The present invention is concerned with pellets comprising a 710-1180 xcexcm (16-25 mesh) sugar core, a coating film of a water-soluble polymer and an antifungal agent, and a seal coating layer wherein the residual concentration of dichloromethane is below 600 ppm; pharmaceutical dosage forms comprising said pellets and a method of preparing said pellets.

The present invention is concerned with novel pellets of itraconazole, a process for preparing said pellets, and oral dosage forms comprising a therapeutically effective amount of such pellets.
The development of efficaceous pharmaceutical compositions of azole antifungals such as itraconazole is hampered considerably by the fact that said antifungals are only very sparingly soluble in water. The solubility and bioavailability of said compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO-85/02767 and U.S. Pat. No. 4,764,604.
In WO-94/05263, published on Mar. 17, 1994, there are disclosed beads having a 25-30 mesh sugar core (600-710 xcexcm) coated with an azole antifungal, more particularly itraconazole (or saperconazole), and a polymer, more particularly, hydroxypropyl methylcellulose. Finished with a sealing film coat, such drug coated cores are referred to as beads. About 460 mg beads, equivalent to about 100 mg itraconazole, are filled into a hard-gelatin capsule (size 0) suitable for oral administration. The capsules are commercially available in many countries under the Trademark Sporanox(trademark). The azole antifungal is easily released from the surface of the coated beads, which leads to improved bioavailability over previously known oral dosage forms of azole antifungals.
The preparation of coated beads as described in WO-94/05263 requires special techniques and special equipment in a purpose-built plant. Indeed, the beads described in the prior art are prepared in a quite complex manner requiring a lot of manipulation steps. First, a drug coating solution is prepared by dissolving appropriate amounts of the antifungal agent and a hydrophilic polymer, preferably hydroxypropyl methylcellulose (HPMC), into a suitable solvent system. A suitable solvent system comprises a mixture of methylene chloride and an alcohol. Said mixture should comprise at least 50% by weight of methylene chloride acting as a solvent for the drug substance. As hydroxypropyl methylcellulose does not dissolve completely in methylene chloride, at least 10% alcohol has to be added. Subsequently, the 25-30 mesh sugar cores are drug-coated in a fluidized bed granulator equipped with a bottom spray insert. Not only should the spraying rate be regulated carefully, but also temperature control in the fluidized bed granulator is crucial. Hence, this process requires a lot of control in order to obtain a good quality product reproducibly. Further, this technique requires the adequate resolution of the issue of residual organic solvents, such as methylene chloride and methanol or ethanol, being present in the coating. In order to remove any solvents which may remain in the drug-coated intermediate product, a drying step in vacuo is required. Subsequently, a seal coating is applied to the dried drug coated cores.
WO-94/05263 explains that the size of the cores is of considerable importance. On the one hand, if the cores are too large, there is less surface area available for applying the drug coating layer, which results in thicker coating layers. This raises problems in the manufacturing process as an intensive drying step is needed to reduce residual solvent levels in the coating layer. The intense drying conditions may adversely affect drug dissolution from the pellets and should therefore be controlled extremely well during the manufacturing process. On the other hand, small cores have a larger total surface available for coating resulting in thinner coating layers. Consequently a far less intensive drying step can be used to decrease residual solvents levels. Cores which were too small, e.g. 500-600 xcexcm (30-35 mesh) cores, however, had the disadvantage of showing considerable tendency to agglomerate during the coating process. Therefore, it was concluded that 600-710 xcexcm (25-30 mesh) cores represented the optimum size where neither agglomeration nor an intensive drying step constrained the process.
It would be highly desirable to have access to pharmaceutical dosage forms comprising drug coated cores wherein the cores are relatively large, 710-1180 xcexcm (25-16 mesh), in particular 710-1000 xcexcm (25-18 mesh) and especially 710-850 xcexcm (25-20 mesh), and wherein the residual solvent levels in said drug coated cores are within the limits set out by the International Conference on Harmonisation (ICH) [ICH Topic Q3C Impurities.: Residual Solvents (CPMP/ICH/283/95) in force as of March 1998]. Therein, dichloromethane and methanol are both considered to be Class 2 solvents whose presence in pharmaceutical products should be limited; their respective Permitted Daily Exposure (PDE) is 6 mg/day and 30 mg/day; their respective concentration limits in pharmaceutical dosage forms are 600 ppm and 3000 ppm.
As mentioned previously, attaining these low residual solvent levels in beads with a relatively large core and a relatively thick drug/polymer coating layer is difficult. As the drug coat grows thicker, it takes longer for the residual solvent to diffuse outwardly. The rate of diffusion of a solute being proportional to its concentration gradient, it follows that lowering pressure should help to reduce the residual solvent levels.
However, the lower pressure at the same time dimishes the efficiency of heat transfer to the drug coated beads when conventional heating techniques are used, and thus, the evaporation of the residual solvents is slowed down. The present invention provides a method of efficiently conveying heat to the drug coated cores in a low pressure environment, thus enabling one to obtain drug coated cores that satisfy the above-mentioned guidelines issued by ICH. The method for the first time allows one to obtain relatively large beads complying with the newest international limits on residual solvents in pharmaceutical products.
Itraconazole or (xc2x1)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one, is a broadspectrum antifungal compound developed for oral, parenteral and topical use and is disclosed in U.S. Pat. No. 4,267,179. Its difluoro analog, saperconazole or (xc2x1)-cis-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methoxypropyl)-3H-1,2,4-triazol-3-one, has improved activity against Aspergillus spp. and is disclosed in U.S. Pat. No. 4,916,134. Both itraconazole and saperconazole consist of a mixture of four diastereoisomers, the preparation and utility of which is disclosed in WO-93/19061: the diastereoisomers of itraconazole and saperconazole are designated [2R-[2xcex1,4xcex1,4(R*)]], [2R-[2xcex1,4xcex1,4(S*)]], [2S-[2xcex1,4xcex1,4(S*)]] and [2S-[2xcex1,4xcex1,4(R*)]]. The term xe2x80x9citraconazolexe2x80x9das hereinafter is to be interpreted broadly and comprises the free base form and the pharmaceutically acceptable addition salts of itraconazole, or of one of its stereoisomers, or of a mixture of two or three of its stereoisomers. The preferred itraconazole compound is the (xc2x1)-(cis) form of the free base form. The acid addition forms may be obtained by reaction of the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxy-propanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxy-butanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
It may be remarked that therapeutically effective plasm levels of itraconazole can be maintained easily for at least 24 hours as its half-life is sufficiently high. The condition is that the itraconazole must reach the plasm. The absorption of dissolved itraconazole from the stomach is in itself not a problem. Thus, there is no need for a sustained release dosage form of itraconazole, an immediate release form will do just as well. In other words, the main problem with the administration of itraconazole in therapeutically effective amounts is in the first place concerned with ensuring that a sufficient amount of itraconazole remains in solution sufficiently long to allow it to get into the circulation, and does not convert into a form that is not readily bioavailable, in particular crystalline itraconazole (which is formed when itraconazole precipitates in an aqueous medium).
Unexpectedly, it has now been found that pellets larger than those described in WO-94/05263, and wherein the residual solvent levels are within the guidelines of ICH, can be manufactured conveniently after all. In these novel pellets, the residual solvent levels are reduced by irradiating the pellets in vacuo with microwave or radiofrequency radiation. Probably, the improved efficacy of the drying process using radiation may be explained by the superior heat transfer; whereas conventional heating relies on energy exchange upon collison of particles, irradiation directly transfers the energy required to evaporate the solvent to the drug coated particle.
The present invention also provides pharmaceutical compositions of itraconazole and a water-soluble polymer which can be administered to a patient suffering from a fungal infection. The dosage forms comprise a therapeutically effective amount of novel pellets as described in detail hereunder.
In particular the present invention is concerned with pellets which comprise (a) a central, rounded or spherical core having a diameter of about 710-1180 xcexcm (25-16 mesh), in particular 710-1000 xcexcm (25-18 mesh) and especially 710-850 xcexcm (25-20 mesh), (b) a coating film of a water-soluble polymer and an antifungal agent and (c) a seal-coating polymer layer, characterized in that the residual solvent levels in said pellets are within the limits set out by the International Conference on Harmonisation (ICH) [ICH Topic Q3C Impurities: Residual Solvents (CPMP/ICH/283/95) in force as of March 1998], that is, the concentration of dichloromethane in said pellets is less than 600 ppm, preferably less than 300 ppm and most preferably less than 250 ppm.
The alcoholic co-solvent that is necessary for applying the drug coat layer to the cores is preferably ethanol, a Class 3 solvent, rather than methanol, a Class 2 solvent, even though ethanol has a higher boiling point and a slightly higher latent heat evaporation and thus requires a larger energy input than methanol.
Cores of the dimensions mentioned herein can be obtained by sieving through nominal standard test sieves as described in the CRC Handbook, 64th ed., page F-114. Nominal standard sieves are characterized by the mesh/hole width (xcexcm), DIN 4188 (mm), ASTM E 11-70 (No), Tyler(copyright) (mesh) or BS 410 (mesh) standard values. Throughout this description and the claims, particle sizes are designated by reference to the mesh/hole width in xcexcm and to the corresponding Sieve No in the ASTM E11-70 standard.
Materials suitable for use as cores in the pellets according to the present invention are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions (about 16-25 mesh, preferably about 20-25 mesh) and firmness. Examples of such materials are polymers e.g. plastic resins; inorganic substances, e.g. silica, glass, hydroxyapatite, salts (sodium or potassium chloride, calcium or magnesium carbonate) and the like; organic substances, e.g. activated carbon, acids (citric, fumaric, tartaric, ascorbic and the like acids), and saccharides and derivatives thereof. Particularly suitable materials are saccharides such as sugars, oligosaccharides, polysaccharides and their derivatives, for example, glucose, rhamnose, galactose, lactose, sucrose, mannitol, sorbitol, dextrin, maltodextrin, cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, starches (maize, rice, potato, wheat, tapioca) and the like saccharides.
A particularly preferred material suitable for use as cores in the pellets according to the present invention is represented by 20-25 mesh sugar cores (USP 22/NF XVII, p. 1989) which consist of 62.5%-91.5% (w/w) sucrose, the remainder being starch and possibly also dextrines, and which are pharmaceutically inert or neutral. Consequently, these cores are also known in the art as neutral pellets.
Pellets obtainable from 20-25 mesh sugar cores comprise approximately, by weight based on the total weight of the pellet: (a) 35 to 60 percent core material; (b) 23 to 37 percent water-soluble polymer; (c) 15 to 25 percent antifungal agent; and (d) 2 to 4 percent seal coating polymer.
The water-soluble polymer in the pellets according to the present invention is a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20xc2x0 C. solution. For example, the water-soluble polymer can be selected from the group comprising
alkylcelluloses such as methylcellulose,
hydroxyalkylcelluloses such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxybutylcellulose,
hydroxyalkyl alkylcelluloses such as hydroxyethyl methylcellulose and hydroxypropyl methylcellulose,
carboxyalkylcelluloses such as carboxymethylcellulose,
alkali metal salts of carboxyalkylcelluloses such as sodium carboxymethylcellulose,
carboxyalkylalkylcelluloses such as carboxymethylethylcellulose,
carboxyalkylcellulose esters,
starches,
pectines such as sodium carboxymethylamylopectine,
chitine derivates such as chitosan,
polysaccharides such as alginic acid, alkali metal and ammonium salts thereof, carrageenans, galactomannans, tragacanth, agar-agar, gummi arabicum, guar gummi and xanthan gummi,
polyacrylic acids and the salts thereof,
polymethacrylic acids and the salts thereof, methacrylate copolymers,
polyvinylalcohol,
polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate,
polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.
Non-enumerated polymers which are pharmaceutically acceptable and have appropriate physico-chemical properties as defined hereinbefore are equally suited for preparing drug coated cores according to the present invention.
The drug coating layer preferably comprises a water-soluble polymer such as hydroxypropyl methylcellulose (Methocel(copyright), Pharmacoat(copyright)), methacrylate (Eudragit E(copyright)), hydroxypropylcellulose (Klucel(copyright)), or a polyvidone. Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC. Said HPMC contains sufficient hydroxypropyl and methoxy groups to render it water-soluble. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water-soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxypropyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule. Hydroxypropyl methylcellulose is the United States Adopted Name for hypromellose (see Martindale, The Extra Pharmacopoeia, 29th edition, page 1435). Preferably hydroxypropyl methylcellulose with low viscosity, i.e. about 5 mPa.s, is used, e.g. hydroxypropyl methylcellulose 2910 5 mPa.s. In the four digit number xe2x80x9c2910xe2x80x9d, the first two digits represent the approximate percentage of methoxyl groups and the third and fourth digits the approximate percentage composition of hydroxypropoxyl groups. 5 mPa.s is a value indicative of the apparent viscosity of a 2% aqueous solution at 20xc2x0 C.
Suitable HPMC include those having a viscosity from about 1 to about 100 mPa.s, in particular form about 3 to about 15 mPa.s, preferably about 5 mPa.s The most preferred type of HPMC having a viscosity of 5 mPa.s., is the commercially available HPMC 2910 5 mPa.s.
Preferred antifungal agents for use as drugs in said drug coating layer are lipophilic azole antifungals, in particular itraconazole. Optimum dissolution results are obtained when the drug substance is present in a solid dispersion or solution state as can be confirmed by differential scanning calorimetry.
The weight-by-weight ratio of drug: polymer is in the range of 1:1 to 1:5, preferably 1:1 to 1:3. In the case of (itraconazole):(HPMC 2910 5 mPa.s), said ratio may range from about 1:1 to about 1:2, and optimally is about 11.5 (or 2:3). The weight by weight ratio of itraconazole to other water-soluble polymers may be determined by a person skilled in the art by straightforward experimentation. The lower limit is determined by practical considerations. Indeed, given the therapeutically effective amount of itraconazole (from about 50 mg to about 300 mg, preferably about 200 mg per day), the lower limit of the ratio is determined by the maximum amount of mixture that can be processed into one dosage form of practical size. When the relative amount of water-soluble polymer is too high, the absolute amount of mixture needed to reach the therapeutic level will be too high to be processed into one capsule or tablet. Capsules of size 0 can contain about 460 mg, minimally 35% of which comprises the cores, the remaining 65% (300 mg) being the maximum amount of antifungal and polymer. Consequently, the lower limit of the amount of itraconazole over hydroxypropyl methyl cellulose will be about 1:5 (50 mg itraconazole+250 mg water-soluble polymer).
On the other hand, if the ratio is too high, this means the amount of itraconazole is relatively high compared to the amount of water-soluble polymer, then there is the risk that the itraconazole will not dissolve sufficiently in the water-soluble polymer, and thus the required bioavailability will not be obtained. The 1:1 upper limit is determined by the fact that it was observed that above said ratio not all of the itraconazole had dissolved in the HPMC. It will be appreciated that the upper limit of 1:1 may be underestimated for particular water-soluble polymers. Since this can be established easily but for the experimentation time involved, solid dispersions wherein the ratio drug:polymer ratio is larger than 1:1 are also meant to be comprised within the scope of the present invention.
The drug coating layer of the pellets as described hereinabove may further comprise one or more pharmaceutically acceptable excipients such as, for example, plasticizers, flavors, colorants, preservatives and the like. Said excipients should be inert, in other words, they should not show any degradation or decomposition under the manufacturing conditions.
In the current itraconazole:HPMC 2910 5 mPa.s formulations, the amount of plasticizer is preferably small, in the order of 0% to 15% (w/w), preferably less than 5% (w/w), most preferably 0% (w/w). With other water-soluble polymers though, plasticizers may be employed in different, often higher amounts. Suitable plasticizers are pharmaceutically acceptable and include low molecular weight polyalcohols such as ethylene glycol, propylene glycol, 1,2 butylene glycol, 2,3-butylene glycol, styrene glycol; polyethylene glycols such as diethylene glycol, triethylene glycol, tetraethylene glycol; other polyethylene glycols having a molecular weight lower than 1,000 g/mol; polypropylene glycols having a molcular weight lower than 200 g/mol; glycol ethers such as monopropylene glycol monoisopropyl ether; propylene glycol monoethyl ether; diethylene glycol monoethyl ether; ester type plasticizers such as sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, allyl glycollate; and amines such as monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine; triethylenetetramine, 2-amino-2-methyl-1,3-propanediol and the like. Of these, the low molecular weight polyethylene glycols, ethylene glycol, low molecular weight polypropylene glycols and especially propylene glycol are preferred.
A seal coating polymer layer is applied to the drug coated cores to prevent sticking of the pellets which would have the undesirable effect of a concomitant decrease of the dissolution rate and of the bioavailability. Preferably, a thin layer of polyethylene glycol (PEG), in particular polyethylene glycol 20000 (Macrogol 20000) is used as a seal coating polymer layer.
The preferred pellets comprise approximately: (a) 40 to 43 percent sugar core; (b) 30 to 35 percent hydroxypropyl methylcellulose 2910 5 mPa.s; (c) 20 to 25 percent itraconazole; and (d) 2 to 4 percent polyethylene glycol 20000.
In addition, the pellets according to the present invention may further contain various additives such as thickening agents, lubricants, surfactants, preservatives, complexing and chelating agents, electrolytes or other active ingredients, e.g. antiinflammatory agents, antibacterials, disinfectants or vitamins.
The pellets according to the present invention can conveniently be formulated into various pharmaceutical dosage forms. Suitable dosage forms comprise an effective antifungal amount of pellets as described hereinbefore. Preferably, the pellets are filled in hard-gelatin capsules such that an amount of, for example, 100 mg of the active ingredient is available per dosage form. For example, hard-gelatin capsules of size 0 are suitable for formulating pellets comprising 20 to 25 percent by weight itraconazole or saperconazole, equivalent to about 100 mg active ingredient.
The pellets according to the present invention are conveniently prepared in the following manner. A drug coating solution is prepared by dissolving into a suitable solvent system appropriate amounts of an antifungal agent and a water-soluble polymer. A suitable solvent system comprises a mixture of methylenechloride and an alcohol, preferably ethanol which may be denatured, for example, with butanone. Said mixture should comprise at least 50% by weight of methylenechloride acting as a solvent for the drug substance. As hydroxypropyl methylcellulose does not dissolve completely in methylenechloride, at least 10% alcohol has to be added. Preferably a relatively low ratio of methylenechloride/alcohol is used in the coating solution, e.g. a ratio methylene-chloride/ethanol ranging from 75/25 (w/w) to 55/45 (w/w), in particular about 60/40 (w/w). The amounts of solids, i.e. antifungal agent and water-soluble polymer, in the drug coating solution may range from 7 to 10% (w/w) and preferably is about 8.7%.
The drug coating process (on an industrial scale) is conveniently conducted in a fluidized bed granulator (e.g. Glatt type WSG-30 or GPCG-30) equipped with a Wurster bottom spray insert (e.g. an 18 inch Wurster insert). Laboratory scale process development can be performed on a Glatt type WSG-1 with a 6 inch Wurster bottom insert. Obviously, the process parameters depend on the equipment used.
The spraying rate should be regulated carefully. Too low a spraying rate can cause some spray drying of the drug coating solution and result in a loss of product. Too high a spraying rate will cause overwetting with subsequent agglomeration. Agglomeration being the most serious problem, lower spraying rates may be used initially, to be increased as the coating process proceeds and the pellets grow larger.
The atomizing air pressure with which the drug coating solution is applied also influences the coating performance. Low atomizing air pressure results in the formation of larger droplets and an increased tendency toward agglomeration. High atomizing air pressure could conceivably carry the risk of spray drying of the drug solution, but this was found not to be a problem. Consequently, atomizing air pressure may be set at nearly maximum levels.
Fluidizing air volume can be monitored by operating the exhaust air-valve of the apparatus and should be set in such a manner that optimum pellet circulation is obtained. Too low an air volume will cause insufficient fluidization of the pellets; too high an air volume will interfere with the pellet circulation due to countercurrent air streams developing in the apparatus. In the present process optimum conditions were obtained by opening the exhaust air valve to about 50% of its maximum and gradually increasing the opening thereof to about 60% of the maximum as the coating process proceeded.
The coating process is advantageously conducted by employing an inlet-air temperature ranging from about 50xc2x0 C. to about 55xc2x0 C. Higher temperatures may speed up the process but have the disadvantage that solvent evaporation is so rapid that the coating liquid is not spread uniformly on the surface of the pellets resulting in the formation of a drug coating layer with high porosity. As the bulk volume of the coated pellets increases, drug dissolution may decrease significantly to unacceptable levels. Obviously, the optimum process temperature will further depend on the equipment used, the nature of the core and the antifungal agent, the batch volume, the solvent and the spraying rate.
Parameter settings for optimum coating results are described in more detail in the example hereinafter. Running the coating process under those conditions was found to yield very reproducible results.
In order to reduce residual solvent levels in the drug coating layer, the drug coated cores can conveniently be dried in a microwave vacuum apparatus, for example as described in U.S. Pat. No. 4,882,851 by The Fitzpatrick Co. of Elmhurst, Ill. USA. Good results may be obtained using a vacuum ranging from about 150-400 mbar (15-40 kpa), preferably 200-300 mbar (20-30 kPa). Microwave (or radiofrequency) power may applied continuously, but is preferably pulsed as is described in U.S. Pat. No. 5,440,104. After drying, the drug coated cores may be sieved.
The seal coating polymer layer is applied to the drug coated cores in the fluidized bed granulator with Wurster bottom spray insert. The seal coating solution can be prepared by dissolving an appropriate amount of a seal coating polymer into a suitable solvent system. Such a system, is, e.g. a mixture of methylene chloride and an alcohol, preferably ethanol which may be denatured with, for example, butanone. The ratio of methylene chloride/alcohol used may be similar to the ratio used in the drug coating process and thus can range from about 75/25 (w/w) to about 55/45 (w/w) and in particular is about 60/40 (w/w). The amount of seal coating polymer in the seal coating spraying solution may range from 7 to 12% (w/w) and preferably is about 10%. The seal coating spraying solution is advantageously stirred during the seal coating process. The parameter setting for conducting this last step is essentially similar to that used in the drug coating process. Appropriate conditions are described in more detail in the example hereinafter.
Both the drug coating process and the seal coating process are preferably conducted under an inert atmosphere of e.g. nitrogen. The coating equipment should preferably be grounded and provided with an appropriate solvent recovery system containing an efficient condensing system.
The drug coated and seal coated pellets may be filled in hard-gelatin capsules using standard automatic capsule filling machines. Suitable earthing and de-ionisation equipment can advantageously prevent development of electrostatic charges.
Capsule filling speed may influence weight distribution and should be monitored. Good results are obtained when operating the equipment at about 75% to 85% of the maximum speed and in many cases when operating at full speed.
Pharmaceutical dosage forms for oral administration such as tablets comrising the drug coated cores (preferably without a seal coat) are also envisaged. They can be produced by conventional tabletting techniques with conventional ingredients or excipients and with conventional tabletting machines. In addition, they can be produced at low cost. The shape of the tablets may be round, oval or oblong. In order to facilitate the swallowing of large dosage forms by a patient, it is advantageous to give the tablets an appropriate shape. Tablets that can be swallowed comfortably are therefore preferably elongated rather than round in shape. Especially preferred are biconvex oblate tablets. As discussed hereunder in more detail, a film coat on the tablet further contributes to the ease with which it can be swallowed.
Tablets that give an immediate release of antifungal agent upon oral ingestion and that have good bioavailability are designed in such a manner that the tablets disintegrate rapidly in the stomach (immediate release) and that the dug coated cores which are liberated thereby are kept away from one another so that they do not coalesce. Thus, local concentrations of antifungal agent remain low and there is little chance that the drug will precipitate (bioavailability). The desired effect can be obtained by distributing said drug coated cores homogeneously throughout a mixture of a disintegrant and a diluent.
Suitable disintegrants are those that have a large coefficient of expansion. Examples thereof are hydrophilic, insoluble or poorly water-soluble crosslinked polymers such as crospovidone (crosslinked polyvinylpyrrolidone) and croscarmellose (crosslinked sodium carboxymethylcellulose). The amount of disintegrant in immediate release tablets according to the present invention may conveniently range from about 3 to about 15% (w/w) and preferably is about 7 to 9%, in particular about 8.5% (w/w). This amount tends to be larger than usual in tablets in order to ensure that the drug coated cores are spread over a large volume of the stomach contents upon ingestion. Because disintegrants by their nature yield sustained release formulations when employed in bulk, it is advantageous to dilute them with an inert substance called a diluent or filler.
A variety of materials may be used as diluents or fillers. Examples are spray-dried or anhydrous lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. micro-crystalline cellulose Avicel(trademark)), dihydrated or anhydrous dibasic calcium phosphate, and others known in the art, and mixtures thereof. Preferred is a commercial spray-dried mixture of lactose monohydrate (75%) with microcrystalline cellulose (25%) which is commercially availble as Microcelac(trademark). The amount of diluent or filler in the tablets may conveniently range from about 20% to about 40% (w/w) and preferably ranges from about 25% to about 32% (w/w).
The tablet may include a variety of one or more other conventional excipients such as binders, buffering agents, lubricants, glidants, thickening agents, sweetening agents, flavors, and colors. Some excipients can serve multiple purposes.
Lubricants and glidants can be employed in the manufacture of certain dosage forms, and will usually be employed when producing tablets. Examples of lubricants and glidants are hydrogenated vegetable oils, e.g hydrogenated Cottonseed oil, magnesium stearate, stearic acid, sodium lauryl sulfate, magnesium lauryl sulfate, colloidal silica, talc, mixtures thereof, and others known in the art. Interesting lubricants and glidants are magnesium stearate, and mixtures of magnesium stearate with colloidal silica. A preferred lubricant is hydrogenated vegetable oil type I (micronized), most preferably hydrogenated, deodorized Cottonseed oil (commercially available from Karlshamns as Akofine NF(trademark) (formerly called Sterotex(trademark))). Lubricants and glidants generally comprise 0.2 to 7.0% of the total tablet weight.
Other excipients such as coloring agents and pigments may also be added to the tablets of the present invention. Coloring agents and pigments include titanium dioxide and dyes suitable for food. A coloring agent is an optional ingredient in the tablet of the present invention, but when used the coloring agent can be present in an amount up to 3.5% based on the total tablet weight.
Flavors are optional in the composition and may be chosen from synthetic flavor oils and flavoring aromatics or natural oils, extracts from plants leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, bay oil, anise oil, eucalyptus, thyme oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. The amount of flavor may depend on a number of factors including the organoleptic effect desired. Generally the flavor will be present in an amount from about 0% to about 3% (w/w).
As known in the art, tablet blends may be dry-granulated or wet-granulated before tabletting. The tabletting process itself is otherwise standard and readily practised by forming a tablet from desired blend or mixture of ingredients into the appropriate shape using a conventional tablet press.
Tablets of the present invention may further be film-coated to improve taste, to provide ease of swallowing and an elegant appearance. Many suitable polymeric film-coating materials are known in the art. A preferred film-coating material is hydroxypropyl methylcellulose HPMC, especially HPMC 2910 5 mPa.s. Other suitable film-forming polymers also may be used herein, including, hydroxypropylcellulose, and acrylatemethacrylate copolymers. Besides a film-forming polymer, the film coat may further comprise a plasticizer (e.g. propylene glycol) and optionally a pigment (e.g. titanium dioxide). The film-coating suspension also may contain talc as an anti-adhesive. In immediate release tablets according to the invention, the film coat is small and in terms of weight accounts for less than about 3.5% (w/w) of the total tablet weight.
Preferred dosage forms are those wherein the weight of the drug coated cores ranges from 40% to 60% of the total weight of the total dosage form, that of the diluent ranges from 20 to 40%, and that of the disintegrant ranges from 3 to 10%, the remainder being accounted for by one or more of the excipients described hereinabove.
As an example of an oral dosage form comprising 100 mg of itraconazole, the following formula may be given:
sugar cores 710-850 xcexcm (20-25 mesh/192 mg)
itraconazole (100 mg)
HPMC 2910 5 mPa.s (150 mg)
microcrystalline cellulose (452 mg)
hydrogenated vegetable oil Type I micronized (6 mg).
Using the process parameters described above, a convenient, reproducible manufacturing method for preparing pellets comprising a 20-25 mesh core, a drug coat layer of an antifungal agent and a water-soluble polymer and a thin seal-coating polymer layer can be obtained. Pharmacokinetic studies show that the thus obtained pellets have excellent dissolution and bioavailability properties.
Preferred dosage forms according to the present invention are those from which at least 85% of the available itraconazole dissolves within 60 minutes when a dosage form equivalent to 100 mg itraconazole is tested as set forth in USP test  less than 711 greater than  in a USP-2 dissolution apparatus under conditions at least as stringent as the following: 900 mL artificial gastric juice (1.8 g NaCl, 6.3 mL concentrated HCl and 9 g polysorbate 20 diluted with distilled water to 900 mL), 37xc2x0 C. with paddles turning at 100 rpm. Capsules complying with the preceding definition can be said to have Q greater than 85% (60xe2x80x2). Preferably, capsules according to the present invention will dissolve faster and have Q greater than 85% (30xe2x80x2).

Pellets having a core coated with an antifungal and a polymer


The system removes contaminating gases, such as radon, from water using a bubbling action. Contaminated water is sprayed together with air through a duct to a bottom region of a bubbling container. The water and air move generally in the same direction through the system, allowing the flow rate to be varied while maintaining forced air/water contact. The aerated contaminated water bubbles upwardly through the bubbling container and passes through one or more diffusing or mixing plates causing the aerated contaminated water to further break out contaminating gases into the air. At the top region of the bubbling container, the contaminating gases are vented while the decontaminated water flows into a tank. The decontaminated water can then be pumped to a desired location, for example, to a house water system. A control system controls the operation of the system based upon water needs by stopping the introduction of air and water into the system when the decontaminated water in the tank has reached a predetermined level.

The present invention relates to systems and methods for removing contaminating gases from water and more particularly, to a system and method for removing radon from water by bubbling the radon gas out of the contaminated water.
The presence of the radioactive gas radon has been found in water supplies of New England and elsewhere in the world. Radon is a colorless, odorless, radioactive gas produced from the natural decay of uranium. In outdoor air, radon is diluted and not recognized as a health hazard. However, when radon gas is trapped indoors in air or water, in sufficiently high concentrations, it can be dangerous. Radon has been shown in several epidemiological studies to be a very potent carcinogen that causes lung cancer in humans.
Uranium, and therefore radon, is frequently found in granite bedrock deposits, which are common throughout the United States and the world. Radon typically enters a home along with the water from a bedrock well. Because radon is a volatile gas, it is given off by the water during common household activities such as bathing, showering, and washing dishes. Thus, the radon given off by the water becomes an inhalation hazard within a home or other building. The EPA has estimated that, on an average annual basis, each 10,000 pico-curies per liter (pCi/L) concentration of radon in the water supply will translate into an indoor air concentration of 1 pCi/L for homes having average air exchange rates. Currently, acceptable concentrations of radon are considered to be in the range of 300 to 4000 pCi/L. The contamination of drinking water with volatile organic chemicals, such as benzene, vinyl chloride and MTBE, has also recently become recognized as a serious health problem.
Different methods and systems have been developed to remove radon and other contaminating gases, such as volatile organic chemicals, from water. One such system is referred to as decay storage and comprises a large baffled water storage tank. Since radon has a radiological half-life of only 3.785 days, simply holding the contaminated water in a storage tank for approximately a month will greatly reduce the radon level. One problem with this type of decay storage is that it requires a large tank and is not suitable for use in a home where space may be limited.
Another example of decay storage requires accumulation of the radon on an absorbent material such as activated carbon. Since the radon decays relatively rapidly, the concentration of radon on the absorbent bed will initially increase, and then gradually reach an equilibrium with the influent radon concentration in the water. One disadvantage with this type of system is that the absorbent bed give off radioactivity, primarily in the form of gamma rays, as the radon decays, which may itself present a health hazard. A second disadvantage is that it is difficult to legally dispose of the radioactive carbon filter when it becomes fouled by other water-borne contaminants such as iron, sediment or bacteria.
Another method is known as spray aeration, for example, as disclosed in U.S. Pat. No. 4,371,383. In spray aeration systems, numerous cycles of spraying are required to achieve the desired removal efficiency. As a result, a relatively large spray tank would be required to provide a sufficient quantity of treated water for use in the home.
According to other methods, water is distributed through a tank while air is blown through the tank in a different direction than the water, for example, as disclosed in U.S. Pat. Nos. 4,869,832; 5,614,086; and 5,045,215. Because the water path is different than the air movement, the flow rates through these devices are limited in order to maintain the designed air/water contact without bypassing the aeration process. In U.S. Pat. No. 5,045,215, for example, water is sprayed onto a perforated tray 12 with air blown separately up through the perforated tray. Baffles 16 are used to direct the water flow and prevent back-mixing and cross-mixing of the froth, thereby achieving the desired air/water contact. If the water flow rate is increased beyond a certain point, however, the water will overflow the baffle 16 and the desired air/water contact will be bypassed. Blowing too much air will cause a similar result.
U.S. Pat. No. 5,614,086 has similar limitations. A series of double baffles is used to create a channel for cascading water flow. The water is aerated as it passes over and under the baffles. If the water or air rate is increased to a certain point, the water might overflow the baffles and not follow the desired flow path, causing the air/water contact to be bypassed. Thus, the systems and methods disclosed in both of these patents have an inherent limit on the flow rate.
Moreover, the available systems for removing radon often cannot easily be installed into the existing water system in a home. Systems such as those disclosed in U.S. Pat. Nos. 5,045,215 and 5,614,086 utilize external pump systems for pumping decontaminated water to a desired location and thus require a large amount of floor space and greater set-up installation time and effort. These devices, also typically incorporate complex control panels that must be installed and wired, increasing costs and requiring a specialized electrical hook-up.
Accordingly, there is a need for a system for removing radon or other contaminating gases that can easily be installed in a home, for example, without requiring an excessive amount of space. There is also a need for a system and method in which the air/water contact is directly proportional and will not be by-passed, even when the flow rate is increased. There is also a need for a method of removing radon or other contaminating gases from water that is efficient enough to remove the necessary amount of gas while being capable of higher flow rates because of a forced aeration or flow path.
A system for removing contaminating gases from contaminated water comprises a tank for holding decontaminated water and having a gas outlet for venting the contaminating gases removed from the contaminated water. A bubbling container is fluidly coupled to the tank such that decontaminated water flows from a top region of the bubbling container into the tank. A duct is at least partially disposed within the bubbling container with a first end of the duct positioned proximate a bottom region of the bubbling container. A second end of the duct is coupled to a source of contaminated water for introducing the contaminated water to the bottom region of the bubbling container.
In a preferred embodiment, a spraying connection, such as a nozzle/venturi, sprays the water into the second end of the duct. A blower is also coupled to the second end of the duct for blowing air into the duct as the contaminated water is introduced therethrough, thereby further aerating the contaminated water. At least one diffuser is positioned within the bubbling container for breaking up and further mixing the aerated contaminated water with the air. The aerated contaminated water rises to the top region of the bubbling container where the contaminating gases bubble out of the aerated contaminated water. According to one example, the diffuser includes one or more perforated grids disposed within the bubbling container. A pump pumps the decontaminated water from the tank.
The system preferably includes a control system for stopping the introduction of contaminated water and the blowing of air into the duct when the decontaminated water in the tank reaches a predetermined level. The control system preferably includes a normally closed valve coupled between the supply of contaminated water and the duct. The normally closed valve is opened when the decontaminated water is below the predetermined level. The control system further includes a float switch within the tank for switching off a power supply to the blower and to the normally closed valve when the decontaminated water in the tank reaches the predetermined level.
The present invention also features a method of removing contaminating gases from contaminated water. The method comprises the steps of supplying the contaminated water and introducing air together with the contaminated water into the bottom region of the bubbling container such that the air and the contaminated water flow generally in the same direction into the bubbling container through a forced flow path. The aerated contaminated water is forced to bubble up through the bubbling container to a top region of the bubbling container where the contaminating gases bubble out of the aerated contaminated water leaving decontaminated water to flow out of the bubbling container. The contaminating gases are vented and the decontaminated water is pumped to a desired location.
According to the exemplary method, the contaminating gases include radon, the water supply is a home water supply, and the desired location is a home water system. The method preferably includes the step of stopping the supply of contaminated water and the introduction of air when the decontaminated water in the tank reaches a predetermined level.

System and method for removing contaminating gases from water


An antenna, especially for use with mobile radios, that is mounted in an opening of a motor vehicle. The antenna includes at least one radiator with connecting line and the radiator is mounted in the opening behind a nontransparent, nonconductive covering. In one embodiment the radiator is configured as a monopole with matched balancing antennae that are strip conductors laid out on a printed circuit board attached to a ventilation structure mounted in an opening behind a covering nonconductive bumper.

1. Field of the Invention
The present invention relates to a motor vehicle antenna. More particularly, the present invention relates to a motor vehicle antenna intended for mobile radios having at least one radiator integrated in a body opening of a motor vehicle.
2. Description of the Related Technology
Certain prior art antennas are known in several versions. For example, DE 41 16 232 A1 describes an antenna which is integrated into a nonconductive motor vehicle bumper (and thus is not visible). However, as is appreciated, the antenna is greatly endangered in the event of a crash. This applies especially to such an antenna having two probes which are located in the corner areas of the bumper and which are connected to one another by a line and optionally a line coupler. As will be appreciated, the antenna is no longer serviceable due to interruption of the connecting line.
Moreover, the required minimum distance of the radiators from the metallic body which is used as a reflector in modern motor vehicles is becoming more rare because the bumpers are no longer raised for reasons of design and safety, but are located tightly against the body. The mutual distance is thus partially less than 20 mm, by which in the frequency ranges intended for mobile radios overly strong capacitive coupling is formed which essentially causes a short circuit of the antenna.
In a motor vehicle antenna known from DE 198 30 811 A1 this short distance is not possible also due to the radar housing located on the inside of the bumper.
The known bumper antennas thus cannot be used in these motor vehicles, so that their area of application is greatly limited.
In addition, to route the connecting lead into the interior of the body, an additional splash-proof opening is required, and thus the production and installation cost is increased.
A further known antenna type is disk antennas (see for example DE 44 43 596 A1) in which the radiators are integrated into the motor vehicle windows. These do not have the aforementioned disadvantages, but they are located visibly on the vehicle in an unwanted manner.
Therefore objects of the invention are to devise a motor vehicle antenna of the initially mentioned type, which is little endangered by crash damage, and is as simple and economical as possible. It is to be independent of the distance of the radiator from the body in its effectiveness, and does not require a special body penetration for the connecting lead.
These and other objects of the present invention are achieved by providing a motor vehicle antenna having at least one radiator integrated in one body opening and having one connecting lead, wherein at least one radiator is located on a nonconductive, carrier part which is covered by a separate nontransparent and nonconductive attachment part located in and separate from the body opening.
Because the antenna and the connecting lead are not components of the attachment part, the danger of damage, at least in milder collisions, is greatly reduced compared to bumper antennas. Here the attachment part acts as a screen, without additional cost, so that there is no apparent indication of the presence of a mobile radio with the associated danger of theft.
The arrangement of the radiator in the body opening in which the conductive body is therefore not used as a reflector furthermore makes the antenna completely independent of the distance of the attachment part from the radiator. The antenna is thus also suited for use in modern motor vehicles in which this distance is being increasingly reduced.
Last, but not least, in the arrangement of the motor vehicle antenna as claimed in the invention an additional body opening which must be specially sealed for routing the antenna connecting cable is not necessary, but rather shell-side cabling is economically enabled.
The attached claims give other advantageous embodiments of the present invention.
According to one feature of the invention, it is especially advantageous to use a component already present for other purposes as the attachment component (and thus save additional components). For example, according to one embodiment, the attachment part is a plastic bumper. Alternatively, according to another embodiment, the attachment part is an antibumping strip. As will be appreciated, these embodiments are advantageous in that bumpers as well as antibumping strips extend over larger areas within which the body opening can be located.
According to another feature of the invention, the radiator(s) comprise a monopole with a matched balancing antenna and the body opening is of an essentially rectangular configuration, wherein its dimensions in the radiator direction are  greater than ⅙ of the average wavelength (xcex) and orthogonally thereto are  greater than xcex/3. Due to the balancing antenna, a connection at an additional reference potential (such as that of a metal body) can be omitted, further reducing the cost in production and installation. In addition, the execution as a matched balancing antenna and the dimensioning of the body opening results in a barrier to jacket waves on the feed line.
For installation sites with a short height, especially behind relatively narrow antibumping strips, a slot antenna is suited. Here the length of the body opening must be greater than xcex/2, but its height (slot width) is short.
One embodiment of the motor vehicle antenna has a reflector located towards the motor vehicle interior. The use of a reflector is especially effective, regardless of whether it is made as a monopole or a slot antenna. This is because the reflector causes emission only to the outside, therefore in the preferred direction, and with increased power. The distance of the reflector from the radiator can have exactly the value which is optimum in terms of high frequency engineering and is not, as in bumper antennas, shortened as a compromise which adversely affects the radiation properties.
If air passage or pressure equalization is necessary (as in ventilation openings of a motor vehicle body), the configuration of the reflector is a lattice-like pattern which may be the optimum solution because it meets both requirements and is built to save material and weight.
With an antenna arrangement comprising two interconnected radiators, the pattern can be advantageously matched to the requirements of the individual case within certain limits.
For example, the directional effect can be intensified in certain angular ranges. But it is also possible to produce at least approximately an omni-directional radiation pattern by an arrangement of the two probes lengthwise on opposite sides of the motor vehicle body; which is generally desirable for receiving or transmitting in motor vehicles due to the continually changing directions of travel.
According to another aspect of the invention, a dual band antenna may be formed with minimum cost. According to this aspect, the length of the monopole, and optionally of the balancing antennas, is dimensioned for a lower frequence range. One blocking element at a time is inserted into the monopole and optionally the balancing antenna(s), for the upper frequency range, such that their length between the blocking element and the antenna terminal point (A) is matched to the upper frequency range. Notably, with this configuration, it can be designed, for example, for the D network and E network. Frequency ranges for these networks, depending on whether in Europe or the United States, are for the D network (0.88-0.96 Gigattertz (xe2x80x9cGHzxe2x80x9d)) and for the E network D (1.71-1.99 (GHz)). Of course it is also possible to further increase the frequency range of the motor vehicle antenna by connecting additional blocking elements.
These blocking elements are made simply and feasibly as LC elements, or alternatively, they are made as line tuned circuits.
According to the invention, the monopole, and optionally the balancing antenna(s), comprise printed circuits on a circuit board. This configuration gives a structure of the motor vehicle antenna which is especially simple and economical in production and installation. The radiator and balancing antenna parts can be made very exact here. In addition, the board imparts stability to the radiator in spite of the thin conductor and moreover can be mounted much more favorably than pure antenna wires.
In addition, the LC blocking elements can be easily inserted into the printed conductors according to both mechanical and also electrical requirements, advantageously for example, in Surface Mounted Device (xe2x80x9cSMDxe2x80x9d) technology (i.e. SMD components inserted into printed circuits).
Finally, the dielectric of the board also acts electrically so that the radiator and balancing antennas can be made smaller.
In most applications the body openings are not sealed tight or are covered by the attachment parts. In one advantageous embodiment of the invention, the circuit broads (optionally with the blocking elements) are surrounded with insulating material, preferably potting material. More preferably, it is contemplated that the entire circuit board be jacketed splash proof with insulation material. To do this it is especially simple and feasible to extrusion-coat or pot the component. In this version, it is moreover possible to create almost any outside contour and thus to optimally match the component to the shape of the installation surface.
The casting compound moreover makes it possible to impart a defined elasticity to the jacketed component or to preserve its elasticity; this is especially advantageous when these components are attached to strongly vibrating or oscillating elements, such as for example, motor vehicle parts.
The use of thermoplastic hot-melt cements as a casting compound is especially advantageous because, as a result of its short hardening time and the possibility of using an injection molding process in the low pressure range, it allows time-saving and economical production.
Moreover, as a result of cementing by the hot-melt cement, absolute tightness and moreover high strain relief of the parts routed out of the jacketing, such as for example cable jackets, are achieved. The thermoplastic hot-melt cement in cable jackets of thermoplastic, for example PVC or PE, forms a chemical compound with the latter at least on the surface, a compound which is absolutely tight and which ensures high strain relief.
Advantageously, the circuit board is attached to a nonconductive carrier part which is already present for other purposes. This ensures not only a stable arrangement, but this radiator component can be retrofitted at any time on the motor vehicle. It can of course also be integrated as original equipment on or in a plastic carrier part.
One especially suitable installation site for the antenna as claimed in the invention is the ventilation openings which are located on both sides of the trunk compartment in most passenger cars for pressure equalization when the motor vehicle doors are quickly closed. These openings are covered by the plastic bumpers and are not easily visible behind them.
In these body openings, generally louver-like ventilation flaps are mounted which are provided with tabs which can move to the outside and which open to the outside on the pressure of the motor vehicle interior and otherwise adjoin the ventilation flaps to prevent the penetration of water.
In this case it is especially advantageous to attach the components which have the monopole (and optionally the balancing antennas) to the ventilation flaps, with the understanding that the mobility of the tabs should not be hindered.
Especially simple and relatively stable mounting may be achieved by use of retaining pins, preferably having elastic projections. The retaining pins are economically produced in one piece with the ventilation flaps, for example, in a injection molding process. Preferably, the retaining pins are made integral with the carrier part (which is preferably the ventilation flaps), and more preferably the carrier part and retaining pins are an injection molding. The antenna part which has the radiator can then be locked simply onto the pertinent ventilation flap for installation.
If in the individual case, the height of the cover is not great enough to cover the radiator which is made as a monopole, its height can be shorted in the conventional manner by a roof capacitance and it can be adapted to circumstances.


A post-tension construction apparatus including a concrete slab, an anchor embedded in the concrete slab, a tendon fixedly received by and extending through the anchor so as to have a portion extending outwardly of one end of the anchor, and a pocket formed in the concrete slab and extending outwardly from one end of the anchor. The pocket has a wall extending outwardly from one end of the anchor. The wall has a pivot point formed thereon. A cutting torch is removably received within the pocket. The cutting torch has a pivot formed thereon which is pivotally engagable with the pivot point of the pocket.

The present invention relates to an apparatus and method for cutting tendons, especially post-tension tendons used in concrete structures, by using an acetylene torch or a plasma cutting torch.
For many years, the design of concrete structures imitated the typical steel design of column, girder and beam. With technological advances in structural concrete, however, its own form began to evolve. Concrete has the advantages of lower cost than steel, of not requiring fireproofing, and of its plasticity, a quality that lends itself to free flowing or boldly massive architectural concepts. On the other hand, structural concrete, though quite capable of carrying almost any compressive load, is extremely weak in carrying significant tensile loads. It becomes necessary, therefore, to add steel bars, called reinforcements, to concrete, thus allowing the concrete to carry the compressive forces and the steel to carry the tensile forces.
Structures of reinforced concrete may be constructed with load-bearing walls, but this method does not use the full potentialities of the concrete. The skeleton frame, in which the floors and roofs rest directly on exterior and interior reinforced-concrete columns, has proven to be most economic and popular. Reinforced concrete framing is seemingly a quite simple form of construction. First, wood or steel forms are constructed in the sizes, positions, and shapes called for by engineering and design requirements. The steel reinforcing is then placed and held in position by wires at its intersections. Devices known as chairs and spacers are used to keep the reinforcing bars apart and raised off the form work. The size and number of the steel bars depends completely upon the imposed loads and the need to transfer these loads evenly throughout the building and down to the foundation. After the reinforcing is set in place, the concrete, a mixture of water, cement, sand, and stone or aggregate, of proportions calculated to produce the required strength, is placed, care being taken to prevent voids or honeycombs.
One of the simplest designs in concrete frames is the beam-and-slab. This system follows ordinary steel design that uses concrete beams that are cast integrally with the floor slabs. The beam-and-slab system is often used in apartment buildings and other structures where the beams are not visually objectionable and can be hidden. The reinforcement is simple and the forms for casting can be utilized over and over for the same shape. The system, therefore, produces an economically viable structure. With the development of flat-slab construction, exposed beams can be eliminated. In this system, reinforcing bars are projected at right angles and in two directions from every column supporting flat slabs spanning twelve or fifteen feet in both directions.
Reinforced concrete reaches its highest potentialities when it is used in pre-stressed or post-tensioned members. Spans as great as one hundred feet can be attained in members as deep as three feet for roof loads. The basic principle is simple. In pre-stressing, reinforcing rods of high tensile strength wires are stretched to a certain determined limit and then high-strength concrete is placed around them. When the concrete has set, it holds the steel in a tight grip, preventing slippage or sagging. Post-tensioning follows the same principle, but the reinforcing tendon, usually a steel tendon, is held loosely in place while the concrete is placed around it. The reinforcing tendon is then stretched by hydraulic jacks and securely anchored into place. Pre-stressing is done with individual members in the shop and post-tensioning as part of the structure on the site.
In a typical tendon tensioning anchor assembly in such post-tensioning operations, there are provided anchors for anchoring the ends of the tendons suspended therebetween. In the course of installing the tendon tensioning anchor assembly in a concrete structure, a hydraulic jack or the like is releasably attached to one of the exposed ends of the tendon for applying a predetermined amount of tension to the tendon. When the desired amount of tension is applied to the tendon, wedges, threaded nuts, or the like, are used to capture the tendon and, as the jack is removed from the tendon, to prevent its relaxation and hold it in its stressed condition.
Metallic components within concrete structures may become exposed to many corrosive elements, such as de-icing chemicals, sea water, brackish water, or spray from these sources, as well as salt water. If this occurs, and the exposed portions of the tendon or anchor suffer corrosion, then they may become weakened due to this corrosion. The deterioration of the anchor or tendon can cause the tendons to slip, thereby losing the compressive effects on the structure, or the anchor can fracture. In addition, the large volume of by-products from the corrosive reaction is often sufficient to fracture the surrounding structure. These elements and problems can be sufficient so as to cause a premature failure of the post-tensioning system and a deterioration of the structure.
Several U.S. patents have considered the problem of anchor and tendon corrosion. For example, U.S. Pat. Nos. 4,896,470 and 5,072,558 disclose tendon tensioning anchor systems in which the metal anchor for the system is encapsulated in plastic and has a tubular portion extending outwardly towards the surface of the post-tensioned concrete body. A sealing cap is fitted to the end of the tubular portion of the plastic encapsulation to provide a fluid tight seal for protecting the post-tensioned tendon, anchor and tensioning wedges from exposure to the elements. Other prior art systems also exist in which the end of the post-tensioned tendon is severed at a point inwardly from the outer surface of the post-tensioned concrete body and means are used to protect the tendon end, anchor and tensioning wedges from exposure to the elements.
When using prior art systems for corrosion protection of the tensioning tendon and related apparatus, it is important that the tendon be terminated at a point inboard from the outside surface of the post-tensioned concrete body. This requires that the end of the tendon be cut just outboard of the tensioning wedges and within the pocket or cavity formed by the pocketformer. The most common method used in the prior art for the cutting of such tensioned tendon at this point is an acetylene torch or cutting torch. Normally, the end of the cutting torch is placed in close proximity to the face of the anchor and within the pocket. Heat is applied directly to the tendon so as to sever the tension from that portion received within the anchor. Unfortunately, the cutting of the tension with a torch at the point near the tensioning wedges can cause the tendon and wedges to become heated and can result in the loss of temper of the metal or loosening of the post-tension wedges. Alternatively, the torch is not brought into close enough proximity to the anchor such that an improper cutting of the tension occurs. In other words, the tension may be cut so that an end of the tendon extends outwardly of the pocket and outwardly of the concrete body. No techniques have been used in the past for placing such a torch in close proximity to the anchor body within the pocket without causing the torch to adversely affect the post- tensioning wedges or the integrity of the anchor.
Another technique used for the cutting of the tendon is a conventional electric saw. However, this requires that a portion of the slab or other concrete structure surrounding the anchor also be cut in order to reach the portion of the tendon which is within the pocket formed in the concrete adjacent to the anchor.
Importantly, U.S. Pat. No. 5,436,425,issued on Jul. 25, 1995 to the present inventor described a system whereby the tendon could be properly cut by using a plasma cutting torch. This method and apparatus utilized a positioning element for interconnecting the head of a plasma cutting torch with the tendon to be severed. A positioning element conforms in shape to the pocket in the concrete body adjacent to the anchor. As such, the positioning element can be placed over the tendon and pushed into the pocket prior to activating the plasma cutting torch for the purposes of severing the tendon. The plasma cutting torch utilizes an air compressor, an electrical power source and electrodes to generate a stream of air, nitrogen or other gaseous plasma at very high temperatures of about 3000xc2x0 C.-5000xc2x0 C. or more. The stream of superheated gaseous plasma cuts through the metal more quickly than in an acetylene torch. The positioning element included a combination clamp and shield member which is releasably engagable with the tendon. The clamp included an attachment means or bracket which is engagable with the cutting head of the plasma torch. The attachment bracket is appropriately sized so as to be friction fitted around the cutting head or could be permanently attached to the cutting head. The positioning element is attached to a bracket and is releasably engagable with the tendon to be cut for positioning the cutting tip a predetermined distance from the longitudinal axis of the tendon. The positioning element includes a pair of depending jaws pivotally attached to a mounting bracket and biased towards a closed position by a spring. Each of the jaws has a semi-circular relieved portion at its inner edge which, when together, provides a circular opening through which the tendon may be received. Once the tendon is received in the center opening, the jaws close upon it.
Unfortunately, in this prior art patented device, it was found that typical construction environments do not utilize plasma cutting torches. These plasma cutting torches are very expensive and are typically not operated in a proper manner by the construction workers. As such, strong resistance to the use of such a plasma cutting torch has occurred. Conventionally, construction workers continue to utilize acetylene torches for the severing of the tendon.
Another problem associated with the use of torches for the cutting of tendons associated with plastic-encapsulated anchors used in a post-tension anchor system is that the cutting torch can impart heat to the tendon to such a sufficient degree as to cause a melting of the encapsulation. Since it is important to maintain the post-tension anchor system in an encapsulated condition, all of the plastic components of such an encapsulated system must be properly maintained. If, for example, the cap-receiving portion of the encapsulated anchor should become deformed or melted by heat, it would be impossible to attach the necessary cap or sealing devices so as to assure that the post-tension system is properly sealed. As such, it is important to be able to avoid the melting of the plastic encapsulations.
In an effort to overcome problems associated with U.S. Pat. No. 5,436,425, the present inventor made an improvement in the cutting torch, as shown by U.S. Pat. No. 6,040,546, issued on Mar. 21, 2000. In this device, the cutting torch apparatus included a first shield having an opening formed therein and adapted to allow the tendon to pass therethrough, a tubular extension extending outwardly of the first shield at the opening, and a bracket member affixed to the first shield and adapted to attach to the cutting torch such that the cutting torch resides on a side of the first shield. A second shield is connected to the bracket member. The second shield has an opening adapted to allow the tendon to extend therethrough. The second shield is arranged in spaced parallel relationship to the first shield. The cutting torch has a nozzle which is interposed between the first shield and the second shield. This device was particularly effective in avoiding the igniting of grease associated with the encapsulated tendon. It further resisted the migration of any flame across the tendon toward the plastic encapsulation. The device also effectively prevented sparks from flying from the pocket.
Unfortunately, with both U.S. Pat. Nos. 5,436,425 and 6,040,546, the shields created a problem in the actual work place environment. After repeated use, the shields would become damaged or deteriorate. The deformation of such shields would prevent the device from operating effectively during the cutting of the tendon. The use of such shielding techniques was often complicated by the fact that the workmen at the construction site would not fully comprehend the proper use of such shielding mechanisms. As such, a need developed so as to simplify the technique of properly spacing the cutting torch from the encapsulation of the anchor and from the wedges of the anchor.
In certain other circumstances, the size of the pockets used with these prior art patents was too large for certain construction purposes. As such, a need developed so as to minimize the size of the pocket required for the effective cutting of the tendon. In all circumstances, the manner of creating a proper tendon-cutting method would require that the method be very simple, easy to use and easy to implement.
It is an object of the present invention to provide a method and apparatus for severing the free end of a post-tension tendon at a point near the tensioning wedges and within the depth of the pocket formed for the anchor member.
It is another object of the present invention to provide such a method and apparatus in which the tendon is cut without substantially heating the tendon and tensioning wedges.
It is still a further object of the present invention to provide a method and apparatus in which the tendon can be cut at the desired location without damaging the post-tensioned concrete body.
It is a further object of the present invention to provide a method and apparatus in which the tendon can be cut by using a conventional acetylene torch.
It is a further object of the present invention to provide such a method and apparatus which is easy to use, relatively inexpensive, easy to implement and simple to manufacture.
These and other objects and advantages of the present invention will become apparent from a reading of the attached specification and appended claims.
The present invention is a cutting torch for use in severing tendons used in post-tension construction. This cutting torch comprises a handle, a head connected to the handle and a nozzle connected to an end of the head. The head of the cutting torch has a pivot formed thereon. The pivot is adapted for engagement with a corresponding pivot point formed within the pocket of the concrete slab.
The cutting torch has the head and the nozzle extending transverse to a longitudinal axis of the handle. The pivot is aligned with the longitudinal axis of the handle. In one embodiment of the present invention, the pivot comprises a protrusion extending outwardly of an exterior surface of the head. This protrusion is adapted to pivotally engage an indentation formed in the concrete slab. Alternatively, the pivot can comprise an indentation extending inwardly of an exterior surface of the head. The indentation is adapted to pivotally engage a protrusion formed in the concrete slab.
The present invention is also a post-tension construction apparatus comprising a concrete slab, an anchor embedded in the concrete slab, a tendon fixedly received by and extending through the anchor and a pocket formed in the concrete slab and extending outwardly from one end of the anchor. The tendon has a portion extending through the pocket. The pocket has a wall extending outwardly from the end of the anchor. This wall has a pivot point formed thereon.
In this post-tension construction apparatus, a cutting torch is removably received within the pocket. The cutting torch has a pivot formed thereon. This pivot is pivotally engagable with the pivot point of the pocket. The cutting torch has a cutting nozzle positioned adjacent to the tendon when the pivot engages the pivot point. The pocket has a space around the tendon suitable for allowing the cutting nozzle to pivot angularly therein such that the cutting nozzle directs a flame across a diameter of the tendon in the pocket. The pivot point can either be a protrusion or an indentation. The pivot can either be a protrusion or an indentation matingly engageable with the shape and size of the pivot point.
The present invention is also a method of cutting a tendon extending outwardly from an end of an anchor embedded in a concrete slab comprising the steps of: (1) forming a pocket in the concrete slab adjacent to an end of the anchor; (2) forming a pivot point in a wall of the pocket extending outwardly from the end of the anchor; (3) forming a pivot on a head of a cutting torch so as to have a size and shape matable with the pivot point, (4) inserting the cutting torch into the pocket such that the pivot engages with the pivot point; (5) directing a cutting nozzle of the cutting torch toward the tendon; and (6) pivoting the cutting nozzle within the pocket such that the tendon is severed by cutting energy from the cutting nozzle.
In this method, the cutting torch can be removed from the pocket when the tendon is severed. The step of forming the pivot point include either forming a protrusion or an indentation on the wall of the pocket. Similarly, the step of forming a pivot comprises forming an indentation or a protrusion on the head of the cutting torch. In the present method, the step of forming a pocket includes the steps of (1) securing the end of the anchor against one end of a pocketformer; (2) affixing an opposite end of the pocketformer against a form board; (3) solidifying concrete over and around the pocketformer and the anchor, and (4) removing the pocketformer from the end of the anchor after the concrete solidifies.

Apparatus and method for severing a tendon used in post-tension construction


A device for processing an audio signal, wherein the device comprises a detection unit adapted for detecting a widening state of the audio signal, and a widening modification unit adapted for modifying a widening characteristic of the audio signal depending on the detected widening state of the audio signal.

Audio playback devices become more and more important. Particularly, audio systems comprising audio manipulating features become more and more important.
U.S. Pat. No. 5,742,687 discloses a signal combining circuit having a first input and a second input for receiving signals which have frequencies in the audio frequency spectrum, and an output. A first signal path between the first input and the output has a first transfer characteristic. A second signal path between the second input and the output has a second transfer characteristic. The transfer characteristics are different which causes a phase shift to occur between signal components passed through the first signal path and signal components passed through the second signal path. The amplitude transfer determined by the transfer characteristics decreases above a predetermined frequency. There is a phase difference between phase transfer characteristics which decreases with frequency. For frequencies below the predetermined frequency the amplitude transfer determined by the first transfer characteristic exceeds that determined by the second transfer characteristic. By interconnecting the first input and the second input, the amplitude transfer between the interconnected inputs and the output as a function of frequency is substantially constant. The signal combining circuit is used in a stereophonic audio reproduction system to enhance the stereo image. The stereophonic audio reproduction system can form part of an audio-visual reproduction system.
However, it may happen with conventional audio playback systems that the audio playback quality is not satisfactory.

Device for and a method of processing an audio signal


Diphosphine of formula IR1R2P—H2C—Ar—CH2PR1R2  (I)are prepared by a process that comprises a) reacting a dimethyl compound of formula IIH3C—Ar—CH3  (II)with a base and an N-substituted aminophosphorous halide to form bis(aminophosphinomethyl) compound of the formula IIIR3R4P—H2C—Ar—CH2—PR3R4  (III)b) reacting the compound of formula III with HCl to form bis(dichlorophosphinomethyl) compound of formula IVCl2P—H2C—Ar—CH2—PCl2  (IV)and c) reacting the compound of formula IV with an organometallic reagent to give the product compound of formula I, wherein groups R1 and R2 are each, independently of one another, a substituted or unsubstituted aromatic, heteroaromatic or aliphatic hydrocarbon group and may have a covalent bond connecting them and Ar is a substituted or unsubstituted aromatic or heteroaromatic hydrocarbon group an R3 and R4 are each, independently of one another, an N-substituted alkylamino or arylamino group.

1. Field of the Invention
The present invention relates to an improved process for preparing diphosphines such as bis(diarylphosphinomethyl)arenes.
2. Description of the Background
Phosphines have many applications in industry. They have industrial importance as antioxidants, metal extractants, flame retardant impregnants, stabilizers for olefins, starting materials for Wittig reagents and, in particular, as ligands for transition metal catalysts.
A review of the important homogeneous catalysts containing phosphine ligands may be found, for example, in B. Cornils, W. A. Herrmann, Applied Homogeneous Catalysis with Organometallic Compounds Vol. 1 & 2, VCH, Weinheim, 1996. Within the group of phosphines, chelating phosphines, in particular diphosphines, are of particular importance as ligands for metal complexes. This is due to the fact that diphosphines form more stable complexes with the appropriate central metal atom and therefore have a more lasting influence on its catalytic properties. Among the known chelating diphosphines, bis(diarylphosphinoalkyl)-1,1′-binaphthyls as constituents of carbonylation catalysts and telomerization catalysts are of industrial interest. EP 0 653 432, EP 0 673 944 and JP 7939059 describe the preparation of bis(diarylphosphinoalkyl)-1,1′-binaphthyls by reaction of 2,2′-dimethylbinaphthyls with a brominating agent to form 2,2′-bis(bromomethyl)-1,1′-binaphthyl, subsequent reaction with an alkyl diphenylphosphinite and subsequent reduction of the bisphosphine oxide formed by means of an organodichlorosilane. This process has a number of fundamental disadvantages: to introduce the phosphorus groups into the target molecules, the latter firstly have to be brominated, and the bromine atoms are then replaced by phosphorus groups. This requires the use of expensive and toxic bromination reagents and results in the formation of superstoichiometric amounts of bromide waste. The bromination of the starting compounds generally leads to product mixtures whose handling is problematical since the arylalkyl bromides formed are lacrymatory substances which are hazardous to health. In addition, the reaction with alkyl diphenylphosphinites leads to the phosphine oxide which has to be reduced in a further step. Starting out from 2,2′-dimethylbinaphthyls, 4 steps are thus necessary to obtain the desired ligands.
Similar syntheses or partial syntheses having the same and sometimes further disadvantages are also described in the literature (M. E. Jung et al., Tetrahedron Lett. 1988, 29, 6199; H. J. Bestmann et al., Chem. Ber. 1974, 2926; T. Hayashi et al., J. Am. Chem. Soc. 1988, 110, 8153).
In EP 0 704 449, unsymmetrically substituted bis(diarylphosphinoalkyl)-1,1′-binaphthyls are prepared from 2,2′-bis(bromomethyl)-1,1′-binaphthyl via corresponding phosphonium salts. This process has the abovementioned disadvantages and is not advantageous for the preparation of symmetrical bis(diarylphosphinoalkyl)-1,1′-binaphthyls since the phosphorus groups have to be introduced into the target molecule in two steps and large amounts of salt waste are formed.

Method for producing diphosphines and the use thereof


The present invention is a computerized medical diagnostic method. It includes a first database containing a correlation of a plurality of diseases with a plurality of indicators associated with each such disease. A second database includes human experience test results associated with each indicator. An individual's test results are then compared with the second database data to determine presence levels for each indicator. Thereafter the presence levels are compared with the data in the first database to provide a pattern matching determination of diseases associated with the various indicator presence levels.. The presence level indicators for an individual may be affected by many environmental and/or personal factors such as age, sex, race, pregnancy, residence location, previous or current diseases, previous or current drug usage, etc., all of which are factors to be considered in creating an accurate analysis system. The present invention provides a method for correlating such factors with the various test indicators to identify therapeutic and/or contraindicated treatments and drugs.

1. Field of the Invention
The present invention relates generally to automated medical diagnosis systems, and more particularly to such systems which compare patient diagnostic data with predetermined ranges of specific indicators to provide a specific disease diagnosis and suggested or contraindicated treatment strategies.
2. Description of the Prior Art
Medical research in the second half of the 20th century has produced, and continues to produce, an ever increasing body of knowledge. The complexity and interrelationships of various diseases and the indicators that may be detected in various diagnostic tests for the diseases are more than sufficient to tax the capacity of most medical practitioners. To aid medical practitioners in disease diagnosis, computerized expert systems have been, and are being developed to collate medical diagnostic data with various diseases to guide physicians in prescribing treatments for their patients. Such prior art medical diagnostic systems do not adequately provide an analytical framework for analyzing the individual patient's diagnostic results to collate such results into a disease indicator pattern. Furthermore, such systems do not address therapeutic and/or contraindicated treatment strategies.