bits also becomes a challenge which the prior art is still struggling to overcome. Historically, large numbers of magnetic domains were present in each bit which contained digital data. Thus, the resulting or induced magnetic fields were relatively large and various forms of known inductive reading techniques were sufficient to ascertain whether the hundreds or thousands of aligned domains in a bit corresponded to a “0” or a “1”. However, as prior art miniaturization recording techniques progressed, the known inductive reading techniques were typically not sensitive enough to determine accurately the alignment of ever decreasing numbers of domains comprising a bit (e.g., signal to noise problems in the storage and/or retrieval of digital data bits were exacerbated). The development of magnetoresistive heads, and the subsequent development of giant magnetoresistive heads, has enabled smaller numbers of domains comprising a digital bit to be read accurately. In both of magnetoresistive and giant magnetoresistive heads, the electrical resistance of one or more materials comprising the read head(s) is examined. In particular, both magnetoresistive and giant magnetoresistive heads are made from materials that exhibit small changes in their electrical resistance as a function of magnetic fields created by oriented domains to which such heads are exposed. Giant magnetoresistive heads are two or three times more sensitive than magnetoresistive heads due to their novel structure which includes layering of different materials stacked on top of each other. One problem that continues in these technologies is the presence of magnetization vortices in the recorded domains. Such vortices may result from the difficulty in achieving uniform domain alignment within a bit due to, for example, the difficulty in applying a required magnetic field (e.g., uniform field) to the domains during the recording or writing process. While use of the magneto-optical Kerr effect and new read heads such as magnetoresistive heads and giant magnetoresistive heads have improved digital data retrieval techniques, further miniaturization is pushing the limits of these systems. Accordingly, additional improvements are necessary in the ability for hardware, combined with suitable programming, to detect even smaller numbers and/or smaller sizes of domains comprising digitized (or analog) data bits. Thus, additional innovations in the detection of stored data are required. In addition to the storage of information digitally, the possibility or promise of storing information in an analog manner continues to intrigue various investigators. While certain improvements have been made in, for example, the processing of analog information (e.g., the advent of VLSI (Very Large Scale Interrogation) chips, the techniques for the storing of analog information need much improvement. Particularly, while analog computing has been known for several decades, an accurate and fast-paced system for the storage and retrieval of information has continued to elude researchers. In this regard, digital computing has received the greatest amount of attention because of it's relative dependability for the storing and retrieving of information in a “1” or a “0” digitized format. Briefly, digital approaches typically include storing a sampling of the analog information that is to be recorded. The number of samples taken (e.g., such sampling typically occurs in predetermined units of space or time) from the analog source will correspond to the accuracy between the original analog image or sound and the stored digital data (i.e., the more digital samples that are recorded of an original analog image or sound, the more accurate the reproduction of the original analog image or sound will be). These techniques of predetermined quantum amounts of sampling of analog images have been adequate for most digitized applications, however, as the need for more accurate recording and retrieval of information occurs (e.g., in, for example, the fields of computing or determining various engineering and scientific relationships in the following representative areas: gravitational; electrostatic; magnetic; thermal; stress; fluid flow field analysis; wave propagation; image processing; etc.), the availability of computing with more accurate data becomes important. However, the digitization of tighter and and/or smaller sampling amounts from an analog source can result in tremendous amounts of digitized data being stored to represent a small actual amount of analog information. This is one area where analog computing has a distinct advantage compared to digital computing. In particular, an analog computer will store only a single piece of information corresponding to a single sampling area, whereas a digital computer will need to store somewhere between, for example, 8 and 16 bits of data to represent the same single piece of information stored in an analog fashion. The large number of bits required to store digital information corresponds to the requirement to store information in an ASCII or Unicode format. However, in order to escape from the current ASCII or Unicode format, analog storage requires a very large number of different data bits (e.g., data corresponding to much greater numbers than merely “0s” and “1's”) to be stored and retrieved. Current prior art techniques have great difficulty in storing and/or reading bits corresponding to anything other than “ 0 's” and “ 1 's”, let alone the attendant problems of storing and/or reading, for example, a near infinite number of possibilities (e.g., 1, 2, 3 . . . n+1). However, when performing complex calculations, the digital process may result in very slow processing times as well as requiring very large memories. It is for this, as well as other reasons, that analog computing is still very attractive. Thus, while advances in the processing of analog information have been made, reliable techniques for the storage and retrieval of analog information are still being sought without any good solutions currently existing. As stated above, with regard to digital computing, much of the recent technical emphasis in data storage and retrieval for both optical and magnetic memory enhancement has been on shrinking more information into smaller areas. The ability to place bits, which are the smallest elements of information used by current digital memory systems, into a binary code format, which is a combination of “0's” or “1's”, into a smaller area on, for example, magnetic and/or optical disk storage media (e.g., a disk or a tape) may soon reach a limit. Thus, current technologies for writing and/or reading binary data onto and/or from current storage media will be pushed to the maximum limit. Computer designers are already facing a performance gap whereby processors can process information faster than the information can be retrieved from computer memory. The majority of the currently proposed approaches for the digital storage of information, suffer from the same problem, namely, that the magnetic and/or optical information which is stored uses a binary code (i.e., a base- 2 number system) which is a combination of “0's” and “1's”. The predominance of the use of a “binary” code has been due to, for example, difficulty in distinguishing signals (e.g., a “0” or a “1”) from background noise. In this regard, many techniques have been proposed which use various hardware, as well as algorithms, which attempt to read accurately the stored information as either a “0” or a “1”. However, certain prior art techniques have been postulated for utilizing codes other than binary. In particular, U.S. Pat. No. 6,154,432, entitled “Optical Storage System” discloses a holographic system which records information in very small spots and postulates that 10 or more digits may be possible to record on a single bit. Accordingly, this holographic technique discloses codes higher order than binary. Further, for example U.S. Pat. No. 5,450,363, entitled “Gray Coding for a Multi Level Cell Memory System” discloses the use of a so-called “gray code” approach (also known as “gray scale” by others) for data storage. This approach also uses a system which is higher order than binary. In particular, reference is made to the storage of multiple bits of information in a single memory cell thus creating a multi-level cell. Still further, U.S. Pat. No. 6,061,005, entitled “Encoding of Data”, discloses a method of encoding data on magnetic cards which uses symbology other than binary, such as trinary, quaternary or even higher symbology, for the recording of information. However, while various techniques have been postulated for systems which use codes higher than binary, none of such codes have been commercially adopted due to, for example, signal to noise ratio problems, etc. In particular, reading errors can occur due to lack of contrast between data values. Such lack of contrast can be caused by random noise (e.g., vibrating inaccurate positioning of recording/reading heads, fidelity loss during recording, etc.) and determinate variations. Accordingly, a need exists for techniques which can be commercially viable which can use codes reliably that are higher order than traditional binary codes for the storage and/or retrieval of information. A very particular combination of “0's” and “1's” is known as the American Standard Code for Information Exchange (i.e., the ASCII code) which assigns a unique code number between 0 and 127 to each of the 128, 7-bit, binary number characters. Table 1 below shows in table form the current ASCII characters arranged by Hexidecimal digits (i.e., 128 different encoding combinations of groups of seven bits). Reading within the Table from left to right and then down, the first 32 values are codes which correspond to various computer control functions such as line feed, carriage return, etc. The 33 rd value corresponds to the “space” character. Values 34-48 correspond to symbols and punctuation marks. Values 49-58 correspond to digits, and so on, until reaching value 128, which corresponds to “delete”. In addition, each of these values also has a corresponding hexidecimal character. For example, the hexidecimal digit corresponding to the “space” character is “20”, while the hexidecimal digit corresponding to the letter “n” is “6E”, and so on. TABLE 1 00 01 02 03 04 05 06 07 08 09 0A 0B 0C 0D 0E 0F 00 NUL SOH STX ETX EOT ENQ ACK BEL BS TAB LF VT FF CR SO SI 10 DLE DC1 DC2 DC3 DC4 NAK SYN ETB CAN EM SUB ESC FS GS RS US 20 ! “ # $ % & ‘ ( ) * + , − . / 30 0 1 2 3 4 5 6 7 8 9 : ; < = > ? 40 @ A B C D E F G H I J K L M N O 50 P Q R S T U V W X Y Z [ \ ] {circumflex over ( )} — 60 ’ a b c d e f g h x j k l m n o 70 p q r s t u v w x y z { | } ˜ DEL These 128 characters are enough characters for North American English to be stored and/or retrieved, but are not enough for many other languages (Note: In ASCII, the eighth bit is used, and is thus normally set to “0”). To represent more than 128 characters, 8-bit (rather than 7-bit) binary numbers are utilized. For each digit in these eight bits there are two choices for the digit, either “0” or “1”. This results in a possibility of an additional 128 characters or a total of 256 different combinations of “0's” and “1's” (i.e., 2 8 ). Accordingly, the current data storage approaches utilize these 256 combinations of “0's” and “1's”. However, these 8-bit numbers still do not provide enough room for all characters that need to be used in the world (e.g., certain Asian languages have thousands of characters each). In addition, there is no universal agreement in the world on what all the characters should be, whether referring to the 128 characters, or the 256 characters, or any number of characters beyond these. However, certain approaches for dealing with all the various languages in the world, which collectively contain many thousands of characters, are beginning to utilize something referred to as the “Unicode”, which uses a 16-bit character set. In order to adopt something similar to the Unicode, even greater strain will be placed on current memory techniques. Whether using an 8-bit, 16-bit, or some other approach, all such approaches have been limited primarily to using a binary system of data storage. However, due to: (1) the impending size barrier for the storage of information on, for example, magnetic and/or optical media; (2) the performance gap between how fast a processor can process information versus how fast a processor can access information; and (3) the goal for a universal adoption of a common set of characters throughout the world, a different approach for the storage of information, either by digital or analog approaches, is clearly needed. The present invention satisfies the current and future data storage needs by using different approaches for the storage and/or retrieval of data; and/or different codes that use a code higher than the current “base- 2 code”. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the invention to provide a means for storing/retrieving digitized information optically. It is an object of the invention to provide a means for storing/retrieving digitized information magnetically. It is an object of the invention to provide a means for storing/retrieving analog information optically. It is an object of the invention to provide a means for storing/retrieving analog information magnetically. It is an object of the invention to provide a storage/retrieval means for utilizing codes other than binary. It is an object of the present invention to provide an increased number of characters that can be stored as a single bit of information. It is an object of the invention to provide the ability to store the 128 ASCII-type characters in a much smaller space than the space that is used in a standard binary code of “0's” and “1's”. It is an object of the invention to provide a means for storing/retrieving codes other than binary. It is an object of the invention to utilize at least a base- 3 optical storing/retrieving system. It is an object of the invention to utilize a least a base- 4 coding storing/retrieving system. It is an object of the invention to utilize at least a base- 6 coding storing/retrieving system. It is an object of the invention to utilize at least a base- 8 coding storing/retrieving system. It is an object of the invention to utilize at least a base- 10 coding storing/retrieving system. It is an object of the invention to utilize particular aspects of the Zeeman effect in connection with the storage/retrieval of digitized information. It is an object of the invention to utilize particular aspects of the Zeeman effect in connection with the storage/retrieval of analog information. It is an object of the invention to utilize different shades or colors of spots or dots in connection the optical storage of digitized information. It is an object of the current invention to utilize different shades or color or spots or dots in connection with the optical storage of analog information. It is an object of the invention to utilize either monochromatic or polychromatic light in connection with the optical storage of digital and analog information. It is an object of the invention to utilize an analog-like approach to the storage of data. The current process of storing bits, which is the smallest element of information used by current memory systems, uses a binary format of only “0's” and “1's”. A bit which is “off” is considered to be “false” or “not set”, while a bit that is “on” is considered to be “true” or “set”. Historically, because bits could only be one of two values, bits have been combined together into larger units in order to represent more characters or values. “Nibbles” are groups of four bits and “bytes” are groups of eight bits (i.e., two “nibbles”). Bytes are typically what are used to store “characters”. “Characters” typically include letters, numbers and/or symbols. For example, the ASCII code uses 128 different encoding combinations to represent: (i) The letters “A-Z” in both upper and lower case (i.e., values 65-90 and 97-122, respectively); (ii) Special characters (e.g., “<”, “.”, “%”, “$” “?”, etc) (e.g., values 33-47); (iii) The numbers 0 - 9 (i.e., values 48-57); and (iv) Certain control codes used for device control (i.e., values 0-31). To represent more than 128 characters, an eighth bit can be utilized. However, the ability to store a binary code of only “0's” and “1's” limits the ability for information to be miniaturized. For example, to store a single character from the ASCII code, at least seven bits of memory (typically eight bits are currently required because the last bit is usually set to zero) are needed. Table 2 sets forth one example of how a typical computer memory system would store the word “Patent”. TABLE 2 ASCII LET- CHAR- BINARY HEXADECIMEL BITS OF TER ACTER NUMBER DIGIT OR BYTE MEMORY P = 80 = 01010000 50 8 a = 97 = 01100001 61 8 t = 116 = 01110100 74 8 e = 101 = 01100101 65 8 n = 110 = 01101110 6E 8 t = 116 = 01110100 74 8 Thus, the letter “P” corresponds to the ASCII character 80 , which is represented by the binary code “01010000”. The first “0” in the sequence is often referred to as “the last bit” and is typically set to “0” for all ASCII characters. The corresponding hexidecimal digit or byte representation is “50”. In order for the computer memory system to store the letter “P”, eight bits must be sent to memory in the order “0-1-0-1-0-0-0-0”. Likewise, to store the letter “a”, eight bits must be sent to memory in the order “0-1-1-0-0-0-0-1”. Accordingly, 48 bits are used to store the six (6) letter word “Patent”. Similarly, when a microprocessor unit accesses the portion of memory containing the set of bits representing the word “Patent”, the same number of bits (i.e., 48) or six (6) bytes must be processed by the microprocessor. Clearly, if the word “Patent” could use a smaller amount of memory, less memory capacity would be needed in a computer and/or the rate at which data could be stored and/or retrieved from memory would be enhanced. In a first aspect of the invention, a coding system that is a higher order system than a binary coding system is utilized for the digitized storage of information. For example, any digital coding system which uses three or more different code characters (i.e., a coding system which operates in “base-3” or greater) will result in a reduction in the number of bits needed to store the same amount of digital information relative to a binary system. Thus, by using a higher order memory system, the possibility of storing more digitized information in a smaller memory area exists. Likewise, the rate of storing and/or retrieving digitized information should also increase due to memory being stored in a physically smaller area. This permits a data retrieval device to function more efficiently. The present invention permits the use of a digitized memory system which is base- 3 or greater. Moreover, as more code characters are used (e.g., higher order systems of more than 10 or more than 20 different characters are utilized) the digitized system begins to behave in a manner which is similar to analog systems and can thus be referred to as “analog-like”. In other words, as the amount of digital sampling of an analog source increases, the recorded digital signal begins to approach the storage of most features of the analog signal. However, current data storage/retrieval techniques utilize, for example, 8 or 16 bits to store a single piece of analog information, which limits the amount of sampling of an analog source that can be reasonably performed when creating a digital representation of the analog source. Accordingly, the digital data storage/retrieval techniques of the present invention can be vastly superior to current digital techniques which utilize only “0's” and “1's” and are limited to sampling much smaller areas of analog sources than would be desirable in many cases (e.g., for complex computer modeling of numerous events, etc.). A first embodiment of an alternative memory storage system of the present invention may function in a manner somewhat analogous to the manner in which a Compact Disk (CD) or Digital Versatile Disk (DVD) player functions. Current CD and DVD technologies utilize a rotating disk comprised of a number of layers of different materials. The layers may include, for example, polycarbonate plastic, aluminum and acrylic. The aluminum in the disk includes a series of plateaus and valleys sometimes referred to as “bumps” and “pits”, respectively. Laser light is caused to focus upon the bumps (plateaus) and pits (valleys) in the rotating disk. The reflection of the laser from the successive plateaus and valleys corresponds to a data stream (e.g., a binary stream) of information. CD's and DVD's use, for example, 16-bit strings of binary coded data. Specifically, laser light reflects differently from a valley compared to the reflection from a plateau and these different reflective properties of the laser, when reflected from these valleys and plateaus, correspond to the binary code data values of “0” and “1” for each bit. In one embodiment of the present invention, a similar concept to the CD and DVD is utilized, however, rather than utilizing valleys and plateaus (i.e., bumps and pits) in an aluminum layer embedded in a polycarbonate plastic CD or DVD, the present invention utilizes at least two data values per bit represented by different intensity, colors or color width (e.g., different wavelength or frequency). These data values can be optically created, stored in dots or spots, and optically examined or interrogated (e.g., by known transmission and/or reflection techniques). These optical dots or spots may be of a size which is approximately the same order of magnitude in size as the bumps and pits which comprise current data tracks used on CD's and DVD's, they may be larger, or they may be smaller. In particular, similar to current CD's and DVD's, these dots or spots can be put together to form strings or tracks of data which begin at an innermost portion of a rotatable CD/DVD disk and extend spirally out therefrom in the form of tracks. Accordingly, current CD's of approximately 12 centimeters in diameter would be an acceptable size. However, if the dots or spots of the present invention are smaller than the “bumps” of the current technology, it is possible for CD's to be smaller in size, if desired, or more data can be placed into the same amount of memory space. Thus, it is possible to put an amount of optical information onto a rotatable disk of approximately 12 centimeters in diameter which exceeds that amount of information which is currently stored on CD's/DVD's. However, it is possible for the dots or spots to be larger in size than current bumps and pits in CD's/DVD's while still storing more information relative to standard CD's/DVD's. This is possible due to at least two effects. First, tracks may be capable of being located closer together due to, for example, lesser amounts of crosstalk between bits (e.g., recording and/or reading operations can take place in a lesser amount of space). Second, if digital codes higher than binary are adopted, less actual bits need to be stored relative to a binary system (e.g., rather than storing 8 or 16 bits to represent a single piece of information, a lesser number of bits can be used to represent the same piece of information that is being stored). It should be noted that as the number of characters that can be stored in a single bit become larger, the digital storage system actually approaches behaviors similar to an analog storage system and can be referred to as “analog-like”. In particular, the present invention is capable of utilizing a coding system other than the binary coding system of “0's” and “1's” now used in CD/DVD systems. For example, a series or range of dots or spots of different color intensities (e.g., white-gray-black), and/or different colors (e.g., red-yellow-violet), and/or both as in varied intensity of polychromatic light, can be placed upon a surface (or embedded somewhere within a material), such as a suitable photoferroelectric material such as “PLZT” (i.e., lead lanthanum zirconate titanate ceramic), which is shaped in the form of, for example, a disk. When, for example, such a disk containing these different intensity data value dots or spots is rotated and interrogated by, for example, a known optical system (e.g., a laser system) with a suitable focusing lens and intensity detecting means (e.g., a suitable photosensitive material or photodiode), the different intensities of the dots or spots can be registered and can be coded to correspond to different values (e.g., “0”, “1”, “2”, “3”, etc.). Thus, rather than using a simple binary or base- 2 system where a black dot corresponds to “0” and a white dot corresponds to “1”, the present invention provides for a larger number of options for digitized data storage. However, as discussed in more detail herein, depending on the sensitivity of the system, this technique could also be used for actual analog computing. Accordingly, for example, in a simple digitized quaternary system having a quaternary code consisting of 0's, 1's, 2's and 3's, there would be 4 different choices of basic digital information storage (i.e., a “base-4” system) rather than only two choices in a binary or base- 2 digital system. Likewise, in a digital system which utilizes 8 different combinations of spots or dots (i.e., a “base-8” system) eight different options exist for encoding a piece of information rather than only two options in a standard binary or base- 2 digital system. The use of a larger number of possibilities other than “0's” and “1's” (e.g., 0, 1, 2, 3, 4, 5, 6, 7, etc.) render it possible to store a much greater amount of information in a much smaller physical area due to the elimination of unneeded bit space. Moreover, as the number of possibilities other than “0's” and “1's” increases, (e.g., systems greater than base- 10 such as base- 20 or greater systems) the closer the digital system comes to being or performing like an analog system, which has certain advantages over digital systems. An apparatus according to the present invention permits suitable optical data to be stored onto an appropriately constructed and shaped optical recording medium by using, for example, a laser light source. The optical recording media (e.g., a PLZT ceramic) can be in the form of a tape, disk, or credit card or any other acceptable shape. Alternatively, a photodiode or photodiode assembly can also be used. In all such cases, a light source (e.g., laser light source) can be used in combination with, for example, various means for controlling the direction, polarization, intensity and/or final color of the light source. Various examples of such systems include the following: (1) a rotatable polarizing filter (or set of filters), sometimes referred to as an analyzer, used in combination with a suitable light source which is subjected to a first polarizing filter(s) selectively modifying the polarized light from the light source. Specifically, once monochromatic or polychromatic light has been polarized into a first direction polarizer the polarized light is directed toward a second polarizer (sometimes referred to as an “analyzer”) which, when rotated, results in, for example, different intensities of light being emitted therefrom. The different intensities of light can be caused to be incident upon an appropriate recording/detecting means; (2) a light source (e.g., a laser light source), which is used in conjunction with a first polarizing filter is caused to be incident on a suitable light diffractor (e.g., a Bragg modulator) which can cause the polarized light from the light source to communicate with one or more of a series of additional polarizing filters (or analyzers) each of which analyzers are rotated, relative to the polarized source, at different angles, thus resulting an different amounts or intensities of light passing through each of the analyzers. Thus, by selectively transmitting the polarized light through the different analyzers (e.g., directed by, for example, the Bragg modulator) different intensities of light can be achieved. Such different intensities can be recorded and/or detected by a suitable means; (3) a light source (e.g., a laser light source) used in combination with an acousto-optic Bragg modulator, whereby different driving signals are input to the Bragg modulator which results in different intensities of light being emitted from the Bragg modulator. The multiple intensity emissions are then directed to a suitable detecting/recording means and are made to correspond to various data points in base- 2 or higher order digital data storage systems; and (4) rather than utilizing polarizing filters to polarize a monochromatic or polychromatic source of light, liquid crystal cells can also be utilized. In particular, light can be caused to be incident upon a liquid crystal cell. Depending upon whether voltage is applied to the liquid crystal cell, the output from the liquid crystal cell is oriented into one direction or another. Liquid crystals of this type can be made of, for example, lithium niobate. However, similar to the embodiments (1)-(3) discussed above, intensities can be varied due to relative polarization directions. The outputs of light from the liquid crystal cell can be directed, by appropriate beam displacers (e.g., a Bragg modulator), toward a suitable recording/detecting means. In each of the examples (1)-(3) discussed above, it is possible that a polychromatic light source could be utilized. In this regard, when polychromatic light is made to be incident upon a first polarizer, and thereafter upon one or more additional polarizers (e.g., analyzers), in addition to different intensities of light flowing through the analyzer(s), a spreading of these different intensities over a particular frequency or wavelength range will also occur. Specifically, when using polychromatic light, a spectrum of frequencies of various intensities results in the formation of a somewhat continuous curve of varying light intensities over a particular frequency or wavelength range. The use of a polychromatic source can therefore result in secondary indicia for determining the value assigned to stored bits of data (e.g., a “0” or a “1”) and thus enhances data storage. For example, not only could the highest intensity of light be recorded/detected, but also the starting and/or ending points which correspond to the lowest frequency intensity of light being emitted, and the highest frequency of light being emitted, respectively, or, alternatively, the area under each curve could also be compared. In other words, more than one piece of information can be checked to verify the accuracy of each data point that is stored and read. The presence of more than a single piece of information can result in more accurate reading of data and thus result in signal/noise improvements. In each of the examples (1)-(4) discussed above, the different intensities or colors of light can be made to be incident upon an appropriate receiving/recording means (e.g., an optical storage means, such as a pohtopolymerisable/photocrosslinkable material, a photodiode assembly, etc.), such output light being suitably focussed onto the appropriate receiving/recording means by known lens or optical systems etc., all of which are discussed in greater detail herein). Suitable materials for recording various intensities or colors of light include the following materials: inorganic photochromic crystals, photorefractive materials, chalcogenide semiconductors, organic and polymer materials, thermoplastic media, reversible recording in Tellerium compounds, photothermal recording in Antimony compounds, magneto-optic recording and light stimulated recombination luminescence. For example, in the simplest embodiment (i.e., that embodiment numbered “(1)” above) for understanding the basic concept for recording various intensities of light (even though this simple embodiment is not as commercially significant as the other embodiments discussed herein), each such recorded intensity corresponds to a different value for a digitized data bit. In this basic case, different intensities can be achieved as follows: a polarized light source, such as a laser and polarized filter or polarizer, when used in combination with at least one rotatable polarizing filter (e.g., an analyzer) can result in light of different intensities being transmitted from the at least one rotatable analyzer. Specifically, when the laser light source is passed through a first polarizing filter and a second polarizer (e.g., an analyzer) is sequentially rotated (e.g., from 0-90°) a predetermined amount each time relative to the first polarizing filter (i.e., either the first or second filter can be rotated), different intensity dots or spots corresponding to data values having different meanings (e.g., “0”, “1”, “2”, etc.) can be produced. The amount of rotation of the analyzer in relation to the polarizing filter can correspond to a different intensity of light being recorded on a suitable optical recording medium (e.g., a photoferroelectric material such as “PLZT”, inorganic photochromic crystals, photorefractive materals, chalcogenide semiconductors, organic and polymer materials, thermoplastic media, reversible recording in Tellerium compounds, photothermal recording in Antimony compounds, magneto-optic recording and light stimulated recombination luminescence). If a photoferroelectric material is utilized, the different intensities of light can be caused to be incident upon the photoferroelectric material by use of, for example, a suitable optic lens system or a fiberoptic cable (or a series of cables) that is capable of accurately directing the optical signal to the photoferroelectric material for the proper recording of the various optical signals. Thus, a large number of different intensity spots or dots corresponding to data values for a single bit can be created. This basic system and apparatus permits higher order coding systems (e.g., base-3 or greater) to be utilized. The manner in which such optical data is stored, on, for example, a rotatable disk, as well as interrogated, can be by techniques which are substantially parallel, and/or use hardware which is similar, to those techniques and/or hardware currently used in CD and DVD systems. For example, a series of bits of an appropriate binary or higher order digital code system can be recorded onto a rotatable disk by starting to record the different intensity dots or spots near a central potion of the disk. The recording continues to record data in a spiral manner to form tracks of data, such data being suitably separated, physically, to avoid corruption and crosstalk, until an outermost radial portion of the disk is encountered. Likewise, such a disk can be read or interrogated by, for example, a laser system which focuses light onto the dots or spots and suitably measures the intensities (e.g., reflectance or transmittance) of the spots of data. The different intensities can be interpreted by suitable algorithms and programs to correspond to different values in the desired coding system. Moreover, by utilizing a digital optical coding technique other than binary, the present invention permits a much more rapid adoption of the desired “Unicode”, which takes into account, for example, all English language characters, Chinese characters, numbers and symbols, etc., in various digitized forms. In another embodiment of the invention, a system which utilizes magnetic memory in combination with a suitable retrieval/reading means is utilized. These memory/retrieval systems can be caused to function, generally, in a manner that is somewhat similar to current magnetic memory systems (e.g., magnetic tapes, cards, disks, hard drives, etc). In addition, these memory systems can also use digital coding/reading systems higher than a base- 2 system, if desired. Still further, these memory systems can also store/retrieve information in an analog or analog-like format. Specifically, it is another object of the invention to utilize certain aspects of the phenomena known as the Zeeman effects to result in a means for the storage and retrieval of information onto/from suitable magnetic media. The term “Zeeman effects”, as used herein, denotes the effects of external magnetic fields on frequencies of atoms, molecules and components thereof, in the broadest sense. Thus, as used herein, the term “Zeeman effect” includes not only what may be considered to be Zeeman effects in the more narrow, classical sense but also other magnetic effects such as magnetic quadropole effects, etc. Digital data may be stored as either a binary code or some higher order code that is greater than the binary or “base-2” code. Moreover, due to the apparent sensitivities of these data storage techniques, data may be stored/retrieved in an analog or analog-like manner due to the inherent operation of the Zeeman effects. Specifically, without wishing to be bound by any particular theory or explanation, it appears that use of the Zeeman effects can result in a somewhat continuous set of differing data values that can be stored/retrieved. The present invention utilizes one aspect of the Zeeman effects in the following general manner. A magnetic field is applied to a suitable media that is capable of receiving and storing at least a portion of the applied magnetic field. One example of such a suitable magnetic material is a ferromagnetic material that is capable of exhibiting different amounts of magnetic domain alignment as a function of increasing magnetic field strength up to its natural magnetic saturation point (i.e., whereby any further increases in applied magnetic field do not result in any measurable further alignment of magnetic domains). Various known materials exist that meet this basic criteria, including many materials currently utilized in the magnetic storage industry (e.g., gamma Fe 2 O 3 , gamma Fe 2 O 3 modified by Co, CrO 2 , etc.). The various materials can be held together by a variety of organic polymers including, for example, vinyl chloride, polyvinylchloride, methylacrylate, polymethylmethyacrylate, polyurethane, epoxy, polyamides, etc. Suitable substrates include typical polyesters for flexible materials and aluminum for rigid materials. The differing amounts of stored magnetic field can result in a corresponding splitting or shifting of the electromagnetic energy frequencies or spectral frequencies (e.g., fine spectrum splitting, hyperfine spectrum splitting, vibrational spectrum splitting, etc.) of one or more atoms or molecules of the magnetic material itself, or similar splitting or shifting in one or more materials that are located contiguous (e.g., in the magnetic material or in a read/write head) to the material containing the stored magnetic fields. In the Zeeman effect, the amount of splitting or shifting of one or more frequency spectrum(s) is a function of the strength of the applied/stored magnetic fields. Typically, the higher the magnetic field strength that is stored/applied (e.g., stored in a first material containing magnetic domains and thereafter applied to (e.g., influencing) a second contiguous material that exhibits Zeeman splitting at the stored magnetic field strengths), the further apart the splitting or shifting will be of one or more of the electromagnetic energy frequencies of a chosen spectrum of the targeted atom(s) or molecule(s). In this Zeeman effect, when a relatively wide splitting of electromagnetic energy frequencies occurs due to the applied magnetic field, the amount of splitting may correspond to frequencies in the microwave region; whereas a narrow splitting will typically correspond to lower frequencies (e.g., radio). The amount of splitting that occurs is important because in order to determine the amount of splitting that has occurred, a suitable interrogating electromagnetic energy is caused to be incident upon, for example, the magnetic material itself or the aforementioned contiguous material. The contiguous material that exhibits Zeeman splitting at the stored magnetic field can be present as, for example, one or more separate sheets of material that are located adjacent to, and/or contiguous with, the material that contains the stored magnetic field. When multiple contiguous materials are utilized, the present invention contemplates the use of a comparative analysis of the differences in Zeeman splitting between two or more such contiguous materials. Alternatively, a material comprising, for example, one or more material(s) that are mixed with the magnetic material (e.g., a binder which holds together at least a portion of the material that stores the magnetic field) could also be used. More specifically, a particular interrogating frequency, or set or sweep of frequencies, needs to be capable of favorably interacting with one or more of the split, shifted or splitting frequencies which result in the magnetic material, or in an alternative embodiment in one or more of the contiguous material(s), due to the different magnetic fields stored therein. In other words, a first magnetic material is desirably chosen so that an applied magnetic field can be reasonably stored therein. However, it is desirable for the magnetic material to be capable of storing reliably several magnetic fields of different strength (e.g., capable of having varying numbers of magnetic domains align with an ever changing magnetic field and such domains remain frozen or pinned so that they do not change with time) and, for example, in one embodiment of the invention, the contiguous material needs to produce split, shifted and/or splitting frequencies in response to the stored magnetic fields. In this regard, if one or more contiguous material(s) are utilized in connection with the magnetic material(s), the contiguous material(s) needs to exhibit a splitting and/or shifting of one or more frequencies, for example, of its rotational, vibrational, etc., bands (e.g., at the atomic level) and the resultant splitting or shifting that occurs in the contiguous material needs to be detectable by an appropriate interrogating electromagnetic source (discussed in greater detail later herein). Alternatively, a contiguous material does not need to be utilized. In this case, the magnetic material per se, or at least a portion thereof, needs to exhibit desirable and detectable splitting and/or shifting of one or more frequencies at varying stored magnetic strengths. Still further, it should be noted that the contiguous material could actually be located in a suitable read head which, similar to magnetoresistive and giant magnetoresistive heads, is influenced by the magnetic field strengths stored in the magnetic media. However, rather than measuring changes in resistivity in materials comprising the read heads, the splitting or shifting of frequencies will be detected by a suitable technique, discussed elsewhere herein. In this embodiment of the invention, the contiguous material may be a solid, a liquid, a gas or plasma (e.g., any material that shows desirable Zeeman splitting effects). With specific regard to interrogating with an applied electromagnetic source to determine the amount of Zeeman splitting and/or shifting that has occurred at a spot on the material that corresponds to a stored bit of data, at least one suitable frequency can be applied as an interrogating frequency, or, alternatively a sweep or combination of frequencies can be applied as interrogating frequencies. In this regard, if a single suitable frequency is chosen as the interrogating frequency, then heterodyne interactions of the various split, shifted and/or splitting frequencies with the single interrogating frequency can be measured and determined. Alternatively, resonance interactions of the various split, shifted and/or splitting frequencies can also be measured and determined. Each such determined heterodyned and/or resonant frequency can be made to correspond, by suitable programming or algorithmic techniques, to various data values. Alternatively, a series or sweep of frequencies which may resonate with or heterodyne with various split, shifted and/or splitting frequencies achieved in the contiguous material can also be utilized. These particular affects will be discussed in much greater detail later herein, however, it should be understood that these data acquisition techniques could be performed using hardware which is somewhat similar to that hardware currently used for magnetoresistive and giant magnetoresistive heads. For example, once an interrogating frequency has been input to a material exhibiting Zeeman splitting and/or shifting, the output (e.g., a heterodyned frequency) can be used as a driving signal or input (e.g., depending on strength or frequency either amplified or unamplified) for various other devices. One example of such other device is an acousto-optic Bragg modulator. In this detection scheme, an appropriate light source is caused to be incident upon an appropriate Bragg modulator. Suitable materials for a Bragg modulator include, for example, lithium niobate crystals and gallium arsenide semiconductor materials. The incident light beam can be caused to be deflected in differing amounts due to different driving signal inputs (e.g., depending on strength or frequency either amplified or unamplified) being directed into the Bragg modulator. In particular, for example, the different heterodyne outputs that correspond to different Zeeman splitting amounts (and thus different data points such as a “0” or a “1”) can be input into a Bragg modulator and cause light which is incident on the Bragg modulator to be deflected in different amounts. Thus, the various Zeeman splitting and/or shifting frequencies that are produced can eventually result in different amounts of light deflection due to the use of a Bragg modulator. The amount of deflection of light can be observed by the use of, for example, the light detection devices discussed earlier herein. Similarly, the different heterodyne outputs could be directed into a suitable filter which, due to the different inputs, would regulate the intensity of light passing therethrough. Accordingly, the different intensities of light could then be detected/recorded by a suitable means discussed elsewhere herein. This particular embodiment of the invention which utilizes differing magnetic fields to result in differing amounts of an appropriate frequency splitting and/or shifting is very suitable to be used for the analog storage/retrieval of information. In particular, a substantial continuum of splitting and shifting frequencies results in most materials that are subjected to a corresponding continuum of changing magnetic field strengths. If a continuum of such differing split, shifted and/or splitting frequencies can be reliably detected, then analog or analog-like (e.g., higher order than binary systems) computing with this technique is facilitated. Additionally, many of the aforementioned embodiments of the invention can also be used in combination with various holographic and/or three dimensional memory approaches. To achieve all the foregoing objects and advantages, and to overcome the looming problem in the art of an impending memory barrier, the present invention discloses various means for storing and retrieving information in a digital and/or analog format. With regard to the digital storage of information, a code other than a binary code for the storage of information can be utilized. The result of using a higher order code for digital information storage (i.e., 3 or more characters) is the ability to store more information in the same amount of area or the same amount of information in a smaller area. Accordingly, the present invention provides significant advancement in the art of data storage and/or data retrieval which will assist in preventing the memory barrier from being realized. |
Apparatus and method for splicing sliver of yarn during yarn formation and processing |
An apparatus (20) and methods are provided for splicing selected portions of sliver (S) such as during yarn formation and processing. The apparatus (20) preferably includes a needle carrying member (35) having a plurality of needles (32) to engage silver (S) when positioned adjacent thereto and a needle engaging member (45) positioned to underlie the needle carrying member (35) and to receive the plurality of needles (32) from the first needle carrying member (35). The apparatus (20) also preferably includes a hand-activated needle actuation device (30, 40) connected to the needle carrying member (35) and the needle engaging member (45) to position the needle carrying member (35) in an open position to allow sliver (S) to be spliced to be readily positioned therebetween and responsive to closing at least portions of the hand (H) of a user for actuating the engaging of the needle carrying member (35) with the sliver (S) and the needle engaging member (45) so that the engaging of plurality of needles (32) of the needle carrying member (35) with the needle engaging member (45) thereby defines a closed position. |
1-18. (canceled) 19. An apparatus for splicing selected portions of sliver, the apparatus comprising: a needle carrying member having a plurality of needles to engage sliver when positioned adjacent thereto; a needle engaging member positioned to receive the plurality of needles from the needle carrying member when the plurality of needles engage the sliver in a closed position; and a hand-activated needle actuation device connected to the needle carrying member and the needle engaging member to position the needle carrying member in an open position so that the plurality of needles is spaced-apart from the needle engaging member to allow sliver to be spliced to be readily positioned therebetween, the hand-activated needle actuation device being responsive to grippingly closing at least portions of a hand of a user to actuate the engaging of the needle carrying member with the sliver and the needle engaging member when the sliver is positioned between the needle carrying member and the needle engaging member so that the engaging of the plurality of needles of the needle carrying member with the needle engaging member thereby defines a closed position. 20. An apparatus as defined in claim 19, wherein the hand-activated needle actuation device includes a first handle portion connected to the needle carrying member and positioned to be gripped by a hand of a user, a second handle portion connected to the needle engaging member and positioned to be gripped by a hand of a user, a pivot member connected to the first and second handle portions to allow either the first or second handle portions to pivot about the pivot member between the respective open and closed positions, and a biasing member connected to the pivot member and positioned to bias the needle carrying member in the open position. 21. An apparatus as defined in claim 19, wherein the hand-activated needle actuation device includes a first handle portion connected to the needle carrying member and positioned to be gripped by a hand of a user, a second handle portion connected to the needle engaging member and positioned to be gripped by a hand of a user, a pivot member connected to the first and second handle portions to allow either the first or second handle portions to pivot about the pivot member between the respective open and closed positions, and a biasing member associated with the first and second handle portions and positioned to bias the needle carrying member in the closed position. 22. An apparatus as defined in claim 19, wherein the needle engaging member includes a body member and a plurality of openings formed in the body member and each extending to a depth in the body member so that none of the plurality of needles extend outwardly from the needle engaging member when in the closed position, the number of the plurality of openings being equal to the number of the plurality of needles, each of the plurality of openings being positioned to underlie a corresponding one of the plurality of needles of the needles carrying member so that the plurality of openings matingly receive the plurality of needles as the plurality of needles pass into and out of the plurality of openings to thereby engage the needles and sliver being carried therewith. 23. An apparatus as defined in claim 22, wherein the body member of the needle engaging member includes a substantially closed bottom, and wherein the bottom underlies each of the plurality of openings so that portions of the bottom define a floor for each of the plurality of openings. 24. An apparatus as defined in claim 19, further comprising a lock associated with the hand activated needle actuation device to lock the hand activated needle actuation device in the closed position so that none of the plurality of needles extend outwardly from the needle engaging member when locked in the closed position. 25. An apparatus as defined in claims 19, wherein each of the plurality of needles includes a needle body and a recessed portion formed in the needle body and positioned to assist in the engaging of and interconnecting of the sliver when each needle engages sliver during movement to the closed position. 26. An apparatus as defined in claims 20, wherein the needle carrying member is detachably connected to at least one of the first handle portion and the second handle portion and defines a needle cartridge to readily remove from the respective first handle portion and second handle portion. 27. An apparatus as defined in claims 26, further comprising at least one replacement auxiliary needle cartridge adapted to be readily positioned in the at least one of the first handle portion and the second handle portion. 28. An apparatus for splicing sliver, the apparatus comprising a base and a needle receiving member associated with the base and positioned to receive a plurality of needles, the apparatus being characterized by having: a first cartridge member detachably connected to the base to be readily removed therefrom, the first cartridge member having a combination of a body portion and a plurality of needles each connected to the body portion, each of the plurality of needles having a recessed portion to engage and intertwine first portions of sliver with adjacent second portions of sliver; and a second auxiliary replacement cartridge member adapted to be detachably connected to the base and to be placed in substantially the same position as the first cartridge member, the second auxiliary replacement cartridge member also having a combination of a body portion and a plurality of needles each connected to the body portion and adapted to be positioned to be received by the needle receiving member, each of the plurality of needles having a recessed portion to engage and intertwine first portions of sliver with adjacent second portions of sliver. 29. An apparatus as defined in claim 28, further comprising a pivot member associated with the first cartridge member and the needle receiving member to allow either the first cartridge member or needle receiving member to pivot about the pivot member between respective open and closed positions, the open position being defined by portions of the first cartridge member being spaced-apart from portions of the needle receiving member to receive the first cartridge member and the closed position being defined by the first cartridge member being received by portions of the needle receiving member when positioned closely adjacent thereto. 30. An apparatus as defined in claim 29, further comprising a biasing member associated with the pivot member and positioned to bias either the first cartridge member or the needle receiving member in a preselected biased position. 31. An apparatus as defined in claim 28, wherein the recessed portion of each of the plurality of needles of the first and second cartridge members includes at least one of the following: a barb, a groove, and a channel. 32. An apparatus as defined in claims 28, a lock associated with the first cartridge member and the needle receiving member to lock the first cartridge member and the needle receiving member in a closed position. 33. A method of splicing sliver, the method being characterized by the steps of: grippingly closing a first handle portion and a second handle portion of a sliver splicer having at least one sliver engaging member by a hand of a user so that the at least one sliver engaging member engages and splices sliver positioned adjacent thereto when in a closed position, the at least one sliver engaging member having a plurality of needles each including a recessed portion to engage and intertwine first portions of the sliver with second portions of the sliver to thereby join the first portions to the second portions of the sliver; and releasingly opening the first handle portion and the second handle portion by the hand of the user from the closed position to an open position to thereby release the spliced portion of sliver from the at least one sliver engaging member. 34. A method as defined in claim 33, further comprising the steps of removing the spliced portion from adjacent the at least one sliver engaging member, grippingly closing the first handle portion and the second handle portion to the closed position without sliver positioned therebetween, and locking the first handle portion and the second handle portion in the closed position. 35. A method as defined in claim 34, further comprising removing the spliced portion from adjacent the at least one sliver engaging member and biasingly closing the first handle portion and the second handle portion to the closed position without sliver positioned therebetween. 36. A method as defined in claim 35, wherein none of the recessed portion of each of the plurality of needles is exposed when in the closed position. 37. A method of splicing sliver comprising joining first portions of sliver with a plurality of needles having a recessed portion to engage and intertwine with adjacent second portions of sliver, the method characterized by having: the plurality of needles being connected to a body portion so that the body portion and the plurality of needles in the combination define a needle cartridge member; and replacing the needle cartridge member with an auxiliary cartridge member also having a body portion and a plurality of needles connected to the body portion. 38. A method as defined in claims 37, wherein each of the plurality of needles includes a needle body, and wherein the recessed portion is formed in the needle body and positioned to assist in the engaging of and interconnecting of the sliver when each needle engages sliver. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In the textile industry, yarn is formed of a plurality of slivers. To form the yarn, however, various steps are required to obtain the type and texture of the yarn desired. During sliver processing, sliver is often provided for shipment and use in cans or other containers which allow a first end of the sliver to be drawn or pulled from the can. A second end of the sliver is often left available for splicing to the first end of another can. This splicing is conventionally accomplished by a hand-type braid, twist, or other connection between the second end of the first can and the first end of the second can to join these respective ends of sliver together so that when the first can of sliver empties, the second can is ready to go for additional sliver processing. This hand-type braiding or twisting of the sliver has also become somewhat of a specialty of different textile personnel in sliver handling and processing. This manual procedure, however, can be time consuming, labor intensive, costly, inconsistent from person to person forming the braid or twist, and often is not strong or secure enough when the sliver is further handled or processed. Other types of automatic splicing systems have been developed over the years. Examples can be seen in U.S. Pat. No. 5,544,389 by Onoue et al. titled “Sliver Piecing In Spinning Machines,” U.S. Pat. No. 5,140,722 by Akiyama titled “Sliver Piecing Device Having Fiber Entangling Needles And Air Jets,” U.S. Pat. No. 5,058,241 by Haigh et al. titled “Method And Apparatus For Combining Fibres Formed Into Slivers For Supply To Textile Machinery,” U.S. Pat. No. 4,445,318 by Becker et al. titled “Method And Device For Making A Knot-Free Thread Connection By Splicing,” U.S. Pat. Nos. 4,969,323 and 4,982,563 each by Stahlecker and each titled “Sliver Splicing Arrangement For A Spinning Machine,” U.S. Pat. No. 2,608,725 by Strew titled “Sliver Piecing Device,” U.S. Pat. No. 3 , 308 , 520 by Gagnon titled “Process Of Splicing Tow,” U.S. Pat. No. 5,359,758 by Stahlecker et al. titled “Process And An Arrangement For The Piercing Of A Sliver,” Japanese Patent Document Application No. 05105652 by Takashi titled “Sliver Joining Apparatus In Spinning Machine,” and German Patent Document No. 90-210593/28 titled “Automatic Splicer For Roving On Ring-Spinning Frame—Has Needle Arrangement To Felt Fibres.” These automated systems, however, can be quite expensive to install, can be costly to operate, can have various complex mechanical and/or electrical problems, can take up additional floor space in manufacturing environments, can be bulky and awkward to use, and can often require extensive special training for personnel or the hiring of special personnel to oversee this automated equipment. |
<SOH> SUMMARY OF THE INVENTION <EOH>With the foregoing in mind, the present invention advantageously provides an apparatus and methods for splicing slivers of yarn during formation and processing which is compact, relatively simple to use, and readily portable. The present invention also advantageously provides an apparatus and methods for splicing various types of textile slivers which is relatively inexpensive and does not require extensive personnel training to understand and operate. The present invention additionally advantageously provides an apparatus and methods for splicing various types of textile sliver which allows the user to easily handle, carry, and tote and which is of such a size as to be easily inserted into a pocket of a garment or a carrying case worn by the user. The present invention still also advantageously provides an apparatus and methods for splicing textile sliver which forms a substantially secure connection between ends of sliver being spliced or joined for later handling and/or processing. The present invention further advantageously provides an apparatus and methods for splicing textile sliver which is less complex, easy to repair or replace parts, and is readily adaptable to various splicing needs and situations. More particularly, the present invention provides an apparatus for splicing selected portions of sliver which preferably includes a needle carrying member having a plurality of needles to engage sliver when positioned adjacent thereto, a needle engaging member positioned to receive the plurality of needles from the first needle carrying member when the plurality of needles engage the sliver in a closed position, and a hand-activated needle actuation device connected to the needle carrying member and the needle engaging member to position the needle carrying member in an open position so that the plurality of needles is spaced-apart from the needle engaging member to allow sliver to be spliced to be readily positioned therebetween and responsive to grippingly closing at least portions of the hand of a user to actuate the engaging of the needle carrying member with the sliver and the needle engaging member when the sliver is positioned between the needle carrying member and the needle engaging member so that the engaging of plurality of needles of the needle carrying member with the needle engaging member thereby defines a closed position. The present invention also advantageously provides an apparatus for splicing sliver which preferably includes a first handle portion having at least one sliver engaging member, a second handle portion positioned to receive the at least one sliver engaging member in a closed position, and a pivot member associated with the first and second handle portions to allow either the first or second handle portions to pivot about the pivot member between respective open and closed positions. The open position preferably is defined by portions of the first handle member having the at least one sliver engaging member being spaced-apart from portions of the second handle portion positioned to receive the at least one sliver engaging member, and the closed position preferably is defined by the at least one sliver engaging member of the first handle portion being received by the portions of the second handle member when positioned closely adjacent thereto. The apparatus preferably further includes a biasing member associated with the pivot member and positioned to bias either the first or the second handle portions in a preselected biased position. The present invention additionally provides an apparatus for splicing sliver which preferably includes a first handle portion having a first handle body and at least one sliver engaging member detachably connected to the first handle body to thereby define a cartridge member, a second handle portion pivotally connected to and positioned to receive the at least one sliver engaging member and pivot between open and closed positions. The open position is preferably defined by the at least one sliver engaging member being spaced-apart from portions of the second handle portion positioned to receive the at least one sliver engaging member, and the closed position preferably is defined by the at least one sliver engaging member of the first handle portion being received by the portions of the second handle member when positioned closely adjacent thereto. The apparatus preferably also includes a biasing member positioned to bias either the first or the second handle portions in a preselected biased position. The present invention further provides methods of splicing sliver. A first method preferably includes grippingly closing a handle portion of a sliver splicer having at least one sliver engaging member by the hand of a user so that the at least one sliver engaging member engages and splices sliver positioned adjacent thereto and releasingly opening the handle portion by the hand of the user to thereby release the spliced portion of sliver from the at least one sliver engaging member. Another method of splicing sliver, according to the present invention, preferably includes closing a handle portion of a needle engaging member having a plurality of needles so that the plurality of needles engages and splices sliver positioned adjacent thereto and opening the handle portion of the needle engaging member so that the plurality of needles release the spliced portions of sliver therefrom. Yet another method of splicing sliver according to the present invention preferably includes joining first portions of sliver with a plurality of needles each having a recessed portion to engage and intertwine with adjacent second portions of sliver, the plurality of needles being connected to a body portion so that the body portion and the plurality of needles in combination define a needle cartridge member and replacing the needle cartridge member with an auxiliary cartridge member also having a body portion and a plurality of needles connected to the body portion. The apparatus and methods of the present invention provide additional manufacturing, handling, processing, and formation flexibility in the use of the splicers for sliver. For example, manufacturing personnel can walk around a facility with an apparatus of the present invention positioned in a pocket, holster, or harness when the splicing apparatus or splicer is preferably in a locked closed position so that the manufacturing personnel can readily remove the splicer, unlock the splicer, accomplish the splicing function, relock the splicer, and return the splicer to the pocket, holster, or harness. Additionally, the splicing apparatus of the present invention can be strapped to a chain or belt which can enhance carrying and portability. Further, when one or more needles or other sliver engaging members are damaged, according to one embodiment of the present invention, a cartridge member can readily be removed which carries the needles and replaced with an auxiliary cartridge member. This cartridge replacement, for example, prevents the need to replace the entire splicing apparatus and saves money and reordering time. Also, because the splicing apparatus is portable, compact, and relatively of simple construction and low cost, many different types of manufacturing personnel can use the splicing apparatus and can readily order additional or readily replace the entire splicing apparatus if desired without incurring extensive costs. |
Production of nanoparticles from methyl vinyl ether and maleic anhydride for the administration of hydrophilic pharmaceuticals, more particularly of puric and pyrimidinic bases |
Manufacture of nanoparticles on the basis of methyl vinyl ether and maleic acid for the administration of pharmaceuticals of an hydrophilic nature, in particular analogs of puric and pyrimidinic bases. The nanoparticles are obtained by desolvation with an hydroalcoholic phase of a methyl vinyl ether and maleic acid copolymer solution in acetone. The particles obtained are next treated with cross-linking agents (diamines or proteins) for the purpose of prolonging their useful life and are, possibly, incubated with a pharmaceutical which will be transported on the surface. The nanoparticles can carry the pharmaceutical likewise encapsulated which would then be added during the desolvation. In the case of the nanoparticle-ligand conjugates, the nanoparticles previously obtained and containing inside the pharmaceutical to be transported are incubated with the ligand or molecule which will contribute the property of specifically recognising a particular receptor of the organism. These pharmaceutical forms have as objective to improve the transport of the pharmaceutical or biologically active molecule to its site of action and/or absorption. This property improves the specificity and effectiveness of said pharmaceuticals. |
1. a process for the manufacture of nanoparticles and ligand-nanoparticle conjugates with site specific delivery or targeting properties, able to carry drugs or biologically active molecules on their surface or in their interior characterized by the desolvation of poly(methyl vinyl ether-co-maleic anhydride)copolymer, dissolved in an organic solvent, and subsequent cross-linkage reaction with polyfunctional chemical compounds, including polyamines and polyhydroxyls: 2. A process according to claim 1, that comprises: a) desolvation of the poly(methyl vinyl ether-co-maleic anhydride)polymer dissolved in a polar organic phase at a concentration between 0.01 and 10% w/v, which may optionally contain a drug or biologically active molecule, with a hydroalcoholic solution in an organic phase/hydroalcoholic solution ratio of 1/1 to 1/10; b) elimination of the organic solvents by conventional methods such as filtration, centrifugation or evaporation, including the use of vacuum, among others; c) stabilization of the resulting nanoparticles with cross-linking agents; d) optionally, incubation of the nanoparticles with either the drug or the biologically active molecule or, alternatively, the ligand with targeting properties; e) purification of either the obtained nanoparticles or conjugates by conventional techniques such as ultracentrifugation, centrifugation, tangential filtration, among others; f) optional freeze-drying of the obtained nanoparticles or conjugates. 3. A process according to claim 1, characterized in that nanoparticles or conjugates are produced in a way which permits encapsulation of the drug or biologically active molecule in their interior, that comprises: i) the addition of said drug or biologically active molecule in step a) and, ii) optionally, the addition of a second drug or a different biologically active molecule or, alternatively, a ligand with targeting properties in step d). 4. A process according to claim 1, characterized in that nanoparticles are produced with the drug or biologically active molecule on outer layer, that comprises: i) the addition of the aforesaid drug or biologically active molecule in step d) and, ii) optionally, the addition of another drug or biologically active molecule in step a). 5. A process according to claim 1, characterized in that unloaded nanoparticles are produced consisting of carrying out step a) and step d) without adding any drug or biologically active molecule or ligand. 6. A process according to claim 1, characterized in that step c) is carried out by using polyamine or polyhydroxyl type polyfunctional reagents, including among them proteins and polymeric macromolecules such as non-ionic surfactants or polyvinylpyrrolidone. 7. A process according to claim 1, characterized in that step c) is carried out using the cross-linking agent 1,3-diaminopropane (DP) at a concentration ranging between 0 and 1 mg DP/mg poly(methyl vinyl ether co maleic anhydride). 8. A process according to claim 1, characterized in that step c) is carried out using albumin, such as human serum albumin or bovine serum albumin, at a concentration ranging between 0 and 10 mg albumin/mg poly(methyl vinyl ether co maleic anhydride). 9. A process according to claim 1, characterized in that step f) is carried out by adding mannitol or sacarose as a cryoprotector agent at a concentration ranging between 0.1 and 10% in weight. 10. A process according to claim 1, characterized in that the ligands used in the production of the nanoparticle conjugates have the characteristics of being able to recognize specific structures, or cellular or tissular receptors located on the surface or inside specific cell types in the organism. 11. A process according to claim 10, characterized in that the ligands used are lectins, carbohydrates, monoclonal antibodies, vitamins, amino acids, lipids or molecules of a peptidic nature. 12. A process according to claim 11, characterized in that the ligand is the Sambucus nigra lectin which is bound at a concentration ranging between 1 and 100 mg lectin/mg nanoparticles. 13. A process according to claim 1, characterized in that the drugs or the biologically active molecules incorporated inside the nanoparticles and conjugates possess a hydrophilic character and are soluble in organic polar solvents. 14. A process according to claim 13, characterized in that which the drug incorporated is the anti-tumor drug 5-fluorouridine. 15. A process according to claim 14, characterized in that 5-fluorouridine is dissolved in acetone at a concentration ranging between 0.1 and 3.33 mg/mL and then added to the poly(methyl vinyl ether co maleic anhydride)aceton solution, in order to obtain a drug/polymer ratio ranging between 0.01 and 0.4 mg/mg. 16. A process according to claim 1, characterized in that the drug or biologically active substance is carried on the surface of the nanoparticles and in which step d) of incubation is produced in an aqueous solution. 17. A process according to claim 16, characterized in that the drugs or biologically active molecules incorporated into the surface of the nanoparticles are of hydrophilic character or are soluble in aqueous solutions. 18. A process according to claim 17, characterized in that the drugs or biologically active molecules are either analogs of puric or pyrimidinic bases, or they are compounds of protein nature such as peptides, proteins, glycoproteins, lipoproteins, or they are carbohydrates. 19. A process according to claim 18, characterized in that the drug incorporated in the surface of the nanoparticles is the anti-tumor agent 5-fluorouridine. 20. A process according to claim 19, characterized in that 5-fluorouridine is dissolved in water and, subsequently, added to the suspension of nanoparticles at a concentration ranging between 10 and 1000 μg drug/mg polymer, obtaining concentrations greater than 200 μg of drug bounded to the surface per mg nanoparticles. 21. A process according to claim 17, characterized in that the incorporated drug is the antiviral agent ganciclovir. 22. A process according to claim 21, characterized in that the ganciclovir is dissolved in water and then added to a suspension of nanoparticles, at a concentration ranging between 0.1 and 20 mg drug/mg polymer, obtaining entrapment efficiencies greater than 20% of the initially added ganciclovir. 23. A process according to claim 17, characterized in that the incorporated drug is an oligonucleotide. 24. A process according to claim 23, characterized in that the incorporated drug is an antisense oligonucleotide. 25. A process according to claim 24, characterized in that the incorporated drug is the antisense oligonucleotide ISIS 2922. 26. A process according to claim 25, characterized in that ISIS 2922 is dissolved in water and later added to the suspension of nanoparticles at a concentration ranging between 0.1 and 200 μg drug/mg polymer, producing nanoparticles whose superficially-bounded drug concentration is greater than 2 μg per mg nanoparticle. 27. Nanoparticles or conjugates obtainable by a manufacturing process according to claim 1, characterized by having an approximate average size of less than 500 nm. 28. Nanoparticles or conjugates according to claim 27, characterized by showing a biphasic release profile, with a first phase of immediate release of up to 60% of the loaded drug or biologically active molecule, followed by a second phase in which the drug or biologically active molecule is released slowly and in a sustained release manner. 29. Nanoparticles or conjugates characterized in that they have the following composition: 13-99% w/w poly(methyl vinyl ether co maleic anhydride), 0.001-15% w/w cross-linking agent, optionally, 0.001-15% w/w drug or biologically active molecule, optionally, 0.01-4.5% w/w ligand with specific targeting properties, optionally, 70-82% w/w cryoprotector. 30. Use of A method comprising using the nanoparticles and conjugates according to claim 27 for the administration of drugs or biologically active molecules to a patient. 31. A method comprising using the nanoparticles and conjugates according to claim 27 in the administration of third generation colloidal pharmaceutical forms to a patient. 32. A method comprising using the nanoparticles and conjugates of claim 27 for the pellicular coating of macroscopic pharmaceutical forms such as tablets, granules, granulates and pellets. 33. A method comprising using the nanoparticles and conjugates of claim 27 loading 5-fluorouridine in the preparation of compositions that are useful in the treatment of certain diseases such as colon cancer, cancers of the gastrointestinal tract, breast cancer, cancers of the cervix and endometrium, as well as cancers of the head and neck, liver, ovary, pancreas, prostrate and skin. 34. A method comprising using the nanoparticles and conjugates of claim 27 loading ganciclovir in the preparation of compositions which are useful for the treatment of infections induced by human cytomegalovirus. 35. A method comprising using the nanoparticles and conjugates of claim 27, loading ganciclovir, as adjuvant, in the preparation of gene therapy compositions, which incorporate suicide genes and, in particular, the thymidine quinase gene. 36. A method comprising using the nanoparticles and conjugates of claim 27 loading the antisense oligonucleotide ISIS 2922 in the preparation of compositions useful for the treatment of infections induced by human cytomegalovirus. |
<SOH> TECHNICAL FIELD OF THE INVENTION <EOH>The present invention is within the scope of the procedures for the production of non-biological vectors, nanoparticles and nanoparticle-ligand conjugates, for the transport and administration of pharmaceuticals or active biological molecules of hydrophilic nature through the use of the methyl vinyl ether and maleic anhydride copolymer, poly(methyl vinyl ether-co-maleic anhydride), as priority element. |
Method for the administration of a subscriber card for mobile telephony equipment of the type with auxiliary reader and embedded system for the implementation of the method |
The invention concerns a method for the administration of a subscriber SIM card 3 inserted in the main smartcard reader of a mobile telephone of the type including a second smartcard reader, using an additional administrator smartcard temporarily inserted in this second reader. The administrator smartcard includes at least one specific loader (Ch) applet and one or more files (fl-fn) corresponding to the applets (A1-An) which can be loaded in the SIM card under the control of the loader (Ch). The administrator card complies with the Sim Toolkit standard. The method can also be used to carry out the deletion, modification and various operations on data or applets (A1-An) present in the SIM card: display, determination of the memory space, etc. The invention also concerns an embedded system, more particularly a smartcard, for the implementation of the method. |
1. Administration method for an embedded system for a device of type including a first embedded system reader, the main reader, designed to take the said embedded system and a second embedded system reader, the auxiliary reader, the said embedded system including means for the computer processing and storage of data, wherein it consists of loading in the said storage means of the said embedded system at least one item of digital data contained in an additional embedded system, the administration system, inserted in the said auxiliary embedded system reader, under the control of a specific software module contained in the said additional embedded system. 2. Method according to claim 1, wherein it consists of performing the addition, deletion, modification and management/display administration operations under the control of the said specific software module. 3. Method according to claim 1, wherein it includes at least the following steps: temporary insertion of the said administration embedded system in the said auxiliary embedded system reader; conversion of the said digital data item(s) in the first format into a series of digital data in a second format under the control of the said specific software module; and the selective transfer of the said digital data item(s) in the said second format to the said embedded system and its loading in the said storage means of this embedded system, via the said auxiliary and main embedded system readers, under the control of the said specific software module. 4. Method according to claim 1, wherein the same administration embedded system becomes “master” on powering up although inserted in the said auxiliary embedded system reader. 5. Method according to claim 1, wherein the said device transmits, on being put into service, a command for automatic activation of the said specific software module and in that, the said device including display means, it initialises the display of an interactive menu on the said display means, enabling a user to select one of the said items of digital data for loading in the said storage means of the said embedded system, guiding the user through the loading operations. 6. Method according to claim 1, wherein the said specific software module and the said digital data item(s) to be loaded in the said storage means of the said embedded system are applets encoded in JAVA (registered trademark) language. 7. Method according to claim 1, wherein the said administration of the said embedded system includes the scanning, under the control of the said specific software module, of its storage means, in order to determine predetermined attributes associated with the said digital data item(s) loaded in these storage means and the display of these attributes on the display means of the said device. 8. Method according to claim 1, wherein it includes an additional step, before the loading, which consists of determining whether the remaining memory space is sufficient to perform the said loading, and, in case of negative result, execution of an additional step which consists of the selective and optional deletion, after the choice by a user of the said device and under the control of the said specific software module, of at least one of the said digital data items, in order to release sufficient memory space to carry out the said loading. 9. Method according to claim 1, wherein the said device is a mobile telephony device, the said embedded system is a subscriber embedded system, the said administration embedded system complies with the so-called SIM Toolkit standard, in that it includes an operating system in compliance with this standard enabling the transmission of at least so-called proactive commands in compliance with standard ETSI 11.14, in that the communication protocol used for the loading complies with standard ISO 7816, including the so-called APDU commands, and in that the said proactive commands can be used to activate and send APDU commands, in order to set up a communication session between the said administration and subscriber embedded systems, and obtain the said selective transfer of at least one digital data item and their loading in the storage means of the said subscriber embedded system. 10. Embedded system including means for the computer processing and storage of digital data, characterised in that it includes, in its storage means, a specific software module, including at least one component consisting of a loader program (Ch) and at least one item of digital data in order to load at least one of the said digital data items in the said storage means of a second embedded system, for a device when the said system is inserted in an auxiliary reader of the said device. 11. Embedded system according to claim 10, wherein the said specific software module stored in the said storage means of the said administration embedded system and the said digital data item(s) to be loaded in the said storage means of the said embedded system are applets encoded in JAVA (registered trademark). |
Estimating signal strength measurements in a telecommunications system |
The number of measurements being performed in a telecommunications system can be reduced by performing a predetermined measurement in Cell A and in co-located Cell B, step 1, for example a received signal code power (RSCP) measurement. The difference between the two signals is determined, and stored for future reference, step 3. Once the difference value has been established, the mobile station no longer needs to perform measurements on both Cell A and Cell B. Instead, if a subsequent measurement is made on Cell A, step 5, the network can estimate the measurement for Cell B based on the difference signal previously determined, step 7. |
1. A method of estimating a signal measurement in a telecommunications system, the method comprising the steps of: performing a first measurement in first and second co-located cells of the telecommunications system; determining a difference value between the measurements; and using the difference value to estimate a second measurement for the second cell, based on a second measurement being made in the first cell. 2. A method as claimed in claim 1, wherein the second measurement is the same type of measurement as the first measurement. 3. A method as claimed in claim 1, wherein the second measurement is a different type of measurement to the first measurement, but having a predetermined relationship to the first measurement. 4. A method as claimed in claim 3, wherein the second measurement is a CPICH Ec/No measurement. 5. A method as claimed in any one of claims 1 to 4, wherein the first measurement is a received signal code power (RSCP) measurement. 6. A method as claimed in any one of the preceding claims, wherein the measurements are performed at a mobile station in the telecommunications system and the difference value stored at a network side of the telecommunications system. 7. A method as claimed in any one of the preceding claims, wherein the method of estimating a measurement is used to evaluate which cells should belong to an active set on a frequency other than the frequency being used. 8. A method of handover in a cellular telecommunications system, the method of handover using a method of estimating a signal strength measurement as defined in any one of claims 1 to 7. 9. A telecommunications system in which signal strength measurements are performed in two or more co-located cells, the system comprising: means for measuring a first measurement in first and second co-located cells of the telecommunications system; means for determining a difference value between the measurements; and means for estimating a second measurement for the second cell, based on a second measurement being made in the first cell and the previously determined difference value. 10. A system as claimed in claim 9, wherein the second measurement is the same type of measurement as the first measurement. 11. A system as claimed in claim 9, wherein the second measurement is a different type of measurement to the first measurement, but having a predetermined relationship to the first measurement. 12. A system as claimed in claim 11, wherein the second measurement is a CPICH Ec/No measurement. 13. A system as claimed in any one of claims 9 to 12, wherein the first measurement is a received signal code power (RSCP) measurement. 14. A system as claimed in any one of claims 9 to 13, wherein the measurements are performed at a mobile station in the telecommunications system and the difference value stored at a network side of the telecommunications system. 15. A system as claimed in any one of claims 9 to 14, having means for evaluating which cells should belong to an active set on a frequency other than the frequency being used. 16. A method of estimating a signal measurement substantially as hereinbefore described, with reference to, and as shown in FIG. 1 or 2 of the accompanying drawings. 17. A telecommunications system substantially as hereinbefore described, with reference to, and as shown in FIG. 1 or 2 of the accompanying drawings. 18 A communications node for a telecommunications system in which signal strength measurements are performed in two or more co-located cells, the communications node comprising: means for receiving a first measurement from first and second co-located cells of the telecommunications system; means for determining a difference value between the measurements; and means for estimating a second measurement for the second cell, based on a second measurement being made in the first cell and the previously determined difference value. 19. A communications node as claimed in claim 18, wherein the second measurement is the same type of measurement as the first measurement. 20. A communications node as claimed in claim 18, wherein the second measurement is a different type of measurement to the first measurement, but having a predetermined relationship to the first measurement. 21. A communications node as claimed in claim 20, wherein the second measurement is a CPICH Ec/No measurement. 22. A communications node as claimed in any one of claims 18 to 21, wherein the first measurement is a received signal code power (RSCP) measurement. 23. A communications node substantially as hereinbefore described, with reference to, and as shown in FIG. 1 or 2 of the accompanying drawings. 24. A method of estimating a signal measurement in a communications node of a telecommunications system, the method comprising the steps of: receiving a first measurement from first and second co-located cells of the telecommunications system; determining a difference value between the measurements; and using the difference value to estimate a second measurement for the second cell, based on a second measurement being made in the first cell. 25. A method as claimed in claim 24, wherein the second measurement is the same type of measurement as the first measurement. 26. A method as claimed in claim 24, wherein the second measurement is a different type of measurement to the first measurement, but having a predetermined relationship to the first measurement. 27. A method as claimed in claim 26, wherein the second measurement is a CPICH Ec/No measurement. 28. A method as claimed in any one of claims 24 to 27, wherein the first measurement is a received signal code power (RSCP) measurement. 29. A method of estimating a signal measurement in a communications node of a telecommunications system, the method being substantially as hereinbefore described, with reference to, and as shown in FIG. 1 or 2 of the accompanying drawings. 30. A mobile communications terminal for use in a telecommunications system as described in any one of claims 9 to 15. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In a telecommunications system, for example a wideband CDMA system (WCDMA), there is always a desire to communicate using the least amount of power. Therefore, all transmissions should ideally be performed at the lowest possible power level, while still maintaining an acceptable quality level. However, there are certain factors which act against this general desire to reduce power levels. Certain communication techniques have an inherent need for the power levels to be increased, both in the mobile station and the network. For example, data compression can be used to transmit a given amount of data in less time, resulting in gaps being created to allow inter-frequency or inter-RAT (Radio Access Technology) measurements to be carried out. In addition to the peak power being increased during the data compression, the average power also needs to be increased to compensate for the channel estimates that are not being updated during the time gaps, resulting in the receiver not being optimally tuned after the time gaps. While increased inter-frequency and inter-RAT measurements typically have the disadvantage of increasing the average power consumption when using real time services with requirements of low delays, for example speech, they also have a degrading effect in that they reduce the available channelization-codes. During data compression a code for a lower spreading factor needs to be used, which typically blocks several codes used for higher spreading factors in the downlink. The gaps in transmission mentioned above can also occur in other ways. For example, reducing the number of bits to be transmitted by reducing the number of extra bits which are used for error correction during some frames (i.e. code puncturing), or scheduling data transmission from a higher layer. It is known to reduce the power requirement (and in turn improve data throughput) by reducing the number of measurements carried out in the telecommunications system. One known example of how this may be achieved is based on the use of neighbouring cell lists, and thresholds for starting measurements. This type of solution suffers from the disadvantage that each neighbouring cell is treated equally as if they were adjacent neighbours using different antennas covering different, but to some extent overlapping, geographical areas. The reduction in these schemes is based on limiting the number of neighbouring cells included in the list, and on handover statistics and propagation predictions when cell planning is performed. The aim of the present invention is to provide a method of estimating measurements in a telecommunications system, thereby reducing the number of measurements being performed. This has the advantage of reducing power consumption and increasing the capacity of the system. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to a first aspect of the present invention, there is provided a method of estimating a signal measurement in a telecommunications system, the method comprising the steps of: performing a first measurement in first and second co-located cells of the telecommunications system; determining a difference value between the measurements; and using the difference value to estimate a second measurement for the second cell, based on a second measurement being made in the first cell. According to another aspect of the present invention, there is provided a telecommunications system in which signal strength measurements are performed in two or more co-located cells, the system comprising: means for measuring a first measurement in first and second co-located cells of the telecommunications system; means for determining a difference value between the measurements; and means for estimating a second measurement for the second cell, based on a second measurement being made in the first cell and the previously determined difference value. According to another aspect of the present invention, there is provided a communications node for a telecommunications system in which signal strength measurements are performed in two or more co-located cells, the communications node comprising means for receiving a first measurement from first and second co-located cells of the telecommunications system, means for determining a difference value between the measurements, and means for estimating a second measurement for the second cell, based on a second measurement being made in the first cell and the previously determined difference value. |
Plasma surface graft process for reducing thrombogenicity |
In accordance with the present invention, there is provided a novel process for modifying the surface properties of a material that is suitable for contact with animal tissue so as to enhance its hemocompatibility and make it less thrombogenic when in use. This process comprises: Exposing the surface of the material to plasma treatment conditions in order to create reactive groups on said surface; activating a molecule with an activator to produce a reactive molecular species capable of forming convalent bonds with the reactive groups created on the surface of the material to form convalent bonds. The invention further encompasses the materials produced by this process as well as devices, such as vascular prosthesis, that are comprised of these process-modified materials. |
1. A process for modifying the surface properties of a material suitable for contact with a living tissue comprising: Exposing the surface of the material to plasma treatment conditions in order to create reactive groups on said surface; Activating a molecule with an activator to produce a reactive molecular species capable of forming strong bonds with the reactive groups created on the surface of the material; and Contacting the reactive molecular species with the reactive groups created on the surface of the material to form strong bonds. 2. A process as defined in claim 1, wherein said strong bonds are covalent bonds. 3. A process as defined in claim 1 or 2, wherein the resulting surface of the material is compatible with living tissue. 4. A process as defined in claim 3, wherein said tissue is blood tissue. 5. A process as defined in claim 1, wherein: said plasma is ammonia Radio Frequency (RF) plasma and said reactive groups are amine groups; said molecule is selected from the group consisting of choline, heparin, and other molecules known to those skilled in the art for their hemocompatibility, said activator is phosphoryl chloride (POCl3) and said reactive molecular species is the oxyphosphorodichlorinated derivative of said molecule; and said strong bonds are phosphoamide-type covalent bonds. 6. A process as defined in claim 5, wherein said plasma treatment conditions consist of the application of a RF power of between about 5 watts to about 500 watts for a time of about 10 seconds to about 30 minutes at a pressure of about 50 mtorr to about 5 torr. 7. A process as defined in claim 6, wherein said plasma treatment conditions consist of the application of a RF power of about 20 watts for a time of about 250 seconds at a pressure of about 300 mtorr. 8. A process as defined in claim 6, wherein said plasma treatment conditions consist of the application of a RF power of about 15 watts for a time of about 100 seconds at a pressure of about 250 mtorr. 9. A process as defined in claim 7 or 8, wherein the third step is performed within about 2 hours of the first step. 10. A process as defined in any one of claims 1 to 9, wherein said material suitable for contact with a living tissue is material implantable in an animal's body. 11. A process as defined in claim 10, wherein said material implantable in an animal's body is selected from the group consisting of: Microporous expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), polyvinylchloride (PVC), polyethylenes, polyesters (such as polyethylene terephtalate—PET), polypropylenes, polyurethanes, polycarbonates, silicones, PVDF and polymer-coated materials, such as metals and ceramics for example. 12. A process as defined in claim 11, wherein said material implantable in an animal's body is ePTFE. 13. A process as defined in claim 12, wherein said ePTFE is that of the internal surface of a vascular prosthesis. 14. A process as defined in claim 13, wherein said vascular prosthesis has an inner diameter of about 1 to 30 mm. 15. A material implantable in an animal's body produced by the process of any one of claims 1 to 14. 16. A vascular prosthesis produced by the process of claim 13 or 14. 17. A device comprising a material as defined in claim 15. 18. A device as defined in claim 17, wherein said device is to be used in contact with an animal's tissue. 19. A device as defined in claim 18, wherein said tissue is blood tissue. 20. A device as defined in claim 18 or 19, wherein said device is selected from the group consisting of: An implant, a prosthesis, an artificial organ, a stent, a cardiac valve, an apparatus contacting blood during an extra-corporal blood circulation, an apparatus contacting blood during a dialysis treatment or any other material with surfaces coming in contact with blood. 21. Use of a device as defined in any one of claims 17 to 20 for preventing thrombosis. 22. A material suitable for contact with a living tissue characterized in having a surface that is resistant to neutrophil adhesion, platelet adhesion and activation but that enhances the development of fibroblasts and endothelial cells. 23. A material as defined in claim 22 which is plasma-treated ePTFE with grafted PRC. 24. A device comprising a material as defined in claim 22 or 23. 25. A device as defined in claim 24, wherein said device is selected from the group consisting of: An implant, a prosthesis, an artificial organ, a stent, a cardiac valve, an apparatus contacting blood during an extra-corporal blood circulation, an apparatus contacting blood during a dialysis treatment or any other material with surfaces coming in contact with blood. 26. Use of a device as defined in claim 24 or 25 for preventing thrombosis. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Approximately 350 000 synthetic vascular prostheses are implanted each year as arterial bypasses in Western countries and Japan. Made of Dacron™ (polyethyleneterephthalate) or microporous Teflon™ (expanded polytetrafluoroethylene, or ePTFE), they perform quite well in large-diameter vessels under high flow conditions but have a low patency rate when used as small-diameter bypasses (i.e., coronaries) or as medium-diameter bypasses in low-flow conditions and high-resistance locations (i.e., leg arteries). (The patency rate relates to a biomaterial's ability to remain pervious to blood flow when replacing an artery). A study on 398 ePTFE vascular prostheses implanted as medium-diameter bypasses and retrieved following complications revealed that 65% of them had to be explanted due to thrombosis. (1 ) Endothelial cell lining is the natural blood-compatible surface that covers the inside surface of blood vessels and heart chambers, and it is recognized to be the best possible hemocompatible surface. The principal techniques that have been proposed in the past to promote endothelial cell adhesion and spreading onto the luminal surfaces of vascular prostheses are: (1) endothelial cell seeding; (2) graft pre-treatment with endothelial cell mitogens; (3) increasing structural porosity; and (4) coating the surface with a protein matrix. While several attempts have been made, the complete endothelial cell coverage of the blood-exposed inside prosthetic surfaces has never been observed in humans. It is therefore evident that increasing the patency rate of arterial prostheses is a high priority in current cardiovascular research. It has been shown in many instances that surface modification through plasma treatment is one of the most promising techniques that may be used to improve specific hemocompatibility and general biocompatibility of polymeric materials. (2,3) One advantage of the plasma treatment is that it allows formation of a covalent bond between the modifier and the surface to be treated, unlike other approaches where a coating is deposited inside the prosthesis without formation of a covalent bond (4,5) , where the bond is ionic (6) or where the bioactive substance is incorporated in the biomaterial. (7) Following to the covalent bonding of the modifier to the surface of the material, made possible by plasma treatment, a molecule chosen for its biocompatibility properties can be covalently attached to the modifier either directly or through a spacer molecule. Clinically, the increased stability of a surface treatment involving plasma treatment could result in improved limb salvage rates and a possible future use in small-diameter coronary bypass operations. This, in turn, could minimize the incidence of re-operation for patients and lower social healthcare costs related to surgical interventions of this type. Plasma treatment of biomaterials is not the only process that can yield covalent bonding of molecules possessing desirable hemocompatibility and/or biocompatibility. However, the processes that are described in the relevant prior art frequently involve several steps. (8-14) To date, most of the experiments performed to improve the performance of biomaterial surfaces have been based on flat specimens of material, particularly polymeric sheets. Unfortunately, few experiments involving the use of plasma to activate the surface have been carried out directly on commercial prostheses with a non-planar geometry. Experiments done at the University of Washington, (2,15-20) which consisted mainly in treating commercial Dacron™ arterial prostheses with a plasma treatment in a tetrafluoroethylene (TFE) gas environment so as to coat the internal surfaces of the prostheses with potentially more biocompatible CF 3 groups, were a precursor to the development of the new commercial Radio Frequency Glow Discharge (RFGD)-treated vascular grafts. (17) Yet, despite the existence of many surface treatment systems for biomaterial surfaces, few have resulted in the treatment, as opposed to the coating, of the internal surface of tubular devices. (21-23) Over the last 30 years, a number of studies have been designed to test the ability of plasma to either treat or coat the surfaces of biomedical devices with a view to enhancing their biocompatibility or to modulate the interactions of polymers and tissue when prostheses are implanted in situ. (16,24-30) Plasma polymerizable gas has been used to coat various substrates with a thin polymeric layer, (15,17-19,24,31,32) while non-polymerizable gas has been applied to treat substrate surfaces. (33-38) Despite the fact that many approaches have been developed to coat or treat the surface of biomaterials, the introduction of amino groups through RFGD treatment is particularly interesting for two reasons. First, amino groups are known to facilitate cellular spreading on a biomaterial surface. (39-41) Second, amino groups react readily with other chemical functional groups, allowing for the attachment of specific molecules through interactions sufficiently strong to prevent the leaching of these molecules by the blood stream. (42) For example, amino groups can be used to ionically immobilize heparin, a well-known polysaccharide anticoagulant. (22) While many efforts have been made in the last 20 years in the field of cardiovascular prosthetic devices to develop surfaces with improved human blood compatibility, an acceptable long-term blood-compatible synthetic material has yet to be achieved. The complexity of the interactions between blood and synthetic materials constitutes a major interfacial problem in this respect. |
<SOH> SUMMARY OF THE INVENTION <EOH>Surface treatments allow a modulation of the surface properties of a biomaterial to enhance its interfacial reaction with a biological environment. Low pressure plasma surface treatments are particularly advantageous in the design and development of new biocompatible materials, since they permit surface modifications without altering the bulk of the materials' properties. (43) In the context of the present invention, they are particularly useful for modulating different tissue/biomaterial interface properties, but their ultimate utility may reside in their significant improvement of the hemocompatibility of vascular prostheses. Thus, in accordance with the present invention, there is provided a novel process for modifying the surface properties of a material that is to be placed in contact with living tissues. This process comprises: Exposing the surface of the material to plasma treatment conditions in order to create reactive groups on the surface of the material; Activating a molecule with an activator to produce a reactive molecular species capable of forming strong bonds with the reactive groups created on the surface of the material; and Contacting the reactive molecular species with the reactive groups created on the surface of the material to form strong bonds. Preferably, the strong bonds formed are covalent bonds. In a preferred embodiment, the molecule selected for activation is compatible with living tissue, including human tissue. In a specific embodiment the novel process of the present invention further comprises the following features: the plasma is ammonia Radio Frequency (RF) plasma and the reactive groups are amine groups; the molecule selected for activation is chosen from the group consisting of choline, heparin, and other molecules known to those skilled in the art for their hemocompatibility, the activator is phosphoryl chloride (POCl 3 ) and the reactive molecular species is the oxyphosphorodichlorinated derivative of the molecule; and the strong bonds are phosphoamide-type covalent bonds. In a preferred embodiment of the specific embodiment above, the RF power is between about 5 watts to about 500 watts and is applied for a time of about 10 seconds to about 30 minutes at a pressure of about 50 mtorr to about 5 torr. Those skilled in the art will recognize that care has to be taken in order to avoid combinations of time and power that would deliver excessive amounts of energy to the treated surface. Such conditions lead to a microscopically brittle surface. Preferably, the RF power is about 20 watts and is applied for a time of about 250 seconds at a pressure of about 300 mtorr. In yet another preferred embodiment, the RF power is about 15 watts and is applied for a time of about 100 seconds at a pressure of about 250 mtorr. Ideally, the third step of the process is performed within about 2 hours of the first step. The novel process of the present invention is particularly suitable for an implantable material selected from the following group: expanded polytetrafluoroethylene (ePTFE), polytetrafluoroethylene (PTFE), polyethylenes, polyesters, polypropylenes and polyurethanes. In a preferred embodiment, the implantable material is ePTFE, and the treated surface is the internal surface of a vascular prosthesis. In a more preferred embodiment, the vascular prosthesis has an inner diameter of about 1 to 30 mm. The present invention further comprises the materials produced by the novel process, as well as devices comprising these materials, including any of the following: an implant, a prosthesis, an artificial organ, a stent, a cardiac valve, an apparatus contacting blood during an extra-corporal blood circulation, an apparatus contacting blood during a dialysis treatment or any other material with surfaces coming in contact with blood. Additionally, the present invention is meant to cover the use of any such device, particularly to prevent thrombosis in an animal, including a human being. By controlling the RF power, the ammonia pressure, and the treatment duration, the atomic substitution percentage may be modulated and up to 15% of the surface atoms may be substituted with nitrogen, as probed by X-ray photoelectron spectroscopy (XPS). On the surface, different chemical species are present after the treatment, such as amine and imine groups. Storage in air for up to 80 days shows a defluorination of the surface and a slow decrease of the surface nitrogen concentration during this storage. Ammonia RF Plasma treatment can be successfully used to uniformly treat the internal surface of an ePTFE arterial prosthesis despite the fact that care has to be taken to prevent a significant surface reorganization upon exposure to the atmosphere. (44,45) The ammonia RF plasma-treated internal surfaces of vascular prostheses may be reacted with a substance whose molecular structure can render the prostheses more hemocompatible and non-thrombogenic when in use. The molecule is preferably activated phosphorylcholine (PRC) or any other molecule with similar properties, wherein the two hydroxyl groups on the phosphate moiety have been substituted with chlorine to form the dichloro derivative of the molecule. This dichloro derivative readily reacts with the amino groups resulting from the ammonia RF plasma treatment of the inside surfaces of the vascular prostheses, allowing for the effective anchoring of the molecule. It is an object of the present invention to provide a novel process for producing a material suitable for contact with a living tissue. This material is characterized in having a surface that is resistant to neutrophil adhesion and thrombosis but that enhances the development of fibroblasts and endothelial cells. The process may be used, for example, to treat the inside surfaces of devices, such as vascular prostheses, so as to enhance their hemocompatibility and make them less thrombogenic when in use. A further object of the invention is therefore to provide devices treated with the novel process of the present invention. Other objects, advantages and features of the present invention will become more apparent upon reading of the following non restrictive description of preferred embodiments thereof, given by way of example only with reference to the accompanying drawings. |
Central Fastening Element for an Axially Symmetric Gas Spring |
In a central fastening element for an axially symmetric, vehicle gas spring, which includes a bellows that has central bores or cutouts in the region of its end faces, the fastening element being fixed to the vehicle body, protruding from the surroundings of the attachment point in a direction normal to it, and being encompassed by the bores or cutouts. The fastening element includes a shaped stud or a shaped cap, the maximum outer diameter of the stud or the cap being at least less than one fifth of the maximum outer diameter of the gas-spring bellows. A device may be provided which allows a gas spring to be installed in a simple manner and allows the spring bellows to rotate with respect to the suspension and/or the vehicle body during the initial installation and/or the initial operation. |
1-9. (canceled) 10. A central fastening element for an axially symmetric, vehicle gas spring including a bellows having one of central bores and cutouts in a region of an end face, the fastening element configured to be fixed to a vehicle body and to protrude from surroundings of an attachment point in a normal direction and to be encompassed by the one of the bores and cutouts, comprising: at least one of a stud and a cap, one of the at least one of the stud and the cap shaped, a maximum outer diameter of the one of the stud and the cap at least less than one fifth of a maximum outer diameter of the bellows, the one of the stud and the cap including at least one necked-down portion having a diameter less than the maximum outer diameter of the one of the stud and the cap, the end face elastic in a zone of contact with the one of the stud and the cap. 11. The fastening element according to claim 10, wherein a base of the bellows axially and radially surrounds the one of the stud and the cap without a sealing joint. 12. The fastening element according to claim 10, further comprising an integrated supply line. 13. The fastening element according to claim 10, wherein the cap includes an internal thread, the stud having an external thread, the cap substantially completely surrounding the stud, the cap arranged to one of directly and indirectly contact the vehicle body. 14. The fastening element according to claim 10, wherein the stud is arranged to be screwed into a tapped hole of the vehicle body, the stud having a surface oriented in a direction normal to an axis of the stud, the surface arranged to one of directly and indirectly rest against the vehicle body. 15. The fastening element according to claim 10, wherein the stud is arranged to be screwed into a nut fastened to the vehicle body. 16. The fastening element according to claim 10, wherein a base of the bellows includes at least two superposed layers, at least one of the layers made of metal, at least one of the layers made of metal. 17. The fastening element according to claim 10, wherein a base of the bellows is arranged to rest against at least two surface sections of the one of the stud and the cap oriented in axially opposite directions. 18. The fastening element according to claim 10, wherein a base of the bellows is arranged to rest against a surface section of the one of the stud and the cap oriented in a direction of the vehicle body and against the vehicle body in a region of attachment of the one of the stud and the cap. 19. The fastening element according to claim 10, wherein the cap includes an internal thread, the stud having an external thread, the cap substantially completely surrounding the stud, the cap one of directly and indirectly contacting the vehicle body. 20. The fastening element according to claim 10, wherein the stud is screwed into a tapped hole of the vehicle body, the stud having a surface oriented in a direction normal to an axis of the stud, the surface one of directly and indirectly resting against the vehicle body. 21. The fastening element according to claim 10, wherein the stud is screwed into a nut fastened to the vehicle body. 22. The fastening element according to claim 10, wherein a base of the bellows rests against at least two surface sections of the one of the stud and the cap oriented in axially opposite directions. 23. The fastening element according to claim 10, wherein a base of the bellows rests against a surface section of the one of the stud and the cap oriented in a direction of the vehicle body and against the vehicle body in a region of attachment of the one of the stud and the cap. 24. The fastening element according to claim 10, wherein the fastening element is fixed to a vehicle body. 25. The fastening element according to claim 10, wherein the fastening element protrudes from the surroundings of the attachment point in the normal direction. 26. The fastening element according to claim 10, wherein the fastening element is encompassed by the one of the bores and cutouts. 27. A device, comprising: an axially symmetric, vehicle gas spring including a bellows having one of central bores and cutouts in a region of an end face; and a fastening element configured to be fixed to a vehicle body and to protrude from surroundings of an attachment point in a normal direction, the fastening element encompassed by the one of the bores and cutouts, the fastening element including at least one of a stud and a cap, one of the stud and the cap shaped, a maximum outer diameter of the one of the stud and the cap at least less than one fifth of a maximum outer diameter of the bellows, the one of the stud and the cap including at least one necked-down portion having a diameter less than the maximum outer diameter of the one of the stud and the cap, the end face elastic in a zone of contact with the one of the stud and the cap. |
<SOH> BACKGROUND INFORMATION <EOH>Such a device is described in European Published Patent Application No. 0 123 171. The gas spring includes, inter alia, a vertical U-bellows and two axially symmetric bodies terminating it on the upper and lower sides. On the upper side, the gas spring is fixed to the vehicle body, e.g., to the vehicle frame, with the aid of a bolt. This bolt is seated in a bore of the frame and is screwed to the axially symmetric upper body, a so-called plug. The U-bellows itself is fastened to the axially symmetric, upper member with the aid of a tension band. In this case, the diameter of the plug is as large as the inner diameter of the U-bellows. This type of fastening requires that the bolthead on the upper side of the frame be accessible during installation. This makes it difficult to automate the installation of the gas spring. The gas spring tends to twist during installation, and while compressing and rebounding. Therefore, the tightening torque of the bolt must be selected to be high enough to prevent the connection between the gas spring and the vehicle body from loosening or releasing in response to vibrations and shock. It is an object of the present invention to provide a fastening element, which renders simple installation possible and allows the bellows to rotate with respect to the suspension and/or the vehicle frame during the initial installation and/or the initial operation. |
<SOH> SUMMARY <EOH>This object may be achieved by providing a fastening element as described herein. To this end, the fastening element may include a shaped stud or a shaped cap, the maximum outer diameter of the stud or the cap being at least less than one fifth of the maximum outer diameter of the gas-spring bellows. The cap or the stud has at least one necked-down portion or waist, whose outer diameter is less than the above-mentioned, maximum diameter of the cap or stud. The end face is elastic in the zone in which it comes into contact with the stud or the cap. The central fastening element may be attached to the vehicle body prior to the installation of the gas spring and may protrude from the vehicle body in a direction normal to it. During installation, the gas spring is attached to, for example, the strut of the suspension and, e.g., pressed, together with it, against the shaped stud or the shaped cap. In the following, the term, stud, also includes the shaped cap. The elastic zone of the end face of the gas spring comes into contact with the stud in response to being slid up, and then engages with it in the manner of a snap fastener. The stud has a necked-down portion, which is encompassed by the bore or the cutout in a form-locked or force-locked manner. This type of fastening may allow the gas spring to be installed in an automated manner. In this case, and during initial operation, the gas spring may rotate on the stud, which means that the twisting of the U-bellows and the increased wear caused by it are prevented. The keyed connection between the stud and spring prevents vibrations and shock from detaching the fastening element. The base of the gas-spring bellows surrounds the stud axially and radially. Consequently, the gas spring is fixed in position in the axial and radial directions after installation. For example, it may not detach when the vehicle is jacked up, or in response to a pressure drop. The gas spring may be attached at its upper and lower ends in the same manner. Supply lines may be run through the fastening element into the interior of the gas spring. At least some regions of the base of the gas-spring bellows may be made of an elastic material, e.g., rubber. This may allow the base to act as a damping layer. The base may also be made up of multiple layers, e.g., a rubber layer and a metallic layer. In this case, the gas-spring bellows is attached to the metallic layer. The metallic layer is simultaneously used for increasing the strength of the gas-spring base. Several rubber and metallic layers may also be combined. To attach the gas spring, e.g., this rubber layer is compressed between two surface sections of the stud oriented in opposite, axial directions, or between a surface section oriented in the direction of the vehicle body, and the vehicle body. If the base of the gas spring is made out of multiple layers, the inner layer may be, for example, a metallic layer. The gas-spring bellows is then attached to this. This layer may be constructed in such a manner, that it supports the rubber layer and holds the position of the gas spring on the stud. Further details of the fastening element according to the present invention are set forth below in the subsequent description of several schematically represented, example embodiments. |
Methods and compositions for inhibiting hiv-coreceptor interactions |
Novel methods and compositions are provided for inhibiting interactions between human immunodeficiency viruses (HIVs) and viral coreceptors, including CXCR4 and/or CCR5 coreceptors. The anti-coreceptor binding agent includes a novel peptide portion of the gp120 envelope protein of HIV-1, as well as peptide analogs and mimetics of this peptide, that specifically binds to, or modulates activity of, the coreceptors(s). The anti-coreceptor binding agent is useful as a prophylactic or therapeutic treatment to prevent or inhibit HIV binding to a susceptible cell and thereby reduces infection and/or moderates or treats related diseases. In alternative embodiments, the peptides, analogs and mimetics are effective to inhibit direct co-receptor binding by HIV virus, coreceptor binding by HIV gp120 proteins or peptides, HIV fusion with target host cells, HIV virion entry into host cells, HIV replication, and HIV transmission between cells and hosts. In more detailed embodiments, the anti-coreceptor binding agents of the invention are multi-tropic by exhibiting activity against HIV interactions with multiple, CXCR4 and CCR5, coreceptors. |
1. A composition comprising an effective amount of an anti-coreceptor binding agent to inhibit binding of a CXCR4 and/or CCR5 coreceptor of a subject by an HIV virus or viral protein, wherein the anti-coreceptor binding agent is a gp120 peptide, peptide analog or mimetic that specifically binds the CXCR4 and/or CCR5 coreceptor. 2. The composition of claim 1, wherein the gp120 peptide, peptide analog or mimetic is between about 12 and about 24 amino acid residues in length and comprises a conserved CXXXXXXW amino acid sequence motif, wherein X is any naturally occurring or synthetic amino acid or amino acid analog. 3. The composition of claim 1, wherein the peptide, peptide analog or mimetic is modified by addition, admixture, or conjugation of additional amino acids, peptides, proteins, chemical reagents or moieties which do not substantially alter the anti-coreceptor binding activity of the peptide. 4. The composition of claim 1, wherein the anti-coreceptor binding agent is a peptide comprising an allelic variant among native HIV gp120 peptide sequences. 5. The composition of claim 1, wherein the anti-coreceptor binding agent is formulated for delivery to subject selected from an isolated or bound coreceptor, a membrane or cell preparation comprising the coreceptor, a cell population, tissue or organ expressing the coreceptor, or a mammalian patient. 6. The composition of claim 5, wherein the anti-coreceptor binding agent is combined with a pharmaceutically acceptable carrier, diluent, excipient, or adjuvant for administration in a prophylactic or therapeutic effective dose to a mammalian patient to prevent or inhibit HIV infection or a related disease condition or symptom in the patient. 7. The composition of claim 1, wherein the anti-coreceptor binding inhibits one or more biological activities mediated by or associated with HIV-coreceptor interactions selected from (a) direct co-receptor binding by HIV virus, (b) coreceptor binding by a HIV gp120 protein or a peptide fragment or derivative thereof, (c) HIV fusion with target host cells, (d) HIV virion entry into host cells, (e) HIV replication, and/or (f) HIV cell-cell or host-host transmission. 8. The composition of claim 1, wherein the anti-coreceptor binding agent comprises an effective formulation of an HIV-1 peptide, peptide analog or mimetic for in vivo administration to inhibit one or more biological activities selected from (a) direct co-receptor binding by HIV-1 virus, (b) coreceptor binding by a HIV-1 gp120 protein or a peptide fragment or derivative thereof, (c) HIV-1 fusion with target host cells, (d) HIV-1 virion entry into host cells, (e) HIV-1 replication, and/or (f) HIV-1 cell-cell or host-host transmission. 9. The composition of claim 1, wherein the anti-coreceptor binding agent is an HIV-1 peptide, peptide analog or mimetic formulated for administration to a mammalian patient in a prophylactically or therapeutically effective dose to prevent or inhibit HIV-1 infection or an HIV-1-related disease condition or symptom. 10. The composition of claim 1, wherein the anti-coreceptor binding agent is a peptide that includes a conserved “CXXXXXXW” amino acid sequence motif, wherein X is any amino acid, and wherein the peptide is from about 12-17 amino acids in length and is selected from peptide 15K, comprising an amino acid sequence IRKAHCNISRAKWND (SEQ ID NO:8), or a corresponding or overlapping native peptide sequence or peptide analog that shares substantial sequence identity to the reference peptide sequence of 15K. 11. The composition of claim 10, wherein the peptide includes one or more residues occurring naturally or by substitution at a relative, aligned position corresponding to a designated position for peptide 15K, selected from: Position 1—I, M, K, S, T, L, A, V, R, P, or N; Position 2—R, G, E, K, S, T, or I; Position 3—Q, K, R, L, E, P, A, V, S, T, H, or D; Position 4—A, T, P, V, E, or S; Position 5—H, Y, F, Q, N, I, or V; Position 7—N, D, H, T, K, E, S, I, Q, V, G, or A; Position 8—I, L, V, Y, D, A; Position 9—S, N, D, T, K, Y, I, or P; Position 10—R, K, G, S, A, E, D, I, T, W, or N; Position 11—A, R, K, T, S, G, E, D, N, Q, H, V, I, or L; Position 12—K, D, R, E, K, Q, N, T, S, G, A, V, L; Position 14—N, Q, D, E, K, R, A, S, T, G, M, Y, I, H, or V; and/or Position 15—D, N, K, E, T, Q, R, S, A, I, M, or P. 12. The composition of claim 1, wherein the anti-coreceptor binding agent exhibits multi-tropic activity characterized by effective inhibition of HIV viral, or gp120 protein or peptide binding to multiple, CXCR4 and CCR5, coreceptors. 13. The composition of claim 12, wherein the multi-tropic anti-coreceptor binding agent is an HIV-1 peptide, peptide analog or mimetic effective to inhibit one or more biological activities of both T cell tropic (lymphotropic) and macrophage tropic (m-tropic) HIV-1 viruses selected from (a) direct co-receptor binding by viruses, (b) coreceptor binding by viral gp120 proteins or peptide fragments or derivatives thereof, (c) viral fusion with target host cells, (d) virion entry into host cells, (e) viral replication, and/or (f) viral cell-cell or host-host transmission. 14. A method for inhibiting human immunodeficiency virus (HIV) interaction with a CXCR4 and/or CCR5 coreceptor comprising exposing a subject to an effective amount of an anti-coreceptor binding agent to inhibit binding of the CXCR4 and/or CCR5 coreceptor by an HIV virus or viral protein, wherein the anti-coreceptor binding agent is a gp120 peptide, peptide analog or mimetic that specifically binds the CXCR4 and/or CCR5 coreceptor. 15. The method of claim 14, wherein the gp120 peptide, peptide analog or mimetic is between about 12 and about 24 amino acid residues in length and comprises a conserved CXXXXXXW amino acid sequence motif, wherein X is any naturally occurring or synthetic amino acid or amino acid analog. 16. The method of claim 14, wherein the peptide, peptide analog or mimetic is modified by addition, admixture, or conjugation of additional amino acids, peptides, proteins, chemical reagents or moieties which do not substantially alter the anti-coreceptor binding activity of the peptide. 17. The method of claim 14, wherein the anti-coreceptor binding agent is a peptide comprising an allelic variant among native HIV gp120 peptide sequences. 18. The method of claim 14, wherein the subject is an isolated or bound CXCR4 and/or CCRS coreceptor, a membrane or cell preparation comprising the coreceptor, a cell population, tissue or organ expressing the coreceptor, or a mammalian patient. 19. The method of claim 18, wherein the subject comprises a cell population, tissue or organ selected for in vivo or ex vivo treatment or diagnostic processing. 20. The method of claim 18, wherein the subject is a mammalian patient susceptible to HIV infection and the anti-coreceptor binding agent is administered in a prophylactic or therapeutic effective dose to prevent or inhibit HIV infection or a related disease condition or symptom. 21. The method of claim 14, wherein the anti-coreceptor binding agent is administered to the subject in an amount effective to inhibit one or more biological activities mediated by or associated with HIV-coreceptor interactions selected from (a) direct co-receptor binding by HIV virus, (b) coreceptor binding by a HIV gp120 protein or a peptide fragment or derivative thereof, (c) HIV fusion with target host cells, (d) HIV virion entry into host cells, (e) HIV replication, and/or (f) HIV cell-cell or host-host transmission. 22. The method of claim 14, wherein the anti-coreceptor binding agent is an HIV-1 peptide, peptide analog or mimetic administered to the subject in an amount effective to inhibit one or more biological activities selected from (a) direct co-receptor binding by HIV-1 virus, (b) coreceptor binding by a HIV-1 gp120 protein or a peptide fragment or derivative thereof, (c) HIV-1 fusion with target host cells, (d) HIV-1 virion entry into host cells, (e) HIV-1 replication, and/or (f) HIV-1 cell-cell or host-host transmission. 23. The method of claim 14, wherein the anti-coreceptor binding agent is an HIV-1 peptide, peptide analog or mimetic administered to a mammalian patient in a prophylactically or therapeutically effective dose to prevent or inhibit HIV-1 infection or an HIV-1-related disease condition or symptom. 24. The method of claim 14, wherein the anti-coreceptor binding agent is a peptide that includes a conserved “CXXXXXXW” amino acid sequence motif, wherein X is any amino acid, and wherein the peptide is from about 12 to about 17 amino acids in length and is selected from peptide 15K, comprising an amino acid sequence IRKAHCNISRAKWND (SEQ ID NO:8), or a corresponding or overlapping native peptide sequence or peptide analog that shares substantial sequence identity to the peptide sequence of 15K. 25. The method of claim 24, wherein the peptide includes one or more residues occurring naturally or by substitution at a relative, aligned position corresponding to a designated position for peptide 15K, selected from: Position 1—I, M, K, S, T, L, A, V, R, P, or N; Position 2—R, G, E, K, S, T, or I; Position 3—Q, K, R, L, E, P, A, V, S, T, H, or D; Position 4—A, T, P, V, E, or S; Position 5—H, Y, F, Q, N, I or V; Position 7—N, D, H, T, K, E, S, I, Q, V, G, or A; Position 8—I, L, Y, D, A; Position 9—S, N, D, T, K, Y, I, or P; Position 10—R, K, G, S, A, E, D, I, T, W, or N; Position 11—A,R,K,T, S, G, E, D,N, Q, H, V, I, or L; Position 12—K, D, R, E, K, Q, N, T, S, G, A, V, L; Position 14—N, Q, D, E, K, R, A, S, T, G, M, Y, I, H, or V; and/or Position 15—D, N, K, E, T, Q, R, S, A, I, M, or P. 26. The method of claim 14, wherein the anti-coreceptor binding agent exhibits multi-tropic activity characterized by effective inhibition of HIV viral, or gp120 protein or peptide binding to multiple, CXCR4 and CCR5, coreceptors. 27. The method of claim 26, wherein the multi-tropic anti-coreceptor binding agent is an HIV-1 peptide, peptide analog or mimetic administered to the subject in an amount effective to inhibit one or more biological activities of both T cell tropic (lymphotropic) and macrophage tropic (m-tropic) HIV-1 viruses selected from (a) direct co-receptor binding by viruses, (b) coreceptor binding by viral gp120 proteins or peptide fragments or derivatives thereof, (c) viral fusion with target host cells, (d) virion entry into host cells, (e) viral replication, and/or (f) viral cell-cell or host-host transmission. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The envelope glycoprotein of the human immunodeficiency virus type I (HIV-1) mediates in the fusion of viral and host cell membranes necessary for virion entry (Freed et al., J. Biol. Chem. 270:23883-23886, 1995). The envelope glycoprotein of HIV-1 is produced by the enzymatic cleavage from a gp160 precursor protein to produce the external gp120 protein and the transmembrane gp41 protein (Capon et al., Annu. Rev. Immunol. 9:649-678, 1991). Several studies have identified specific portions or domains of the gp120 protein that may elicit humoral and/or cell-mediated immune responses to HIV in susceptible host subjects, and may therefore be useful to formulate anti-HIV reagents and methods for prevention and treatment of HIV infection and related diseases. These general HIV peptide studies describe a large, diverse assemblage of gp120 peptides that are proposed as candidates for therapeutic use, primarily in vaccine formulations to prevent and treat HIV infection and related disease. For example, U.S. Pat. No. 5,691,135 describes various peptides that are selected for the ability to inhibit HIV infection by stimulating VH3 and VH4 antibody responses. The peptides are proposed for administration to a patient as an antigen in sufficient quantity to induce antibodies that exhibit superantigen binding to gp120. The disclosure considers 31 peptides obtained from the AIDS Research and Reference Program, NIH, which peptides correspond to sequences from gp120 and gp41 from different strains of HIV. Additional gp120 peptides are described in U.S. Pat. No. 5,939,074. In particular, this references describes peptides that are useful as “multideterminant peptide antigens” for eliciting both cell-mediated and humoral immune responses against HIV. Additional studies have identified particular regions of the gp120 that are proposed to determine specific interactions between gp120 and CD4, which is the primary receptor on target cells mediating cellular entry by HIV-1 (Arthos et al., Cell 57:469481, 1989; Clayton et al., Nature 339:548-551, 1989; Kwong et al., Nature 393:648-659, 1998; and Landau et al., Nature 334:159-162, 1988). In addition to CD4 binding, cellular entry by HIV-1 is thought to require additional interactions between the virus and one or more “coreceptors” on the surfaces of target cells. Briefly, the HIV-1 particles are proposed to bind initially to the CD4 receptor, and then subsequently to a chemokine receptor present on the target cells, which is used by the virus as a “coreceptor” for mediating cellular entry. Different strains of HIV-1 preferentially utilize different chemokine receptors that are variably expressed among HIV-1 target cells. In particular, some strains of HIV-1, referred to as “lymphotropic” strains, bind CXCR4 chemokine receptors predominantly expressed on lymphocyte target cells, while other HIV-1 strains, termed “monocyte tropic” strains, bind CCR5 receptors predominantly expressed on cells of monocyte lineage. Thus, the major viral coreceptors are CXCR4 (Berson et al., J. Virol. 70:6288-6295, 1996), which has a native function as a chemokine receptor for stromal derived factor-1 (SDF-1), and CCR5 (Alkhatib et al., Science 272:1955-1958, 1996; Deng et al., Nature 381:661-666, 1996; and Dragic et al., Nature 381:667-673, 1996), which functions naturally as a receptor for several chemokines, including macrophage inflammatory protein-1β (MIP-1β). It is proposed that a conformational change occurs in gp120 following HIV binding of CD4, and that this conformation change exposes one or more binding sites on the gp120 molecule that mediate additional interactions between HIV and chemokine receptor, which are referred to in this context as “viral coreceptors” (Kwong et al., Nature 393:648-659, 1998, incorporated herein by reference). Recent studies suggest a complicated, multi-step binding and activation model, wherein the association of gp120 with CD4 yields a CD4-gp120 complex, which subsequently associates with the viral coreceptor resulting in a structural rearrangement (e.g., conformational change) of gp120 that facilitates interaction of the gp41 envelope protein subunit with the host cell membrane, leading to viral entry (Helseth et al., J. Virol. 64:6314-6318, 1990; and Weissenhom et al., Nature 387:426-430, 1997). Within this emergent field of investigation, numerous studies have focused on structure-function mapping of chemokine receptors, with the goals of determining binding determinants and mechanisms of action of the receptors. Yet additional research has focused on chemokine mapping studies. From these studies chemokine-derived peptides have been identified that reportedly comprise binding determinants of the chemokines capable of blocking native chemokine receptor-ligand interactions. Further studies, focusing alternatively on HIV gp120 mapping, report production and testing of gp120 peptides capable of blocking HIV-coreceptor binding and HIV infectivity. With regard to chemokine receptor studies, numerous articles report that chemokine receptors play a direct role as coreceptors for HIV cell entry. Briefly, as noted above, it is reported that specific interactions between the HIV envelope glycoprotein gp120 and one or more chemokine receptors mediate viral entry into target cells. More specifically, monocyte-tropic or “m-tropic” HIV strains bind to a distinct chemokine receptor, CCR5, for cell entry, while T cell lymphotropic or “T-tropic” virus use mainly CXCR4 receptors for cell entry. More detailed, structure-function analyses have been directed toward identifying specific HIV binding determinants of chemokine receptors mediating their activity as coreceptors for HIV entry. In conjunction with these reports, certain references focus on a concept of blocking chemokine receptor activity (e.g., receptor binding with chemokines, or with gp120) using competitive inhibitors. Proposed inhibitors of chemokine receptor binding interactions include peptide inhibitors that mimic structures of chemokines, or of gp120, binding determinants or related structural domains. These studies follow more basic research which shows that intact chemokines, the normal ligands of chemokine receptors, can compete with cognate chemokines, or with HIV, for binding to the target receptors. Referring specifically to chemokine mapping studies focusing on chemokine structure-function, various publications attempt to identify and characterize receptor binding determinants of chemokines. As noted above, certain of these references also describe chemokine-based peptides reportedly capable of blocking chemokine-receptor binding and other activities mediated by receptor-ligand (chemokine or HIV) interactions. One such study is presented in a publication by Reckless et al., ( Biochem. J. 340:803-811, 1999). This study identifies a number of chemokine-derived peptides, including a peptide designated “peptide 3”, based on a human chemokine, monocyte chemotactic protein-1 (MCP-1). Reckless and colleagues report that the peptide 3 inhibits cell migration induced by a wide range of chemokines. Moreover, peptide 3 reportedly binds to THP-1 cells and inhibits THP-1 migration, reportedly by acting as a chemokine receptor antagonist. On this basis, the authors propose that peptide 3 and its derivatives, including peptides ranging from 6-15 residues in length, may be useful as chemokine inhibitors. A number of related reports focus on a distinct portion of chemokines as prospective receptor binding determinants. In particular, the reports focus on the N-terminal region of chemokines comprising a structural element called the “N-loop”. This distinct element follows the first two cysteine residues of a model chemokine, and is proposed to play an important role in chemokine-receptor interactions. Other parts of chemokine molecules have also been proposed to contribute significantly as structural determinants of interactions between chemokines and their cognate receptors. For example, Crump et al., ( EMBO J. 16:6996-7007, 1997), teach that the N-terminal eight residues of the chemokine SDF-1 form an important receptor binding site. At this site, two residues (Lys-1 and Pro-2) were proposed to be directly involved in receptor activation. Disruption of these residues reportedly abolished activation. It has further been reported that SDF-1 includes a second receptor binding motif at residues 12-17 of the chemokine loop region, termed the “RFFESH motif”. Thus, it has been widely considered that the N-terminal region and so called N-loop following the first two cysteine residues of chemokines play the most important role in mediating the interactions between chemokines and their cognate receptors (Clark-Lewis et al., J. Biol. Chem. 266:23128-23134, 1991; Crump et al., EMBO J. 16:6996-7007, 1997; and Pakianathan et al., Biochemistry 36:9642-9648, 1997). In one of these studies, Clark-Lewis et al. reported that a C-terminally truncated form of IL-8 missing the α-helix and β-turn within this region manifested greatly reduced chemotactic activity. Additional confirmation of the primary significance of this segment of chemokines for receptor binding is provided by a recent observation that the biological activity of human MIP-1β is strongly reduced by substitutions of Arg-45, and Arg-47, with Serine (Czaplewski et al., J. Biol. Chem. 274:16077-16084, 1999, incorporated herein by reference). Finally, a peptide corresponding to the MCP-1 sequence just preceding the C-terminal α-helix was reported to inhibit chemotaxis of THP-1 cells indicating the importance of this region for chemokine function (Reckless et al., Biochem. J. 340:803-1121, 1999). Additional structure-function data for the CC chemokine RANTES have been reported by Pakianathan et al., ( Biochemistry 36:9642-9648, 1997). Notably, a number of the foregoing publications point to a complex, multi-determinant model of interactions between chemokines and their native receptors. In this context, Pakianathan et al. believe the data indicates that RANTES interacts with each of its receptors in a distinct and specific manner and supports a two-site model of interaction between chemokines and their receptors. Protein mapping studies of HIV gp120 envelope have reported identification of structural determinants of gp120 responsible for mediating HIV-coreceptor interactions. Among these studies, Rizzuto et al., Science 280:1949-1953, 1998, have described a conserved gp120 structure that is reportedly important for binding to CCR5, and have postulated generally that this structural determinant should facilitate development of pharmacologic or immunologic inhibitors of virus-receptor interactions. Rizzuto et al., suggested “that the CCR5-binding site is likely composed of conserved gp120 elements near or within the bridging sheet and V3 loop residues.” In another report addressing gp120 structure-function analysis relating to coreceptor binding, Verrier et al., ( AIDS Res. Hum. Retroviruses 15:731-743, 1999), studied the effect of linear V3 peptides (21-30 amino acids in length) on infectivity of different strains of HIV-1. These studies also pointed to the V3 loop as an important determinant of coreceptor choice, whereby single amino acid substitutions in V3 were reported to dramatically alter coreceptor usage. In conjunction with this disclosure, Verrier et al., reported that artificial, linear peptides of V3 could compete with intact gp120 for binding to CCR5 and CXCR4 and block HIV entry into cells. More specifically, the authors reported that the most efficient peptides for blocking fusion were derived from the middle of V3, and therefore did not include sequences at the C-terminal or N-terminal ends of V3 that form the base of the V3 loop. Also significantly, Verrier et al., (supra) pointed to a “pattern of restriction” between multiple gp120 binding determinants, whereby peptides from different HIV strains (m-tropic versus lymphotropic) discriminate in their fusion-blocking activity in a pattern that “follows the coreceptor usage of the parental envelopes from which the peptides were derived.” This indicates that the candidate peptides described by Verrier et al., (supra) would not exhibit multi-specific blocking potential against both m-tropic and lymphotropic HIV-coreceptor interactions. In a related study, Sakaida et al., ( J. Virol. 72:9763-9670, 1998) reported that synthetic cyclized (but not linear) V3 peptides of CXCR4 and dual-tropic strains of HIV-1 (but not a CCR5 strain) can prevent binding of anti-CXCR4 antibodies, potentially by binding to the coreceptor and acting as a competitive inhibitor. These same peptides reportedly inhibited calcium mobilization by the chemokine SDF-1 in a T cell line. The reference proposes that V3 loop peptides can directly bind to the relevant chemokine receptor and determine coreceptor usage, and postulates that such peptides can serve as HIV-1 reagents. Like Verrier et al., (supra) Sakaida and coworkers conclude that the coreceptor binding activities of V3 peptides are strain-dependent. More detailed reports pertaining to the role of V3 in mediating HIV-coreceptor interactions focus on specific sites or residues within the V3 domain as reportedly critical or important residues for coreceptor binding. For example, Tugarinov et al., ( Structure Fold Des. 8:385-395, 2000), report that a conserved, central loop sequence, GPG, within the V3 loop plays a primary role in maintaining the conformation of the loop to mediate coreceptor binding. Kato et al. ( J. Virol. 73:5520-5526, 1999) suggest that three specific residues, confined to the central, loop portion of V3 and located distant from the C-terminal segment, are particularly important for coreceptor usage. Xiao et al., ( Virology 240:83-92, 1998), identify a consensus motif S/GXXXGPGXXXXXXXE/D, covering the central portion of the V3 loop and excluding the C-terminal portion, as a critical motif for coreceptor binding. Wang et al., Proc. Natl. Acad. Sci. USA 95:5740-5745, 1998), studied whether certain V3 residues conserved among HIV-1, HIV-2 and SIV determine the utilization of CCR5 as a coreceptor. They concluded that Arg-298 (at the beginning of V3 loop) has an importance for CCR5 utilization. The authors suggested that this residue may represent a highly conserved structural element and a useful target for developing anti-viral therapies. In another study by Wang et al., ( Proc. Natl. Acad. Sci. USA 96: 4558-4562, 1999), additional V3 residues reported to be critical for CCR5 utilization are identified by alanine scanning mutagenesis. One of the identified residues, A 328 , is located at the C-terminus of V3, and its substitution reportedly results in a 1,000-fold reduction of CCR5 binding activity. However, this residue is only one of two “highly conserved” residues and six “critical” residues identified for CCR5 utilization. Most of these residues are distinctly located at the C-terminal or central loop portion of V3, including R 298 , K 305 , I 307 , R 313 , and F 315 . Wang and colleagues propose that “these highly invariable residues” as well as others identified in a “bridging sheet” portion of the molecule may represent “targets for antiviral designs aimed at blocking the coreceptor entry step of HIV-1 replication.” Based on the foregoing articles, there is a broadly-confirmed disclosure of V3 as a critical domain for mediating HIV-coreceptor interactions. A large number of important or critical residues are indicated, with a substantial range of discrepancy between reports implicating different residues as being important, or critical, for coreceptor binding functions. These references that focus on V3 uniformly teach away from excluding important “critical” or “highly conserved” V3 residues. At the same time, these references focusing on the V3 domain uniformly fail to implicate other sequence elements that may be present in the gp120 molecule outside the V3 loop portion thereof. Coupled with these teachings, a host of related publications point to yet additional components of gp120 that may be essential for HIV-coreceptor interactions. Because these components appear to be complex and potentially interact to achieve coreceptor binding, their disclosure adds further complexity to understanding gp120 structure-function relationships for mediating coreceptor binding and cell entry. In particular, Tugarinov et al., ( Structure Fold Des. 8:385-395, 2000), teach the importance of the GPG motif of V3, but also teach that “[h]igh affinity binding of gp120 to the chemokine receptors requires participation of other domains in gp120 such as the CD4i epitope.” Rizzuto et al., ( Science 280:1949-1953, 1998), suggest that the “CCR5-binding site is likely composed of conserved gp120 elements near or within the bridging sheet and V3 loop residues.” They further proposed that CD4 binding may distort the V1/V2 stem, repositioning the stem allowing the formation of the β-sheet important for CCR5 binding. They also noted that substitution of Asp for Thr 123 , located in the V1/V2 stem and which contact CD4, significantly decreased CCR5 binding. This report parallels others which point to a favored model of a “conformational binding site” in gp120 for mediating HIV-coreceptor interactions. According to this model, effective binding of coreceptors by gp120 involves initial binding of the gp120 to a CD4 receptor, which brings about a “CD4 induced” conformational change in gp120 involving distant residues—that in turn leads to formation of a conformational binding determinant on gp120 to mediate HIV-coreceptor interactions. In this context, Wu et al., ( Nature 384:179-183, 1996) suggested that HIV-1 attachment to CD4 creates a high-affinity binding site for CCR-5, leading to membrane fusion and virus entry. Consistent with this model, recent studies have identified yet additional sites of gp120 which are reportedly important, or essential, for mediating HIV-coreceptor interactions. These sites are generally distinct from V3, and also from the V3-flanking regions. For example, Cho et al., ( J. Virol. 72:2509-2515, 1998), report that V1/V2 and V3 confer on HIV-1 the ability to use CXCR4 coreceptors, but that the V4 and V5 regions are also “required in conjunction with regions V1 and V3 of HIV-1DH 12 gp120 for efficient utilization of CXCR4.” Este et al., ( Mol. Pharmacol. 52:98-104, 1997), point to structural determinants in each of the V2, V3 and C3 regions of gp120 for determining cell tropism and coreceptor utilization. Hoffman et al., ( Mol. Membr. Biol. 16:57-65, 1999), concluded the V3 loop was implicated in regulating viral tropism, but, that other regions of Env, such as the V1- and V2-loops, modulated the effects of the V3-loop. They also acknowledged that some important exceptions to this model suggested that understanding of virus tropism and Env-chemokine receptor interactions was incomplete. Collectively, these studies point to numerous components of gp120 that may be important or essential for HIV-coreceptor interactions, and which may in fact involve multiple interactions whereby different parts of gp120 are required to work together to achieve efficient HIV-coreceptor interactions. This complexity and the proposed requirement for multiple, distant binding determinants on gp120 to form a conformational binding determinant for coreceptor usage, may be generally considered to teach away from the utility of small peptides for effectively blocking HIV-coreceptor binding interactions, particularly to block multiple HIV strains infecting different target cell types. Moreover, while the foregoing, separate bodies of literature individually discuss models of conserved binding elements of chemokines, or of gp120, as determinants for mediating coreceptor interactions, these reports do not teach or suggest identification of conserved binding determinants shared between gp120 and chemokines. On the contrary, complex functional interactions and distinct binding mechanisms and determinants previously proposed for gp120 and chemokines may be considered to lead away from investigations aimed at identifying common binding determinants or mechanisms between gp120 and chemokines. This conclusion is well supported in the literature reviewed herein above. Based on these and other teachings, there does not appear to be a clear suggestion in the literature to use a common blocking agent for coreceptor interactions by chemokines and HIV aimed at, or patterned after, a shared binding determinant between these two distinct molecules. The literature does not point toward any such common structural domain or binding determinant between HIV gp120 and chemokines, and the distinct structure-function reports for how HIV and chemokines are thought to interact with the subject receptors leads away from this path of inquiry. In view of the foregoing teachings and unsolved questions in the literature, there remains an urgent need in the art for additional tools and methods to combat HIV infection and related disease. Related to this fundamental goal, there remains a clear need for additional therapeutic agents and methods targeting HIV viral entry into host cells, preferably that will include compositions and methods to block gp120 binding to different coreceptors to inhibit viral entry and infection and ameliorate HIV-related disease. Surprisingly, the instant invention fulfills these objects and satisfies additional objects and advantages which will become apparent from the following description. |
<SOH> SUMMARY OF THE INVENTION <EOH>The instant invention provides novel methods and compositions for inhibiting interactions between human immunodeficiency viruses (HIVs) and chemokine receptors, termed “viral coreceptors” in this context. The methods of the invention generally comprise exposing a CXCR4 or CCR5 coreceptor of a subject to an effective amount of an anti-coreceptor binding agent of the invention to inhibit binding of the coreceptor by an HIV virus or viral protein. Typically, the anti-coreceptor binding agent is a gp120 peptide, peptide analog or mimetic that specifically binds the coreceptor. Within certain methods of the invention, the subject is an isolated or bound coreceptor, a membrane or cell preparation comprising the coreceptor, a cell population, tissue or organ expressing the coreceptor, or a mammalian patient. In more detailed embodiments, the subject comprises a cell population, tissue or organ selected for in vivo or ex vivo treatment or diagnostic processing. Alternatively, the subject may be a mammalian patient susceptible to HIV infection and the anti-coreceptor binding agent is administered in a prophylactic or therapeutically effective dose to prevent or inhibit HIV binding to a susceptible cell and thereby preventing or inhibiting infection or a related disease condition or symptom. In typical aspects of the invention, the anti-coreceptor binding agent is administered to the subject in an amount effective to inhibit one or more biological activities mediated by or associated with HIV-coreceptor interactions selected from (a) direct co-receptor, e.g., CXCR4 and/or CCR5, binding by HIV virus, (b) coreceptor binding by a HIV gp120 protein or a peptide fragment or derivative thereof, (c) HIV fusion with target host cells, (d) HIV virion entry into host cells, (e) HIV replication, and/or (f) HIV cell-cell or host-host transmission. In more specific embodiments, the anti-coreceptor binding agent is an HIV-1 peptide, peptide analog or mimetic and is administered to the subject in an amount effective to inhibit one or more biological activities selected from (a) direct co-receptor, i.e., CXCR4 and/or CCR5, binding by HIV-1 virus, (b) coreceptor binding by a HIV-1 gp120 protein or a peptide fragment or derivative thereof, (c) HIV-1 fusion with target host cells, (d) HIV-1 virion entry into host cells, (e) HIV-1 replication, and/or (f) HIV-1 cell-cell or host-host transmission. Often, the anti-coreceptor binding agent is an HIV-1 peptide, peptide analog or mimetic administered to a mammalian patient in a prophylactically or therapeutically effective dose to prevent or inhibit HIV-1 binding infection, to a susceptible host, HIV-1 or an HIV-1-related disease condition or symptom. In more detailed methods and compositions of the invention, the gp120 peptide, peptide analog or mimetic is between about 12 and about 24 amino acid residues in length and comprises a conserved CXXXXXXW amino acid sequence motif identified within the amino acid sequence of gp120 proteins of HIV isolates and also among diverse chemokines, wherein X is any naturally occurring or synthetic amino acid or amino acid analog. The peptide, peptide analog or mimetic can be modified in a wide variety of ways and forms, e.g., by addition, admixture, or conjugation of additional amino acids, peptides, proteins, chemical reagents or moieties which do not substantially alter the anti-coreceptor binding activity of the peptide. Often, the anti-coreceptor binding agent of the invention is a peptide comprising an allelic variant that is found among native HIV gp120 peptide sequences. Within more detailed embodiments, the anti-coreceptor binding agent is a peptide of between about 12-17 amino acids in length that includes a conserved “CXXXXXXW” amino acid sequence motif, which is selected from an exemplary “reference” peptide designated 15K comprising an amino acid sequence IRKAHCNISRAKWND (SEQ ID NO:8), or is alternatively represented by a corresponding or overlapping native peptide sequence or peptide analog that shares substantial sequence identity to the reference amino acid sequence of 15K. In various specific embodiments, the peptide includes one or more residues occurring naturally or by substitution at a relative, aligned position corresponding to a designated position for peptide 15K, selected from: Position 1—I, M, K, S, T, L, A, V, R, P, or N; Position 2—R, G, E, K, S, T, or I; Position 3—Q, K, R, L, E, P, A, V, S, T, H, or D; Position 4—A, T, P, V, E, or S; Position 5—H, Y, F, Q. N, I, or V; Position 7—N, D, H, T, K, E, S, I, Q, V, G, or A; Position 8—I, L, V, Y, D, A; Position 9—S, N, D, T, K, Y, I, or P; Position 10—R, K, G, S, A, E, D, I, T, W, or N; Position 11—A, R, K, T, S, G, E, D, N, Q, H, V, I, or L; Position 12—K, D, R, E, K, Q, N, T, S, G, A, V, L; Position 14—N, Q, D, E, K, R, A, S, T, G, M, Y, I, H, or V; and/or Position 15—D, N, K, E, T, Q, R, S, A, I, M, or P. In yet additional embodiments of the invention, the anti-coreceptor binding agent exhibits multi-tropic activity characterized by effective inhibition of HIV viral, or gp120 protein or peptide binding to multiple, CXCR4 and CCR5, coreceptors. Often, the multi-tropic anti-coreceptor binding agent is an HIV-1 peptide, peptide analog or mimetic administered to the subject in an amount effective to inhibit one or more biological activities of both T cell tropic (lymphotropic) and macrophage tropic (m-tropic) HIV-1 viruses selected from (a) direct co-receptor binding by viruses, (b) coreceptor binding by viral gp120 proteins or peptide fragments or derivatives thereof, (c) viral fusion with target host cells, (d) virion entry into host cells, (e) viral replication, and/or (f) viral cell-cell or host-host transmission. Within the methods and compositions of the invention, the anti-coreceptor binding agent may be formulated in various combinations with a pharmaceutically acceptable carrier, diluent, excipient, adjuvant or other active or inactive agents, in an amount or dosage form sufficient to prevent, reduce or even alleviate HIV infection or related disease conditions or symptoms. In yet additional aspects of the invention, the anti-coreceptor binding agent of the invention is administered according to the foregoing methods in a combinatorial formulation or coordinate treatment with one or more additional anti-HIV, antibacterial, antiviral or other therapeutically active agent(s). Within related methods and compositions, the anti-coreceptor binding agent is admixed or co-administered, simultaneously or sequentially with one or more additional anti-HIV, antibacterial, antiviral or other therapeutically active agent(s) to prevent, reduce or even alleviate HIV infection or related conditions in a mammalian patient. The instant invention also includes kits, packages and multicontainer units containing the anti-coreceptor binding agent, optionally with other active or inactive ingredients, and/or means for administering the same for use in the diagnosis, management and/or prevention and treatment of HIV and related conditions. Typically, these kits include a diagnostic or pharmaceutical preparation of the anti-coreceptor binding agent, typically formulated with a biologically suitable carrier and optionally contained in a bulk dispensing container or unit or multi-unit dosage form. Optional dispensing means can be provided, for example an intranasal spray applicator. Packaging materials optionally include a label or instruction which indicates a desired use of the kit as described herein below. Additional aspects of the invention include polynucleotide molecules and vector constructs encoding anti-coreceptor binding peptides and peptide analogs. Also provided are peptide vaccines and other immunogenic compositions that elicit an immune response involving production of antibodies targeting one or more epitopes of gp120 recognized by antibodies that specifically bind an anti-coreceptor binding peptide of the invention. In addition, the invention provides, antibodies, including monoclonal antibodies, and immunotherapeutic methods and compositions comprising such antibodies that specifically recognize anti-coreceptor binding peptides of the invention, for use as diagnostic and therapeutic reagents. Also provided within the invention are a variety of additional diagnostic and therapeutic tools and reagents as set forth in detail in the following description. |
Method and apparatus to stress test medicament inhalation aerosol device by inductive heating |
The invention relates to a method and apparatus for heat stress testing medicament aerosol inhalation devices, such as metered dose inhaler. An electrical induction work coil (24, 26, 28) is used to heat the inhalers to 55° C.±5 C.°. Heated inhalers are subsequently weighed to detect and reject nonconforming inhalers where a nonconforming amount of propellant has leaked. |
1. An apparatus for heating medicinal inhalation devices comprising: an electrical power supply, and one or more induction coils. 2. The apparatus of claim 1, further including a microprocessor for controlling the power supply in the range of 100-130 amps to heat the inhalation devices to a temperature in the range of 50-60° C. 3. The apparatus of claim 2, further including a cooling system comprising a condenser and a pump, wherein the apparatus includes a single induction coil, and wherein a liquid coolant is pumped through the induction coil, and wherein the electrical power supply has a maximum power output of 20 kilowatts and operates in the range of 80-90% efficiency. 4. The apparatus of claim 2, wherein the power supply provides up to 20 kva and 50-450 kHz, and wherein 140 volts is applied to the one or more induction coils. 5. The apparatus of claim 2, wherein the induction coil is constructed from copper tubing and silver soldered joints. 6. The apparatus of claim 5, wherein the induction coil is a single, continuous coil in the shape of a loop having first and second bridges on first and second ends of the loop, respectively, and wherein the first and second bridges are suitably sized and configured to directly heat each entire inhalation device. 7. The apparatus of claim 6 further including: a conveyor, and a computer-controlled gating assembly for indexing a predetermined number of medicinal inhalation devices along the conveyor between the first and second bridges of the induction coil, wherein the medicinal inhalation devices are metered dose inhalers. 8. The apparatus of claim 7, wherein the gating assembly further includes first and second heat exchangers suitably adapted and positioned to heat a first and last metered dose inhaler indexed within the one or more induction coils. 9. The apparatus of claim 8, wherein the first and second heat exchanger each comprise an aluminum canister adapted to be cooled. 10. The apparatus of claim 7, wherein the gating assembly is adapted to index 32 metered dose inhalers per heating cycle, wherein 4 slugs of 8 metered dose inhalers per slug are indexed each cycle, and wherein the cycle time is in the range of 30-40 seconds. 11. The apparatus of claim 7, wherein the conveyor has a line speed in the range of 100-140 metered dose inhalers per minute. 12. The apparatus of claim 7 further including an infrared thermometer to measure the temperature of the metered dose inhalers. 13. The apparatus of claim 12, wherein the measured temperatures are fed to the microprocessor, and wherein the microprocessor adjusts the power supply to heat the metered dose inhalers to a temperature of about 55° C. 14. The apparatus of claim 7 further including a weighing device to check the weight of the heated metered dose inhalers. 15. An apparatus for heating medicinal inhalation devices comprising: an electrical power supply means, and one or more induction coil means. 16. A process of heat stress testing medicinal inhalation devices to detect and reject nonconforming or leaking devices comprising the acts of: providing one or more inhalation devices, and induction heating the one or more inhalation devices. 17. The process of claim 16, wherein the inhalation devices are metered dose inhalers, and wherein the metered dose inhalers are provided continuously at a line speed in the range of 100-140 inhalers per minute. 18. The process of claim 17 further including the act of: indexing the continuously provided metered dose inhalers. 19. The process of claim 18, wherein the metered dose inhalers are indexed in slugs of 8 providing 32 metered dose inhalers per induction heating cycle. 20. The process of claim 17, wherein the metered dose inhalers are heated to a temperature in the range of 50-60° C. 21. The process of claim 20, wherein the metered dose inhalers are heated to a temperature of about 55° C. 22. The process of claim 21, wherein the temperature of the metered dose inhalers, the indexing and the induction heating is computer process controlled. 23. The process of claim 18 further including the acts of: check weighing the heated metered dose inhalers, and rejecting any nonconforming or leaking metered dose inhalers. 24. A process of heat stress testing medicinal inhalation devices to detect and reject nonconforming or leaking devices comprising the steps of: providing one or more inhalation devices, and induction heating the one or more inhalation devices. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In the art of manufacturing medicament aerosol inhalation devices, recent attention has been aimed at detecting and rejecting potential and actual nonconforming devices. For example, a small percentage of aerosol inhalation devices leak or will leak due to manufacturing defects, such as broken or tom gaskets, loss of proper sealing, defective valve, swollen gasket(s), etc. Such defects cause a loss of aerosol propellant, which adversely affects or otherwise alters the performance of the inhalation device. Recently, the Food and Drug Administration (“FDA”) has become very concerned with leaking (or otherwise nonconforming or defective) aerosol inhalation devices, particularly MDI's. The performance of an MDI can be significantly altered when the propellant leaks, particularly where the propellant leaks in significantly amounts or at a significant rate. For example, a “gross leaker” may not deliver the medicament at all to the patient. MDI's that leak at more than an insignificant rate may under deliver the medicament. In other words, the medicament delivery from a leaking MDI does not conform to the dosing regimen set forth and approved by the FDA. In that case, the patient may not even realize that the insufficient medicament is being delivered to the lungs. As a result, the FDA has begun requiring manufacturers to stress test aerosol inhalation devices and subsequently weigh the stressed devices to detect actual and potential nonconforming devices. Leaking MDI's will weigh less than what they are supposed to weigh. Stressed MDI's that lose a predetermined amount of propellant are rejected as nonconforming. The FDA has set conforming standards. The FDA has also set a temperature standard of 55° C.±5 C.° for heat stress testing the MDI's. Many methods and apparatus are available for heating MDI's. The present invention involves using electromagnetic induction heating to heat the electro-conductive materials present in the MDI, such as primarily the aluminum canister. Electromagnetic induction is a method of henerating heat within a metal part. Any electrical conductor can be heated by electromagnetic induction. As alternating current from the generator flows through the inductor, or work coil, a highly concentrated, rapidly alternating magnetic field is established within the coil. The magnetic field thus induces an electric potential in the part to be heated. The part represents a closed circuit. The induced voltage causes current to flow within the part. Eddy currents are typically established. The resistance of the part to the flow of the induced current causes heating. The pattern of heating obtained by induction is determined by a number of factors: the shape of the induction coil producing the magnetic field, the number of turns in the coil, the operating frequency, the alternating current power input, and the nature of the work pieces. The rate of heating obtained by the coils depends on the strength of the magnetic field to which the part is exposed. In the work piece, this becomes a function of the induced currents and the resistance to electrical flow. The depth of current penetration depends upon work piece permeability, resistivity, and the alternating current frequency. Since the first two factors vary comparatively little, the greatest variable is frequency. Depth of current penetration decreases as frequency increases. High frequency current is generally used when shallow heating is desired. Intermediate and low frequencies are used in applications requiring deeper heating. The induction coil and associated components and the processes thereof of the present invention are advantageous. The present invention advantageously heats and stress tests MDI's in a relatively short period of time (i.e., dwell time), which permits in-line processing at high throughput. The present invention also advantageously employs a few relatively simple processing and material handling equipment resulting in low investment, reduced maintenance, high efficiency, and reliability. The present invention is further advantageous in that only the electroconductive portions of the MDI are heated significantly reducing the heating of plastic components (e.g., gaskets and valve components) that are susceptible to being unnecessarily damaged by heat. Still further, the present invention advantageously heat stress tests the MDI's without exposing the MDI's to steam or moisture (except any negligible moisture associated with the sealed heat exchangers) which can ingress into the MDI reducing product performance. Further benefits and advantages of the present invention are set forth herein. |
<SOH> SUMMARY OF THE INVENTION <EOH>One aspect of the invention is an apparatus for heating medicinal inhalation devices. The apparatus includes an electrical power supply and one or more induction coils. Preferably, the apparatus further includes a microprocessor for controlling the power supply in the range of 100-130 amps, preferably 110-115 amps, and more preferably about 113 amps, to heat the inhalation devices to a temperature in the range of 50-60° C., preferably around 55° C. By “about” or the like language as used herein, it is meant to include those values surrounding the recited value or range of values that achieve substantially the same desired ultimate result. The apparatus also preferably further includes a cooling system including a condenser and a pump, wherein a liquid coolant is pumped through the induction coil. Preferably, the power supply provides up to 20 kilowatts (kW) at a frequency in the range of 240-440 kHz. A voltage of 140 volts may be applied to the induction coils. The electrical power supply may be operated in the range of 80-90% efficiency, preferably about 85%. The induction coil may be constructed from copper tubing and silver soldered joints. Preferably, the induction coil is a single, continuous coil in the shape of a loop having two bridges, one at each end of the loop, respectively. The bridges are suitably sized and configured to directly heat each entire inhalation device. In other words, the bridges of the induction coil may be 4 inches in height for heating metered dose inhalers (“MDI's”) that are 2-3 inches in height. Examples of MDI's that may be stress tested by this invention include those disclosed in U.S. Pat. Nos. 6,170,717; 6,131,566; 6,143,277; and 6,149,892, which are incorporated herein by reference. Another aspect of the invention is an apparatus including the electrical powers supply and induction coil(s) described herein above, a conveyor, and a gating assembly for indexing a predetermined number of medicinal inhalation devices along the conveyor between the bridges of the induction coil. Preferably, the gating assembly further includes two heat exchangers suitably adapted and positioned to heat the first and last metered dose inhaler cycled and indexed within the induction coil. The heat exchanger may include an aluminum canister (similar to the canister used in the MDI's) adapted to be cooled by circulating cooling water. Preferably, the gating assembly is adapted and controlled to index 32 metered dose inhalers per heating cycle. The MDI's are indexed one slug at a time where each slug may include 8 MDI's. Each heating cycle may include 4 slugs of 8 metered dose inhalers per slug. The heating cycle time may be in the range of 30-40 seconds. As such, the conveyor may have a line speed in the range of 100-140 metered dose inhalers per minute. An infrared thermometer may also be employed to measure the temperature of the metered dose inhalers. Preferably, the measured temperatures are fed to the microprocessor, whereby the microprocessor adjusts the power supply to heat the metered dose inhalers to the desired temperature, for example 55° C.±5 C.°. A check weighing device is also preferably employed to check the weight of the heated metered dose inhalers. Any nonconforming and/or leaking (e.g., gross leakers) MDI's are detected and summarily rejected/discarded. Another aspect of the invention is a process or method of heat stress testing medicinal inhalation devices to detect and reject nonconforming or leaking devices. In general, the process includes providing one or more inhalation devices, and induction heating the one or more inhalation devices. Preferably, the inhalation devices are metered dose inhalers, whereby the metered dose inhalers are provided continuously (e.g., continuous runs) at a line speed in the range of 100-140 inhalers per minute. Preferably, the process also includes indexing the continuously provided metered dose inhalers. The metered dose inhalers may be indexed in slugs of 8 providing 32 metered dose inhalers per induction heating cycle. During the heating cycle, the metered dose inhalers are preferably heated to a temperature in the range of about 50-60° C., preferably about 55° C. The temperature of the metered dose inhalers, the indexing, the induction heating, and other steps in the process may be computer process controlled by a microprocessor and other suitable electronic (e.g., sensors) and electromechanical equipment and instruments (e.g., pneumatic actuators). The process preferably also includes the steps of check weighing the heated metered dose inhalers, and rejecting any nonconforming or leaking metered dose inhalers. |
Detachable substrate or detachable structure and method for the production thereof |
The invention relates to the preparation of a thin layer comprising a step in which an interface is created between a layer used to create said thin layer and a substrate, characterized in that said interface is made in such way that it is provided with at least one first zone (Z1) which has a first level of mechanical strength, and a second zone (Z2) which has a level of mechanical strength which is substantially lower than that of the first zone. Said interface can be created by glueing surfaces which are prepared in a differentiated manner, by a layer which is buried and embrittled in a differentiated manner in said zones, or by an intermediate porous layer. |
1. A method of preparing a thin layer comprising a step of producing an interface between a layer intended to form part of said thin layer and a substrate, wherein said interface is produced so as to have at least a first region having a first level of mechanical strength and a second region having a second level of mechanical strength significantly greater than the first level of mechanical strength, and wherein the first region is included within the second. 2. A method according to claim 1, wherein the second region constitutes a periphery of a wafer of which the first region constitutes a core of the wafer. 3. A method according to claim 1, wherein the first region is divided into fragments, each fragment being surrounded by the second region. 4. A method according to claim 1 wherein the interface is produced between a surface of the substrate and a surface of the layer and wherein the step of producing the interface includes a step of preparing at least one of the surfaces, and a bonding step during which the surface is of the substrate and the surface of the layer are bonded by molecular adhesion bonding. 5. A method according to claim 4, wherein the step of producing the interface includes a step of preparing the surface of the substrate and the surface of the layer. 6. A method according to claim 4, wherein the step of preparing at least one of the surface includes a treatment step of locally increasing the roughness of the surface in the first region. 7. A method according to claim 6, wherein the treatment step comprises localized acid etching of the surface in the first region. 8. A method according to claim 7, wherein the localized acid etching comprises etching with hydrofluoric acid, the surface in said second region being protected from said etching by a nitride layer, that is eliminated after etching. 9. A method according to claim 4, wherein the step of preparing at least one of the surfaces comprises a step in which the surface is roughened entirely and a step in which the roughness of some portions is enhanced to obtain greater bonding forces. 10. A method according to claim 9, wherein the roughness of some portions is reduced by one or more of chemical polishing, mechanical treatment, chemical-mechanical treatment, or dry etching. 11. A method according to claim 1 wherein the step of producing the interface includes a step of weakening a buried layer in a starting substrate, whereby at least a first region is made weaker than a second region, said buried layer being disposed between the layer and the substrate. 12. A method according to claim 11, wherein the weakening step includes a step of implanting at least one gaseous element, said implantation step being carried out differently for the first and second regions. 13. A method according to claim 1, wherein the step of producing the interface comprises a treatment step adapted to render a surface layer of the substrate porous, said treatment step being carried out in such a way as to render the first region more porous than the second region, and being followed by a covering step during which the layer is produced on top of said porous layer. 14. A method according to claim 13, wherein the substrate comprises silicon and the treatment step comprises electrolysis in an hydrofluoric acid medium. 15. A method according to claim 1, wherein the step of producing the interface is followed by a step of separating the layer from the substrate. 16. A method according to claim 15, wherein the method further comprises, after the step of producing the interface, a step of cutting at least one fragment of the layer containing the first region and the second region so that the second region extends along a periphery of the at least one fragment and a separation step during which the substrate and the thin layer are lifted off. 17. A method according to claim 15, wherein the method further comprises, between the step of producing the interface and the step of separating the layer from the substrate, a step of cutting the second region relative to the first region. 18. A method according to claim 15, wherein the method further comprises, between the step of producing the interface and the lift-off step, a step of producing in the layer all or part of microelectronic, optical or mechanical components. 19. A method according to claim 18, wherein each component is produced facing the first region of low mechanical strength surrounded by the second region of higher mechanical strength. 20. A method according to claim 15, wherein the method further comprises between the step of producing the interface and the separation step, there is a bonding step during which the layer is bonded to a second substrate. 21. A method according to claim 15, wherein said bonding step includes molecular adhesion bonding. 22. A method according to claim 15, wherein said bonding step comprises adhesive bonding. 23. A method according to claim 22, wherein said adhesive bonding comprises an adhesive that is hardened by UV radiation. 24. A method according to claim 15, wherein the lift-off step is carried out by comprises acid etching and application of mechanical stresses. 25. A method according to claim 1, wherein the layer comprises silicon. 26. An assembly comprising a layer on a substrate, said layer being connected to said substrate at an interface of which at least a selected first region has a first level of mechanical strength and a selected second region has a second level of mechanical strength significantly greater than the first level, and wherein the first region is included in the selected second region. 27. An assembly according to claim 26, wherein the selected second region constitutes a periphery of a wafer of which the selected first region constitutes a core of the wafer. 28. An assembly according to claim 26, wherein the selected first region is divided into fragments, each fragment being surrounded by a selected second region. 29. An assembly according to claim 26, wherein a fragment cut out in the layer contains the selected first region and the second region so that the selected second region extends along a periphery of said fragment. 30. An assembly according to any one of claims 26 to 29, wherein the layer includes all or part of a micro-electronic, optical or mechanical component. 31. An assembly according to claim 30, wherein said component faces the selected first region of low mechanical strength surrounded by the selected second region of higher mechanical strength. 32. An assembly according to claim 26, wherein the interface is produced between a surface of the substrate and a surface of the layer that and wherein the surfaces are molecular adhesion bonded. 33. An assembly according to claim 26, wherein at least one surface of the interface has greater roughness in said selected first region than in the selected second region. 34. An assembly according to claim 26, wherein the interface is formed by a buried layer in a starting substrate, the selected first region being weakened more than the selected second region. 35. An assembly according to claim 26, wherein the interface is formed by a porous layer between the layer and said substrate, the layer having different porosities in the selected first and selected second regions. 36. An assembly according to claim 26, wherein the layer is additionally bonded to a second substrate. 37. An assembly according to claim 36, wherein the second substrate is bonded by molecular adhesion. 38. An assembly according to claim 36, wherein the second substrate is adhesive bonded. 39. An assembly according to claim 38, wherein adhesive bonding comprises an adhesive that is hardened by UV radiation. 40. An assembly according to claim 26, wherein the layer comprises silicon. |
<SOH> FIELD OF THE INVENTION <EOH>The invention relates to the production of components from a thin layer on a substrate and the production of this thin layer/substrate assembly. The substrate can be an initial or intermediate substrate and can be detachable, i.e. adapted to be separated from the thin layer. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Objects, features and advantages of the invention will emerge from the following description, which is given by way of non-limiting illustrative example and with reference to the accompanying drawings, in which: FIG. 1 is a diagrammatic partial plan view of a surface on which two regions are prepared so that they have different molecular bonding characteristics, FIG. 2 is a view in section taken along the line II-II in FIG. 1 , FIG. 3 is a view of a combination comprising a thin layer on a substrate with an interface of the FIG. 1 type, FIG. 4 is a diagrammatic view in section of the whole of a thin layer on a substrate, FIG. 5 is a view in section of a substrate wafer provided with a protective layer, FIG. 6 is a view of the FIG. 5 wafer after recessing it, FIG. 7 is a view of the same wafer after filling the recess with a deposit of oxide, FIG. 8 is a view of said wafer covered with the oxide deposit after polishing, FIG. 9 is a view of the wafer after elimination of surplus oxide coating, FIG. 10 is a view of the wafer after fixing a thin layer or after fixing a thick layer and then thinning it, FIG. 11 is a variant of FIG. 10 , in which the oxide coating penetrates into the substrate and into the thin layer, FIG. 12 is a variant of FIG. 10 , in which the oxide coating is on the thin layer, FIG. 13 is a variant of FIG. 11 , in which the oxide occupies different regions in the substrate and in the thin layer, FIG. 14 shows a variant in which the interface is formed of a layer formed by regions of different materials (in this example SiO 2 and Si 3 N 4 ), FIG. 15 is a variant of FIG. 10 , showing a plurality of regions formed by the oxide, FIG. 16 is a variant of FIG. 14 , showing an intermediate layer formed of a plurality of regions of different materials, FIG. 17 shows concentric and alternating rings Z 1 and Z 2 , FIG. 18 shows an array of regions Z 1 in an overall region Z 2 , FIG. 19 is a diagrammatic view of the assembly from FIG. 4 after depositing a surface layer, FIG. 20 is another view after molecular bonding of a final substrate, FIG. 21 is another view after application of a lift-off operation, FIG. 22 is a diagrammatic view of a wafer obtained after lifting off and polishing, FIG. 23 is a view of a separable assembly of the FIG. 4 type, FIG. 24 is a view thereof after production of some or all of the components, for example a first transistor gate, FIG. 25 is a view thereof after deposition of oxide, FIG. 26 is a view thereof after planarization by CMP, FIG. 27 is a view thereof after molecular adhesion bonding (including heat treatment), FIG. 28 is a view thereof after separation and deoxidization, FIG. 29 is a view of a separable assembly of the FIG. 4 type, FIG. 30 is a view thereof after production of components, FIG. 31 is a view thereof after separation with no transfer to a target substrate, by hydrofluoric etching and/or application of mechanical forces, FIG. 32 is a view thereof after separation into a final substrate and a substrate that can be recycled, FIG. 33 is a variant of FIG. 30 , after cutting of trenches or notches between components, FIG. 34 is a view thereof showing a component in the process of being lifted off, for example after hydrofluoric etching, FIG. 35 is a view analogous to FIG. 4 , FIG. 36 is a diagrammatic view in section of the FIG. 35 assembly after adhesive bonding of a transparent substrate, FIG. 37 is a view of the upper portion of this assembly after lifting off and polishing, FIG. 38 is a view of the upper portion of this assembly after lifting off and polishing, FIG. 39 is a view of an assembly analogous to that of FIG. 4 showing regions eliminated by chemical and mechanical cutting, FIG. 40 is a view thereof after bonding an upper substrate, FIG. 41 is a view to a larger scale of an assembly including interleaved regions Z 1 and Z 2 , FIG. 42 is a view of an assembly analogous to that of FIG. 4 , FIG. 43 is a view thereof after deposition of an epitaxial stack based on GaN, FIG. 44 is a view thereof after bonding a substrate, FIG. 45 is a view thereof at the time of lifting off, FIG. 46 is a view of the upper portion thereof after polishing, FIG. 47 is a view thereof after removal of the layer under the stack, FIG. 48 is a view of a substrate including a buried weak layer, and FIG. 49 is a view of a substrate including a buried weak layer portion. detailed-description description="Detailed Description" end="lead"? |
Elastic meth(acrylic) adhesive compositions |
Described is an adhesive composition with a high elasticity, measured in terms of elongation at break, and an elastic behavior approaching the ideal Hook law in the stress-strain diagram. Said adhesive composition comprises (a) at least one mono-functional meth(acrylic) monomer A whose homo-polymer or co-polymer exhibit a glass transition temperature (Tg) between 40° C. and 140° C., (b) at least one monofunctional meth(acrylic) monomer B of the following structure (B): wherein R is H or CH3, R′ is H or (CH2)nCH3 with n=0 to 2, in particular CH2CH3 or H, and R″ is C3-C20-alkyl or phenoxy or O—(CH2)n—H3 or O—[(CH2)2—O]s; 0 to 2, in particular (CH2)nCH3 wherein n is 3 or 10 to 13, and c) at least one liquid elastomer C in the molecular weight range of 1000 to 9000 with (meth)acrylic derivative groups, preferably (meth)acrylic ester groups, whereby the components A, B, and C are present in the following amounts: B based on the total weight of A+B+C=5 to 20% by weight, C based on the total weight of A+C=30 to 70% by weight. |
1. An adhesive composition comprising (a) at least one monofunctional meth(acrylic) monomer A whose homopolymer or co-polymer exhibit a glass transition temperature (Tg) between 40° C. and 140° C., (b) at least one monofunctional meth(acrylic) monomer B of the following structure (B): wherein R is H or CH3, R′ is H or (CH2)nCH3, with n=0 to 2, in particular CH2CH3 or H, and R″ is C3-C20-alkyl or phenoxy or O—(CH2)n—CH3, or O-[(CH2)2—O]n—CH2—CH3 with n=0 to 2, in particular (CH2)nCH3 with n=3 or 10 to 13, and c) at least one liquid elastomer C in the molecular weight range of 1000 to 9000 with (meth)acrylic derivative groups, whereby the components A, B, and C are present in the following amounts: B based on the total weight of A+B+C=5 to 20% by weight, C based on the total weight of A+C=30 to 70% by weight. 2. The adhesive composition of claim 1, wherein the at least one monomer A is selected from (meth)acrylic esters, in particular linear or branched or cyclic C1-C6-alkyl esters, or heterocyclic or aromatic esters, much preferred the group consisting of methyl methacrylate, tetrahydrofurfuryl methacrylate, cyclohexylmethacrylate, cyclic trimethylolpropane formal acrylate, isobornylmethacrylate, benzylmethacrylate, dicyclopentadienyloxyethylmethacrylate, t-butylmethacrylate, isobornylacrylate, dihydrodicyclopentadienylacrylate (DHDCPA), and mixtures thereof, in particular methyl methacrylate, tetrahydrofurfuryl methacrylate, and mixtures thereof. 3. The adhesive composition of claim 1, wherein the at least one monomer B is selected from linear or branched C6-C15-alkyl esters, in particular from the esters wherein R′ is CH2CH3 and R″ is (CH2)3CH3, or R′ is H and R″ is (CH2)nCH3 with n=10-13, much preferred n=10, or mixtures thereof. 4. The adhesive composition of claim 3 wherein the one or more (meth)acrylate ester(s) are one or more acrylate ester(s), preferably lauryl acrylate, 2-ethyl hexyl acrylate, or mixtures thereof. 5. The adhesive composition of anyone claim 1, wherein the ethylenically unsaturated (meth)acrylic groups of the liquid elastomer C are chosen from the group consisting of (meth)acrylic functionalized butadiene, isoprene based polymer or block-copolymer, PU-(meth)acrylate obtainable through the syntheses of a polyethylene polyol or polypropylene polyol, a diisocyanate and a hydroxy functionalyzed ethylenically unsaturated monomer. 6. The adhesive composition of claim 5, wherein the PU-(meth)acrylate is obtainable through a synthesis using polyols with low unsaturation and narrow molecular weight distribution as obtainable through double metal cyanide complex catalysis. 7. The adhesive composition of claim 1, wherein the amount of B based on the total weight of A+B+C=5 to 12% by weight. 8. The adhesive composition of claim 1, wherein the amount of C based on the total weight of A+C=40 to 60% by weight. 9. The adhesive composition of claim 1 that furthermore contains at least one initiator, preferably an organic peroxide and/or at least one catalyst, preferably selected from the group consisting of tertiary amines and salts of transition metals and complexes of transition metals. 10. The adhesive composition of claim 9 wherein the initiator is benzoylperoxide, and/or the tertiary amine is selected from the group consisting of N,N-dimethylaniline, N,N-dimethyl-p-toluidine, N,N-diethylaniline, N,N-diethyltoluidine, N,N-bis(2-hydroxyethyl)-p-toluidine, N-ethoxylated p-toluidine, N-alkylmorpholine or mixtures thereof, or the salts and complexes of transition metals are selected from the group consisting of salts and complexes of cobalt, nickel, copper and mixtures thereof. 11. The adhesive composition of claim 1 that contains at least one further compound, in particular a filler or thixotropic agent. 12. Use of an adhesive composition of anyone claim 1 for bonding applications with materials having different thermal expansion coefficients, in particular for bonding applications in motor vehicles including trucks, and in rail cars, e.g. for bonding of side panels of trailers or direct glazing. 13. A method for bonding materials having different thermal expansion coefficients, wherein said bonding is performed by application of an adhesive composition of claim 1 between said materials. |
<SOH> BACKGROUND ART <EOH>The long term performance of bonding is dependent on the elastic behavior of the adhesive. The first-generation meth(acrylic) adhesives are brittle, with very low elongation at break. Many approaches are known to increase the flexibility of methacrylic adhesives. One of said efforts to improve flexibility has led to the addition of solid non-reactive elastomers that are dissolved in the meth(acrylic) monomers. Such compositions are called rubber-toughened adhesive compositions. The elastomers are solids at room temperature, and commercially available as large particles or granulates. This approach is described in several patent documents, such as: U.S. Pat. No. 3,890,407, U.S. Pat. No. 4,106,971, U.S. Pat. No. 4,263,419, U.S. Pat. No. 3,725,504, U.S. Pat. No. 4,200,480, U.S. Pat. No. 3,994,764, EP 0 641 846. The disadvantage of such formulations is that they can only be mixed homogeneously with special equipment like extruders or kneaders due to the high viscosity of the polymer that is formed in the monomer solution. Moreover, this type of compositions suffers from the limitation that the monomer, or the monomer mixture, must be chosen such that the non-reactive thermoplastic polymer is soluble therein. Practically, methyl methacrylate is the only monomer with high dissolving properties, and thus the only monomer that allows a polymer-in-monomer composition with up to 30% polymer content. Such low molar mass monomers, like methyl methacrylate, have a strong odor and are highly flammable. Polymer-in-monomer compositions resulting from this approach have a rubbery, stringy consistency and a high viscosity that makes their handling difficult. Due to the high viscosity of the mixture, only a limited amount of fillers can be used making the formulation expensive. A high viscosity is also limiting the adhesion of the formulation, as it limits the wetting of the substrate. A further approach is the addition of liquid, low-molar mass elastomers that dissolve in the monomers. A number of patent documents describe such approach to increase the flexibility of the systems by adding liquid reactive elastomers to the reactive monomer (mixtures) to increase the flexility of the adhesives, namely U.S. Pat. No. 4,769,419; U.S. Pat. No. 4,331;765 and EP 0,561,352 disclosing mixtures of monomers and liquid rubber. DE 2,610,423; U.S. Pat. No. 4,439,600; EP 0,640,672; DE 2,319,637 and U.S. Pat. No. 4,223,115 disclose mixtures of monomers and acrylic functionalised polyurethanes. In U.S. Pat. No. 4,223,115 the composition optionally contains a dissolved elastomer, e.g. NBR (nitrile-butadiene-rubber), polychloroprene. Flexibility is measured in terms of elongation at break. During deformation, however, all the above mentioned prior-art adhesives show a visco-elastic behavior with a significant viscous component. This means that during the deformation the binder matrix of the adhesive shows plastic flow and is being damaged. The visco-elastic behavior of the material is reflected in the shape of the stress-strain curve, measured at an elongation speed relevant to the practical application. The plot of the prior-art adhesives is not linear, and this even for the compositions of U.S. Pat. No. 4,439,600 (see above) although elastic behavior is claimed. The plastic flow component during deformation reduces the number of deformation cycles an adhesive can perform before failing. This significantly reduces the life span of an adhesive bond under dynamic load. It was therefore an object of the present invention to provide meth(acrylic) adhesive compositions with a high elasticity, measured in terms of elongation at break, and an elastic behavior approaching the ideal Hook law in the stress-strain diagram. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The invention will be better understood and objects other than those set forth above will become apparent when consideration is given to the following description thereof and the annexed Figures, wherein: FIG. 1 shows a stress-strain diagram for the inventive composition of Example 1. FIG. 2 shows a stress-strain diagram for the inventive composition of Example 2. FIG. 3 shows a stress-strain diagram for the inventive composition of Example 3. FIG. 4 shows a stress-strain diagram for the comparative composition of Example 4. FIG. 5 shows a stress-strain diagram for the state of the art composition of Example 5. detailed-description description="Detailed Description" end="lead"? |
Fluorescent life hammer |
The invention relates to safety device (1) for breaking glass, provided with a housing (2) and a head (4), wherein the head is provided with a relatively hard end (14), wherein at least a part of the housing is provided with a fluorescent outer surface (30). The invention also relates to a method for manufacturing a safety device, wherein at least two housing parts (2) are injection-molded, provided at least a part of the outer surface with an in-mold label (20) which is of fluorescent design, which housing parts are assembled for forming the housing of the safety device, wherein between at least a part of the parts of the housing a head is included extending at least partly outside the housing and being provided with at least one relatively hard end. |
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