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The invention relates to a method for the treatment of an oestrogen-dependent proliferative disorder of the uterus such as endometriosis and uterine fibroids in a patient, by administering an aromatase inhibitor to the patient intravaginally. This achieves high local levels of aromatase inhibitor Locally, and therefore avoids some of the adverse reactions that are observed when aromatase inhibitors are delivered orally. Further, intravaginal delivery allows inhibition of the local lesional production without significantly affecting the circulating levels which have been produced by the ovaries. This results in minimal side-effects and will allow for longer term treatment than current therapies. |
1. A method of treating or preventing an oestrogen-dependent proliferative disorder of the uterus in a patient comprising administering to the patient an aromatase inhibitor intravaginally. 2. A method according to claim 1, wherein the oestrogen-dependent proliferative disorder of the uterus is endometriosis. 3. A method according to claim 1, wherein the oestrogen-dependent proliferative disorder of the uterus is uterine fibroids. 4. A method according to claim 1, wherein said aromatase inhibitor compounds is delivered intravaginally using an intra-vaginal delivery device. 5. A method according to claim 1, wherein said aromatase inhibitor compound is administered as part of a pharmaceutical formulation. 6. A method according to claim 5, wherein the pharmaceutical formulation contains a bioadhesive agent and/or absorption enhancer. 7. A method according to claim 1, wherein said aromatase inhibitor is a compound that inhibits the formation of an oestrogen from its precursor by an aromatase enzyme. 8. A method according to claim 7, wherein said aromatase inhibitor is selected from the group consisting of anastrozole; letrozole; exemestrane; vorozole; YM 511 (Yamanouchi Pharmaceutical); YM 553 (Yamanouchi Pharmaceutical); [(4-bromobenzyl)(4-cyanophenyl)amino]azoles and their azine analogs; 4-N-substituted amino-4H-1,2,4-triazole derivatives; 3-[N-(2-cholorbenzyl)amino]-6-(1H-imidazol-1-yl)pyridazine dihydrochloride (CAS 124070-28-3, MFF-279); aminoglutethimide; 4-hydroxy-androstenedione; 4-hydroxy-4-androstene-3,17-dione; 4-acetoxy-4-androstene-3,17-dione; fadrozole hydrochloride (CGS 16949A) (Bonzol; Mitsubishi-Tokyo Pharmaceuticals Inc); formestane; 1-methylandrosta-1,4-diene-3,17-dione; 1-methylandrosta-1,4-diene-3, 17-dione 17a-oxa-D-homooandrosta-1,4-diene-3,17-dione; androsta-4,6-diene-3,17-dione; androsta-4,6-dien-17.beta.-ol-3-one acetate; androsta-1,4,6-triene-3,17-dione; 4-androstene-19-chloro-3,17-dione; 4-androstene-3,6,17-trione; compounds described in “Endocrinology” (1973), vol. 92(3): 874; the 19-alkynylated steroids disclosed in German patent application 3,124,780; the 10-(1,2-propadienyl) steroids described in German patent application 3,124,719; the 19-thioandrostane derivatives described in EP-A-0,100,566; 4-androsten-4-ol-3,17-dione and its esters; the 1-methyl-15.alpha.-alkyl-androsta-1,4-diene-3,17-diones described in German patent application 3,539,244; the 10.beta.-alkynyl-4,9(11)-estradiene derivatives described in German patent application 3,644,358; 1,2.beta.-methylene-6-methylene-4-androstene-3,17-dione; or mixtures of any of these aromatase inhibitor compounds. 9. A method according to claim 1, wherein the amount of aromatase inhibitor that is administered in one dose is between 100 μg and 1g, preferably between 100 μg and 10 mg. 10. A method according to claim 9, wherein the frequency of dosage is either daily, weekly, monthly, or quarterly (three monthly). 11. A pharmaceutical formulation comprising an aromatase inhibitor compound as recited in claim 1, for use in the treatment of an oestrogen-dependent proliferative disorder of the uterus by intravaginal administration. 12. (canceled) 13. An intra-vaginal device comprising an aromatase inhibitor compound in a therapeutically-effective amount. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the invention, there is provided a method of treating or preventing an oestrogen-dependent proliferative disorder of the uterus in a patient, by administering an aromatase inhibitor to the patient intravaginally. The inventors have discovered that the vagina provides an excellent route for the administration of an aromatase inhibitor to treat or prevent the incidence of oestrogen-dependent proliferative disorders of the uterus such as endometriosis and uterine fibroids. It has been found, through biopsy of endometrial lesions and uterine fibroids, followed by the specific amplification of nucleic acids that encode aromatase by performing quantitative PCR (QPCR), that significantly elevated levels of aromatase are expressed in endometrial lesions and fibroids. Aromatase activity is barely detectable in normal (eutopic) endometrium and myometrium. This inappropriate aromatase activity gives rise to local biosynthesis of oestrogen. Upregulation of VEGF results from increased oestrogen. This favours the accumulation of oestrogen and VEGF in endometriotic tissues, which may contribute to the establishment and growth of vasculature of the lesions through oestrogen-induced VEGF production. Additionally, oestrogen-dependent induction of cyclooxygenase gives rise to elevated concentration of prostaglandin E 2 (PGE 2 ). PGE 2 has been shown to be a potent stimulator of aromatase expression in endometriotic stromal cells (Noble, L. S. et al. 1997 J. Clin. Endocrinol. Metab. 82 No. 2 600-606). Thus, a positive feedback loop is formed and this favours continuous production of oestrogen in the endometriotic tissues. Aromatase inhibitors are considered to break this cycle by blocking local production of oestrogen in endometriosis. However, these inhibitors also decrease or block oestrogen formation in other tissues, such as the ovary and subcutaneous fat. The increased levels of PGE 2 may be responsible for some of the symptoms of endometriosis, such as pain. Inhibition of oestrogen production with an aromatase inhibitor has been noted by Bulun et al to result in a reduction in the size of an endometrial lesion in one patient (Takayama, K. et al 1998 Fertil. Steril. 69 No. 4 709-713). Intrinsic molecular aberrations in pelvic endometriotic implants have been previously proposed to contribute significantly to development of endometriosis. For example, aberrant expression of aromatase, certain cytokines and tissue metalloproteinases, deficiency of 17β-hydroxysteroid dehydrogenase (17β-HSD) type 2 and resistance to the protective action of progesterone are some of these molecular abnormalities (see Khorram et al., 1993, American Journal of Obstetrics and Gynecology, 169: 1545-1549; Sharpe-Timms et al., 1995, Journal of Clinical Endocrinology and Metabolism, 80: 3784-3787; Noble et al., 1996, Journal of Clinical Endocrinology and Metabolism, 81: 174-179; Osteen et al., 1996, Seminars in Reproductive Endocrinology, 15: 301-308; Bruner et al., 1997, Journal of Clinical Investigation, 99: 2851-2857; Zeitoun et al., 1998, Journal of Clinical Endocrinology and Metabolism, 83: 4474-4480; and Zeitoun et al., 1999, Molecular Endocrinology, 13: 239-253). A number of studies have demonstrated that oestrogen is produced in endometriotic implants in the pelvis and at other sites through the expression of the aromatase enzyme, (see Takayama and Bulun, 2001, Nippon Rinsho; 59 Suppl 1:157-60; Kudoh et al., 1997, J Steroid Biochem Mol Biol; 63(1-3); 75-80; Bulun et al., 2000, Hum Reprod Update; 6(5): 413-8; Kitawaki et al., 2000, J Clin Endocrinol Metab; 85(9): 3292-6; Bulun et al., 2000, J Mol Endocrinol; 25(1):3542; Bulun et al., 1999, Endocr Relat Cancer; 6(2): 293-301; Bulun et al., 2000, Trends Endocrinol Metab; 11(1): 22-7; Zeitoun et al., 1999, Fertil Steril; 72(6): 961-9; Zeitoun et al., 1999, Mol Endocrinol; 13(2): 239-53; Takayama et al., 1998 Fertil Steril; 69(4): 709-13; and Bulun et al., 1997, J Steroid Biochem Mol Biol; 61(3-6): 133-9). Prostaglandins in endometriotic cells have been proposed to stimulate aromatase activity to increase oestrogen biosynthesis. In turn, oestrogen stimulates prostaglandin formation and the growth of endometriotic implants. It is also known that endometrial lesions are oestrogen-dependent. During the earlier stages of the development of the lesions, the oestrogen is supplied by the systemic circulation and the source of the hormone is predominantly the ovaries; a small and variable amount of oestrogen may be produced by adipose tissue. Growth of lesions is thought to relatively slow during the early stages but later a number of cellular and molecular changes have been documented. Of particular significance is the local lesional production of oestrogen. This occurs when the mesenchymal elements of endometrial lesions begin the aberrant synthesis of certain enzymes. The local production of oestrogen stimulates growth of glandular tissue and also promotes synthesis of pain-mediators, especially the prostaglandins. With time, the local production of oestrogen becomes more significant than ovarian-synthesized circulating hormone. It is well established that reduction in ovarian production of oestrogen ameliorates the symptoms of endometriosis. However the current methods for achieving this involve very significant ovarian suppression to circulating levels where a number of oestrogen-dependent organs become compromised. For example, bone mineral density is critically dependent on adequate levels of oestrogen. For this and other reasons, treatment with agents such as the gonadotrophin-releasing hormone agonists can only be used for six months. The inventors have now recognized that a significant proportion of existing endometrial lesions may be targeted by the transvaginal delivery of an aromatase inhibitor. This achieves high local levels of aromatase inhibitor locally, and therefore avoids some of the adverse reactions that are observed when aromatase inhibitors are delivered orally. By transvaginal delivery is meant the movement of aromatase inhibitor molecules from the vaginal cavity into the surrounding tissues via a simple diffusion process. The invention exploits the highly vascularised nature of the vaginal mucosal tissue (which leads to a copious blood supply) to deliver an aromatase inhibitor composition to localised areas and the underlying tissues that are diseased. Delivery of the aromatase inhibitor through the tissue wall is thus fast and this route of administration facilitates achieving a concentration of drug that is effective to treat or prevent the disorder. A significant effect of the invention is that intravaginal delivery allows inhibition of the local lesional production without significantly affecting the circulating levels which have been produced by the ovaries. This results in minimal side-effects and will allow for longer term treatment than current therapies. The lowering of the locally high levels of oestrogen will reduce growth of lesions and also lower the rates of production of inflammatory mediators which lead to the major symptom of pain. The vasculature of the female reproductive tract consists of a number of vascular plexuses of different origin, and there are anastomoses between a number of the key vessels including the vaginal, ovarian and uterine arteries as well as between the uterine and deep perineal branches of the pudendal artery. For example, the arterial supply to the vagina is from the vaginal branch of the uterine artery, occasional vaginal branches of the internal iliac arteries, possible twigs from the middle rectal arteries, and branches from the internal pudendal arteries. These vaginal arteries course along the lateral vaginal walls, along the walls of the uterus, and anastomose with the ovarian artery. The ascending branches of the uterine artery lead to the tubal arterial branch and anastomoses with the ovarian artery. Venous return from the vaginal venous plexus drains into the internal iliac vein, and the uterine venous return is along uterine veins, which generally parallel the arterial supply. Lymphatic drainage of the vagina drains into the external and internal iliac nodes, as well as into the superficial inguinal nodes. Lymphatic drainage of the uterus parallels the uterine blood supply. The absorption of drugs through the vaginal mucosa and into the systemic vasculature is known, and it has been observed by others that a “uterine first pass effect” occurs whereby, for example, the ovarian and uterine tissue levels of some drugs given vaginally are higher than would be expected from oral administration of the same doses. The exact mechanism of this “first uterine pass” effect is not yet fully understood. Four hypotheses can be put forth to explain the uterine first pass effect: (1) transvaginally administered drugs may transit to the uterus and other local tissues through the local circulatory system; (2) there may be direct diffusion of drug into the uterus and other local tissues; (3) drugs may reach the uterus through the lymphatics; or (4) a “counter-current” redistribution of drug may occur between arteries and veins. By an “oestrogen-dependent proliferative disorder of the uterus” is meant any oestrogen-dependent non-malignant disorder that occurs in females that stems from uterine tissue. Particular examples of oestrogen-dependent proliferative disorders of the uterus that are included within the terms of the invention are endometriosis and uterine fibroids. Humans are preferred patients for treatment, although non-human mammals, such as domesticated and companion animals, may also be treated. Endometriosis is the name given for the occurrence of endometrium tissue, found at ectopic sites in the body. Endometriotic lesions may be determined histologically using markers or by looking for endometrial glands and stromal elements in tissue at ectopic sites. Although this tissue type may be in any anatomical location, it is generally to be found in the region of the ovary, peritoneum, or recto-vagina and it is endometriotic lesions in these locations that may be particularly beneficially treated according to the method of the present invention. Uterine fibroids, or uterine leiomyomas are a second oestrogen-dependent proliferative disorder of the uterus, marked by the presence of one or more benign tumours found consisting of connective tissue and muscle found on the uterine wall. Fibroids may lie just below the uterine lining or near the uterus' outer covering, whilst others are located near the cervix, or close to the openings of the fallopian tubes. They are usually detected on abdominal and pelvic examination as well as on internal examination, which may reveal the uterus to be enlarged and/or detect the fibroid as a smooth, firm lump. Ultrasound is the most useful test for diagnosing fibroids as these tumours have a characteristic appearance that distinguishes them from pelvic cysts. According to the invention, an aromatase inhibitor should be delivered intravaginally. By “intravaginally” is meant that an aromatase inhibitor is administered via the vagina, such that the inhibitor crosses the vaginal mucosa to enter the blood and/or lymphatic system by way of local absorption though the highly vascularised tissue in this area. Vaginal administration of an aromatase inhibitor for the treatment of endometriosis and fibroids is anticipated to lead to both improved efficacy, and to a reduced adverse effects profile compared to oral therapy. Of great significance is the fact that an effective concentration of aromatase inhibitor may effectively be delivered to the diseased tissue itself, i.e. the endometrial lesion or uterine fibroid, both of which disorders generally present in tissues or organs that are close to the vagina, such as in the vaginal tissues, uterus, ovaries and fallopian tubes, rectovaginal region and cul-de-sac and other tissues and organs within the peritoneal cavity. In addition, such levels of aromatase inhibitor are expected to affect newly-shed endometrial cells travelling up the fallopian tubes and into the peritoneum, reducing their rate of growth and the probability of implantation. The oral delivery of a drug such as an aromatase inhibitor may involve the destruction of the aromatase inhibitor by local conditions such as those that are encountered in the stomach. First-pass metabolism by the liver is also a problem suffered by the oral delivery route. Furthermore, in order to achieve a concentration of aromatase inhibitor that is effective at the diseased tissue, a large dose must be administered that then leads to high systemic levels of inhibitor compound. The oral use of aromatases to treat metastatic breast cancer has been associated with a variety of adverse events including hot flushes, dizziness, oedema, sweating, nausea, vomiting, chest or back pain, fatigue, headache, insomnia, dyspnoea, asthenia, emotional lability, and depression. By administering the aromatase inhibitor via the vaginal route, a much lower concentration of inhibitor compound needs to be used than would be necessary if the inhibitor were to be administered parenterally, for example, by the oral route. The method of the invention yields significant local levels of aromatase inhibitor while maintaining circulating blood levels that are low enough to avoid most undesired side effects. This means that susceptible tissues will be exposed to a much lower concentration of inhibitor, whilst diseased areas will be exposed to a much higher concentration of inhibitor than would be achieved using any other method of administration. The oral route is also not suitable for certain types of drug compound—in order to be effectively absorbed into the blood, an orally-delivered drug compound must be orally-active, which means that it is either passively transported or actively transported. Only a small proportion of drug molecules fulfil all these criteria, which thus limits the number of drug compounds that might be used to treat an oestrogen-dependent proliferative disorder of the uterus. The oral route is also precluded when vomiting has occurred, or is likely to occur, or when the patient is unable to swallow successfully. Intra-vaginal devices are known that are suitable for the delivery of aromatase inhibitors intravaginally, according to the method of the invention. Suitable devices include those of the type where a medicament is impregnated into the device, and of the type that carries an encapsulated medicament. Movement of pharmaceutical molecules from the vaginal cavity into the surrounding tissues will generally occur via a simple diffusion process. Net diffusion may be given by the equation: in-line-formulae description="In-line Formulae" end="lead"? Net diffusion= k.D .( C vag −C tiss ); in-line-formulae description="In-line Formulae" end="tail"? where k is a constant, D is the diffusion constant for the molecule, C vag is the molecular concentration in the vagina at the surface of the mucosa and C tiss is the molecular concentration in the tissue surrounding the vagina. In order to achieve maximum rates of uptake of pharmaceuticals from the vaginal cavity across the vaginal mucosa and into the surrounding tissues and body fluids, C vag should be maintained at as high a level as possible. Examples of devices suitable for the intravaginal delivery of an aromatase inhibitor include those described in U.S. Pat. No. 4,309,997, U.S. Pat. No. 4,318,405, U.S. Pat. No. 5,273,521, U.S. Pat. No. 5,299,581, GB 1,581,474, U.S. Pat. No. 5,954,688, U.S. Pat. No. 4,402,693, U.S. Pat. No. 3,948,265, U.S. Pat. No. 6,086,909, U.S. Pat. No. 3,545,439, U.S. Pat. No. 3,902,493, U.S. Pat. No. 2,739,593, U.S. Pat. No. 3,521,637, U.S. Pat. No. 3,884,233, U.S. Pat. No. 4,286,596, U.S. Pat. No. 6,197,327, U.S. Pat. No. 5,527,534, EP-A-0,703,802, GB 2,069,336, U.S. Pat. No. 4,601,714, U.S. Pat. No. 5,299,581, U.S. Pat. No. 6,159,174, WO99/18884, WO99/40966, W000/48539 and co-owned, co-pending International patent application PCT/GB01/01789. Other examples of suitable devices will be clear to those of skill in the art. The aromatase inhibitor may also be administered intravaginally as a bioadhesive formulation, for example, in the form of a gel, cream, tablet, pill, capsule, suppository, film, or any other pharmaceutically acceptable form that remains in the vaginal cavity and does not wash away easily. If applied as a bioadhesive formulation, the formulation should remain attached to the epithelial surfaces of the vaginal mucosa for a significant period, at the minimum, for example, between about 30 minutes to twenty-four hours. This preferred level of bioadhesion may advantageously be attained by the inclusion of a bioadhesive agent in the pharmaceutical formulation, such as a cross-linking agent, so that an appropriate level of bioadhesion results. Suitable formulations are described, for example, in U.S. Pat. No. 4,615,697. Suitable aromatase inhibitors for use in the methods of the present invention include any compound that inhibits the formation of oestrogens from their precursors by an aromatase enzyme. Such compounds can be used either alone or in combination with other aromatase inhibitor compounds. Certain classes of suitable aromatase inhibitors include non-steroidal, weak steroid and steroidal aromatase inhibitors. Examples of aromatase inhibitors that are suitable for use in the present invention include anastrozole (Armimidex); letrozole; exemestane; vorozole; YM 511 (Yamanouchi Pharmaceutical); YM 553 (Yamanouchi Pharmaceutical); [(4-bromobenzyl)(4-cyanophenyl)amino]azoles and their azine analogs; 4-N-substituted amino-4H-1,2,4-triazole derivatives; 3-[N-(2-chlorobenzyl)amino]-6-(1H-imidazol-1-yl)pyridazine dihydrochloride (CAS 124070-28-3, MFI-279); aminoglutethimide; 4-hydroxy-androstenedione; 4-hydroxy-4 -androstene-3,17-dione; 4-acetoxy-4-androstene-3,17-dione; fadrozole hydrochloride (CGS 16949A) (Bonzol; Mitsubishi-Tokyo Pharmaceuticals Inc); formestane; 1-methylandrosta-1,4-diene-3,17-dione; 1-methylandrosta-1,4-diene-3,17-dione (described in German patent application 3,322,285); testolactone (17a-oxa-D-homoandrosta-0,1,4-diene-3,17-dione) (described in “Journal of Clinical Endocrinology and Metabolism”, (1979) 49: 672); androsta-4,6-diene-3,17-dione; androsta-4,6-dien-17.beta.-ol-3-one acetate; androsta-1,4,6-triene-3,17-dione; 4-androstene-19-chloro-3,17-dione; 4-androstene-3,6,17-trione; compounds described in “Endocrinology” (1973), vol. 92(3): 874; the 19-alkynylated steroids disclosed in German patent application 3,124,780; the 10-(1,2-propadienyl) steroids described in German patent application 3,124,719; the 19-thioandrostane derivatives described in EP-A-0,100,566; 4-androsten4-ol-3,17-dione (described in “Endocrinology” 1977, 100(6): 1684 and in U.S. Pat. No. 4,235,893), and its esters; the 1-methyl-15.alpha.-alkyl-androsta-1,4-diene-3,17-diones described in German patent application 3,539,244; the 10.beta.-alkynyl-4,9(11)-estradiene derivatives described in German patent application 3,644,358; 1,2.beta.-methylene-6-methylene-4-androstene-3,17-dione (described in EP-A-0 250 262); or mixtures of any of these aromatase inhibitor compounds. A number of references detail the effect of aromatase inhibitors such as those listed above in inhibiting oestrogen production, including the following: Kudoh et al., 1997, J Steroid Biochem Mol Biol, 63(1-3): 75-80; Okada et al., 1997, Chem Pharm Bull (Tokyo), 45(8): 1293-9; Okada et al., 1997, Chem Pharm Bull (Tokyo), 45(3): 482-6; Okada et al., 1996, Chem Pharm Bull (Tokyo), 44(10):1871-9; Kudoh et al., 1996, J Steroid Biochem Mol Biol, 58(2): 189-94; Kudoh et al., 1995, J Steroid Biochem Mol Biol, 54(5-6): 265-71. The dosage of the aromatase inhibitor that is administered should be therapeutically-effective, i.e. a dosage amount that is necessary to treat, ameliorate, or prevent the oestrogen-dependent proliferative disorder of the uterus, or to exhibit a detectable therapeutic or preventative effect. This dosage will vary depending on various factors such as the potency of the inhibitor compound, its toxicity in the treated patient, the general health, age and weight of the patient, the hormonal levels of the patient, the patient's diet, the time and frequency of administration, drug combination(s), reaction sensitivities, tolerance/response to therapy, the stage of the disease, the degree of spread of diseased tissue, the lifetime of the inhibitor compound in its active state, the solubility of the compound, its absorption characteristics across the vaginal mucosa, the eventual tissue concentration to be attained and so on. [This dosage amount can be determined by routine experimentation and is within the judgement of the clinician.] For any aromatase inhibitor compound, a therapeutically effective dosage can be estimated initially either in cell culture assays, for example, endometrial or smooth muscle cells from fibroids of neoplastic cells, or in animal models, usually mice, rabbits, dogs, or pigs, primates such as baboons, macaques, and so on. The animal model may also be used to determine the appropriate concentration range for administration. Such information can then be used to determine useful dosages for humans. Generally, the amount administered in one dose will be between 100 μg and 1 g, preferably between 100 μg and 10 mg of an aromatase inhibitor such as 1-methylandrosta-1,4-diene-3,17-dione, or a biologically-equivalent dose of any other aromatase inhibitor as listed above. The amount selected will depend, of course, on the dosage prescribed, but undesirably high dosages may advantageously be avoided by using intravaginal delivery, as the concentration of inhibitor compound in the vicinity of the vaginal tissue wall is maintained at a high level. The frequency of dosage may also be varied so as to administer an aromatase inhibitor most effectively. Conveniently, the dose may be repeated either daily, weekly, monthly, or quarterly (three monthly). Of course, the actual amount that is administered will be altered to take the dosage frequency into account. In order to be administered intravaginally, the aromatase inhibitor should preferably be administered as part of a pharmaceutical formulation, including a pharmaceutically-acceptable carrier. Such carriers include large, slowly metabolised macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, polyethylene glycol, PDMS, microspheres, hydrogels, and inactive virus particles, provided that the carrier does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. Pharmaceutically acceptable salts can also be used, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulphates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like. A thorough discussion of pharmaceutically acceptable carriers is available in Remington's Pharmaceutical Sciences (Mack Pub. Co., N.J. 1991). Pharmaceutically acceptable carriers in the pharmaceutical formulations of the invention may additionally contain liquids such as water, saline, glycerol and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, lubricants, plasticizing agents, preservatives, gel formers, tablet formers, pill formers, suppository formers, film formers, cream formers, disintegrating agents, coatings, binders, vehicles, colouring agents, taste and/or odour controlling agents, humectants, viscosity controlling agents, pH-adjusting agents, absorption enhancers, and the like, may be present in such compositions. According to a further aspect of the invention, there is provided a pharmaceutical formulation comprising an aromatase inhibitor compound, for use in the treatment of an oestrogen-dependent proliferative disorder of the uterus by intravaginal administration. The invention also provides the use of an aromatase inhibitor compound in the manufacture of a medicament for the treatment of an oestrogen-dependent proliferative disorder of the uterus by intravaginal administration. The invention also provides an intra-vaginal device comprising an aromatase inhibitor compound according to any one of the embodiments of the invention described above, in a therapeutically-effective amount. The inhibitor compound may be coated onto the intra-vaginal device, impregnated or absorbed into the device, or applied to the device by any suitable means that allows the compound to be attached or bonded to the device, yet which allows the compound to be available for absorption into the vaginal mucosa, as will be clear to those of skill in the art. A particular preferred example of a suitable intra-vaginal device is that described in co-pending, co-owned International patent application PCT/GB01/01789. Various aspects and embodiments of the present invention will now be described in more detail by way of example. It will be appreciated that modification of detail may be made without departing from the scope of the invention. |
System for monitoring and controlling access to reservoirs and a cover |
A system for monitoring and controlling access to reservoirs is described, which comprises: (i) a supervision system (10); (ii) at least one energy-distribution and communication system (20); and (iii) at least one cover (30), the energy-distribution and communication system (20) being associable with the supervision system (10) and with the cover (30), and the supervision system (10) being remotely associable with the energy-distribution system (20) Further, a reservoir cover (30) provided with a covering portion (302) and an articulation device (303), the covering (302) being associated with the articulation device (303), the cover (30) comprising an actuation device, a lock element (305) and a lock receiving element (304), the actuation device selectively actuating the lock element (305), which is selectively associated with the lock receiving element (304). |
1. A system for monitoring and controlling access to reservoirs, comprising: (i) a supervision system; (ii) at least one energy-distribution and communication system; and (iii) at least one cover actuated by the supervision system through the energy-distribution and communication system, wherein the supervision system is positioned remotely from the reservoirs, the supervision system comprising a first information-processing circuit associated to at least one energy-distribution and communication system and to at least one cover, the cover comprising a covering portion that comprises an hermetic compartment where a lock element actuated by a step motor and a plurality of monitoring and controlling sensors are mounted. 2. The system according to claim 1, wherein the covering portion comprises an articulation device containing a pin and a sensor, the sensor being axially associated to the pin. 3. The system according to claim 2, wherein the covering portion is bascule moved by means of the articulation device. 4. The system according to claim 1, wherein the cover comprises a second information-processing circuit associated to the step motor and controlling the step motor rotation. 5. The system according to claim 4, wherein the step motor rotation is transformed into the lock element linear movements, said linear movements being locking and unlocking movements. 6. The system according to claim 4, wherein the monitoring and controlling sensors are controlled by the second information-processing circuit, the second information-processing circuit comprising a secondary control system with routines. 7. The system according to claim 6, wherein the cover comprises at least one battery associated to the step motor and a data-storing device associated to the second information-processing circuit. 8. The system according to claim 1, wherein the cover comprises at least one communication interface simultaneously connected to the supervision system and the energy-distribution and communication system. 9. The system according to claim 1, wherein the supervision system comprises a data-input device associated to a view finder and to the energy-distribution and communication system by the first information-processing circuit. 10. The system according to claim 9, wherein the supervision system comprises a main control system associated to the first information-processing circuit, the main control system having routines. 11. The system according to claim 10, wherein the supervision system stores information and data processed by the first information-processing circuit by means of a data-exchange device. 12. The system according to claim 11, wherein the supervision system comprises a communication device associated to the first information-processing circuit, the communication device transmitting data to distinct remote systems. 13. The system according to claim 1, wherein the supervision system comprises a remote console associated to the energy-distribution and communication system. 14. The system according to claim 1, wherein the energy-distribution and communication system comprises at least one battery and a plurality of safety barriers associated to an energy supply. 15. The system according to claim 14, wherein the energy-distribution and communication system is associated to the supervision system by means of at least one serial channel. 16. The system according to claim 15, wherein at least one cover is associated to at least one safety barrier of the energy-distribution and communication system by means of a cable. 17. The system according to claim 16, wherein the safety barrier comprises voltage-limiting diodes and current-limiting resistors. 18. A cover for reservoirs, wherein comprises a covering portion containing an hermetic compartment where a lock element actuated by a step motor and a plurality of monitoring and controlling sensors are mounted to monitor and control the covering portion. 19. The cover according to claim 18, wherein the hermetic compartment is positioned in a base of the covering portion, this hermetic compartments being composed by a first projection perpendicular to the based, the first projection containing a first end fixed to the base and a second end opposite the first end and associated to a plate. 20. The cover according to claim 19, wherein the plated is metallic and comprises a cable connector. 21. The cover according to claim 18, wherein the covering portion comprises an articulation device containing a pin and a sensor, the sensor being axially associated to the pin. 22. The cover according to claim 21, wherein the covering portion is bascule moved by means of the articulation device. 23. The cover according to claim 22, wherein the articulation device is associated to a holding chamber of the reservoirs. 24. The cover according to claim 18, wherein comprises a second information-processing circuit associated to the step motor and controlling the step motor rotation. 25. The cover according to claim 24, wherein that the step motor rotation is transformed into the lock element linear movements, said linear movements being locking and unlocking movements. 26. The cover according to claim 25, wherein by locking of the covering portion the lock element is associated to a lock receiving element disposed closer to the hermetic compartment. 27. The cover according to claim 24, wherein the monitoring and controlling sensors are controlled by the second information-processing circuit, the second information-processing circuit comprising a secondary control system with routines. 28. The cover according to claim 18, wherein the cover comprises at least one battery associated to the step motor and a data-storing device associated to the second information-processing circuit. |
<SOH> BRIEF DESCRIPTION OF THE INVENTION <EOH>The invention has the objective of providing a system for monitoring and controlling access to reservoirs, which comprises: (i) a supervision system; (ii) at least one energy-distribution and communication system; and (iii) at least one cover, the enemy distribution system being associable with the supervision system and with the cover, and the supervision system being remotely associable with the energy-distribution and communication system. A further objective of this invention is to provide a reservoir cover provided with a covering portion and an articulation device, the covering being associated with the articulation device and comprising an actuation device, a locking element and a lock-receiving element, the actuation device selectively actuating the locking element, which selectively is associated with the lock-receiving element. |
Chemokine receptor antagonists and methods of use thereof |
Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by: formula (1) or physiologically acceptable salt thereof. |
1. A compound having the formula: or physiologically acceptable salt thereof, wherein: n is one to four; M is >NR2 or >CR1R2; R1 is —H, —OH, —N3, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR3R4, —NR3R4 or R1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R2 is —OH, a halogen, an acyl group, a substituted acyl group, —NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group), —O-(substituted or unsubstituted aliphatic group), —C(O)-(substituted or unsubstituted aromatic group) or —C(O)-substituted or substituted aliphatic group); R3, R4, R5 and R6 are independently —H, au acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring; R70 and R71 are independently —H, —OH, —N3, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR3R4, —NR3R4, an acyl group, a substituted acyl group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group); R72 and R73 are independently —O, —N3, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —O—C(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR3R4, —NR3R4, an acyl group, a substituted acyl group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group); Z is X1 is —CH2—O, —O—CH2—, —S—, —CH2—, —CH2—CH2—, —CH2—S—, —S—CH2—, —NRc—CH2—, —CH2—NRc—, —SO—CH2—, —CH2—SO—, —S(O)2—CH2—, —CH2—S(O)2, —CH═CH—, —NRc—CO—, a bond, —O—, or —CO—NRc—, Rc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; Rings A and B are independently unsubstituted or substituted; said acyl group is an aliphatic carbonyl aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl; said aliphatic group is a C1-C6 alkenyl or alkynyl; said aromatic group is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinoylinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, benzocyclopentyl, benzocyclohexyl; said non-aromatic heterocyclic group is a five to eight-membered non-aromatic ring which contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; said substituted aliphatic group is substituted with one or more substituents selected form the group consisting of oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR25R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OCt—OC(O)R20, —(O)R20, —(O)y—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q(aryl), -Q(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group); said substituted non-aromatic heterocyclic ring is substituted with one or more substituents selected from the group consisting of ═O, ═S, electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group); said substituted aromatic group, substituted benzyl group, Ring A when substituted and Ring B when substituted, are substituted with one or more substituents selected from the group consisting of electron withdrawing group, aliphatic group, substituted aliphatic group, aromatic group, substituted aromatic group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group); Q is —O—, —S—, —S(O)—, —S(O)—, —OS(O)2—, —C(O)—, —OC(O)—, —C(O)O)—, —S(O)2NH—, —NHS(O)2—, —C(NR23)NHNH—, —NHNHC(NR23)—, —NR24C(O)— or —NR24S(O)2—; R20, R21 and R22 are independently —H, an aliphatic group, an aromatic group, a non-aromatic heterocyclic group, —NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromatic group) or —NHC(O)—O-(non-aromatic heterocyclic group) or R21 and R22, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring; R23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group; R24 and R25 are independently —H, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R24 and R25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring. R 0 is a —H, —OH, —NH2, an aromatic group or a substituted aromatic group. t is zero to three; u is zero or one; p is one to five. 2. The compound of claim 1 wherein Ring A is unsubstituted and B is substituted para to the carbon atom of ring B that is bonded to X1 in ring C, and Z is represented by the structural formula: wherein R40 is —OH, —COOH, —NO2, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR24R25, —CONR24R25, —NR24C(O)-(aliphatic group), —NR24C(O)-(substituted aliphatic group), —NR24S(O)2-(aliphatic group), —NR24S(O)2(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —C(O)-(aliphatic group), —C(O)-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22 or —(O)u—(CH2)t—NHC(O)O—R20; R20, R21 or R22 are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R21 and R22, taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring; R24 and R25 are independently —H, an aliphatic group or a substituted aliphatic group; u is zero on one; and t is an integer from zero to 3. 3. The compound of claim 2 wherein M is >CR1R2; R1 is —H or —OH; and R2 is substituted aromatic group, wherein said substituted aromatic group is 4-halophenyl. 4. The compound of claim 3 wherein said 4-halophenyl is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-fluorophenyl. 5. The compound of claim 4 wherein said 4-halophenyl is 4-chlorophenyl. 6. The compound of claim 3 wherein X1 is —CH2—O—. 7. The compound of claim 2 wherein at least one of R70, R71, R72 and R73 is an aliphatic group or a substituted aliphatic group; wherein said aliphatic group is a C1-C6 alkyl and said substituted aliphatic group is a C1-C6 alkyl substituted with a substitutent selected from the group consisting of —OH, —(O)u—(CH2)t—C(O)OR20 and —O-(aliphatic group); t is zero to three; u is zero or one; and R20 is C1-C6 alkyl. 8. The compound of claim 7 wherein R70 and R71 are both —H; R72 and R73 are independently selected from the group consisting of C1-C6 alkyl and substituted C1-C6 alkyl. 9. The compound of claim 8 wherein R72 is —CH3. 10. A method for treating a disease associated with aberrant leukocyte recruitment, aberrant leukocyte activation or aberrant leukocyte recruitment and activation, comprising administering to a subject in need thereof an effective an effective amount of a compound according to claim 1. 11. A pharmaceutical composition comprising a compound according to claim 1 and a physiologically acceptable carrier. 12. A compound having the formula: or physiologically acceptable salt thereof, wherein: n is one to four; M is >CR1R2; R1 is —OH; R2 is 4-halophenyl; R70 and R71 are —H, and R72 and R73 are —CH3; or R70 and 71 are —CH3, and R72 and R73 are —H; Z is X1 is —CH2—O—, and R40 is selected from the group consisting of: 13. The compound of claim 12 wherein R40 is 14. The compound of claim 12 wherein said 4-halophenyl is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-fluorophenyl. 15. The compound of claim 14 wherein said 4-halophenyl is 4-chlorophenyl. 16. The compound of claim 15 wherein R70 and R71 are —H, R72 and R73 are —CH3 n is two, and the compound has the structure: 17. The compound of claim 16 wherein R40 is 18. A method for treating a disease associated with aberrant leukocyte recruitment, activation or recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of claim 12. 19. A method for treating a disease associated with aberrant leukocyte recruitment, activation or recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of claim 17. 20. A pharmaceutical composition comprising a compound of claim 12 and a physiologically acceptable carrier. 21. A compound having the structure: or a physiologically acceptable salt thereof, wherein R2 is 4-halophenyl; and R40 is selected from the group consisting of: 22. The compound of claim 21 wherein R40 is 23. The compound of claim 21 wherein R2 is selected from the group consisting of 4-chlorophenyl, 4-bromophenyl and 4-fluorophenyl. 24. The compound of claim 23 wherein R2 is 4-chlorophenyl. 25. The compound of claim 22 wherein R2 is 4-chlorophenyl. 26. A pharmaceutical composition comprising the compound of claim 21 and a physiologically acceptable carrier. 27. A method for treating a disease associated with aberrant leukocyte recruitment, aberrant leukocyte activation or aberrant leukocyte recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of claim 21. 28. A method for treating a disease associated with aberrant leukocyte recruitment, aberrant leukocyte activation or aberrant leukocyte recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of claim 25. 29. The method of claim 27 or claim 28 wherein said disease is selected from the group consisting of arthritis, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus, psoriasis, multiple sclerosis, inflammatory bowel diseases, rejection of a transplanted organ or tissue, graft versus host disease, allergy and asthma. 30. The method of claim 29 wherein said disease is multiple sclerosis. 31. The method of claim 29 wherein said disease is arthritis, and said arthritis is rheumatoid arthritis. 32. A compound having the formula: or physiologically acceptable salt thereof, wherein: n is an integer from one to four; M is >NR2, >CR1R2—O— or —CH2—CR1R2—O—; q1 is an integer from zero to three; q2 is zero or one; R1 is —H, —OH, —N3, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —O—C(O)-(substituted aliphatic group), —COOH, —CN, —CO—NR3R4, —NR3R4 or R1 is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R2 is —OH, a halogen, an acyl group, a substituted acyl group, —NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group); R3, R4, R5 and R6 are independently —H, and acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R1 and R2, R3 and R4, or R5 and R6 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring; Z is: X1 is —S—, —CH2—, —CH2—CH2, —CH2—S—, —S—CH2—O—CH2—, —CH2—O—, —NR —CH2—, —CH2—NR —, —SO—CH2—, —CH2—SO—, —S(O)2—CH2—, —CH2—S(O)2—, —CH═CH—, —NRc—CO—, a bond, —O—, or —CO—NRc—, Rc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl said aliphatic group is a C1-C6 alkyl, alkenyl or alkynyl; said aromatic group is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl, N-imidazolyl, 2-imidazoyl, 4-imidazoyl, 5-imidazoyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, benzocyclopentyl, benzocyclohexyl; said non-aromatic heterocyclic group is a five to eight-membered non-aromatic ring which contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; said subtitled aliphatic group is substituted with one or more substituents selected from the group consisting of oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(CH2)p-(substituted group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group); said substituted non-aromatic heterocyclic ring is substituted with one or more substituents selected from the group consisting of ═O, ═S, electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group); said substituted aromatic group and substituted benzyl group are substituted with one or more substituents selected from the group consisting of electron withdrawing group, halo, azido, —CN, —CONR25R25, —NR24R25, —OS(O)2NR25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O))—R20, -Q-H, Q-aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group; Q is —O—, —S—, S(O)—, S(O)2—, —OS(O)2—, —C(O)—, OC(O)—, —C(O)O, —C(O)C(O)—O—, —O—C(O)C(O)—, —NHC(O)—, —NHC(O)—, OC(O)NH—, —NH—C—(O)—NH—, —S(O)2NH—, NHS(O)2—, —C(NR23)NHNH—, —NHNHC(NR23)—, NR24C(O)—or —NR24S(O)2—; R20, R21 and R22 are independently —H, an aliphatic group, an aromatic group, a non-aromatic heterocyclic group, —NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromatic group) or —NHC(O)—O-(non-aromatic heterocyclic group) or R21 and R22, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring; R23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group; R24 and R25 are independently —H, —OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R24 and R25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring; R60 is a —H, —OH, —NH2, an aromatic group or a substituted aromatic group; t is zero to three; u is zero or one; p is one to five; and R40 is selected from the group consisting of 33. The compound of claim 32 wherein: q1 is one; q2 is one; M is >CR1R2; R1 is —H or —OH; and R2 is a substituted aromatic group. 34. The compound of claim 33 wherein R2 is phenyl substituted with a halogen. 35. The compound of claim 34 wherein R2 is 4-chlorophenyl. 36. The compound of claim 35 wherein n is 2, X1 is —CH2—O—, and R1 is —OH. 37. A method of treating a disease associated with aberrant leukocyte recruitment, activation or recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound of claim 32. 38. A pharmaceutical composition comprising a compound of claim 32 and a physiologically acceptable carrier. 39. A compound having the formula: or physiologically acceptable salt thereof, wherein: n is one to four; R2 is —OH, a halogen, an acyl group, a substituted acyl group, —NR5R6, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group); R and R are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R5 and R6 taken together with the atom to which they are bonded, from a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring; Z is: X1 is —S—, —CH2, —CH2—CH2—, —CH2—S—, —S—CH2—, —O—CH2—, CH2—O—, —NRc—CH2—, —CH2—NRc—, —SO—CH2—, CH2—SO—, —S(O)2—CH2—, —CH2—S(O)2—, —CH═CH—, —NRc—CO—, a bond, —O—, or —CO—NR—, Rc is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; Rings A and B are independently unsubstituted or substituted; said acyl group is an aliphatic carbonyl, aromatic carbonyl, aliphatic sulfonyl or aromatic sulfonyl; said aliphatic group is a C1-C6 alkyl, alkenyl or alkynyl; said aromatic group is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl, 2-anthracyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, tetrahydronaphthyl, 2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl, 2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl, 2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinolinyl, 3-quinolinyl, 1-isoindolyl, 3-isoindolyl, acridinyl, 3-benzisoxazolyl, benzocyclopentyl, benzocyclohexyl; said non-aromatic heterocyclic group is a five to eight-membered non-aromatic ring which contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; said substituted aliphatic group is substituted with one or more substituents selected from the group consisting of oxo group, epoxy group, non-aromatic heterocyclic ring, benzyl group, substituted benzyl group, aromatic group or substituted aromatic group electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group); said substituted non-aromatic heterocyclic ring is substituted with one or more substituents selected from the group consisting of ═O, ═S, electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q-(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group); said substituted aromatic group, substituted benzyl group, Ring A when substituted and Ring B when substituted, are substituted with one or more substituents selected from the group consisting of electron withdrawing group, halo, azido, —CN, —CONR24R25, —NR24R25, —OS(O)2NR24R25, —S(O)2NR24R25, —SO3H, guanidino, oxalo, —C(═NR60)NR21R22, ═NR60, —(O)u—(CH2)t—C(O)OR20, —(O)u—(CH2)t—OC(O)R20, —(O)u—(CH2)t—C(O)—NR21R22, —(O)u—(CH2)t—NHC(O)O—R20, -Q-H, -Q-(aliphatic group), -Q-(substituted aliphatic group), -Q(aryl), -Q-(aromatic group), -Q-(substituted aromatic group), -Q-(CH2)p-(substituted or unsubstituted aromatic group), -Q-(non-aromatic heterocyclic group) or -Q-(CH2)p-(non-aromatic heterocyclic group); Q is —O—, —S—, —S(O)—, —S(O)2, —OS(O)2—, —C(O)—, OC(O)—, —C(O)O—, —C(O)C(O)—O—, —O—C(O)C(O)—, —NHC(O)—, —OC(O)NH—, —NH—C(O)—NH—, —S(O)2NH—, —NHS(O)2—, —C(NR23)NHNH—, —NHNHC(NR23)—, —NR24C(O)— or —NR24S(O)2—, R20, R21 and R22 are independently —H an aliphatic group, an aromatic group, a non-aromatic heterocyclic group, —NHC(O)—O-(aliphatic group), —NHC(O)—O-(aromatic group) or —NHC(O)—O-(non-aromatic heterocyclic group) or R21 and R22, taken together with the nitrogen atom to which they are bonded, can form a substituted or unsubstituted non-aromatic heterocyclic ring; R23 is —H, an aliphatic group, a benzyl group, an aryl group or non-aromatic heterocyclic group; R24 and R25 are independently —H, —OH, an aliphatic group, a substituted aliphatic group, a benzyl group, an aryl group, non-aromatic heterocyclic group or R24 and R25 taken together with the nitrogen atom to which they are bonded can form a substituted or unsubstituted non-aromatic heterocyclic ring; R 0 is a —H, —OH, —NH2, an aromatic group or a substituted aromatic group; t is zero to three; u is zero or one; p is one to five. 40. The compound according to claim 39 wherein R2 is —NR5R6. 41. The compound of claim 40 wherein: R5 is aliphatic group or substituted aliphatic group; and R0 is benzyl or substituted benzyl; or R5 and R0 taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring. 42. The compound of claim 41 wherein R5 is ethyl, and R6 is substituted benzyl, wherein said substituted benzyl is substituted with a halogen. 43. A method for treating a disease associated with aberrant leukocyte recruitment activation or recruitment and activation, comprising administering to a subject in need thereof an effective amount of a compound according to claim 39. 44. A pharmaceutical composition comprising a compound according to claim 39 and a physiologically acceptable carrier. 45. A prodrug of the compound of claim 12. 46. The compound of claim 39 wherein said compound has a formula selected from the group consisting of: |
<SOH> BACKGROUND OF THE INVENTION <EOH>Chemoattractant cytokines or chemokines are a family of proinflammatory mediators that promote recruitment and activation of multiple lineages of leukocytes and lymphocytes. They can be released by many kinds of tissue cells after activation. Continuous release of chemokines at sites of inflammation mediates the ongoing migration of effector cells in chronic inflammation. The chemokines characterized to date are related in primary structure. They share four conserved cysteines, which form disulfide bonds. Based upon this conserved cysteine motif, the family is divided into two main branches, designated as the C—X—C chemokines (α-chemookines), and the C—C chemokines (β-chemokines), in which the first two conserved cysteines are separated by an intervening residue, or adjacent respectively (Baggiolini, M. and Dahinden, C. A., Immunology Today, 15:127-133 (1994)). The C—X—C chemokines include a number of potent chemoattractants and activators of neutrophils, such as interleukin 8 (IL-8), PF4 and neutrophil-activating peptide-2 (NAP-2). The C—C chemokines include RANTES (Regulated on Activation, Normal T Expressed and Secreted), the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β), eotaxin and human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2, MCP-3), which have been characterized as chemoattractants and activators of monocytes or lymphocytes but do not appear to be chemoattractants for neutrophils. Chemokines, such as RANTES and MIP-1α, have been implicated in a wide range of human acute and chronic inflammatory diseases including respiratory diseases, such as asthma and allergic disorders. The chemokine receptors are members of a superfamily of G protein-coupled receptors (GPCR) which share structural features that reflect a common mechanism of action of signal transduction (Gerard, C. and Gerard, N. P., Annu Rev. Immunol., 12:775-808 (1994); Gerard, C. and Gerard, N. P., Curr. Opin. Immunol., 6:140-145 (1994)). Conserved features include seven hydrophobic domains spanning the plasma membrane, which are connected by hydrophilic extracellular and intracellular loops. The majority of the primary sequence homology occurs in the hydrophobic transmembrane regions with the hydrophilic regions being more diverse. The first receptor for the C—C chemokines that was cloned and expressed binds the chemokines MIP-1α and RANTES. Accordingly, this MIP-1α/RANTES receptor was designated C—C chemokine receptor 1 (also referred to as CCR-1; Neote, K., et al., Cell, 72:415-425 (1993); Horuk, R et al., WO 94/11504, May 26, 1994; Gao, J.-I. et al., J. Exp. Med., 177:1421-1427 (1993)). Three receptors have been characterized which bind and/or signal in response to RANTES: CCR 3 mediates binding and signaling of chemokines including eotaxin, RANTES, and MCP-3 (Ponath et al., J. Exp. Med., 183:2437 (1996)), CCR 4 binds chemokines including RANTES, MIP-1α, and MCP-1 (Power, et al., J. Biol. Chem., 270:19495 (1995)), and CCR 5 binds chemokines including MIP-1α, RANTES, and MIP-1β (Samson, et al., Biochem. 35: 3362-3367 (1996)). RANTES is a chemotactic chemokine for a variety of cell types, including monocytes, eosinophils, and a subset of T-cells. The responses of these different cells may not all be mediated by the same receptor, and it is possible that the receptors CCR 1 , CCR 4 and CCR 5 will show some selectivity in receptor distribution and function between leukocyte types, as has already been shown for CCR 3 (Ponath et al.). In particular, the ability of RANTES to induce the directed migration of monocytes and a memory population of circulating T-cells (Schall, T. et al., Nature, 347:669-71 (1990)) suggests this chemokine and its receptor(s) may play a critical role in chronic inflammatory diseases, since these diseases are characterized by destructive infiltrates of T cells and monocytes. Many existing drugs have been developed as antagonists of the receptors for biogenic amines, for example, as antagonists of the dopamine and histamine receptors. No successful antagonists have yet been developed to the receptors for the larger proteins such as chemokines and C5a. Small molecule antagonists of the interaction between C—C chemokine receptors and their ligands, including RANTES and MIP-1α, would provide compounds useful for inhibiting harmful inflammatory processes “triggered” by receptor ligand interaction, as well as valuable tools for the investigation of receptor-ligand interactions. |
<SOH> SUMMARY OF THE INVENTION <EOH>It has now been found that a class of small organic molecules are antagonists of chemokine receptor function and can inhibit leukocyte activation and/or recruitment. An antagonist of chemokine receptor function is a molecule which can inhibit the binding and/or activation of one or more chemokines, including C—C chemokines such as RANTES, MIP-1α, MCP-2, MCP-3 and MCP-4 to one or more chemokine receptors on leukocytes and/or other cell types. As a consequence, processes and cellular responses mediated by chemokine receptors can be inhibited with these small organic molecules. Based on this discovery, a method of treating a disease associated with aberrant leukocyte recruitment and/or activation is disclosed as well as a method of treating a disease mediated by chemokine receptor function. The method comprises administering to a subject in need an effective amount of a compound or small organic molecule which is an antagonist of chemokine receptor function. Compounds or small organic molecules which have been identified as antagonists of chemokine receptor function are discussed in detail hereinbelow, and can be used for the manufacture of a medicament for treating or for preventing a disease associated with aberrant leukocyte recruitment and/or activation. In one aspect, the compound has the formula: or a physiologically acceptable salt thereof, wherein Z, n, M, R 70 , R 71 , R 72 and R 73 are as described herein. The invention also relates to the disclosed compounds and small organic molecules for use in treating or preventing a disease associated with aberrant leukocyte recruitment and/or activation. The invention also includes pharmaceutical compositions comprising one or more of the compounds or small organic molecules which have been identified herein as antagonists of chemokine function and a suitable pharmaceutical carrier. The invention further relates to novel compounds which can be used to treat an individual with a disease associated with aberrant leukocyte recruitment and/or activation and methods for their preparation. |
Production and use of a polar lipid-rich fraction containing stearidonic acid and gamma linolenic acid from plant seeds and microbes |
The production and use, and in particular, the extraction, separation, synthesis and recovery of polar lipid-rich fractions containing gamma linolenic acid (GLA) and/or stearidonic acid (SDA) from seeds and microorganisms and their use in human food applications, animal feed, pharmaceuticals and cosmetics. |
1. A method for providing a human, animal or aquaculture organism diet supplement enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA) comprising the steps: a) producing a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and b) providing said GLA- and/or SDA-enriched polar lipid-rich fraction in a form consumable by humans and animals. 2. A method for treating a deficiency in at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA) comprising the steps: a) producing a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and b) providing said GLA- and/or SDA-enriched polar lipid-rich fraction to treat said deficiency. 3. The method of claim 2, wherein said deficiency results in an inflammatory condition, an auto-immune condition, a woman's health condition or an infant's health condition. 4. A method for treating chronic inflammatory disease states of the lung, including but not limited to COPD, asthma and cystic fibrosis, comprising the steps: a) producing a GLA- and/or SDA-enriched purified phospholipid fraction from seeds or microbes; b) blending said GLA- and/or SDA-rich phospholipid fraction with at least one of EPA-, GLA- or SDA-rich oils; and c) producing an aerosol for the treatment of said disease states. 5. A method for the treatment of skin lesions, induced burn, UV-irradiation or other skin disorders comprising the steps: a) producing a GLA- and/or SDA-enriched purified phospholipid fraction from seeds or microbes; b) blending said GLA- and/or SDA-rich phospholipid fraction with at least one EPA-, GLA- or SDA-rich oil; and c) producing a lotion or creme for the treatment of said skin disorders. 6. A method for treating cachexia or fat malabsorption comprising the steps: a) producing a GLA- and/or SDA-enriched purified phospholipids; b) blending said GLA- and/or SDA-rich polar lipid fractions with at least one other purified phospholipid; c) blending said GLA- and/or SDA-rich polar lipid fractions with at least one DHA, EPA, GLA- or SDA-rich oil; and d) producing a liquid or dry dietetic product for the treatment of said disease states. 7. A method for the treatment of H.pylori-infection of the gastrointestinal tract comprising the steps: a) producing a GLA- and/or SDA-enriched purified phospholipid fraction from seeds or microbes; b) blending said GLA- and/or SDA-rich phospholipid fraction with at least one EPA-, GLA- or SDA-rich oil; and c) producing a fat emulsion or a dietetic product for the treatment of said disease. 8. A method for providing a fat blend enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA) comprising the steps: a) extracting a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and b) mixing said GLA- and/or SDA-enriched polar lipid-rich fraction with another oil. 9. The method of claim 8, wherein said another oil is selected from the group consisting of fish oil, microbial oil, vegetable oil, GLA-containing oil, SDA-containing oil and mixtures thereof. 10. A method for providing a blend of polar lipids enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA) comprising the steps: a) extracting a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and b) mixing said GLA- and/or SDA-enriched polar lipid-rich fraction with another polar lipid. 11. The method of claim 10, wherein said another polar lipid is selected from the group consisting of soy polar lipids, rapeseed polar lipids, sunflower polar lipids, safflower polar lipids, canola polar lipids, linseed polar lipids, flaxseed polar lipids, peanut polar lipids, egg yolk polar lipids and mixtures thereof. 12. A fat blend enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA) comprising: a) a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and b) another oil. 13. The oil of claim 12, wherein said another oil is selected from the group consisting of fish oil, microbial oil, vegetable oil, GLA-containing oil, SDA-containing oil and mixtures thereof. 14. A blend of polar lipids enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA), produced by a method comprising the steps of: a) extracting a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and b) mixing said GLA- and/or SDA-enriched polar lipid-rich fraction with another polar lipid. 15. The method of claim 14, wherein said another polar lipid is selected from the group consisting of soy polar lipids, rape seed polar lipids, sunflower polar lipids, safflower polar lipids, canola polar lipids, linseed polar lipids, flaxseed polar lipids, peanut polar lipids, egg yolk polar lipids and mixtures thereof. 16. Purified phospholipids enriched with at least one gamma linolenic acid (GLA) and stearidonic acid (SDA) derived from polar lipid-rich fraction extracted from seeds or microbes. 17. The purified phospholipids of claim 16, wherein said GLA- and/or SDA-enriched phospholipid-fraction is in a form consumable by humans and animals. 18. A dietetic, pharmaceutical or cosmetic composition, comprising a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes. 19. A dietetic, pharmaceutical or cosmetic composition, comprising the fat blend of claim 12. 20. A dietetic, pharmaceutical or cosmetic composition, comprising the blend of polar lipids of claim 14. 21. A dietetic, pharmaceutical or cosmetic composition, comprising the purified phospholipids of claim 16. 22. The method of claim 1, wherein said seeds are from the plant families Boraginaceae, Onagraceae, Saxifragaceae, Scrophulariaceae or Cannabaceae. 23. The method of claim 1, wherein said seeds are selected from the group consisting of borage, echium, evening primrose and black currant. 24. The method of claim 1, wherein said microbes are selected from fungi, microalgae and bacteria. 25. The method of claim 1, wherein said microbes are selected from the group of genera consisting of Mortierella, Mucor, Blastocladiella, Choanephora, Conidiobolus, Entomophthora, Helicostylum, Phycomyces, Rhizopus, Beauveria, and Pythium. 26. The method of claim 1, wherein GLA comprises at least two weight percent of the total fatty acids of the polar lipid fraction. 27. The method of claim 1, wherein SDA comprises at least two weight percent of the total fatty acids of the polar lipid fraction. 28. The method of claim 1, wherein said seeds have been genetically modified. 29. The method of claim 1, wherein said seeds have been genetically modified to increase the production of at least one of SDA or GLA. 30. The method of claim 1, wherein said seeds are seeds from a plant selected from the group consisting of canola, rapeseed, linseed, flaxseed, sunflower, safflower, soybeans, peanuts and corn. 31. The method of claim 1, wherein said polar lipid-rich fraction is extracted from said seeds or microbes using alcohol. 32. The method of claim 1, wherein said polar lipid-rich fraction is derived as a by-product of oil extraction from said seeds or microbes using hexane and other nonpolar solvents. 33. The method of claim 1, wherein said polar lipid-rich fraction is extracted from said seeds or microbes by use of gravity or centrifugal extraction technology. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Polyunsaturated fatty acids of the omega-6 and omega-3 series represent a special class of bioactive lipids in that they are important structurally in membranes in the body, but also participate directly and indirectly in communication between cells through the eicosanoid pathways and by their influence of these fatty acids on gene expression. Two of these fatty acids GLA (gammalinolenic acid; C18:3n-6) and SDA (stearidonic acid; C18:4n-3) have been shown to be effective in treating inflammatory conditions, autoimmune conditions, women's health conditions (e.g. menopause and premenstrual disorders) and fatty acid imbalances in infants and animals. Recent evidence indicates that some polyunsaturated fatty acids may be more bioavailable when supplied in a phospholipid form than in a triglyceride form. GLA and SDA have historically been supplied to the nutritional supplement markets in the form of oil extracted from seeds. However recent evidence indicates that some polyunsaturated fatty acids may be more bioavailable in a phospholipid form rather than in a triglyceride form. This may be because of the bipolar nature of phospholipids making them readily solubilized in the gut and available for digestion and uptake. This same bipolar property of phospholipids additionally would make these fatty acids, such as GLA and SDA, more functional in topical applications such as creams and lotions because of their ability to participate in emulsification processes. The present inventors propose that there may be important advantages in supplying GLA and SDA in the form of phospholipids and improved processes for recovering polar lipids enriched in these fatty acids are also needed. Examples of polar lipids include phospholipids (e.g. phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerols), cephalins, sphingolipids (sphingomyelins and glycosphingolipids), and glycoglycerolipids. Phospholipids are composed of the following major structural units: fatty acids, glycerol, phosphoric acid, and amino alcohols. They are generally considered to be structural lipids, playing important roles in the structure of the membranes of plants, microbes and animals. Because of their chemical structure, polar lipids exhibit a bipolar nature, exhibiting solubility or partial solubility in both polar and non-polar solvents. The term polar lipid within the present description is not limited to natural polar lipids but also includes chemically modified polar lipids. Although the term oil has various meanings, as used herein, it will refer to the triacylglycerol fraction. One of the important characteristics of polar lipids, and especially phospholipids, is that they commonly contain polyunsaturated fatty acids (PUFAs: fatty acids with 2 or more unsaturated bonds). In many plant, microbial and animal systems, they are especially enriched in the highly unsaturated fatty acids (HUFAs: fatty acids with 4 or more unsaturated bonds) of the omega-3 and omega-6 series. Although these highly unsaturated fatty acids are considered unstable in triacylglycerol form, they exhibit enhanced stability when incorporated in phospholipids. The primary sources of commercial PUFA-rich phospholipids are soybeans and canola seeds. These biomaterials do not contain any appreciable amounts of GLA or SDA unless they have been genetically modified. The phospholipids (commonly called lecithins) are routinely recovered from these oilseeds as a by-product of the vegetable oil extraction process. For example, in the production of soybean or canola oil, the beans (seeds) are first heat-treated and then crushed, ground, and/or flaked, followed by extraction with a non-polar solvent such as hexane. Hexane removes the triacylglycerol-rich fraction from the seeds together with a varying amount of polar lipids (lecithins). The extracted oil is then de-gummed (lecithin removal) either physically or chemically as a part of the normal oil refining process and the precipitated lecithins recovered. This process however has two disadvantages: (1) the seeds must be heat-treated before extraction with hexane, both increasing the processing cost and denaturing the protein fraction, thereby decreasing its value as a by-product; and (2) the use of the non-polar solvents such as hexane also presents toxicity and flammability problems that must be dealt with. The crude lecithin extracted in the “de-gumming” process can contain up to about 33% oil (triacylglycerols) along with sterols and glucosides. One preferred method for separating this oil from the crude lecithin is by extraction with acetone. The oil (triacylglycerols) is soluble in acetone and the lecithin is not. The acetone solution is separated from the precipitate (lecithin) by centrifugation and the precipitate dried under first a fluidized bed drier and then a vacuum drying oven to recover the residual acetone as the product is dried. Drying temperatures of 50-70° C. are commonly used. The resulting dried lecithins contain approximately 24% by weight of oil (triacylglycerols). Process temperatures above 70° C. can lead to thermal decomposition of the phospholipids. However, even at temperatures below 70° C. the presence of acetone leads to the formation of products that can impair the organoleptic quality of the phospholipids. These by-products can impart musty odors to the product and also a pungent aftertaste. What is needed is an improved process for effectively recovering polar lipids and phospholipids rich in GLA and SDA from biomaterials that enables the use of these fatty acid in food, nutritional supplement, pharmaceutical and cosmetic applications. Furthermore the fractions are needed as an ingredient in feed for companion animals and in aquaculture. |
<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with the present invention, an improved process is provided for recovering polar lipids enriched in gamma linolenic acid (GLA) and/or stearidonic acid (SDA) from native biomaterials such as seeds and microorganisms and the use thereof. In one embodiment of the present invention, a method is provided for providing a human, animal or aquaculture organism diet supplement enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA). The method includes the steps of producing a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and providing the GLA- and/or SDA-enriched polar lipid-rich fraction in a form consumable by humans and animals. Preferably, the animals are companion animals. In another embodiment of the present invention, a method is provided for treating a deficiency in at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA). The method includes the steps of producing a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and providing the GLA- and/or SDA-enriched polar lipid-rich fraction to treat the deficiency. The deficiency can lead to an inflammatory condition, an autoimmune condition, a woman's health condition or an infant's health condition. In another embodiment of the present invention, a method is provided for treating chronic inflammatory disease states of the lung, including but not limited to chronic obstructive pulmonary disease (COPD), asthma and cystic fibrosis. The method includes the steps of producing a GLA- and/or SDA-enriched purified phospholipid fraction from seeds or microbes; blending the GLA- and/or SDA-rich phospholipid fraction with at least one of EPA-, GLA- or SDA-rich oils; and producing an aerosol, such as by providing an aerosol delivery system, for the treatment of the disease states. In another embodiment of the present invention, a method is provided for the treatment of skin lesions, induced burn, UV-irradiation or other skin disorders. The method includes the steps of producing a GLA- and/or SDA-enriched purified phospholipid fraction from seeds or microbes; blending the GLA- and/or SDA-rich phospholipid fraction with at least one EPA-, GLA- or SDA-rich oil; and producing a lotion or cream for the treatment of the skin disorders. In another embodiment of the present invention, a method is provided for treating cachexia or fat malabsorption. The method includes the steps of producing a GLA- and/or SDA-enriched purified phospholipids; blending the GLA- and/or SDA-rich polar lipid fractions with at least one other purified phospholipid; blending the GLA- and/or SDA-rich polar lipid fractions with at least one DHA, EPA, GLA- or SDA-rich oil; and producing a liquid or dry dietetic product for the treatment of the disease states. The cachexia or fat malabsorption can result from the illnesses such as cancer and Crohn's disease. The at least one other purified phospholipid can be obtained from sources such as soybeans, rapeseed, canola, corn, peanuts, flax seed, linseed, sunflower, safflower, and eggs. In another embodiment of the present invention, a method is provided for the treatment of H. pylori -infection of the gastrointestinal tract. The method includes the steps of producing a GLA- and/or SDA-enriched purified phospholipid fraction from seeds or microbes; blending the GLA- and/or SDA-rich phospholipid fraction with at least one EPA-, GLA- or SDA-rich oil; and producing a fat emulsion or a dietetic product for the treatment of the disease. In another embodiment of the present invention, a method is provided for providing a fat blend enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA). The method includes the steps of extracting a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and mixing the GLA- and/or SDA-enriched polar lipid-rich fraction with another oil. Preferably, the another oil is selected from the group consisting of fish oil, microbial oil, vegetable oil, GLA-containing oil, SDA-containing oil and mixtures thereof. In another embodiment of the present invention, a method is provided for providing a blend of polar lipids enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA). The method includes the steps of extracting a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and mixing the GLA- and/or SDA-enriched polar lipid-rich fraction with another polar lipid. Preferably, the another polar lipid is selected from the group consisting of soy polar lipids, rapeseed polar lipids, sunflower polar lipids, safflower polar lipids, canola polar lipids, linseed polar lipids, flaxseed polar lipids, peanut polar lipids, egg yolk polar lipids and mixtures thereof. In another embodiment of the present invention, a fat blend is provided that is enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA) comprising a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and another oil. Preferably, the another oil is selected from the group consisting of fish oil, microbial oil, vegetable oil, GLA-containing oil, SDA-containing oil and mixtures thereof. In another embodiment of the present invention, a method is provided for providing a blend of polar lipids enriched with at least one of gamma linolenic acid (GLA) and stearidonic acid (SDA). The method includes the steps of extracting a GLA- and/or SDA-enriched polar lipid-rich fraction from seeds or microbes; and mixing the GLA- and/or SDA-enriched polar lipid-rich fraction with another polar lipid. Preferably, the another polar lipid is selected from the group consisting of soy polar lipids, rape seed polar lipids, sunflower polar lipids, safflower polar lipids, canola polar lipids, linseed polar lipids, flaxseed polar lipids, peanut polar lipids, egg yolk polar lipids and mixtures thereof. In another embodiment of the present invention, purified phospholipids enriched with at least one gamma linolenic acid (GLA) and stearidonic acid (SDA) derived from polar lipid-rich fraction extracted from seeds or microbes are provided. Preferably, the GLA- and/or SDA-enriched phospholipid-fraction is in a form consumable by humans and animals. Preferably, polar lipid-rich fractions of the methods or products of the present invention can be used as an ingredient of dietetic, pharmaceutical and cosmetic applications. As used herein, the term dietetic includes nutritional supplements (in gel-cap, tablet, liquid, emulsion, powder or any other form) and food. The term pharmaceutical includes all compounds ingested (including special enteral and parenteral nutrition products) or injected or received intravenously, for the treatment of diseases or metabolic imbalances. Preferably, fat blends of the methods or products of the present invention can be used as an ingredient of dietetic, pharmaceutical and cosmetic applications. Preferably, blends of polar lipids of the methods or products of the present invention can be used as an ingredient of dietetic, pharmaceutical or cosmetic applications. Preferably, purified phospholipids of the methods or products of the present invention can be used as an ingredient of dietetic, pharmaceutical or cosmetic applications. Preferably, seeds useful in the methods and products of the present invention are from the plant families Boraginaceae, Onagraceae, Saxifragaceae, Scrophulariaceae or Cannabaceae, and more preferably, the seeds are selected from the group consisting of borage, echium, evening primrose and black currant. Preferably, the microbes useful in the methods and products of the present invention are selected from fungi, microalgae and bacteria. More preferably, the microbes are selected from the group of genera consisting of Mortierella, Mucor, Blastocladiella, Choanephora, Conidiobolus, Entomophthora, Helicostylum, Phycomyces, Rhizopus, Beauveria , and Pythium. Preferably, the GLA of the products and methods of the present invention makes up at least two weight percent of the total fatty acids of the polar lipid fraction. Preferably, the SDA of the products and methods of the present invention makes up at least two weight percent of the total fatty acids of the polar lipid fraction. Preferably, the plant seeds of the products and methods of the present invention have been genetically modified, and more preferably, the seeds have been genetically modified to increase the production of at least one of SDA and GLA. Preferably, the seeds of the methods and products of the present invention are selected from the group consisting of canola, rapeseed, linseed, flaxseed, sunflower, safflower, soybeans, peanuts and corn. Preferably, the polar lipid-rich fraction is extracted from the seeds or microbes using alcohol. In an alternative embodiment of the present invention, the polar lipid-rich fraction is derived as a by-product of oil extraction, e.g. by de-gumming, from the seeds or microbes using hexane and other nonpolar solvents. Preferably, the polar lipid-rich fraction is extracted from the seeds or microbes by use of gravity or centrifugal extraction technology. detailed-description description="Detailed Description" end="lead"? |
Polycrystalline tft uniformity through microstructure mis-alignment |
Methods of making a polycrystalline silicon thin-film transistor having a uniform microstructure. One exemplary method requires receiving a polycrystalline silicon thin film having a grain structure which is periodic in at least a first direction, and placing at least portions (410, 420) of one or more thin-film transistors on the received film such that they are tilted relative to the periodic structure of the thin film. |
1. A method of making a polycrystalline device including two or more thin-film transistors of substantially uniform microstructure, comprising the steps of: (a) receiving a polycrystalline silicon thin film having a grain structure which is periodic in at least a first direction; and (b) placing at least portions of two or more thin-film transistors on said received film tilted at an angle relative to said periodic structure of said thin film, such that that the number of long grain boundaries in any of said portions remains substantially uniform. 2. The method of claim 1, wherein said receiving step comprises the step of receiving a polycrystalline silicon thin film formed by a sequential lateral solidification process. 3. The method of claim 1, wherein said portions of said two or more thin-film transistors comprise active channel regions having a width W. 4. The method of claim 3, wherein said periodic structure of said thin film is λ, m is a variable, and said placing step comprises the step of placing said active channel regions on said received film such that said active channel regions are tilted at an angle θ relative to said periodic structure of said thin film, where W sin(θ)=mλ. 5. The method of claim 4, wherein m substantially equal to an integer. 6. The method of claim 4, wherein m is equal to an integer. 7. The method of claim 4, wherein m is equal to the integer 1. 8. A method of making a device including thin-film transistors, comprising the steps of: (a) receiving a polycrystalline silicon thin film having a grain structure which is periodic in at least a first direction in an amount λ; and (b) placing at least portions of one or more thin-film transistors having a width W on said received film tilted at an angle θ relative to said periodic structure λ of said thin film, such that W sin(θ)=mλ, where m is substantially equal to an integer. 9. The method of claim 8, wherein said receiving step comprises the step of receiving a polycrystalline silicon thin film formed by a sequential lateral solidification process. 10. The method of claim 8, wherein said portions of said one or more thin-film transistors comprise active channel regions having a width W. 11. The method of claim 10, wherein m is equal to an integer. 12. The method of claim 10, wherein m is equal to the integer 1. 13. A device including two or more polycrystalline silicon thin-film transistors of substantially uniform microstructure, comprising: (a) a polycrystalline silicon thin film having a grain structure which is periodic in at least a first direction; and (b) at least two or more thin-film transistor portions placed on said received film, each tilted at an angle relative to said periodic structure of said thin film, such that that the number of long grain boundaries in any of said portions remains substantially uniform. 14. The device of claim 13, wherein said polycrystalline silicon thin film comprises thin film formed by a sequential lateral solidification process. 15. The device of claim 13, wherein said portions of said two or more thin-film transistors comprise active channel regions having a width W. 16. The device of claim 13, wherein said periodic structure of said thin film is λ, m is a variable, and said active channel regions are tilted at an angle θ relative to said periodic structure of said thin film, where W sin(θ)=mλ. 17. The device of claim 16, wherein m is substantially equal to an integer. 18. The device of claim 16, wherein m is equal to an integer. 19. The device of claim 16, wherein m is equal to the integer 1. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Technical Field The present invention relates to semiconductor processing techniques, and more particularly, techniques for fabricating semiconductors suitable for use at thin-film transistor (“TFT”) devices. 2. Background Art Semiconductor films, such as silicon films, are known to be used for providing pixels for liquid crystal display devices and organic light emitting diode display devices. Such films are commonly processed via excimer laser annealing (“ELA”) methods, where an amorphous silicon film is irradiated by an excimer laser to be crystallized. Significant effort has gone into the refinement of “conventional” ELA (also known as line-beam ELA) processes in the attempt to improve the performance of the TFT devices placed on the processed semiconductor thin films. For example, U.S. Pat. No. 5,766,989 issued to Maegawa et al., the entire disclosure of which is incorporated herein in its entirety by reference, describes the ELA methods for forming polycrystalline thin film and a method for fabricating a TFT. The '989 patent attempts to address the problem of non-uniformity of characteristics across the substrate, and provide certain options for apparently suppressing such non-uniformities. However, the details of the beam-shaping approach used in conventional ELA methods make it extremely difficult to reduce the non-uniformities in the semiconductor films and to improve the performance characteristics of such films. For example, in a low-temperature polycrystalline silicon (“LTPS”) process, when the size of the grains becomes comparable to the dimensions of the channel region of the TFT, large device-to-device non-uniformity results. This is caused by the randomness of the microstructure, i.e., the random location of the grains and thus the grain boundaries. Such non-uniformity, especially when perpendicular to the current flow, can act as a current barrier. Further, when the transistor is in its off-state, carriers are generated at the grain boundary, which contribute to the off-current. This is especially the case when the grain boundary is in or close to the drain-channel junction. Therefore, it has been realized that control over the microstructure is needed in order to ensure a uniform TFT process, both with respect to periodicity and location. Regarding the former, the film should be uniform, exhibiting periodicity in the location of the grains and thus the grain boundaries. Regarding the latter, the location of the grains and thus the grain boundaries should be controlled so that their contribution to the electrical characteristics is the same for every single device. In an pulsed-laser, e.g., an excimer laser, irradiaton process to obtain LTPS films, control over the TFT microstructure may be obtained through the use lithography to induce such periodicity. The use of lithography also accounts for location control, since the accurate alignment procedure of the lithographic process is used. Unfortunately, the use of lithography requires at lease one extra processing step, which in turn increases complexity and thus costs. Alternatively, control over the TFT microstructure may be obtained through the use of sequential lateral solidification (“SLS”) techniques. For example, in U.S. Pat. No. 6,322,625 issued to Im and U.S. patent application Ser. No. 09/390,537 (the “'537 application”), which is assigned to the common assignee of the present application, the entire disclosures of which are incorporated herein by reference, particularly advantageous apparatus and methods for growing large grained polycrystalline or single crystal silicon structures using energy-controllable laser pulses and small-scale translation of a silicon sample to implement sequential lateral solidification have been described. As described in these patent documents, at least portions of the semiconductor film on a substrate are irradiated with a suitable radiation pulse to completely melt such portions of the film throughout their thickness. In this manner, when the molten semiconductor material solidifies, a crystalline structure grows into the solidifying portions from selected areas of the semiconductor film which did not undergo a complete melting. Thereafter, the beam pulses irradiate slightly offset from the crystallized areas so that the grain structure extends into the molten areas from the crystallized areas. Using the system shown in FIG. 1 , an amorphous silicon thin film sample is processed into a single or polycrystalline silicon thin film by generating a plurality of excimer laser pulses of a predetermined fluence, controllably modulating the fluence of the excimer laser pulses, homogenizing the modulated laser pulses in a predetermined plane, masking portions of the homogenized modulated laser pulses into patterned beamlets, irradiating an amorphous silicon thin film sample with the patterned beamlets to effect melting of portions thereof corresponding to the beamlets, and controllably translating the sample with respect to the patterned beamlets and with respect to the controlled modulation to thereby process the amorphous silicon thin film sample into a single or polycrystalline silicon thin film by sequential translation of the sample relative to the patterned beamlets and irradiation of the sample by patterned beamlets of varying fluence at corresponding sequential locations thereon. While the system of FIG. 1 is highly advantageous in generating uniform, high quality polycrystalline silicon and single crystal silicon which exhibit periodicity and thereby solves a problem inherent with conventional ELC techniques, the technique does adequately not account for control over grain boundaries. For example, in the simplest form, SLS requires two pulses to crystallize the amorphous precursor into an LTPS film with partial periodicity, e.g., the 2-shot material shown schematically in FIG. 2 a . The periodicity is only in one direction, shown by long grain boundaries 210 , 220 , 230 , 240 , 250 that are parallel to each other and which also have a protrusion to them. However, the position of the short grain boundaries is not at all controlled. The spacing between the parallel grain boundaries can be increased, and this material is in general called n-shot material. Likewise, FIG. 2 b shows a so-called 4-shot material in which the grain boundaries are periodic in both directions. Again, the spacing between the grain boundaries can be increased, and is generally referred to as 2n-shot material. While SLS techniques offer periodicity, such techniques do not offer accurate control of the location of grain boundaries. Referring to FIGS. 2 c - d , the LTPS film produced includes a varying number of long grain boundaries perpendicular to the current flow, and the possibility of having a perpendicular grain boundary in or out of a TFT drain region. Both problems become more severe when grain size is increasing and/or when channel dimensions are decreasing, i.e., when the size of the grains becomes comparable to the dimensions of the channel region. While there has been a suggestion in U.S. Pat. No. 6,177,301 to Jung to misalign TFT channel regions with respect to the grain growth direction, that suggestion is made without taking into account the underlying need to maintain uniformity in TFT microstructure. Accordingly, there exists a need for a TFT manufacturing technique that provides for control over both the periodicity of grain boundaries and the location of TFTs in order to provide for uniformity in TFT microstructure. |
<SOH> SUMMARY OF THE INVENTION <EOH>An object of the present invention is to provide a TFT manufacturing technique that provides for control over both the periodicity of grain boundaries and the location of TFTs in order to provide for uniformity in TFT microstructure. Another object of the present invention is to provide a device having uniformity in TFT microstructure. In order to meet these and other objects of the present invention which will become apparent with reference to further disclosure set forth below, the present invention provides methods of making a polycrystalline silicon thin-film transistor having a uniform microstructure. One exemplary method requires receiving a polycrystalline silicon thin film having a grain structure which is periodic in at least a first direction, and placing at least portions of one or more thin-film transistors on the received film such that they are tilted relative to the periodic structure of said thin film. The polycrystalline silicon thin film may be formed by a sequential lateral solidification process, e.g., a two shot sequential lateral solidification process. Advantageously, the portions of said one or more thin-film transistors may be active channel regions having a width W. Where the periodic structure of the thin film is λ and m is a variable, the placing step involves placing active channel regions on the received film such that they are tilted at an angle θ relative to said periodic structure of said thin film, where W sin(θ)=mλ. The variable m is selected such that that the number of grain boundaries in any of the one or more thin-film transistors remains relatively controlled, and is preferably approximately equal to an integer. The present invention also provides a device including a polycrystalline silicon thin-film transistor having a uniform microstructure. In an exemplary embodiment, the device includes polycrystalline silicon thin film having a grain structure which is periodic in at least a first direction, and at least portions of one or more thin-film transistors, placed on the thin film such that they are tilted relative to said periodic structure of the film. The accompanying drawings, which are incorporated and constitute part of this disclosure, illustrate preferred embodiments of the invention and serve to explain the principles of the invention. |
Pen |
The invention relates to a pen comprising a cartridge (10), a retaining sleeve (12) for housing the cartridge at least partially, a locking device (14) that can be actuated by a twisting motion for interlocking the cartridge (10) and the retaining sleeve (12) and a cap (16) for protecting the cartridge. According to the invention, said cap (16) can be displaced axially in relation to the locking device from a first operating position, in which it can be rotated relative to the locking device, into a second operating position, in which it is rotatably coupled to the locking device. The invention is characterised in that the cartridge (10) can be displaced axially in relation to the locking device (14), at least by a length that is equal to the distance between the first and the second operating position of the cap. |
1. A pen comprising a cartridge (10), a retaining sleeve (12) for at least partially accommodating the cartridge (10), a locking device (14) which can be actuated by rotation for locking the cartridge (10) and the retaining sleeve (12) together, and a cap (16) for protecting the cartridge (10), wherein the cap (16) is axially displaceable with respect to the locking device (14) from a first operating position in which it is rotatable with respect to the locking device (14) into a second operating position in which it is rotationally coupled to the locking device (14) characterised in that the cartridge (10) is axially displaceable with respect to the locking device (14), by at least a distance which is equal to the spacing between the first and the second operating positions of the cap (16). 2. A pen according to claim 1 further comprising an elastic return device (44) which biases the cartridge (10) in a direction axially out of the retaining sleeve (12). 3. A pen according to claim 2 wherein the return device is a coil spring (44). 4. A pen according to claim 1 whererin the cap (16) can be screwed to the cartridge (10). 5. A pen according to claim 1 whererin the locking device (14) can be screwed to the retaining sleeve (12). 6. A pen according to claim 1 wherein the locking device (14) has an abutment which is remote from a working end (24) of the cartridge (10) and with which there co-operates an abutment (32), which is towards the working end (24), on the cartridge (10). 7. A pen according to claim 1 wherein the pen further comprises a component (50, 52) of a coupling device (46, 48, 50, 52) serving for rotational coupling of the cap (16) to the locking device (14) is on the end of the cap (16), which end is towards the locking device (14) in the fitted condition. 8. A pen according to claim 1 wherein the pen further comprises at least one projection (50, 52) on the cap (16) which serves for rotational coupling of the cap (16) to the locking device (14). 9. A pen according to claim 1 whererin the pen further comprises at least one projection (46, 48) on the locking device (14) which serves for rotational coupling of the cap (16) to the locking device (14). 10. A pen according to claim 1 whererin the cartridge (10) is rotatable with respect to the locking device (14) and is rotationally coupled to the retaining sleeve (12). |
Method for treating a gas mixture by adsorption |
The gas mixture comprises at least a main constituent to be produced and impurities to be separated from said mixture. The treatment method consists in using at least two adsorbers which follow in offset manner a common cycle during which there are successively an adsorption phase and a regeneration phase using a regenerating gas. Furthermore, it consists in subjecting at the beginning of the adsorption phase (steps I or IV) and/or at the beginning of the use of regenerating gas (step VI), to only part of the gas mixture flow to be treated, respectively the regenerating gas flow, until said adsorber is saturated, respectively substantially discharged, in at least one of the main constituents to be produced, while maintaining at least another adsorber in adsorption phase. The invention is useful for treating a mixture rich in carbon monoxide and hydrogen. |
1-19. (canceled) 20. An adsorption process for the treatment of a gaseous mixture comprising at least one main constituent to be produced and impurities to be separated from said mixture comprising the steps of: supplying said gaseous mixture to N adsorbers, wherein said N is at least two; operating each adsorber in succession through adsorption and regeneration phases in an offset manner of the same cycle of period T; providing to a first adsorber as it is starting its adsorption phase a portion of said gaseous mixture until said first adsorber is substantially saturated; and providing to at least one other adsorber, as it is terminating its adsorption phase, the remainder of said gaseous mixture. 21. The process according to claim 20, wherein the treated portion from said first adsorber and the treated remainder from said at least one other adsorber are mixed to form the treated gaseous mixture. 22. The process according to claim 20, wherein the duration of the adsorption phase of said first adsorber and said at least one other adsorber is between T/N inclusive and 2T/N noninclusive. 23. The process according to claim 20, wherein the treatment of said gaseous mixture is substantially provided by a single adsorber terminating its adsorption phase. 24. The process according to claim 20, wherein after said first adsorber has been subjected at the start of the adsorption phase to said portion of said gaseous mixture to be treated, further comprises: a paralleling step, wherein about half of said treated gaseous mixture is obtained from said first adsorber starting its adsorption phase and half of said treated gaseous mixture is obtained from said at least one other adsorber. 25. An adsorption process for the treatment of a gaseous mixture consistency comprising at least one main constituent to be produced and impurities to be separated from said mixture comprising the steps of: supplying said gaseous mixture to N adsorbers, wherein said N is at least two; operating each adsorber in succession through adsorption and regeneration phases during the regeneration phase, in an offset manner of the same cycle of period T; and providing to a first adsorber as it is starting its regeneration phase, a portion of the regeneration gas until said first adsorber is substantially discharged of said at least one main constituent to be produced. 26. The process according to claim 25, wherein said portion of regeneration gas from said first adsorber and the remaining regeneration gas from the at least one other adsorber are combined to form the discharged gas stream. 27. The process according to claim 26, wherein said portion and said remaining regeneration gas are directly mixed together. 28. The process according to claim 26, wherein said portion from said first adsorber is mixed with another portion of regeneration gas coming from said at least one other adsorber terminating its regeneration phase. 29. The process according to claim 25, wherein said regeneration phase of each adsorber comprises the steps of: depressurizing said adsorber; and repressurizing said adsorber. 30. The process according to claim 25, wherein said regeneration phase of each adsorber further comprises heating said regeneration gas. 31. The process according to claim 20, wherein said portion of gaseous mixture to said first adsorber comprises less than about half of the total gaseous mixture to be treated. 32. The process according to claim 31, wherein said portion comprises less than about one-third. 33. The process according to claim 32, wherein said portion comprises from about 5% to about 20%. 34. The process according to claim 25, wherein said portion of the regeneration gas to said first adsorber comprises less than about half of total regeneration gas flow. 35. The process according to claim 34, wherein said portion comprises less than about one-third. 36. The process according to claim 35, wherein said portion comprises from about 5% to about 20%. 37. The process according to claim 20, wherein the amount of time wherein said portion of said gaseous mixture to said first adsorber comprises an amount of time greater than about 1% of the total adsorption phase period. 38. The process according to claim 37, wherein said amount of time is greater than about 5%. 39. The process according to claim 38, wherein said amount of time is from about 10% to about 20%. 40. The process according to claim 25, wherein the amount of time wherein said portion of regenerating gas to said first adsorber comprises an amount of time greater than about 1% of the regeneration phase period. 41. The process according to claim 40, wherein said amount of time is greater than about 5%. 42. The process according to claim 41, wherein said amount of time is from about 10% to about 20%. 43. The process according to claim 20, wherein said gaseous mixture comprises hydrogen and carbon monoxide as its main constituents. 44. The process according to claim 43, wherein said gaseous mixture further comprises water and carbon dioxide as its impurities. 45. The process according to claim 44, wherein said treated gaseous mixture is cryogenically separated into a substantially pure carbon monoxide stream and a hydrogen-rich stream. 46. The process according to claim 44, wherein said treated gaseous mixture is separated by permeation into a stream with a predetermined ratio of hydrogen to carbon monoxide and into a hydrogen-rich stream. 47. The process according to claim 21, wherein a part of the treated portion of said gaseous mixture from said first adsorber is directed to a waste network. 48. The process according to claim 26, wherein a part of the treated portion of said gaseous mixture from said first adsorber is directed to a waste network. |
Method for fabricating electroluminescent element |
The main object of the present invention is to provide a method for manufacturing an EL element by the photolithography method, capable of preventing color mixture of the edge part of the pattern formed light emitting part, and the different light emitting layer to be laminated later, and preventing the pixel narrowing while providing the advantages of the photolithography method of high light emitting efficiency, high taking out efficiency, the simple manufacturing process, and the high precision pattern formation. In order to achieve the above mentioned object, the present invention provides a method for manufacturing an electro luminescent element of forming a plurality of kinds of light emitting parts on a base substance by patterning light emitting layers of different kinds by a plurality of times by the photolithography method, on the base substance with an electrode layer formed, comprising: a process of forming a light emitting layer and a photoresist layer in this order, on the base substance; a process of pattern exposing and then developing the photoresist layer, so as to the part corresponding to a predetermined light emitting part of the photoresist layer remains; a process of forming a light emitting part which its surface is covered with the photoresist layer, by removing the light emitting layer which is bared because the photoresist layer is removed; a process of forming a photoresist layer on the base substance, so as to cover the light emitting part; and a process of pattern exposing and then developing the photoresist layer, so as not to bare the light emitting part and the end part thereof. |
1-5. (canceled) 6. A method for manufacturing and electroluminescent element comprising; a process of forming a light emitting layer and photoresist layer in this order, on a base substance; a process of pattern exposing and then developing the photoresist layer, so as to a part corresponding to a predetermined light emitting part of the photoresist layer remains; a process of forming a light emitting part which its surface is covered with the photoresist layer, by removing the light emitting layer which is bared because the photoresist layer is removed; a process of forming a photoresist layer on the base substance, so as to cover the light emitting part; and a process of pattern exposing and then developing the photoresist layer, so as not to bare the light emitting part and the end part thereof, wherein a plurality of kinds of light emitting parts are formed on the base substance by patterning light emitting layers of different kinds by a plurality of times by a photolithography method, on the base substance with an electrode layer formed. 7. The method for manufacturing an electroluminescent element according to claim 6, wherein a process of peeling off the photoresist layer remaining on the light emitting part, and then a process of forming a photoresist layer, are conducted after the process of forming the light emitting part. 8. A method for manufacturing an electroluminescent element comprising; a process of forming a light emitting layer and photoresist layer in this order, on a base substance; a process of pattern exposing and then developing the photoresist layer, so as to a part corresponding to all of the light emitting part of the photoresist layer remains; a process of forming a light emitting part which its surface is covered with the photoresist layer, by removing the light emitting layer which is bared because the photoresist layer is removed; a process of forming a photoresist layer on the base substance, so as to cover the light emitting part; and a process of pattern exposing and then developing the photoresist layer, so as not to bare the predetermined light emitting part and the end part thereof; a process of removing the light emitting part which is bared because the photoresist layer is removed, wherein a plurality of kinds of light emitting parts are formed on the base substance by patterning light emitting layers of different kinds of plurality of times by a photolithography method, on the base substance with an electrode layer formed. 9. The method for manufacturing an electroluminescent element according to claim 8, wherein a process of peeling off the photoresist remaining on all of the light emitting part, and then a process of forming a photoresist layer, are conducted after the process of forming the light emitting part. 10. The method for manufacturing an electroluminescent element according to claim 6, wherein the process of removing the light emitting layer or light emitting part which is bared because the photoresist layer is removed, is a process of removing by dry etching. 11. The method for manufacturing an electroluminescent element according to claim 7, wherein the process of removing the light emitting layer or light emitting part which is bared because the photoresist layer is removed, is a process of removing by dry etching. 12. The method for manufacturing an electroluminescent element according to claim 8, wherein the process of removing the light emitting layer or light emitting part which is bared because the photoresist layer is removed, is a process of removing by dry etching. 13. The method for manufacturing an electroluminescent element according to claim 9, wherein the process of removing the light emitting layer or light emitting part which is bared because the photoresist layer is removed, is a process of removing by dry etching. |
<SOH> BACKGROUND TECHNOLOGY <EOH>An EL element couples a hole and an electron, injected from counter electrodes, in a light emitting layer, excites the fluorescent substance in the light emitting layer by the energy, and emits a light of the color corresponding to the fluorescent substance, attracts the attention as a self light emitting flat display element. In particular, an organic thin film EL display using an organic substance as a light emitting material has a high light emitting efficiency and capable of realizing a high luminance light emission even with less than 10V applied voltage, capable of emitting a light in a simple element structure, and thus application thereof to the advertisement of displaying a specific pattern by light emission and other inexpensive simple displays is expected. In the manufacturing of the display using such EL element, in general, an electrode layer and an organic EL layer are patterned. As methods for patterning the EL element, a method of deposition of the light emitting material via a shadow mask, a method of divisional coating by ink jetting, a method of destroying a specific light emitting dye by the ultraviolet ray irradiation, a screen printing method, or the like can be presented. However, in these methods, it was impossible to provide a method for manufacturing an EL element, capable of realizing all of, a high light emitting efficiency, a high light taking out efficiency, a simple manufacturing process, and a high precision pattern formation. As means for solving these problems, a method for manufacturing an EL element of forming a light emitting layer by patterning using a photolithography method has been proposed. According to the method, compared with the conventionally conducted patterning method by the deposition, since a vacuum equipment comprising a highly accurate alignment mechanism, or the like is not needed, manufacturing can be conducted relatively easily and inexpensively. In contrast, compared with the patterning method using the ink jet method, it is preferable in that a pre-process to a structure, base substance, or the like for aiding patterning, is not conducted. Furthermore, from the relationship with the ejection accuracy of an ink jet head, the photolithography method is considered as a more preferable method for a high precision pattern formation, and thus it is advantageous. As a method for forming a plurality of light emitting parts by such photolithography method, for example, a method shown in FIG. 5 has been proposed. First, as shown in FIG. 5A , a patterned first electrode layer 32 is formed on a base substance 31 , and furthermore, a first light emitting layer coating solution 33 is coated on the entire surface thereon. Then, as shown in FIG. 5B , a positive type resist 34 is coated on the entire surface, and as shown in FIG. 5C , masking only the part, which a first light emitting part is to be formed, with a photomask 35 , it is exposed with an ultraviolet ray 36 excluding the part. By developing the same with a resist developing agent and cleaning with water, the resist in the exposed part is removed a shown in FIG. 5D . Furthermore, by developing with a solvent of the light emitting layer, as shown in FIG. 5E , the bared first light emitting layer 33 is removed, so that the resist and a first light emitting part 33 ′ covered with the resist remain. Then, by the same method for forming the first light emitting part 33 ′, as shown in FIG. 5F , a second light emitting layer coating solution 37 is coated on the entire surface. At the time, as it is apparent from FIG. 5F , there is a part where the second light emitting layer coating solution 37 coated on the entire surface and the first light emitting part 33 ′ are contacted with each other. That is, as mentioned above, the first light emitting part 33 ′ remaining on the base substance 31 has its surface covered with the positive type resist, but the end part “a” developed with the light emitting layer developing agent is bared. Therefore, when the second light emitting layer coating solution 37 is coated thereon, the first light emitting part 33 ′ and the second light emitting layer coating solution are contacted at the end part “a”. At the time, there is a problem of generating troubles of color mixture or pixel narrowing due to elution of the first light emitting part into the second light emitting layer coating solution. Furthermore, as shown in FIG. 5G , the positive type resist 34 is coated on the entire surface, and as shown in FIG. 5H , masking the parts, which the first and second light emitting parts are to be formed, with the photomask 35 , the other part is exposed with the ultraviolet ray 36 . By developing the same with a resist developing agent, cleaning with water, and furthermore, developing with a solvent of the light emitting layer, as shown in FIG. 5I , only the bared second light emitting layer 37 is removed so that a second light emitting part 37 ′ covered with the resist 34 is formed. Furthermore, by the same method for forming the first and second light emitting parts, as shown in FIG. 5J , a third light emitting layer coating solution 38 is coated. At the time, as it is apparent from FIG. 5J , the first light emitting part and the third light emitting layer coating solution are contacted at the end part “a” of the first light emitting part 33 ′ formed initially, and furthermore, the second light emitting part and the third light emitting layer coating solution are contacted at the end part “b” of the second light emitting part 37 ′. Similarly, at the time, there is a possibility of generating troubles of color mixture, pixel narrowing, or the like due to elution of the first light emitting part 33 ′ and the second light emitting part 37 ′ into the third light emitting layer coating solution. Furthermore, as shown in FIG. 5K , the positive type resist 34 is coated on the entire surface, and masking the parts, which the first, second and third light emitting parts are to be formed, with the photomask 35 , the other part is exposed with the ultraviolet ray 36 . By developing the same with a resist developing agent, cleaning with water, and developing with a solvent of the light emitting layer, as shown in FIG. 5L , only the bared third light emitting layer 38 is removed so that only the part covered with the resist remains. Furthermore, by conducting a peeling treatment with a resist peeling solution, the layers above the part which the resist is formed are peeled off so that the light emitting parts of three colors including the first light emitting part 33 ′, the second light emitting part 37 ′ and the third light emitting part 38 ′ are formed in a bared state as shown in FIG. 5M . Finally, as shown in FIG. 5N , by forming a second electrode layer 39 on these light emitting parts, an EL element which discharges an EL light emission 40 to the lower direction in the figure can be manufactured. As mentioned above, according to the photolithography method, since the patterned end part “a” of the first light emitting part and the end part “b” of the second light emitting part are not covered with the photoresist layer, there is a problem that the patterned light emitting parts elute into the light emitting layer coating solution to be coated later at the end part thereof so as to generate color mixture and pixel narrowing at the time of coating the subsequent light emitting layer coating solution. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a process diagram showing a first example of a first embodiment according to the method for manufacturing an EL element of the present invention. FIG. 2 is a process diagram showing a second example of the first embodiment according to the method for manufacturing an EL element of the present invention. FIG. 3 is a process diagram showing a first example of a second embodiment according to the method for manufacturing an EL element of the present invention. FIG. 4 is a process diagram showing a second example of the second embodiment according to the method for manufacturing an EL element of the present invention. FIG. 5 is a process diagram showing the conventional method for manufacturing an EL element. detailed-description description="Detailed Description" end="lead"? |
Heat sink for semiconductor components or similar devices, method for producing the same and tool for carrying out said method |
A heat sink for semiconductor components or similar devices, especially produced from an extruded aluminum alloy. The heat sink comprises cooling ribs which rise at a distance from a base plate and which are clamped in an insert groove made in the surface of the base plate, laterally limited by longitudinal or intermediate ribs with a coupling base that has an approximately rectangular cross-section. The coupling bases are held in their insert grooves in a form-fit and are cold-welded with the base plate at least in some sections. Cross ribs extend at a distance to one another on the surfaces of the intermediate ribs and have the form of upset heels that are linked with the coupling base in a form-fit. |
1-17 (cancelled): 18. A heat sink, comprising: a base plate having a surface; at least two spaced apart intermediate ribs on the surface, wherein the spaced apart intermediate ribs extend substantially parallel to each other in a longitudinal direction and define therebetween an insertion groove; at least one cooling rib having a coupling base which engages in the insertion groove, wherein the coupling base is held in an interlocking manner in the insertion groove; and a plurality of spaced apart transverse ribs on the intermediate ribs, wherein the transverse ribs extend substantially perpendicular to the insertion groove and abut the coupling base of the at least one cooling rib. 19. A heat sink according to claim 18, including a plurality of spaced apart intermediate ribs defining a plurality of insertion grooves for securing the coupling base of a plurality of cooling ribs. 20. A heat sink according to claim 18, wherein one of the coupling base and the insertion groove has a substantially rectangular cross-section. 21. A heat sink according to claim 18, wherein one of the coupling base and the insertion groove has a substantially trapezoidal cross-section. 22. A method of producing a heat sink comprising: providing a base plate having a surface, at least two spaced apart intermediate ribs on the surface, wherein the spaced apart intermediate ribs extend substantially parallel to each other in a longitudinal direction and define therebetween an insertion groove; inserting into the insertion groove at least one cooling rib having a coupling base which engages in the insertion groove, wherein the coupling base is held in an interlocking manner in the insertion groove; and thereafter forming by pressure on a top surface of the intermediate ribs a plurality of spaced apart transverse ribs on the intermediate ribs, wherein the transverse ribs extend substantially perpendicular to the insertion groove and abut the coupling base of the at least one cooling rib. 23. A method according to claim 22, including providing a plurality of spaced apart intermediate ribs defining a plurality of insertion grooves for securing the coupling base of a plurality of cooling ribs. 24. A method according to claim 23, including providing a tool for forming the transverse ribs, the tool comprises a plate insertion section which is insertable between two adjoining cooling ribs, the plate insertion section includes a bottom edge having a plurality of teeth with tooth front edges serving as pressure faces for the intermediate ribs of the base plate. 25. A method according to claim 24, wherein the length (n) of the tooth front edge corresponds to the spacing of transverse ribs on the surface of an intermediate rib. 26. A method according to claim 25, wherein the teeth have tooth flanks which are outwardly inclined from the tooth front edge at an acute angle (w1). 27. A method according to claim 24, wherein the free end of the teeth is one of cross-sectionally pitch circle-shaped, trapezoidal, and triangular in design. 28. A method according to claim 24, wherein a spatula-like tool plate with a linear arrangement of the tooth front edges of teeth are provided in a crenellated manner. 29. A method according to claim 28, wherein a side edge which are inclined at an angle (w1) issues from the linear section of the tooth front edges, at least at one end. 30. A method according to claim 29, wherein the teeth are arranged on one insertion section of the tool plate, of which the cross-sectional width (s1) is less than the spacing (z) of the cooling ribs from one another, and is abutted by a gripping section. 31. A method according to claim 30, wherein the thickness (s) of the gripping section is greater than the spacing (z) of the cooling ribs from one another. 32. A method according to claim 24, wherein the tool is a circular toothed disc. 33. A method according to claim 24, arranging a further tool plate with a linear bottom edge downstream in a feed direction (x) of the heat sink after the tool plate containing the teeth. 34. A method according to claim 24, wherein the bottom edge of the tool plate partially has teeth and is partially designed in a linear manner. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The invention relates to a heat sink for semiconductor components or similar devices, in particular made of an extruded aluminium alloy, with cooling ribs projecting from a base plate at a spacing from one another, and each being held in a clamping manner by a coupling base which is approximately rectangular in cross-section in an insertion groove which is introduced into the surface of the base plate, by means of longitudinal or intermediate ribs laterally bordering this insertion groove. The invention also relates to a method for producing a heat sink of this type and a tool for this. Heat sinks of this type can be inferred from DE 25 02 472 A1; insertion grooves of the base housing which taper conically towards the groove base are provided for the cooling ribs on a heat sink for thyristors. These are pressed with over-dimension into the insertion grooves which are provided with longitudinal grooves in the two side walls. While in this case a minimum thickness of the rib is required in order to be able to receive the necessary pressure forces in the joining method, only an interlocking bond can be achieved in the method according to DE 35 18 310 A1. According to the teaching of this document, extruded solid profiles with lateral recesses are inserted in an interlocking manner as cooling ribs into the insertion grooves of the separately produced base plate. The groove walls of the insertion groove, after insertion of the cooling rib, are formed by a tool which is wedge-like in design and can be retracted between two cooling ribs, the tool being inserted into an auxiliary groove with a V-shaped cross-section and partially pressing the material of the housing base into parallel grooves of the cooling rib. In both cases the insertable number of ribs—and therefore the achievable heat-dissipating surface—is limited, on the one hand, by the required minimum thickness of the cooling ribs and, on the other hand, by the required minimum width of the intermediate grooves. In light of the prior art, the inventors have set themselves the task of developing a new heat sink form and new manufacturing method, owing to which a higher number of ribs and therefore a larger surface can be achieved with simultaneously improved heat transfer between the heat sink base and inserted cooling ribs. |
<SOH> SUMMARY OF THE INVENTION <EOH>The foregoing object is achieved by the present invention. According to the invention, transverse ribs, as compression beads, extend spaced from one another on the surfaces of the intermediate ribs on the base plate of the heat sink and abut the coupling base of cooling ribs in an interlocking manner and improve the bond. According to a further feature of the invention, the low intermediate ribs and insertion grooves have a rectangular to slightly trapezoidal cross-section. Within the scope of the invention is a method for producing a heat sink, in which after insertion of the cooling rib, the intermediate rib of the base plate is formed by pressure on the rib surface thereof and transverse ribs, as compression beads, extending on the surface of the intermediate ribs at a spacing from one another between two cooling ribs are produced and in which a transverse pressure component and a relative movement are generated between the coupling base and the groove walls flanking it. Owing to the press pressure exerted from above, after insertion of the coupling base onto the intermediate ribs, by a comparatively wide and blunt pressing edge, the intermediate ribs are thus partially formed and said compression beads are produced on the intermediate rib and rest in an interlocking manner on the coupling base. Apart from the transverse pressure components forming during the forming process, a relative movement is achieved between the groove walls and the coupling base which by interaction leads at least partially to cold weldings. After the actual pressure process, the transverse ribs produced thereby can be again subjected to pressure and thus additionally compressed. A tool which is designed so as to be lowerable between two cooling ribs and is equipped with a plurality of teeth which offer tooth front edges serving as pressure faces for the intermediate ribs of the base plate at the bottom edge of a plate-like insertion section, has proven particularly advantageous for this method. The length of these tooth front edges preferably corresponds to the spacing of transverse ribs on the surface of the intermediate rib. Tooth flanks which are outwardly inclined at an acute angle issue from the tooth front edge. It has also proved favourable for the free end of the teeth to be cross-sectionally pitch circle-shaped or trapezoidal or even rectangular in design. In a preferred configuration, the tool is produced as a spatula-like tooth plate with linear arrangement of the tooth front edges of teeth provided in a crenellated manner, wherein a side edge which is inclined at an angle is to issue from the linear section of the tooth front edges, at least at one end. According to a different feature of the invention, the teeth are arranged on an insertion section of the tool plate, the cross-sectional width of which is less than the spacing of the cooling ribs from one another and abuts a gripping section which can preferably be connected to a whole tool. Moreover, the thickness of the gripping section is to be greater than the spacing of the cooling ribs from one another to ensure the stability in the pressure process. In another configuration, the tool plate is to be a circular toothed disc which rotates about a shaft and in the process machines the tangentially running heat sink. According to the invention a tool plate with a linear bottom edge can be arranged downstream in the feed direction of the moved heat sink from the tool plate containing the teeth. The process sequence described by means of pressing with a clocked feed of the profile parts to be connected can also be carried out in a rolling manner. In this instance, the base plate which is fitted with the cooling ribs, as a base profile, traversing a station with circular toothed discs and subsequent even discs. However, it is also possible to design a tool such that the bottom edge of the tool plate partly has teeth and is partly linear in design. |
Antimicrobial, anti-inflammatory, wound-healing and disinfecting glass and use thereof |
The invention relates to an antimicrobial, anti-inflammatory and disinfecting glass, whereby the glass comprises: 30-95 wt. % SiO2,0-40 wt. % Na 2O, 0-40 wt. % K2O, 0-40 wt. % Li2O, 0-35 wt. % CaO, 0-10 wt. % MgO, 0-10 wt. % Al2O3, 0-15 wt. % P2O5 wt. % B2O3?, 0-10 wt. % NaF, 0-10 wt. % LiF, 0-10 wt. % KF, 0-10 wt. % CaF2, 0-5 wt. % Ag2O, 0-10 wt. % MgF2,0-2 wt. % Fe2O3and 0-10 wt. % XJy, where X═Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Ag or Zn and y=1 or y=2 and the sum of XJy>is 10 ppm. |
1. An antimicrobial, ant-inflammatory and disinfecting glass, whereby the glass contains: 30-60 wt % SiO2 2-40 wt % Na2O 0-40 wt % K2O 0-40 wt % Li2O 5-40 wt % CaO 0-10 wt % MgO 0-10 wt % Al2O3 1-15 wt % P2O5 0-5 wt % B2O3 0-10 wt % NaF 0-10 wt % LiF 0-10 wt % KF 0-10 wt % CaF2 0-5 wt % Ag2O 0-10 wt % MgF2 0-2 wt % Fe2O3 0-10 wt % XIy, where X is Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, Ba, Ag, Zn and y=1 or 2 and where the sum of XIy is >10 ppm, preferred >100 ppm, especially preferred >500 ppm, especially >1 wt %, especially preferred >2 wt %. 2. The antimicrobial, ant-inflammatory and disinfecting glass, according to claim 1, wherein the sum of Na2O+K2O+Li2O≧5 wt %. 3. The antimicrobial, anti-inflammatory and disinfecting glass, according to claim 1, wherein the glass contains: 5-35 wt % Na2O 2-10 wt % P2O5 4. The antimicrobial, anti-inflammatory and disinfecting glass powder wherein the glass powder consists of a glass of composition according to claim 1. 5. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4, wherein the glass particle size is ≦100 μm. 6. The antimicrobial, anti-inflammatory and disinfecting glass powder according to claim 4, wherein the particle size is ≦20 μm, especially ≦10 μm. 7. The antimicrobial, anti-inflammatory and disinfecting glass powder according to claim 4, wherein the glass particle size is <5 μm. 8. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4, wherein the glass particle size is <1 μm. 9. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4, as a food preserving additive and as a foodstuff supplement. 10. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4, for use in cosmetic products. 11. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4, for use in deoderant products. 12. The antimicrobial, anti-inflammatory and disinfecting glass powder, according claim 4, for use in antiperspiration means or antiperspirants. 13. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4 for use in dyes and lacquers. 14. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4 for use in medicinal products and preparations. 15. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4 for use in plastics and polymers. 16. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4 for use in sanitary paper. 17. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4 for use in purification means. 18. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4 for use in the field of medicine. 19. The antimicrobial, anti-inflammatory and disinfecting glass, according to claim 4, wherein the glass powder according to claim 4 for use in the field of medicine, especially for the care of wounds. 20. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4 for use in dental medicine. 21. The antimicrobial, anti-inflammatory and disinfecting glass powder, according to claim 4 for use in the field of dental medicine as an antimicrobial and disinfecting additive in dental hygiene. 22. The antimicrobial, ant-inflammatory and disinfecting glass powder, according to claim 4 for use in the field of dental medicine as an anti-inflammatory additive for avoidance of gum bleeding. |
Strip conductor arrangement and method for producing a strip conductor arrangement |
An interconnect arrangement comprises a substrate made from a first insulating material with a substrate surface, at least two interconnects which are arranged next to one another in the substrate, a buffer layer made from a second insulating material above the substrate and comprising a buffer-layer surface, which is parallel to the substrate surface, at least one cavity, which is arranged between the interconnects and, with respect to the buffer-layer surface, extends deeper into the substrate than the interconnects, and a covering layer made from a third insulating material, which is arranged above the buffer layer and completely closes off the cavity with respect to the buffer-layer surface. |
1-34. (canceled) 35. A method for fabricating an interconnect arrangement, comprising: producing at least two electrically conductive interconnects in a substrate below a substrate surface by means of a first lithography and etching method, the substrate comprising a first electrically insulating material and the interconnects comprising an electrically conductive material, and the interconnects being arranged next to one another in the substrate, producing a buffer layer made from a second electrically insulating material above the substrate surface, the buffer layer comprising a buffer-layer surface which is parallel to the substrate surface, producing a cavity, which runs between the interconnects and extends from the buffer-layer surface through the buffer layer into the substrate, by means of a second lithography and etching method, the cavity, with respect to the buffer-layer surface, extending deeper into the substrate than the interconnects, producing a covering layer made from a third electrically insulating material above the buffer layer, so that the cavity is completely closed off with respect to the buffer-layer surface, and wherein the interconnect arrangement is formed from the substrate, the interconnects, the buffer layer and the covering layer, and arranging a supporting layer made from a fourth electrically insulating material above the buffer-layer surface, the fourth electrically insulating material being different from the first, second or third electrically insulating material, the third electrically insulating material being adapted for optional selective deposition only on the fourth electrically insulating material. 36. A method for fabricating an interconnect arrangement, comprising: producing at least two electrically conductive interconnects in a substrate below a substrate surface by means of a first lithography and etching method, the substrate comprising a first electrically insulating material and the interconnects comprising an electrically conductive material, and the interconnects being arranged next to one another in the substrate, producing a buffer layer made from a second electrically insulating material above the substrate surface, the buffer layer comprising a buffer-layer surface which is parallel to the substrate surface, producing a cavity, which runs between the interconnects and extends from the buffer-layer surface through the buffer layer into the substrate, by means of a second lithography and etching method, the cavity, with respect to the buffer-layer surface, extending deeper into the substrate than the interconnects, producing a covering layer made from a third electrically insulating material above the buffer layer, so that the cavity is completely closed off with respect to the buffer-layer surface, and wherein the interconnect arrangement is formed from the substrate, the interconnects, the buffer layer and the covering layer, and producing from the buffer-layer surface several cavities extending between the interconnects. 37. A method according to claim 35, in which the interconnects are produced as buried interconnects in the substrate. 38. A method according to claim 35, further comprising, before the covering layer is produced, producing an additional cavity between the buffer-layer surface and the interconnects above the interconnects, the additional cavity extending less deeply into the buffer layer or the substrate, respectively, than the cavity. 39. A method according to claim 35, in which the covering layer is produced in a process with a low edge coverage. 40. A method according to claim 35, further comprising producing a plurality of cavities, which extend between the interconnects, starting from the buffer-layer surface. 41. A method according to claim 36, further comprising producing a supporting layer made from a fourth electrically insulating material above the buffer-layer surface, the fourth electrically insulating material being different from the first, second or third electrically insulating material, and the third electrically insulating material optionally being deposited selectively only on the fourth electrically insulating material. 42. A method according to claim 35, wherein the cavity is produced by first producing a suitable etching mask on the supporting layer, then using an etching process in regions of the supporting layer which are not covered by the etching mask to remove material from the supporting layer, the buffer layer and the substrate in a predetermined way, and then removing the etching mask. 43. A method according to claim 42, further comprising providing a substrate which comprises a stop layer below the interconnects, relative to the substrate surface, and in which the etching process for producing the cavity in the substrate is delimited at the bottom by means of the stop layer. 44. A method according to claim 43, further comprising selectively removing the stop layer in the region of the cavity, so that regions of the substrate which are arranged below the stop layer are uncovered. 45. A method according to claim 35, wherein the producing a covering layer comprises selectively depositing third electrically insulating material only on the fourth electrically insulating material, at least until the cavity has been completely closed off, and then partially removing the third electrically insulating material which has been deposited on the supporting layer by chemical mechanical polishing to level the covering layer. 46. A method according to claim 35, further comprising producing an additional stop layer, adapted for application of additional interconnect layers thereto, above the supporting layer and the covering layer. 47. A method according to claim 35, in which the interconnects are arranged at a spacing from one another which is less than the extent of the cavity in the direction of the spacing between the interconnects above and/or below the interconnects. 48. A method according to claim 35, in which the producing the interconnects comprising producing the interconnects at substantially the same depth with respect to the substrate surface, further wherein producing the cavity comprising producing the cavity extending substantially vertically into the substrate. 49. A method according to claim 35, further comprising encapsulating the interconnects with a thin encapsulation layer made from an encapsulation material, the encapsulation material being mechanically harder than the electrically conductive material, mechanically harder than the first electrically insulating material and mechanically harder than the second electrically insulating material. 50. A method according to claim 35, in which the interconnects are produced at least partially on electrically conductive regions in the substrate, for making electrical contacts between various interconnect layers. 51. A method according to claim 35, in which the cavity is formed as partially extending into the covering layer. 52. A method according to claim 35, in which the covering layer, in the region of the buffer layer, extends partially into the cavity, the covering layer, as seen from the buffer-layer surface, comprising a decreasing edge coverage in the cavity, so that the covering layer in the cavity does not extend all the way to the substrate surface. 53. A method according to claim 35, in which the covering layer covers the buffer layer and in which there is at least one additional cavity between the interconnects and the buffer-layer surface, the cavity extending deeper into the buffer layer or the substrate than the additional cavity. 54. A method according to claim 35, further comprising forming, above the supporting layer and the covering layer, an additional stop layer adapted for provision of additional interconnects thereon. 55. A method according to claim 35, in which the interconnects are arranged at a distance from one another which is less than the extent of the cavity in the direction of the spacing between the interconnects above and/or below the interconnects. 56. A method according to claim 35, in which the first electrically insulating material and the second electrically insulating material are identical. 57. A method according to claim 35, in which the first electrically insulating material and/or the second electrically insulating material and/or the third electrically insulating material and/or the fourth electrically insulating material are/is a low-k material which has a relative dielectric constant εr in the range between 1 and 4. 58. A method according to claim 35, in which the first electrically insulating material and/or the second electrically insulating material and/or the third electrically insulating material and/or the fourth electrically insulating material comprise(s) an organic material. 59. A method according to claim 35, in which the first electrically insulating material and/or the second electrically insulating material and/or the fourth electrically insulating material comprise(s) silicon dioxide. 60. A method according to claim 49, in which the encapsulation material is a nitride compound. 61. A method according to claim 35, in which the interconnects are arranged at least partially on electrically conductive regions in the substrate for making electrical contacts between various interconnect layers. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The invention relates to an interconnect arrangement and to a method for fabricating an interconnect arrangement. Integrated circuit arrangements are being produced with an ever greater packing density. The result of this is that interconnects in metallization layers are at an ever decreasing spacing from one another. As a result, capacitances which are formed between the interconnects rise and lead to high signal propagation times, high power losses and crosstalk. Hitherto, SiO 2 , the relative dielectric constant of which is ε r =3.9, has primarily been used as the dielectric for providing insulation between the interconnects. There are a number of known methods for reducing the relative dielectric constant ε r and therefore for reducing the capacitance between interconnects within an interconnect layer, for example from J. G. Fleming et al.: “Lowering of Intralevel Capacitance Using Air Gap Structures”, Conference Proceedings ULSI XII, Materials Research Society, pp. 471-477, 1997; T. Ueda et al.: “A Novel Air Gap Integration Scheme for Multi-level Interconnects using Self-aligned Via Plugs”, IEEE Proc. 1998 Symp. VLSI Techn. Digest of Technical Papers, pp. 46-47, 1998; B. Shieh et al.: “Integration and Reliability Issues for Low Capacitance Air-Gap Interconnect Structure”, IEEE Proc. 1998 IITC, pp. 125-127, 1998; B. Shieh et al.: “Air-Gap Formation During IMD Deposition to Lower Interconnect Capacitance”, IEEE Electron Device Letters, Vol. 19, No. 1, pp. 16-18, 1998; B. Shieh et al.: “Air gaps lower k of interconnect dielectrics”, Solid State Technology, pp. 51-58, February 1999; T. Ueda et al.: “Integration of 3 Level Air Gap Interconnect for Sub-quarter Micron CMOS”, IEEE Proc. 1999 Symp. VLSI Techn. Digest of Technical Papers, 1999; V. Arnal et al.: “Integration of a 3 Level Cu—SiO 2 Air Gap Interconnect for Sub 0.1 micron CMOS Technologies”, IEEE Proc. 2001 IITC, 2001; and V. Arnal et al.: “A Novel SiO 2 -Air Gap Low K for Copper Dual Damascene Interconnect”, Conference Proceedings ULSI XVI, Materials Research Society, pp. 71-76, 2001. According to the prior art, cavities are produced between the interconnects within an interconnect layer. The insulating dielectric, which determines the capacitance between the interconnects, therefore has a relative dielectric constant ε r which is almost equal to 1. For insulation purposes, the interconnects themselves are enclosed at the top and bottom by solid SiO 2 layers. Since the capacitances of the insulating layers above and below also make a not insignificant contribution to the overall capacitance between interconnects which adjoin one another within a layer, and these insulating layers still consist of solid SiO 2 material, the high relative dielectric constant ε r of these insulating layers has a considerable influence onto the overall capacitance between the adjacent interconnects. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention is therefore based on the problem of providing an interconnect arrangement and a method for fabricating an interconnect arrangement in which the cavities between the interconnects take up as much space as possible, with a suitable geometry and distribution. The problem is solved by an interconnect arrangement and by a method for fabricating an interconnect arrangement. An interconnect arrangement comprises a substrate made from a first electrically insulating material with a substrate surface. Furthermore, at least two electrically conductive interconnects, which comprise an electrically conductive material, are arranged in the substrate. Moreover, the interconnect arrangement comprises a buffer layer made from a second electrically insulating material above the substrate surface, the buffer layer comprising a buffer-layer surface, which is parallel to the substrate surface. At least one cavity extends from the buffer-layer surface through the buffer layer into the substrate, the cavity being arranged between the interconnects and, with respect to the buffer-layer surface, extending deeper into the substrate than the interconnects. Above the buffer layer, there is arranged a covering layer which comprises a third electrically insulating material and completely closes off the cavity with respect to the buffer-layer surface. In a method for fabricating an interconnect arrangement, first of all at least two electrically conductive interconnects are produced in a substrate below a substrate surface, the substrate comprising a first electrically insulating material and the interconnects comprising an electrically conductive material. The interconnects are arranged next to one another in the substrate. Then, a buffer layer made from a second electrically insulating material is produced above the substrate surface, the buffer layer comprising a buffer-layer surface, which is parallel to the substrate surface. Then, a cavity, which runs between the interconnects and extends from the buffer-layer surface through the buffer layer into the substrate, is produced, the cavity, with respect to the buffer-layer surface, extending deeper into the substrate than the interconnects. Finally, a covering layer made from a third electrically insulating material is produced above the buffer layer, so that the cavity is completely closed off with respect to the buffer-layer surface. The substrate, the interconnects, the buffer layer and the covering layer therefore form the interconnect arrangement. One advantage of the invention is that, on account of the very large cavity as insulating layer between adjacent interconnects, the effective relative dielectric constant ε r of the insulating layer between the adjacent interconnects deviates only slightly from one, and therefore the capacitance between these interconnects is reduced. The interconnect arrangement allows a considerable reduction in the overall capacitance within an integrated circuit. A further advantage of the interconnect arrangement is that the cavity considerably reduces undesirable leakage fields between the interconnects, which are produced by the interconnects above and/or below the actual interconnect layer in the interconnect arrangement. Therefore, the effective relative dielectric constant ε r , which is influenced both by the relative dielectric constant of the cavity and by that of the surrounding material, is approximately two. In this case, the value of the effective relative dielectric constant ε r is dependent on the geometry of the entire interconnect arrangement. Furthermore, there is the advantage of a high stability during the fabrication of the interconnect arrangement, since, during the planarization of the interconnects in a chemical mechanical polishing (CMP) operation during production of the interconnects, the latter are still embedded in the solid substrate. The cavity is only introduced into the substrate after the interconnects have been produced, and therefore the mechanical stability of the substrate is only reduced at that time. Moreover, coupling capacitances between the interconnects are avoided on account of etching and/or CMP stop layers. This is because these stop layers, during production of the cavity, preferably by means of etching, are interrupted in such a manner that adjacent interconnects are not in physical contact as a result of a stop layer of this type. After completion of the interconnect arrangement, the cavity preferably contains air, a vacuum or an electrically insulating gas in order to improve the resistance to electrical spark-overs, for example sulphur hexafluoride (SF 6 ). The interconnects may be buried in the substrate. The cavity preferably extends partially into the covering layer situated on the substrate. This contributes to an additional reduction in the effective relative dielectric constant ε r . In a preferred embodiment of the interconnect arrangement according to the invention, the covering layer, in the region of the buffer layer, extends partially into the cavity. In this case, the covering layer, as seen from the buffer-layer surface, comprises a decreasing edge coverage in the cavity, so that the covering layer in the cavity does not extend all the way to the substrate surface. This configuration of the interconnect arrangement results from the method which is used to fabricate the cavity or the covering layer, as described below. The decreasing edge coverage within the cavity is important so that, according to this embodiment of the invention, there is no increase in the effective relative dielectric constant ε r . The covering layer preferably covers the buffer layer, and there is at least one additional cavity between the interconnects and the buffer-layer surface, above the interconnects. Consequently, this additional cavity can extend less deeply into the substrate than the cavity, since the additional cavity is delimited at the bottom by the interconnects. The additional cavity allows the effective relative dielectric constant ε r to be additionally reduced, since consequently it is also possible to dispense with a solid insulating layer with a high effective relative dielectric constant ε r above the interconnects. To allow additional interconnect layers to be applied to the interconnect arrangement, the covering layer is preferably delimited by a covering-layer surface which is arranged parallel to the substrate surface. Preferably a plurality of cavities extends between two adjacent interconnects into the substrate starting from the buffer-layer surface. If a plurality of cavities of small volume are used instead of a single cavity of large volume, the small cavities being separated from one another by means of thin partition walls, it is possible to increase the stability of the interconnect arrangement according to the invention. The thin partition walls then serve as a type of mechanical support for additional interconnect layers arranged above the interconnect arrangement according to the invention. Obviously, the thin partition walls can also be referred to as posts. According to a preferred embodiment of the interconnect arrangement according to the invention, a supporting layer made from a fourth electrically insulating material is arranged above the buffer-layer surface. The fourth electrically insulating material is different from the first, second and third electrically insulating material, and the third electrically insulating material can be deposited selectively only on the fourth electrically insulating material. It is preferable for a stop layer to be provided in the substrate below the interconnects relative to the substrate surface. This stop layer delimits the cavity at the bottom. The stop layer is designed in particular as a barrier for the etching process which is to be used to fabricate the cavity, so that during the etching of the substrate the depth of the cavity which is to be etched can be set exactly. If, in a separate etching process in uncovered regions of the stop layer, the latter is removed selectively until regions of the substrate which lie below it have been uncovered, the depth of the cavity can additionally be increased by the thickness of the stop layer. This allows the effective relative dielectric constant ε r to be reduced further. In addition, an additional stop layer may be provided above both the supporting layer and the covering layer, and additional interconnect layers can then be provided on the additional stop layer. In this case, the additional stop layer serves as a barrier to protect the structures located beneath this additional stop layer during fabrication of the additional interconnect layers located above it. The interconnects are preferably arranged at a spacing from one another which is less than the extent of the cavity in the direction of the spacing between the interconnects above and/or below the interconnects. Obviously, the shape of the cavity is then similar to an “I” or to a bone. The greater extent of the cavity above and/or below the interconnects contributes to additionally reducing the effective relative dielectric constant ε r . It is preferable for the first electrically insulating material and the second electrically insulating material to be identical. Furthermore, the first electrically insulating material and/or the second electrically insulating material and/or the third electrically insulating material and/or the fourth electrically insulating material are/is preferably a low-k material which has a relative dielectric constant ε r in the range between 1 and 4. Since the covering layer also makes a contribution to the overall capacitance between adjacent interconnects, it should be ensured that the third electrically insulating material, which is used for the covering layer, also has a low relative dielectric constant ε r . In a preferred embodiment of the interconnect arrangement according to the invention, the first electrically insulating material and/or the second electrically insulating material and/or the third electrically insulating material and/or the fourth electrically insulating material include(s) an organic material. However, the first electrically insulating material and/or the second electrically insulating material and/or the fourth electrically insulating material of the interconnect arrangement preferably include(s) silicon dioxide (SiO 2 ). If organic material is used, it is preferable for polymers to be applied in a methane environment during a PECVD process (PECVD= p lasma e nhanced c hemical v apour d eposition). The interconnects are preferably arranged at substantially the same depth with respect to the substrate surface, and the cavity extends substantially vertically into the substrate. According to a further preferred embodiment of the interconnect arrangement according to the invention, the interconnects are encapsulated by a thin encapsulation layer made from an encapsulation material. The encapsulation material is mechanically harder than the electrically conductive material, mechanically harder than the first electrically insulating material and mechanically harder than the second electrically insulating material. The encapsulation of the interconnects serves to increase the resistance of the interconnects to electromigration if a mechanically soft material, for example an organic material, is selected as the first electrically insulating material and/or as the second electrically insulating material. The encapsulation material may, for example, be a nitride compound. The interconnects may be arranged at least partially on electrically conductive regions in the substrate, so that electrical contacts can be made between various interconnect layers. In a preferred method for fabricating an interconnect arrangement, an additional cavity is produced above the interconnects between the buffer-layer surface and the interconnects before the covering layer is produced. In this case, the additional cavity is delimited at the bottom by the interconnects, so that the additional cavity extends less deeply into the buffer layer or into the substrate than the cavity. In a preferred embodiment of the method, the covering layer is produced in a process with a low edge coverage, i.e. in a non-conformal process. A process of this type ensures that only small amounts of third electrically insulating material, from which the covering layer is formed, can penetrate into the cavity. Therefore, undesirable filling of the cavity with third electrically insulating material is hindered. The third electrically insulating material of the covering layer is preferably deposited by means of a CVD process (CVD= c hemical v apour d eposition) with the minimum possible edge coverage. For this purpose, the CVD process is operated in the diffusion-determined parameter range, preferably by means of an increased pressure. As an alternative to using a CVD process, the third electrically insulating material for fabricating the covering layer may also be applied by means of a sputtering process. A third electrically insulating material, which possibly has penetrated deep into the cavity, can be removed again during an interruption to the production of the covering layer with the aid of a short isotropic etch, for example a wet-chemical etch or a dry etch in a downstream etching process. A downstream etching process of this type which can be used in accordance with the invention is described in T. Kusuki et al., Extended Abstracts of the Electrochemical Society, Vol. 93, No. 1, p. 375, 1993. Alternatively, the third electrically insulating material may also be applied by means of what is known as a spin-on process if the third electrically insulating material has a sufficient surface tension. In this case, the wetting of the buffer-layer surface should be kept as low as possible, so that as little third electrically insulating material as possible penetrates into the cavity. The covering layer may, for example, be produced in such a manner that, first of all, third electrically insulating material is deposited above the buffer-layer surface by means of a non-conformal process, until the cavity is closed off at the top. Then, third electrically insulating material is deposited above this by means of a conformal standard process. The geometry of the cavity should be selected in such a manner that during the non-conformal process scarcely any third electrically insulating material penetrates into the cavity which forms. As a result, there is only a slight coverage of the cavity walls with third electrically insulating material, with the result that the relative dielectric constant ε r of the overall interconnect arrangement is only influenced to an insignificant extent. In the case of relatively small feature sizes, such as for example a very large scale integrated circuit (VLSI circuit), it is no longer possible to detect any coverage of the cavity walls with third electrically insulating material. The cavity is preferably produced as follows: First of all, a suitable etching mask is produced on the supporting layer. Then, material from the supporting layer, the buffer layer and the substrate is removed in a predetermined way by means of an etching process in regions of the supporting layer which are not covered by means of the etching mask. Finally, the etching mask is removed again. The cavity is preferably closed up in the following way: First of all, third electrically insulating material is deposited selectively only on the fourth electrically insulating material at least until the cavity has been completely closed off. Then, the third electrically insulating material which has been deposited on the supporting layer is partially removed again by means of chemical mechanical polishing. In this way, the covering layer is levelled, so that a planar surface is formed for interconnect layers which are additionally to be applied above the covering layer. |
Nanoscale electronic devices & frabrication methods |
The invention relates to a method of forming a conducting nanowire between two contacts on a substrate surface wherein a plurality of nanoparticles is deposited on the substrate in the region between the contacts, and the single nanowire running substantially between the two contacts is formed by either by monitoring the conduction between the contacts and ceasing deposition at the onset of conduction, and/or modifying the substrate to achieve, or taking advantage of pre-existing topographical features which will cause the nanoparticles to form the nanowire. The resultant conducting nanowires are also claimed as well as devices incorporating such nanowires. |
1. A method of forming at least a single conducting chain of nanoparticles between a number of contacts on a substrate comprising or including the steps of: a. forming contacts separated by a distance smaller than 10 microns on the substrate, b. preparing a plurality of nanoparticles, and c. randomly depositing a plurality of nanoparticles on the substrate at least in the region between the contacts until the particles form at least one chain of nanoparticles between the contacts through which conduction can occur. 2. A method as claimed in claim 1 wherein the contacts are separated by a distance less than 1000 nm. 3. A method as claimed in claim 2 wherein the contacts are separated by a distance less than 100 nm. 4. A method as claimed in claim 3 wherein the nanoparticles are composed of two or more atoms, which may or may not be of the same element. 5. A method as claimed in claim 2 wherein the nanoparticles may be of uniform or non-uniform size, and the average diameter of the nanoparticles is 0.5 nm to 1,000 nm. 6. A method as claimed in claim 1 wherein the deposition step includes directing a beam of the nanoparticles towards the substrate to deposit the nanoparticles on the substrate. 7. A method as claimed in claim 6 wherein the nanoparticle preparation and deposition steps are via inert gas aggregation and the nanoparticles are atomic clusters made up of a plurality of atoms which may or may not be of the same element. 8. A method as claimed in claim 7 wherein the substrate is an insulating or semiconductor material. 9. A method as claimed in claim 8 wherein the substrate is selected from silicon, silicon nitride, silicon oxide, aluminium oxide, indium tin oxide, germanium, gallium arsenide or any other III-V semiconductor, quartz, or glass. 10. A method as claimed in claim 9 wherein the nanoparticles are selected from bismuth, antimony, aluminium, silicon, germanium, silver, gold, copper, iron, nickel or cobalt clusters. 11. A method as claimed in claim 1 wherein the contacts are formed by lithography. 12. A method as claimed in claim 1 herein the formation of the a least a single conduction chain is either by: i. monitoring the conduction between the contacts and ceasing deposition at or near to the onset of conduction, or ii. modifying the substrate surface, or taking advantage of pre-existing topographical features, so as to cause the nanoparticles to form a nanowire when deposited in the region of the modification or topographical features. 13. A method as claimed in claim 12 wherein the step of formation of the chain of conducting nanoparticles is step i., and the geometry of the contacts in relation to each other and in relation to nanoparticle size has been optimised so as to increase the likelihood of the formation of a chain of nanoparticles at a surface coverage where conduction would not normally be expected in a macroscopic film or part thereof, of the same particles. 14. A method as claimed in claim 13 wherein the optimisation is via percolation theory calculations, wherein percolation theory defines a percolation threshold, at which such an arrangement or system becomes conducting, and wherein optimisation gives rise to conduction at a surface coverage that is smaller than the percolation threshold. 15. A method as claimed in claim 14 wherein the average nanoparticle diameter is 0.5 nm to 1000 nm, the contacts are spaced apart by between 4-6× the average nanoparticle diameter; and the width of each contact is substantially more than 10× the contact spacing. 16. A method as claimed in claim 15 wherein the overall geometry of contacts is an interdigitated geometry. 17. A method as claimed in claim 16 wherein the conditions are such to discourage diffusion of the nanoparticles on the substrate surface, including the conditions of temperature, surface smoothness, and/or identity. 18. A method as claimed in claim 12 wherein the step of formation of the chain of conducting nanoparticles is via step ii., and wherein the average nanoparticle diameter is between 0.5 nm to 1000 nm. 19. A method as claimed in claim 18 wherein the modification includes formation of a step, depression or ridge in the substrate surface, running substantially between two contacts. 20. A method as claimed in claim 19 wherein the modification comprises formation of a groove having a substantially v-shaped cross-section running substantially between the contacts. 21. A method as claimed in claim 20 wherein the conditions are such to encourage diffusion of the nanoparticles on the substrate surface, including the conditions of temperature, surface smoothness and/or surface type and/or identity. 22. A method as claimed in claim 21 wherein the modification is by lithography, etching, or a combination thereof. 23. A single conducting chain of nanoparticles between a number of contacts on a substrate prepared substantially according to the method as claimed in any one of claims 1 to 22. 24. A method of forming a conducting nanowire between two contacts on a substrate surface comprising or including the steps of: a. forming the contacts separated by a distance smaller than 10 microns on the substrate, b. preparing a plurality of nanoparticles, c. randomly depositing a plurality of nanoparticles on the substrate at least in the region between the contacts, d. monitoring the formation of the conducting nanowire by monitoring conduction between the two contacts, and ceasing deposition at the onset of conduction. 25. A method as claimed in claim 24 wherein the contacts are separated by a distance smaller than 1000 nm. 26. A method as claimed in claim 25 wherein the contacts are separated by a distance smaller than 100 nm. 27. A method as claimed in claim 24 wherein the nanoparticles have an average diameter of 0.5 nm to 1,000 nm. 28. A method as claimed in claim 24 wherein the deposition step includes directing a beam of the nanoparticles towards the substrate to deposit the nanoparticles on the substrate. 29. A method as claimed in claim 28 wherein the nanoparticle preparation and deposition steps are via inert gas aggregation and the nanoparticles are atomic clusters made up of two or more atoms, which may or may not be of the same element. 30. A method as claimed in claim 24 wherein the geometry of the contacts has been optimised by percolation theory calculations to provide a conducting nanowire at a surface coverage of nanoparticles on the substrate, in the region between the contacts, of less than the percolation threshold. 31. (Canceled) 32. (Canceled) 33. A method as claimed in claim 30 wherein the surface coverage is substantially in the region of 20%. 34. A method as claimed in claim 30 wherein the optimal geometry requires: a rectangular region between the contacts or a geometrically equivalent region such as interdigitated contacts; the contacts spaced apart by less than 60× the average nanoparticle diameter, and the width of each contact being between more than 10× the contact spacing. 35. A method as claimed in claim 34 wherein: the contacts are spaced apart by between 4-6× the average nanoparticle diameter; and the length of each contact is substantially more than 10× the contact spacing. 36. A method as claimed in claim 35 wherein the overall geometry of contacts is an interdigitated geometry. 37. A method as claimed in claim 36 wherein the conditions are such to discourage diffusion of the nanoparticles on the substrate surface, including the conditions of temperature, surface smoothness and/or surface type and/or identity. 38. A method as claimed in claim 28 wherein the substrate has a topograhy in the region between the contacts that promotes the formation of a conducting path of nanoparticles between the contacts. 39. A method as claimed in claim 38 wherein the method includes an additional step before or after step a) or b) but at least before step c) of: modifying the surface to provide topographical assistance to the positioning of the depositing nanoparticles in order to give rise to a conducting pathway. 40. A method as claimed in claim 39 wherein the modification includes formation of a step, depression, ridge or groove in the substrate surface, running substantially between two contacts. 41. (Canceled) 42. A method as claimed in claim 40 wherein the modification is by lithography, etching, or a combination thereof. 43. A method as claimed in claim 42 wherein the conditions are such to encourage diffusion of the nanoparticles on the substrate surface, including the conditions of temperature, surface smoothness and/or surface type and/or identity. 44. A method as claimed in claim 24 wherein the substrate is an insulating or semiconducting material. 45. A method as claimed in claim 44 wherein the substrate is selected from silicon, silicon nitride, silicon oxide, aluminium oxide, indium tin oxide, germanium, gallium arsenide or any other Ill-V semiconductor, quartz, or glass. 46. A method as claimed in claim 24 wherein the nanoparticles are selected from bismuth, antimony, aluminium, silicon, germanium, silver, gold, copper, iron, nickel or cobalt clusters. 47. A conducting nanowire between two contacts on a substrate surface prepared substantially according to the method claimed in any one of claims 24 to 43. 48. A method of forming a conducting nanowire between two contacts on a substrate surface comprising or including the steps of: a. forming the contacts separated by a distance smaller than 10 microns on the substrate, b. preparation of a plurality of nanoparticles, c. randomly depositing a plurality of nanoparticles, on the substrate in the region between the contacts, d. achieving a single nanowire running substantially between the two contacts by either: i. monitoring the conduction between the contacts and ceasing deposition at the onset of conduction, or ii. modifying the substrate to achieve, or taking advantage of pre-existing topographical features which will cause the nanoparticles to form the nanowire. 49. A method as claimed in claim 48 wherein the contacts are separated by a distance smaller than 1000 nm. 50. A method as claimed in claim 49 wherein the contacts are separated by a distance smaller than 100 nm. 51. A method as claimed in claim 48 wherein the average diameter of the nanoparticles is 0.5 nm to 1,000 nm, and may be of uniform or non-uniform size. 52. A method as claimed in claim 48 wherein the deposition step includes directing a beam of the nanoparticles towards the substrate to deposit the nanoparticles on the substrate. 53. A method as claimed in claim 52 wherein the nanoparticle preparation and deposition steps are via inert gas aggregation and the nanoparticles are atomic clusters made up of two or more atoms which may or may not be of the same element. 54. A method as claimed in claim 53 wherein the contacts are formed by lithography. 55. A method as claimed in claim 54 wherein the substrate is an insulating or semiconducting material. 56. A method as claimed in claim 55 wherein the substrate is selected from silicon, silicon nitride, silicon oxide, aluminium oxide, indium tin oxide, germanium, gallium arsenide or any other III-V semiconductor, quartz, or glass. 57. A method as claimed in claim 53 wherein the nanoparticles are selected from bismuth, antimony, aluminium, silicon, germanium, silver, gold, copper, iron, nickel or cobalt clusters. 58. A conducting nanowire between two contacts on a substrate surface prepared substantially according to the method claimed in any one of claims 48 to 57. 59. A method of fabricating a nanoscale device including or requiring a conduction path between two contacts formed on a substrate, including or comprising the steps of: A. preparing a conducting nanowire between two contacts on a substrate surface as described in any one of claims 1, 24, or 48. B. incorporating the contacts and nanowire into the nanoscale device. 60. A method as claimed in claim 59 wherein the device includes two or more contacts and includes one or more of the conducting nanowires. 61. A method as claimed in claim 60 wherein the step of incorporation results in any one or more of the following embodiments: 1. two primary contacts having the conducting nanowire between them, and a least a third contact on the substrate which is not electrically connected to the primary contacts thereby capable of acting as a gate or other element in a amplifying or switching device, transistor or equivalent; and/or 2. two primary contacts having the conducting nanowire between them, an overlayer or underlayer of an insulating material and a least a third contact on the distal side of the overlayer or underlayer from the primary contacts, whereby the third contact is capable of acting as a gate or other element in a switching device, transistor or equivalent; and/or 3. the contacts and/or nanowire are protected by an oxide or other non-metallic or semi-conducting film to protect it and/or enhance its properties; and/or 4. a capping layer (which may or may not be doped) is present over the surface of the substrate with contacts and nanowire, which may or may not be the film of 3. 5. the nanoparticles being annealed on the surface of the substrate; 6. the position of the nanoparticles are controlled by a resist or other organic compound or an oxide or other insulating layer which is applied to the substrate and then processed using lithography to define a region or regions where nanoparticles may take part in electrical conduction between the contacts and another region or regions where the nanoparticles will be insulated from the conducting network. 62. A method as claimed in claim 61 wherein the device is a transistor or other switching device, a film deposition control device, a magnetic field sensor, a chemical sensor, a light emitting or detecting device, or a temperature sensor. 63. A method as claimed in claim 62 wherein the device is a deposition sensor monitoring deposition of a nanoparticle film, and includes at least a pair of contacts with an optimised geometry such that the onset of conduction in the device occurs at a surface coverage where conduction would not normally be expected in a macroscopic film of the same particles, wherein the contact spacing can be selected so as to vary the surface coverage at, or near, the onset of conduction and wherein as a result of the predefined contact spacing the onset of conduction in the nanoparticle film is used to sense when a pre-determined coverage of nanoparticles in the film has been achieved. 64. A method as claimed in claim 63 wherein the device is a deposition sensor and the nanoparticles are coated in ligands or an insulating layer such that the onset of tunnelling conduction is used to monitor the film thickness. 65. A device as claimed in claim 61 wherein conduction through the chain is initiated by an applied voltage or current, either during or subsequent to the deposition of the particles. |
<SOH> BACKGROUND TO THE INVENTION <EOH>Nanotechnology has been identified as a key technology for the 21st century. This technology is centred on an ability to fabricate electronic, optical and opto-electronic devices on the scale of a few billionths of a metre. In the future, such devices will underpin new computing and communications technologies and will be incorporated in a vast array of consumer goods. There are many advantages of fabricating nanoscale devices. In the simplest case, such devices are much smaller than the current commercial devices (such as the transistors used in integrated circuits) and so provide opportunities for increased packing densities, lower power consumption and higher speeds. In addition, such small devices can have fundamentally different properties to those fabricated on a larger scale, and this then provides an opportunity for completely new device applications. One of the challenges in this field is to develop nanostructured devices that will take advantage of the laws of quantum physics. Electrical devices with dimensions of ˜100 nm that operate on quantum principles (such as single electron transistors and quantum wires) have generally been proven at only low temperatures (<−100° C.). The challenge now is to translate these same device concepts into structures with dimensions of only a few nanometres, since the full range of quantum effects and novel device functionalities could then be available at room temperature. Indeed, as discussed below, some prototype nanoscale devices have been fabricated that demonstrate such quantum effects at relatively high temperatures. However, as is also discussed below, there remain many challenges to overcome before such devices find commercial applications. In general, there are two distinct approaches to fabricating nanoscale devices: ‘top-down’, and ‘bottom up’. In the ‘top-down’ approach, devices are created by a combination of lithography and etching. The resolution limits are determined by, for example, the wavelength of light used in the lithography process: lithography is a highly developed and reliable technology with high throughput but the current state of the art (using UV radiation) can achieve devices with dimensions ˜10 nm only at great expense. Other lithography techniques (e.g. electron beam lithography) provide (in principle) higher resolution but with a much slower throughput. The ‘bottom-up’ approach proposes the assembly of devices from nanoscale building blocks, thus immediately achieving nanoscale resolution, but the approach usually suffers from a range of other problems, including the difficulty, expense, and long time periods that can be required to assemble the building blocks. A key question is whether or not the top-down and bottom-up approaches can be combined to fabricate devices which take the best features of both approaches while circumventing the problems inherent to each approach. An example of a prior art development which attempts to use this combination of approaches is the highly successful fabrication of transistors from carbon nanotubes [1]. Contacts are fabricated using lithography, and a nanoscale building block (in the form of a nanometre thick carbon nanotube) is used to provide the conducting path between the contacts. These transistors have been shown [2,3] to exhibit quantum transport effects and to have transistor characteristics comparable to those of Si— MOSFETs used in integrated circuits, and are therefore in principle usable in commercial applications. However, the difficulty in isolating and manipulating single nanotubes to form reproducible devices may prevent widespread commercial usage. Hence the development of new techniques for the formation of nanoscale wire structures between electrically conducting contacts is an important technological problem. One simple approach to the formation of nanoscale wires is to stretch a larger wire until it is close to the breaking point with a diameter of just a few atoms (See e.g. Ref [4] and refs therein; similar effects can be achieved using scanning tunnelling microscopes). At this point the break junction can exhibit quantised conductance. This technique, while interesting, is not well suited to device formation since generally the technique is difficult to control, only a single wire can be fabricated at any time, and since multi-terminal devices cannot be easily achieved. Another approach is to use a combination of lithographic and electrochemical techniques to achieve narrow wires and/or contacts with nanometre scale spacing [5]. Electrochemical deposition of Cu allows the observation of quantised conduction and a chemical sensor has been developed from these nanowires [6]. While these devices are promising it remains to be demonstrated that they can be fabricated sufficiently controllably or reproducibly for commercial applications, or that multi-terminal or other electronic devices can be fabricated using this method. The proposal [7] that structures on the scale of a few nanometres could be formed using atomic clusters, which are nanoscale particles formed by simple evaporation techniques (see for example [8,9]), has already caught the imagination of a few groups internationally [10]. It has been shown that clusters can diffuse across a substrate [11] and then line up at certain surface features, thus generating cluster chain structures [12,13,14], although in these cases the chains are usually incomplete (have gaps) and such chains have so far not been connected to electrical contacts on non-conducting substrates. This approach is promising because the width of the wire is controlled by the size of the clusters, but the problem of positioning the clusters to form real devices on useful substrates has yet to be solved. Devices formed using atomic clusters have been reported in Refs [8,15,16]: a network of clusters is formed by an ion beam deposition method [15] between two contacts which are defined using electron beam lithography. In this work clusters were formed by deposition of atomic vapour and not by deposition of preformed nanoparticles onto the substrate. The devices exhibit the Coulomb Blockade effect at T=77K [8] but apparently quantum effects are not visible at room temperature. In this work only clusters of AuPd and Au have been employed and, importantly, in these devices conduction through the cluster network was by tunnelling. No method was described which lead to the controllable formation of a conducting path, and only two terminal devices were described, and hence a device similar to the nanotube transistors described above was not formed. A number of devices (see for example [17,18,19]) have been fabricated which incorporate single (or a very limited number) of nanoscale particles. These devices are potentially very powerful but, equally, are most likely to be subject to difficulties associated with the expense and long time periods that can be required to assemble the building blocks. Device to device reproducibility, and difficulty of positioning of the nanoparticles may be additional problems. Furthermore the preferred embodiment of these devices requires that the nanoparticle be isolated from the contacts by tunnel barriers whose properties are critical to the device performance, since tunnelling currents depend exponentially on the barrier thickness. In some cases the use of a scanning tunnelling microscope leads to a slow and not scalable fabrication process. Recent progress in this area has resulted in the first single electron transistors fabricated with a single atom as the island onto which tunnelling occurs [19]. While this is a significant achievement, and an element of self assembly in the fabrication is attractive, such devices are still far from commercial production and the methods used may not be viable for large scale production. Wet chemical methods (see for example [17]) have also been shown to be useful with respect to fabrication of nanoscale devices and offer some promise as a method of overcoming the difficulties in positioning nanoparticles. While these techniques may still be important in the future, the limitations include the limited range of types of nanoparticles that can be formed using these techniques, the difficulty in coding specific sites to attract nanoparticles, and there are so far unanswered questions regarding their suitability for scaling. Finally we mention that several experiments (see for example [20,21,22,23,24,25]) have been performed on percolation in films of metal nanoparticles. Typically nanoparticles are deposited between electrical contacts and a clear onset of conduction can be observed at the percolation threshold. The experimental literature contains no reports of percolation in films of nanoparticles where the films have nanoscale overall dimensions (i.e. where the contact separation is small) and to our knowledge there are no proposals in the literature for the use of percolating films in nanoscale devices. The use of macroscopic contact separations ensures that even at the percolation threshold the properties of the film are strongly affected by the relatively homogeneous nature of the macroscopic cluster assembled film, even though somewhere in the structure a narrow channel may exist in which a single particle or several neighbouring particles create a narrow wire-like structure. There has been no previous proposal to use nanoscale cluster chains formed at the percolation threshold in nanoscale electronic devices. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to a first aspect of the invention there is provided a method of forming at least a single conducting chain of nanoparticles between a number of contacts on a substrate comprising or including the steps of: a. forming the contacts on the substrate, b. preparing a plurality of nanoparticles, c. deposition of a plurality of nanoparticles on the substrate at least in the region between the contacts, d. formation of a conducting chain of nanoparticles between the contacts. Preferably there are two contacts which are separated by a distance smaller than 10 microns, more preferably the contacts are separated by a distance less than 1000 nm. Preferably the nanoparticles are composed of two or more atoms, which may or may not be of the same element. Preferably the nanoparticles may be of uniform or non-uniform size, and the average diameter of the nanoparticles is between 0.5 nm and 1,000 nm. Preferably the nanoparticle preparation and deposition steps are via inert gas aggregation and the nanoparticles are atomic clusters made up of a plurality of atoms which may or may not be of the same element. Preferably the substrate is an insulating or semiconductor material, more preferably the substrate is selected from silicon, silicon nitride, silicon oxide aluminium oxide, indium tin oxide, germanium, gallium arsenide or any other III-V semiconductor, quartz, or glass. Preferably the nanoparticles are selected from bismuth, antimony, aluminium, silicon, germanium, silver, gold, copper, iron, nickel or cobalt clusters. Preferably the contacts are formed by lithography. Preferably the formation of the at least a single conduction chain is either by: i. monitoring the conduction between the contacts and ceasing deposition at or near to the onset of conduction, and/or ii. modifying the substrate surface, or taking advantage of pre-existing topographical features, so as to cause the nanoparticles to form a nanowire when deposited in the region of the modification or topographical features. In one preferred embodiment the step of formation of the chain of conducting nanoparticles is step i., and the geometry of the contacts in relation to each other and in relation to nanoparticle size has been optimised so as to increase the likelihood of the formation of a chain of nanoparticles at a surface coverage where conduction would not normally be expected in a macroscopic film or part thereof, of the same particles. Preferably the optimisation is via percolation theory calculations, wherein percolation theory defines a percolation threshold, at which such an arrangement or system becomes conducting, and wherein optimisation gives rise to conduction at a surface coverage that is smaller than the percolation threshold. Preferably the average nanoparticle diameter is between 0.5 nm to 100 nm, the contacts are spaced apart by between 4-6× the average nanoparticle diameter; and the width of each contact is substantially more than 10× the contact spacing. Preferably the overall geometry of contacts is an interdigitated geometry. Preferably the conditions are such to discourage diffusion of the nanoparticles on the substrate surface, including the conditions of temperature, surface smoothness, and/or identity. Preferably the nanowire structure is encapsulated in an insulating or dielectric material which protects it from oxidisation and allows the fabrication of a third contact, isolated from the nanowire, and which can therefore act as a gate. Preferably the nanowire structure is fabricated on a multi-layer substrate, one layer of which is electrically conducting and can therefore act as a gate. In an alternative preferred embodiment the step of formation of the chain of conducting nanoparticles is via step ii., and the average nanoparticle diameter is between 0.5 nm to 1000 nm. Preferably the modification includes formation of a step, depression or ridge in the substrate surface, running substantially between two contacts. Preferably the modification comprises formation of a groove having a substantially v-shaped cross-section running substantially between the contacts. Preferably the conditions are such to encourage diffusion of the nanoparticles on the substrate surface, including the conditions of temperature, surface smoothness and/or surface type and/or identity. Preferably the modification is by lithography and etching. According to a second aspect of the invention there is provided a single conducting chain of nanoparticles between a number of contacts on a substrate prepared substantially according to the above method. According to a third aspect of the invention there is provided a method of forming a conducting nanowire between two contacts on a substrate surface comprising or including the steps of: a. forming the contacts on the substrate, b. preparing a plurality of nanoparticles, c. depositing a plurality of nanoparticles on the substrate at least in the region between the contacts, d. monitoring the formation of the conducting nanowire by monitoring conduction between the two contacts, and ceasing deposition at the onset of conduction, wherein the contacts are separated by a distance smaller than 10 microns. Preferably the contacts are separated by a distance smaller than 100 nm. Preferably the nanoparticles have an average diameter between 0.5 nm and 1,000 nm, and may be of uniform or non-uniform size. Preferably the nanoparticle preparation and deposition steps are via inert gas aggregation and the nanoparticles are atomic clusters made up of two or more atoms, which may or may not be of the same element. In one preferred embodiment the geometry of the contacts has been optimised by percolation theory calculations to provide a conducting nanowire at a surface coverage of nanoparticles on the substrate, in the region between the contacts, of less than a percolation threshold coverage of 70%. Preferably the surface coverage is less than 30%; more preferably the surface coverage is substantially in the region of 20%. Preferably the optimal geometry requires: a rectangular region between the contacts (or a geometrically equivalent region such as interdigitated contacts); the contacts spaced apart by less than 60× the average nanoparticle diameter, and the width of each contact being between more than 10× the contact spacing. Preferably: The contacts are spaced apart by between 4-6× the average nanoparticle diameter; and the length of each contact is substantially more than 10× the contact spacing. Preferably the average nanoparticle diameter is substantially between 0.5 nm to 1,000 nm. Preferably the overall geometry of contacts is an interdigitated geometry. Preferably the conditions are such to discourage diffusion of the nanoparticles on the substrate surface, including the conditions of temperature, surface smoothness and/or surface type and/or identity. In an alternative preferred embodiment the topography of the substrate in the region between the contacts is such to promote the formation of a conducting path of nanoparticles between the contacts. Preferably the method includes an additional step before or after step a) or b) but at least before step c) of: i) Modifying the surface to provide topographical assistance to the positioning of the depositing nanoparticles in order to give rise to a conducting pathway. Preferably the modification includes formation of a step, depression or ridge in the substrate surface, running substantially between two contacts. Preferably the modification comprises formation of a groove having a substantially v-shaped cross-section running substantially between the contacts. Preferably the modification is by lithography and etching. Preferably the conditions are such to encourage diffusion of the nanoparticles on the substrate surface, including the conditions of temperature, surface smoothness and/or surface type and/or identity. Preferably the substrate is an insulating or semiconducting material; more preferably the substrate is selected from silicon, silicon nitride, silicon oxide, aluminium oxide, indium tin oxide, germanium gallium arsenide or any other III-V semiconductor, quartz, glass. Preferably the nanoparticles are selected from bismuth, antimony, aluminium, silicon, germanium, silver, gold, copper, iron, nickel or cobalt clusters. According to a fourth aspect of the invention there is provided a conducting nanowire between two contacts on a substrate surface prepared substantially according to the above method. According to a fifth aspect of the invention there is provided a method of forming a conducting nanowire between two contacts on a substrate surface comprising or including the steps of: a. forming the contacts on the substrate, b. preparation of a plurality of nanoparticles, c. depositing a plurality of nanoparticles, on the substrate in the region between the contacts, d. achieving a single nanowire running substantially between the two contacts by either: i. monitoring the conduction between the contacts and ceasing deposition at the onset of conduction, and/or ii. modifying the substrate to achieve, or taking advantage of pre-existing topographical features which will cause the nanoparticles to form the nanowire. Preferably the contacts are separated by a distance smaller than 10 microns; more preferably the contacts are separated by a distance smaller than 100 nm. Preferably the average diameter of the nanoparticles is between 0.5 nm and 1,000 nm, and may be of uniform or non-uniform size. Preferably the nanoparticle preparation and deposition steps are via inert gas aggregation and the nanoparticles are atomic clusters made up of two or more atoms which may or may not be of the same element. Preferably the contacts are formed by lithography. Preferably the substrate is an insulating or semiconducting material. Preferably the substrate is selected from silicon, silicon nitride, silicon oxide, aluminium oxide, indium tin oxide, germanium, gallium arsenide or any other III-V semiconductor, quartz, or glass. Preferably the nanoparticles are selected from bismuth, antimony, aluminium, silicon, germanium, silver, gold, copper, iron, nickel or cobalt clusters. According to a sixth aspect of the invention there is provided a conducting nanowire between two contacts on a substrate surface prepared substantially according to the above method. According to a seventh aspect of the invention there is provided a method of fabricating a nanoscale device including or requiring a conduction path between two contacts formed on a substrate, including or comprising the steps of: A. preparing a conducting nanowire between two contacts on a substrate surface as described in any of the above methods. B. incorporating the contacts and nanowire into the nanoscale device. Preferably the device includes two or more contacts and includes one or more of the conducting nanowires. Preferably conduction through the chain is initiated by an applied voltage or current, either during or subsequent to the deposition of the particles. Preferably the step of incorporation results in any one or more of the following embodiments: 1. two primary contacts having the conducting nanowire between them, and a least a third contact on the substrate which is not electrically connected to the primary contacts thereby capable of acting as a gate or other element in a amplifying or switching device, transistor or equivalent; and/or 2. two primary contacts having the conducting nanowire between them, an overlayer or underlayer of an insulating material and a least a third contact on the distal side of the overlayer or underlayer from the primary contacts, whereby the third contact is capable of acting as a gate or other element in a switching device, transistor or equivalent; and/or 3. the contacts and/or nanowire are protected by an oxide or other non-metallic or semi-conducting film to protect it and/or enhance its properties; and/or 4. a capping layer (which may or may not be doped) is present over the surface of the substrate with contacts and nanowire, which may or may not be the film of 3. 5. the nanoparticles being annealed on the surface of the substrate; 6. the position of the nanoparticles are controlled by a resist or other organic compound or an oxide or other insulating layer which is applied to the substrate and then processed using lithography and/or etching to define a region or regions where nanoparticles may take part in electrical conduction between the contacts and another region or regions where the nanoparticles will be insulated from the conducting network. Preferably the device is a transistor or other switching device, a film deposition control device, a magnetic field sensor, a chemical sensor, a light emitting or detecting device, or a temperature sensor. Preferably the device is a deposition sensor monitoring deposition of a nanoparticle film, and includes at least a pair of contacts with an optimised geometry such that the onset of conduction in the device occurs at a surface coverage where conduction would not normally be expected in a macroscopic film of the same particles, wherein the contact spacing can be selected so as to vary the surface coverage at, or near, the onset of conduction and wherein as a result of the predefined contact spacing the onset of conduction in the nanoparticle film is used to sense when a pre-determined coverage of nanoparticles in the film has been achieved. Preferably the device is a deposition sensor and the nanoparticles are coated in ligands or an insulating layer such that the onset of tunnelling conduction is used to monitor the film thickness. According to an eighth aspect of the invention there is provided a nanoscale device including or requiring a conduction path between two contacts formed on a substrate prepared substantially according to the above method. According to a ninth aspect of the invention there is provided a nanoscale device including or requiring a conduction path between two contacts formed on a substrate including or comprising: i) At least two contacts on the substrate, ii) plurality of nanoparticles forming a conducting chain or path of nanoparticles between the contacts. Preferably there are two contacts which are separated by a distance smaller than 10 microns. Preferably the contacts are separated by a distance less than 1000 nm. Preferably conduction through the chain is initiated by an applied voltage or current, either during or subsequent to the deposition of the particles Preferably the nanoparticles are composed of two or more atoms, which may or may not be of the same element. Preferably the nanoparticles may be of uniform or non-uniform size, and the average diameter of the nanoparticles is between 0.5 nm and 1,000 nm. Preferably the substrate is an insulating or semiconducting material. Preferably the substrate is selected from silicon, silicon nitride, silicon oxide, aluminium oxide, indium tin oxide, germanium, gallium arsenide or any other III-V semiconductor, quartz, or glass. Preferably the nanoparticles are selected from bismuth, antimony, aluminium, silicon, germanium, silver, gold, copper, iron, nickel or cobalt clusters. Preferably the at least a single conduction chain has been formed either by; i. monitoring the conduction between the contacts and ceasing deposition at the onset of conduction, and/or ii. modifying the substrate surface, or taking advantage of pre-existing topographical features, which will cause the nanoparticles to form the nanowire when deposited in the region of the modification or topographical features. In a preferred embodiment the at least single conduction chain was formed by step i. and the average nanoparticle diameter is between 0.5 nm to 1000 nm, the contacts are spaced apart by between 4-6× the average nanoparticle diameter; and the length of each contact is substantially more than 10× the contact spacing. Preferably the overall geometry of the contacts is an interdigitated geometry. In an alternative preferred embodiment the step of formation of the chain of conducting nanoparticles is by step ii., and wherein the average nanoparticle diameter is 0.5 nm to 1000 nm. According to a tenth aspect of the invention there is provided single conducting chain of nanoparticles between a number of contacts on a substrate substantially as described herein with reference to any one or more of the figures and or examples. According to an eleventh aspect of the invention there is provided a conducting nanowire between two contacts on a substrate surface substantially as described herein with reference to any one or more of the figures and or examples. According to a twelfth aspect of the invention there is provided a method of preparing a single conducting chain of nanoparticles between a number of contacts on a substrate substantially as described herein with reference to any one or more of the figures and or examples. According to a thirteenth aspect of the invention there is provided a method of preparing a conducting nanowire between two contacts on a substrate surface substantially as described herein with reference to any one or more of the figures and or examples. |
Accident warning device |
A disaster-related warning apparatus (1) housed in a case (10) installable to a building or equipment, including at least one type of disaster sensing means (20) for outputting a detection signal upon sensing a predetermined type of disaster, and notification means (30) for making an instruction about a location of emergency equipment or appliance prepared for the disaster optically or by an audio message, the notification means being activated in response to the detection signal outputted by the disaster sensing means (20). |
1. A disaster-related warning apparatus housed in a case installable to either of a building and equipment, comprising: at least one type of disaster sensing means for outputting a detection signal upon sensing a predetermined type of disaster; and notification means for making an instruction about a location of either of emergency equipment and appliance prepared for the disaster optically or by an audio message, the notification means being activated in response to the detection signal outputted by the disaster sensing means. 2. The disaster-related warning apparatus according to claim 1, wherein the disaster sensing means includes any of a temperature sensor for sensing heat in case of fire, a gas sensor for sensing smoke in case of the fire, a sound sensor for sensing an alarm sound of an emergency bell, and a vibration sensor for sensing an earthquake. 3. The disaster-related warning apparatus according to claim 1, wherein the notification means includes either of a laser pointer and an LED, and the laser pointer is constituted such that a pointing orientation is arbitrarily adjustable and a beam is swingable within a required range while using a set pointing orientation as a reference. 4. The disaster-related warning apparatus according to claim 1, wherein the notification means includes recording means capable of recording and reproducing at least one type of audio message corresponding to the type of disaster. 5. A disaster-related warning apparatus to be used by being attached onto either of a building and equipment, comprising: fire sensing means for outputting a detection signal upon sensing any of heat and smoke in case of fire and an alarm sound of an emergency bell; earthquake sensing means for outputting a detection signal upon sensing an earthquake; optical notification means capable of making an optical instruction about a location of either of emergency equipment and appliance prepared for a disaster; fire-case audio notification means capable of issuing an audio message to instruct about the location of either of the emergency equipment and appliance prepared for the disaster as well as an audio message corresponding to an occurrence of a fire; earthquake-case audio notification means capable of issuing the audio message to instruct about the location of either of the emergency equipment and appliance prepared for the disaster as well as an audio message corresponding to an occurrence of an earthquake; and controlling means for selecting either one of the fire-case audio notification means and the earthquake-case notification means and activating the optical notification means and the selected one of the fire-case audio notification means and the earthquake-case notification means based on the detection signal outputted by either thereof, wherein the controlling means activates the optical notification means and the fire-case audio notification means upon receiving the detection signal only from the fire sensing means, operates the optical notification means and the earthquake-case audio notification means upon receiving the detection signal only from the earthquake sensing means, and operates the optical notification means and the fire-case audio notification means upon receiving the detection signals from the fire sensing means and the earthquake sensing means. |
<SOH> BACKGROUND ART <EOH>In general, in facilities applying to predetermined requirements, it is obliged to install fire extinguishers and emergency exits, the numbers of which accord with scales of the facilities, in preparation for occurrences of a fire and earthquake. Moreover, also in ordinary households, as well as the fire extinguishers, emergency equipment such as flashlights, portable radios and emergency food is prepared for such disasters though such a preparation is not a duty. These equipment and appliances are ones capable of exerting effects thereof only when being used instantaneously in case of the occurrences of disasters. However, the disasters do not always occur in an arousal period while a mental activity and a physical activity are normal, and for example, sometimes occur during asleep and drinking periods. In such cases, because of an extreme panic and because a body and a mentality are nonarounsal, an installation position of the fire extinguisher, a position of the emergency exit or a position of the flashlight cannot be remembered quickly. This will cause situations where the fire extinguisher is not effectively utilized for initial extinction, it takes time to evacuate, and an evacuation cannot help but being performed while abandoning the emergency equipment such as the flashlight. Specifically, a possibility is extremely high that the emergency equipment and appliances are not effectively utilized in case of a sudden occurrence of the disaster if these emergency equipment and appliances are prepared only in a nominal manner. Conventionally, such problems have been dealt as matters concerning a daily posture, which include an extinction training and the like, and such measures as assisting a person to know the positions of the emergency equipment and appliances by an electromechanical device and the like have not been taken. Even in a large-scale facility built for a business to welcome any guests, such as a hotel obliged to install fire hydrants, the measures against the problems are only taken by providing a red lamp above a door of a fire hydrant cabinet such that any unspecified third party can get to know the presence of the fire hydrant. Specifically, there has conventionally been a problem that the emergency equipment and the emergency appliances, which have been previously prepared for the occurrences of disasters, are difficult to be effectively utilized in case of an actual disaster because of the panic and forgetting of a storage place of the equipment or appliances. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a front perspective view showing a disaster-related warning apparatus according to a first embodiment of this invention. FIG. 2 is a back perspective view of the disaster-related warning apparatus of FIG. 1 . FIG. 3 is a cross-sectional view of principal portions of the disaster-related warning apparatus of FIG. 1 . FIG. 4 is a circuit system diagram of a controller of a disaster-related warning apparatus of this invention. FIG. 5 is an explanatory view showing an example of installation of the disaster-related warning apparatus of this invention. FIG. 6 is a perspective view showing a disaster-related warning apparatus according to a second embodiment of this invention. FIG. 7 is an explanatory perspective view of principal portions of the disaster-related warning apparatus of FIG. 6 . FIG. 8 is a cross-plan view of the principal portions of the disaster-related warning apparatus of FIG. 7 . FIG. 9 is an explanatory perspective view showing principal portions of a disaster-related warning apparatus according to a third embodiment of this invention. FIG. 10 is an explanatory perspective view schematically showing a disaster-related warning apparatus according to a fourth embodiment of this invention. FIG. 11 is a perspective view showing a disaster-related warning apparatus according to a fifth embodiment of this invention. detailed-description description="Detailed Description" end="lead"? |
Elastic band for tying chickens and like animals to be cooked |
The invention concerns an elastic band (11) for tying chickens (31) and other animals to be cooked, which band has an “8”-shape where a first and smaller loop (13) and a second and larger loop (15) are defined, said first and smaller loop being intended for tying the animal's legs (33) and said second and larger loop being intended for tying the neck (35). |
1. An elastic band (11) for tying chickens or other animals (31) to be cooked, said band comprising: a wire (1) of elastic material preferably covered by a spiral-wound wire (5) of different material, wherein said band is “8”-shaped. 2. The elastic band according to claim 1, wherein the two loops (13, 15) defined in said “8”-shaped elastic band have different diameters. 3. The elastic band according to claim 2, wherein said elastic band (11) comprises two pieces of elastic wire of different lengths, joined at the respective ends. 4. The elastic band according to claim 1, wherein the wires in the two loops (13, 15) defined in said “8”-shaped elastic band have different moduli of elasticity. 5. The elastic band according to claim 3, wherein said elastic band (11) comprises two pieces of elastic wire with the same lengths but different elasticity, joined at the respective ends. 6. The elastic band according to claim 1, wherein said wire (5) covering the elastic wire (1) is made of cotton. 7. The elastic band according to claim 1, wherein said wire (5) covering the elastic wire (1) is made of synthetic wire. 8. A method for tying chickens or other animals to be cooked, said method comprising the steps of: a) providing and “8”-shaped elastic band having first and second loops and covered by a spiral-wound wire of a material different than the elastic band; and b) pulling the “8” shaped elastic band such that the chicken neck is made to pass through the second loop of the “8” shaped elastic band. 9. The method as recited in claim 8, wherein the first and second loops defined in the “8” shaped elastic band have different diameters, and wherein the legs of the chicken are introduced into the smaller of the first and second loops and the neck is made to pass through the larger of the first and second loops. |
Apparatus for radially expanding tubular members including a segmented expansion cone |
An apparatus for radially expanding tubular members including a segmented expansion cone. |
1. An apparatus for forming a wellbore casing within a wellbore within a subterranean formation, comprising: a tubular support member; an adjustable tubular expansion cone coupled to the tubular support member; an actuator coupled to the tubular support member for adjusting the size of the adjustable tubular expansion cone; a shoe releasably coupled to the adjustable tubular expansion cone; an expandable tubular member coupled to the shoe defining a longitudinal passage for receiving the tubular support member, the adjustable tubular expansion cone, and the actuator; and one or more sealing members for sealing the interface between the tubular support member and the expandable tubular member. 2. The apparatus of claim 1, wherein the adjustable tubular expansion cone comprises: a tubular body defining a plurality of longitudinal slots and comprising a plurality of internal arcuate expansion cone segments interleaved among the longitudinal slots. 3. The apparatus of claim 1, wherein the actuator comprises: a first tubular member coupled to the tubular support member defining a plurality of first radial passage and comprising a plurality of internal flanges interleaved among the first radial passages; a second tubular member received within the first tubular member defining a plurality of second radial passages interleaved among the first radial passages and comprising a plurality of external flanges interleaved among the first and second radial passages and the internal flanges; and a tubular expansion cone coupled to the second tubular member for radially expanding the adjustable tubular expansion cone. 4. A method of forming a wellbore casing within a wellbore within a subterranean formation, comprising: positioning an expandable tubular member and an adjustable tubular expansion cone within the wellbore; increasing the size of the adjustable tubular expansion cone within the expandable tubular member; and plastically deforming and radially expanding the expandable tubular member using the adjustable tubular expansion cone. 5. The method of claim 4, wherein increasing the size of the adjustable tubular expansion cone within the expandable tubular member comprises: positioning a tubular segmented expansion cone within the expandable tubular member; positioning a tubular expansion cone within the expandable tubular member; and displacing the tubular expansion cone relative to the tubular segmented expansion cone. 6. An apparatus for forming a wellbore casing within a wellbore within a subterranean formation, comprising: means for positioning an expandable tubular member and an adjustable tubular expansion cone within the wellbore; means for increasing the size of the adjustable tubular expansion cone within the expandable tubular member; and means for plastically deforming and radially expanding the expandable tubular member using the adjustable tubular expansion cone. 7. The apparatus of claim 6, wherein the means for increasing the size of the adjustable tubular expansion cone within the expandable tubular member comprises: means for positioning a tubular segmented expansion cone within the expandable tubular member; means for positioning a tubular expansion cone within the expandable tubular member; and means for displacing the tubular expansion cone relative to the tubular segmented expansion cone. 8. An adjustable expansion cone for plastically deforming and radially expanding a tubular member, comprising: an adjustable tubular expansion cone; and an actuator for adjusting the tubular adjustable expansion cone. 9. The adjustable expansion cone of claim 8, wherein the adjustable tubular expansion cone comprises: a tubular body defining a plurality of longitudinal slots and comprising a plurality of internal arcuate conical expansion cone segments interleaved among the longitudinal slots. 10. The adjustable expansion cone of claim 8, wherein the actuator comprises: a first tubular member coupled to the adjustable tubular expansion cone defining a plurality of first radial passage and comprising a plurality of internal flanges interleaved among the first radial passages; a second tubular member received within the first tubular member defining a plurality of second radial passages interleaved among the first radial passages and comprising a plurality of external flanges interleaved among the first and second radial passages and the internal flanges; and a tubular expansion cone coupled to the second tubular member for radially expanding the tubular adjustable expansion cone. 11. A method of plastically deforming and radially expanding a tubular member, comprising: positioning an adjustable tubular expansion cone within the tubular member; and increasing the size of the adjustable tubular expansion cone within the expandable tubular member. 12. The method of claim 11, wherein increasing the size of the adjustable tubular expansion cone within the tubular member comprises: positioning a tubular segmented expansion cone within the tubular member; positioning a tubular expansion cone within the tubular member; and displacing the tubular expansion cone relative to the tubular segmented expansion cone. 13. An apparatus for plastically deforming and radially expanding a tubular member, comprising: means for positioning an adjustable tubular expansion cone within the tubular member; and means for increasing the size of the adjustable tubular expansion cone within the expandable tubular member. 14. The apparatus of claim 13, wherein the means for increasing the size of the adjustable tubular expansion cone within the tubular member comprises: means for positioning a tubular segmented expansion cone within the tubular member; means for positioning a tubular expansion cone within the tubular member; and means for displacing the tubular expansion cone relative to the tubular segmented expansion cone. 15. A tubular member, comprising: a tubular body defining a plurality of longitudinal slots; and a plurality of arcuate internal flanges, each flange comprising: an arcuate cylindrical segment end face; trapezoidal side faces; an upper inclined trapezoidal side face; and a lower inclined trapezoidal side face. 16. An apparatus for forming a wellbore casing within a wellbore within a subterranean formation, comprising: a tubular support member; an adjustable tubular expansion cone coupled to the tubular support member, comprising: a tubular body defining a plurality of longitudinal slots and comprising a plurality of internal arcuate expansion cone segments interleaved among the longitudinal slots; an actuator coupled to the tubular support member for adjusting the size of the adjustable tubular expansion cone, comprising: a first tubular member coupled to the tubular support member defining a plurality of first radial passage and comprising a plurality of internal flanges interleaved among the first radial passages; a second tubular member received within the first tubular member defining a plurality of second radial passages interleaved among the first radial passages and comprising a plurality of external flanges interleaved among the first and second radial passages and the internal flanges; and a tubular expansion cone coupled to the second tubular member for radially expanding the adjustable tubular expansion cone; a shoe releasably coupled to the adjustable tubular expansion cone; an expandable tubular member coupled to the shoe defining a longitudinal passage for receiving the tubular support member, the adjustable tubular expansion cone, and the actuator; and one or more sealing members for sealing the interface between the tubular support member and the expandable tubular member. 17. A method of forming a wellbore casing within a wellbore within a subterranean formation, comprising: positioning an expandable tubular member and an adjustable tubular expansion cone within the wellbore; increasing the size of the adjustable tubular expansion cone within the expandable tubular member, comprising: positioning a tubular segmented expansion cone within the expandable tubular member; positioning a tubular expansion cone within the expandable tubular member; and displacing the tubular expansion cone relative to the tubular segmented expansion cone; and plastically deforming and radially expanding the expandable tubular member using the adjustable tubular expansion cone. 18. An apparatus for forming a wellbore casing within a wellbore within a subterranean formation, comprising: means for positioning an expandable tubular member and an adjustable tubular expansion cone within the wellbore; means for increasing the size of the adjustable tubular expansion cone within the expandable tubular member, comprising: means for positioning a tubular segmented expansion cone within the expandable tubular member; means for positioning a tubular expansion cone within the expandable tubular member; and means for displacing the tubular expansion cone relative to the tubular segmented expansion cone; and means for plastically deforming and radially expanding the expandable tubular member using the adjustable tubular expansion cone. 19. An adjustable expansion cone for plastically deforming and radially expanding a tubular member, comprising: an adjustable tubular expansion cone, comprising: a tubular body defining a plurality of longitudinal slots and comprising a plurality of internal arcuate conical expansion cone segments interleaved among the longitudinal slots; and an actuator for adjusting the tubular adjustable expansion cone, comprising: a first tubular member coupled to the adjustable tubular expansion cone defining a plurality of first radial passage and comprising a plurality of internal flanges interleaved among the first radial passages; a second tubular member received within the first tubular member defining a plurality of second radial passages interleaved among the first radial passages and comprising a plurality of external flanges interleaved among the first and second radial passages and the internal flanges; and a tubular expansion cone coupled to the second tubular member for radially expanding the tubular adjustable expansion cone. 20. A method of plastically deforming and radially expanding a tubular member, comprising: positioning an adjustable tubular expansion cone within the tubular member; and increasing the size of the adjustable tubular expansion cone within the expandable tubular member, comprising: positioning a tubular segmented expansion cone within the tubular member; positioning a tubular expansion cone within the tubular member; and displacing the tubular expansion cone relative to the tubular segmented expansion cone. 21. An apparatus for plastically deforming and radially expanding a tubular member, comprising: means for positioning an adjustable tubular expansion cone within the tubular member; and means for increasing the size of the adjustable tubular expansion cone within the expandable tubular member, comprising: means for positioning a tubular segmented expansion cone within the tubular member; means for positioning a tubular expansion cone within the tubular member; and means for displacing the tubular expansion cone relative to the tubular segmented expansion cone. 22. An apparatus for forming a wellbore casing within a wellbore within a subterranean formation, comprising: a tubular support member; an adjustable expansion device coupled to the tubular support member; an actuator coupled to the tubular support member for adjusting the size of the adjustable expansion device; an expandable tubular member coupled to the tubular support member defining a longitudinal passage for receiving the tubular support member, the adjustable expansion device, and the actuator; and one or more sealing members for sealing the interface between the tubular support member and the expandable tubular member. 23. The apparatus of claim 22, wherein the adjustable expansion device comprises: a tubular body defining a plurality of longitudinal slots and comprising a plurality of internal arcuate expansion segments interleaved among the longitudinal slots. 24. The apparatus of claim 22, wherein the actuator comprises: a first tubular member coupled to the tubular support member defining a plurality of first radial passage and comprising a plurality of internal flanges interleaved among the first radial passages; a second tubular member received within the first tubular member defining a plurality of second radial passages interleaved among the first radial passages and comprising a plurality of external flanges interleaved among the first and second radial passages and the internal flanges; and an expansion device coupled to the second tubular member for radially expanding the adjustable expansion device. 25. A method of forming a wellbore casing within a wellbore within a subterranean formation, comprising: positioning an expandable tubular member and an adjustable expansion device within the wellbore; increasing the size of the adjustable expansion device within the expandable tubular member; and plastically deforming and radially expanding the expandable tubular member using the adjustable expansion device. 26. The method of claim 25, wherein increasing the size of the adjustable expansion device within the expandable tubular member comprises: positioning a segmented expansion device within the expandable tubular member; positioning an expansion device within the expandable tubular member; and displacing the expansion device relative to the segmented expansion device. 27. An apparatus for forming a wellbore casing within a wellbore within a subterranean formation, comprising: means for positioning an expandable tubular member and an adjustable expansion device within the wellbore; means for increasing the size of the adjustable expansion device within the expandable tubular member; and means for plastically deforming and radially expanding the expandable tubular member using the adjustable expansion device. 28. The apparatus of claim 27, wherein the means for increasing the size of the adjustable expansion device within the expandable tubular member comprises: means for positioning a segmented expansion device within the expandable tubular member; means for positioning an expansion device within the expandable tubular member; and means for displacing the expansion device relative to the segmented expansion device. 29. An adjustable expansion device for plastically deforming and radially expanding a tubular member, comprising: an adjustable tubular expansion device; and an actuator for adjusting the tubular adjustable tubular expansion device. 30. The adjustable expansion device of claim 29, wherein the adjustable tubular expansion device comprises: a tubular body defining a plurality of longitudinal slots and comprising a plurality of internal arcuate expansion segments interleaved among the longitudinal slots. 31. The adjustable expansion device of claim 29, wherein the actuator comprises: a first tubular member coupled to the adjustable expansion device defining a plurality of first radial passage and comprising a plurality of internal flanges interleaved among the first radial passages; a second tubular member received within the first tubular member defining a plurality of second radial passages interleaved among the first radial passages and comprising a plurality of external flanges interleaved among the first and second radial passages and the internal flanges; and an expansion device to the second tubular member for radially expanding the tubular adjustable expansion device. 32. A method of plastically deforming and radially expanding a tubular member, comprising: positioning an adjustable expansion device within the tubular member; and increasing the size of the adjustable expansion device within the expandable tubular member. 33. The method of claim 32, wherein increasing the size of the adjustable expansion device within the tubular member comprises: positioning a segmented expansion device within the tubular member; positioning an expansion device within the tubular member; and displacing the expansion device relative to the segmented expansion device. 34. An apparatus for plastically deforming and radially expanding a tubular member, comprising: means for positioning an adjustable expansion device within the tubular member; and means for increasing the size of the adjustable expansion device within the expandable tubular member. 35. The apparatus of claim 34, wherein the means for increasing the size of the adjustable expansion device within the tubular member comprises: means for positioning a segmented expansion device within the tubular member; means for positioning an expansion device within the tubular member; and means for displacing the expansion device relative to the segmented expansion device. 36. An apparatus for forming a wellbore casing within a wellbore within a subterranean formation, comprising: a tubular support member; an adjustable expansion device coupled to the tubular support member, comprising: a body defining a plurality of longitudinal slots and comprising a plurality of internal expansion segments interleaved among the longitudinal slots; an actuator coupled to the tubular support member for adjusting the size of the adjustable expansion device, comprising: a first tubular member coupled to the tubular support member defining a plurality of first radial passage and comprising a plurality of internal flanges interleaved among the first radial passages; a second tubular member received within the first tubular member defining a plurality of second radial passages interleaved among the first radial passages and comprising a plurality of external flanges interleaved among the first and second radial passages and the internal flanges; and an expansion device coupled to the second tubular member for radially expanding the adjustable expansion device; a shoe releasably coupled to the adjustable expansion device; an expandable tubular member coupled to the shoe defining a longitudinal passage for receiving the tubular support member, the adjustable expansion device, and the actuator; and one or more sealing members for sealing the interface between the tubular support member and the expandable tubular member. 37. A method of forming a wellbore casing within a wellbore within a subterranean formation, comprising: positioning an expandable tubular member and an adjustable expansion device within the wellbore; increasing the size of the adjustable expansion device within the expandable tubular member, comprising: positioning a segmented expansion device within the expandable tubular member; positioning an expansion device within the expandable tubular member; and displacing the expansion device relative to the segmented expansion device; and plastically deforming and radially expanding the expandable tubular member using the adjustable expansion device. 38. An apparatus for forming a wellbore casing within a wellbore within a subterranean formation, comprising: means for positioning an expandable tubular member and an adjustable expansion device within the wellbore; means for increasing the size of the adjustable expansion device within the expandable tubular member, comprising: means for positioning a segmented expansion device within the expandable tubular member; means for positioning an expansion device within the expandable tubular member; and means for displacing the expansion device relative to the segmented expansion device; and means for plastically deforming and radially expanding the expandable tubular member using the adjustable expansion device. 39. An adjustable expansion device for plastically deforming and radially expanding a tubular member, comprising: an adjustable tubular expansion device, comprising: a tubular body defining a plurality of longitudinal slots and comprising a plurality of internal expansion segments interleaved among the longitudinal slots; and an actuator for adjusting the adjustable tubular expansion device, comprising: a first tubular member coupled to the adjustable tubular expansion device defining a plurality of first radial passage and comprising a plurality of internal flanges interleaved among the first radial passages; a second tubular member received within the first tubular member defining a plurality of second radial passages interleaved among the first radial passages and comprising a plurality of external flanges interleaved among the first and second radial passages and the internal flanges; and an expansion device coupled to the second tubular member for radially expanding the adjustable tubular expansion device. 40. A method of plastically deforming and radially expanding a tubular member, comprising: positioning an adjustable tubular expansion device within the tubular member; and increasing the size of the adjustable tubular expansion device within the expandable tubular member, comprising: positioning a tubular segmented expansion device within the tubular member; positioning an expansion device within the tubular member; and displacing the expansion device relative to the segmented expansion device. 41. An apparatus for plastically deforming and radially expanding a tubular member, comprising: means for positioning an adjustable expansion device within the tubular member; and means for increasing the size of the adjustable expansion device within the expandable tubular member, comprising: means for positioning a segmented expansion device within the tubular member; means for positioning an expansion device within the tubular member; and means for displacing the expansion device relative to the segmented expansion device. 42. A method of radially expanding and plastically deforming a tubular member, comprising: positioning an adjustable expansion device within the tubular member; adjusting a size of the adjustable expansion device within the tubular member; and displacing the adjustable expansion device relative to the tubular member by pulling the adjustable expansion device through the tubular member using fluid pressure. 43. A system for radially expanding and plastically deforming a tubular member, comprising: means for positioning an adjustable expansion device within the tubular member; means for adjusting a size of the adjustable expansion device within the tubular member; and means for displacing the adjustable expansion device relative to the tubular member by pulling the adjustable expansion device through the tubular member using fluid pressure. 44. A method of radially expanding and plastically deforming a tubular member, comprising: positioning an expansion device within the tubular member; and displacing the expansion device relative to the tubular member by pulling the expansion device through the tubular member using fluid pressure. 45. A system for radially expanding and plastically deforming a tubular member, comprising: means for positioning an expansion device within the tubular member; and means for displacing the expansion device relative to the tubular member by pulling the expansion device through the tubular member using fluid pressure. |
<SOH> BACKGROUND <EOH> |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIGS. 1 a - 1 h are fragmentary cross-sectional illustrations of an embodiment of the placement of an apparatus for radially expanding a tubular member within a borehole within a subterranean formation. FIG. 2 is a fragmentary cross-sectional illustration of the injection of a hardenable fluidic sealing material into the apparatus of FIGS. 1 a - 1 h. FIG. 3 is a fragmentary cross-sectional illustration of the apparatus of FIG. 2 after injecting a fluidic material into the apparatus and seating a dart in the tubular dart seat. FIG. 4 is a fragmentary cross-sectional illustration of the apparatus of FIG. 3 after continuing to inject a fluidic material into the apparatus thereby axially displacing the tension sleeve and thereby creating a segmented expansion cone for plastically deforming and radially expanding the expandable tubular member using the expansion segments. FIG. 5 is a fragmentary cross-sectional illustration of the apparatus of FIG. 4 after continuing to inject a fluidic material into the apparatus thereby displacing the tubular locking sleeve from engagement with the locking member of the tubular locking collet. FIG. 6 is a fragmentary cross-sectional illustration of the apparatus of FIG. 5 after continuing to inject a fluidic material into the apparatus thereby displacing the tubular support members, the tubular locking collet, the tubular locking sleeve, and the tubular tension sleeve upwardly in the axial direction thereby further plastically deforming and radially expanding the expandable tubular member. FIG. 7 is a fragmentary cross-sectional illustration of the apparatus of FIG. 6 after continuing to inject a fluidic material into the apparatus thereby continuing to displace the tubular support members, the tubular locking collet, the tubular locking sleeve, and the tubular tension sleeve upwardly in the axial direction thereby further plastically deforming and radially expanding the expandable tubular member. detailed-description description="Detailed Description" end="lead"? |
Button lock |
There is provided a button-operated lock device capable of increasing a setting amount of information in response to operation of a control button, obtaining a large setting amount and a wide-range of selection thereof, enhancing safety performance, simplifying the structure and achieving a small size and a light-weight, thereby achieving a low manufacturing cost, executing such various operations as setting or inputting information and altering thereof correctly, safely, easily and rationally, and preventing decoding or perceiving of preset or inputted information so that any third party is prevented from making a falsification and/or conversion of this device. The button-operated lock comprises a plurality of control buttons (10) axially displacedly arranged and capable of setting or inputting a predetermined information; a control plate (128) for allowing an unlocking procedure at the time of setting or imputing the predetermined information; a driving cam (16) linked to the control plate (128) and capable of being operatively connected to a pair of door handles (4, 5); and a lock element linked to the driving cam (16), wherein a plurality of same or different information can be set or inputted to each of the control buttons (10) and the plurality of same or different information can be set or inputted every time the control button (10) is operated. |
1. A button-operated lock comprising a plurality of control buttons (10) axially displacedly and capable of setting or inputting a predetermined information; a control plate (128) for allowing an unlocking procedure at the time of setting or imputing the predetermined information; a driving cam (16) linked to said control plate (128) and capable of being operatively connected to a pair of door handles (4, 5); and a lock element linked to said driving cam (16), wherein a plurality of same or different information can be set or inputted to each of said control buttons (10) and said plurality of same or different information can be set or inputted every time said control button (10) is operated. 2. A button-operated lock according to claim 1, wherein said setting or inputting information can be controlled in association with the number of times of operation of said control buttons (10). 3. A button-operated lock according to claim 2, wherein a part (34) of control means for said setting or inputting information is built in said control button (10). 4. A button-operated lock according to claim 2, wherein said control means includes a gear button (34) which can be intermittently turned every time said control button (10) is axially displaced. 5. A button-operated lock according to claim 4, wherein said plurality of information can be set or inputted during one turn of said control button (10). 6. A button-operated lock according to claim 1, wherein a lock plate (140) is interposed between said control plate (128) and said driving cam (16), one end of said lock plate (140) is swingably connected to said control plate (128), and the other end of said lock plate (140) is arranged to be engageable with or disengageable from said driving cam (16). 7. A button-operated lock according to claim 2, wherein a terminal gear (66) is arranged to be engageable with said button gear (34), a reset gear (43) is arranged to be engageable with said terminal gear (66), and said reset gear (43) is biased in such a manner as to be able to rotationally return in accordance with a rotation angle displacement thereof. 8. A button-operated lock according to claim 7, wherein said button gear (34) and said terminal gear (66) can be disengaged from each other, and said terminal gear (66) and said reset gear (43) can be normally engaged with each other. 9. A button-operated lock according to claim 7, wherein said reset gear (43) is provided with a stopper (83) which is unable to engage said terminal gear (66). 10. A button-operated lock according to claim 7, wherein said terminal gear (66) is provided with a square hole (76), a clutch shaft (67) capable of rotationally support said terminal gear (67), said clutch shaft (67) being provided with a square shaft (79) which is engageable with and disengageable from said square hole (76), and said square shaft (79) being biased for engagement with said square hole (76). 11. A button-operated lock according to claim 10, wherein a plurality of engagement parts engageable with said square shaft (79) are formed at said square hole (79), and the number of said engagement parts is set to be equal to an amount of information which can be set or inputted by only one control button (10). 12. A button-operated lock according to claim 10, wherein a plurality of control holes are formed in a surface of a case (14) which is exposed to the outside, so that a control tool (154) can be inserted in said control holes, and one end part of said clutch shaft (67) is faced with an inner side opening part of said control hole (12). 13. A button-operated lock according to claim 12, wherein said clutch shaft (67) is axially displaceable through said control tool (154), so that the engagement between said square shaft (79) and said square hole (76) can be released, and said terminal gear (66) is rotatably supported by said clutch shaft (67). 14. A button-operated lock according to claim 12, wherein a cam shaft (80) is projected from the other end of said clutch shaft (67), a control cam (65) is attached to said cam shaft (80) such that said control cam (65) is simultaneously movable with said cam shaft (80), an engagement claw (129) of said control plate (128) is removably received in a cutout groove (72) formed in said control cam (128), and said engagement claw (129) is biased such that said engagement claw (129) is engageable with and disengageable from said cutout groove (72). 15. A button-operated lock according to claim 14, wherein a plurality of passage holes (24) are formed in a back plate (13), which is attached to a back part of said case (14), in such a manner as to face with an end part of said cam shaft (80), and a plurality of check marks (170) are arranged on the outside of said passage holes (24) in isometric positions. 16. A button-operated lock according to claim 12, wherein at the time of setting or inputting information through said control buttons (10), said cutout grooves (72) are directed toward said engagement claw (129) side and positioned in the same phase as said engagement claw (129), and said engagement claws (129) are brought into engagement with said cutout grooves (72), respectively, so that said control plate (128) can allow an unlocking procedure. 17. A button-operated lock according to claim 12, wherein at the time of setting or inputting information through said control buttons (10), said engagement claws (129) are brought into engagement with said control cam (65) and prohibited from being engaged with said cutout grooves (72), so that said control plate (128) is unable to allow an unlocking procedure. 18. A button-operated lock according to claim 12, wherein a block main body (46) on which said terminal gear (66) and said reset gear (43) can be mounted is provided, a memory releasing link (113) is engaged with said block main body (46), said block main body (46) is biased in such a manner as to be able to move toward said control button (10) side, so that said terminal gear (66) and said button gear (34) can be engaged with each other, one end part of said memory releasing link (113) is engaged with said driving cam (16), so that said block main body (46) is brought away from said control button (10) side through the turning motion of said driving cam (16), thereby allowing said terminal gear (66) and said button gear (34) to be disengaged from each other. 19. A button-operated lock according to claim 18, wherein said block main body (46) is provided with a guide groove (59), said memory releasing link (113) is provided with a pin (115) projecting therefrom and engageable with said guide groove (59), said pin (115) is positioned such that it can normally engage one side edge of said guide groove (59), said guide groove (59) is provided at the other end edge thereof with a locking projection (164) engageable with said pin (115), and at the time of engagement between said pin (115) and said locking projection (164), operation of said memory releasing link (113) is prohibited and engagement between said terminal gear (66) and said button gear (34) is prohibited from releasing. 20. A-button-operated lock according to claim 18, wherein said memory releasing link (113) is turnably provided at the other end side thereof with a changeover shaft (123) which is linked to a changeover knob (6) on the indoor side, said changeover shaft (123) is provided with two cams (124), (125) which are different in length, and said two cams (124), (125) is selectively engageable with the other end part of said memory releasing link (113). 21. A button-operated lock according to claim 20, wherein the separation distance between said block main body (46) and said control button (10) is made different in accordance with the lengths of said two cams (124), (125), said two cams are each capable of releasing engagement between said terminal gear (66) and said button gear (34), at the time of engagement with said long side cam (125), engagement between said engagement claw (129) and said cutout groove (72) of said control plate (128) can be maintained, and at the time of engagement with said short side cam (124), engagement between said engagement claw (129) and said cutout groove (72) can be maintained. 22. A button-operated lock according to claim 12 or 18, wherein said case (14) is provided at an inner side surface side thereof with a protection plate (146) such that said protection plate (146) can move along said control holes (12), and a plurality of through-holes (147), which can communicate with said control holes (12), are formed in said protection plate (146), such that one end of said protection plate (146) can engage said driving cam (16). 23. A button-operated lock according to claim 20, wherein engagement between said terminal gear (66) and said button gear (34) is released through turning operation of said door handles (4), (5) or said changeover shaft (123), and said terminal gear (66) is turned by elastic force of a set spring (86) which is formed after said information is set or imputed, so that said control cam (65) or its cutout groove (72) can be returned to its original position. 24. A button-operated lock according to claim 23, wherein after said control cam (65) or its cutout groove (72) is returned to its original position, current information of said control button (10) is set or imputed to turn said button gear (34) by an amount of the set or inputted information, said terminal gear (66) and said reset gear (43) are moved in operative connection to the turning motion of said button gear (66), said terminal gear (66) is biased to return to its original position by an amount of the set or inputted information, the engagement between said terminal gear (66) and said button gear (34) is released through the turning operation of said door handles (4), (5), said terminal gear (66) is reversely turned for offset by an amount of the set or inputted information, thereby releasing the set or inputted current information so that said lock can be unlocked. 25. A button-operated lock according to claim 23, wherein after said control cam (65) or its cutout groove (72) is returned to its original position, said terminal gear (66) is rotatably supported on said clutch shaft (67) through said control tool (154), and the engagement between said square shaft (79) and said square hole (76) is released, so that the original position of said control cam (65) or its cutout groove (72) can be maintained. 26. A button-operated lock according to claim 23, wherein after the original position of said control cam (65) or its cutout groove (72) is maintained through said control tool (154), at the time for altering information where said button gear (34) is turned in the same direction as at the setting or inputting time of information, said control button (10) is operated by an amount equal to the difference between the turning angles of said button gear (34) before and after the alternation of information, then said terminal gear (66) and said reset gear (43) are operatively connected thereto, said terminal gear (66) is biased such that it can turningly return by an amount equal to the difference between said turning angles, said square shaft (79) and said square hole (76) are engaged with each other after said button gear (34) is turned, and the original position of said control cam (65) or its cutout groove (72) is linked to said terminal gear (66), the engagement between said terminal gear (66) and said button gear (34) is released through turning operation of said door handles (4), (5), said terminal gear (66) is turned by an amount equal to the elasticity of said reset spring (86) formed after the alternation of information, and an amount equal to the turning angle of said terminal gear (66) is added to the position of said control cam (65) or its cutout groove (72), so that the setting or inputting information can be altered. 27. A button-operated lock according to claim 26, wherein the number of times of operation of said control button (10) is a quotient obtained by dividing the difference of turning angles of said button gear (34) before and after the alternation of information by a unit operation turning angle of said turning button (10). 28. A button-operated lock according to claim 23, wherein at the time for altering information where said button gear (34) is turned in a reverse direction to the direction at the time of setting or inputting information, said changeover shaft (123) is turned to bring said cam (124) on its short side into engagement with an end part of said memory releasing link (113) and to release the engagement between said terminal gear (66) and said button gear (34), the engagement between said cutout groove (72) and said engagement claw (129) is maintained to maintain the original position of said control cam (65) or its cutout groove (72), said terminal gear (66) is turnably supported on said clutch shaft (67) through said control tool (154), said terminal gear (66) is turningly returned by an amount of elasticity of said reset spring (86) equal to the amount of elasticity necessary for forming the original position, after the original position of said control cam (65) or its cutout groove (72) is released, said changeover shaft (123) is turningly returned to the original position to bring said terminal gear (66) into engagement with said button gear (34), said button gear (34) is turned by an amount equal to the amount of angle of the alternation of information by operating said control button (10) through said control tool (154), then said terminal gear (66) and said reset gear (43) are operatively connected thereto, so that said terminal gear (66) is biased such that it can turningly return by an amount equal to the difference between said turning angles, said square shaft (79) and said square hole (76) are engaged with each other after said button gear (34) is turned, said clutch shaft (67) is linked to said terminal gear (66) to release the engagement between said terminal gear (66) and said button gear (34) through turning operation of said door handles (4), (5), said terminal gear (66) is turned by an amount equal to elasticity of said reset spring (86) formed after the alternation of information, the position of said control cam (65) or its cutout groove (72) is reset by an amount equal to the turning angle of said terminal gear (66), so that the setting or inputting information can be altered. 29. A button-operated lock according to claim 1, wherein a ball retainer (159) for disengageably receiving therein a ball (158) biased toward the inner side of said door handles (4), (5) and adapted to normally turn said door handles (4), (5) and said driving cam (16) but idly turn said door handle (4) and prohibit the turning of said driving cam (16) when excessively large torque acts on said door handle (4), is formed in the shape of a plate, and said ball retainer (159) is mounted on a surface part of said case (14). 30. A button-operated lock according to claim 1, wherein the arrangement of said door handles (4), (5) and said control buttons (10) can be selectively or symmetrically altered together with their inside mechanisms. |
<SOH> BACKGROUND ART <EOH>Recently, a keyless lock of the type requiring the use of no key has been popularized as a door lock to be used for individual dwelling houses, companies, shops, hospitals and the like. As a keyless lock of the type mentioned above, there are a so-called mechanical lock in which the locking and unlocking procedure is made by a structural means and an electric or electronic lock in which the locking and unlocking procedure is made by an electrical means. Of these two types of keyless locks, the mechanical lock, when compared with the electronic or electric lock, has such advantages that there is no worry about power failure or battery exhaustion because no wiring work is required, the user of such a lock is free from electrical trouble such as malfunction, and in addition, the mechanical strength is large. The mechanical lock, in general, includes a plurality of control buttons. Memory information corresponding to the control buttons is stored in association with a cam or link mechanism or a gear train, the memory information of the respective control buttons is combined by the same number as the number of the control buttons, and a password number consisting of the number of digits of the control buttons is set or inputted. At the time of unlocking, the control buttons corresponding to the password number are operated so that the lock can be unlocked. For example, in the invention disclosed in Japanese Patent Publication No. S62-54951 the present applicant previously filed, the respective control buttons are inserted in the slits formed in a case frame in their erected or inverted states, and the numbers of the respective control buttons are set to 1 or 0, i.e., two modes of either “set” or “unset”. Then, it is selectively decided whether the number setting for the respective control buttons is necessary or not so that the password number can be set or inputted by a combination of the corresponding numbers. At the time of unlocking, the control buttons for which the number setting has been made are depressed to engage the slits formed in those buttons with the keyplate. On the other hand, the control buttons for which the number setting has not been made are not depressed to maintain the engagement relation between the slits and the keyplate. Owing to this arrangement, the cam pin can be turned to allow the handle to turn, so that the lock can be unlocked. However, in this conventional device, since only two modes, i.e., number setting and number unsetting, can be obtained for each control button and the setting amount of information for each control button is limited, the number of the password number depends on the number of the control buttons and thus, a sufficient setting amount of information is unobtainable. Since the range of selection thereof is limited, a large enough safety performance is unobtainable. In order to solve those problems, if the number of the control buttons should be increased, the number of the component parts would be increased to that extent. Thus, the construction and the locking and unlocking procedure becomes complicated, and the case frame and the packing plate become large in size, thus resulting in large size and heavy weight of the entire button-operated lock. Moreover, the outer appearance of the door is degraded. Those problems are also common in U.S. Pat. No. 3,115,765. That is, the lock disclosed in the above U.S. patent includes a generally elongate box-like casing. This casing is retractably provided at a face plate thereof with a plurality of key systems which are linked to the control buttons. A plurality of shafts are turnably suspended in the longitudinal direction of the casing. The respective gears are engageably arranged in such a manner as to face with the key system positions of those shafts. The gears are intermittently turned through the pressing operation of those key systems. A control shaft, which is linked to a door handle is disposed at one end of the casing. A slide plate is provided in such a manner as to be engageable with a cam disposed at the control shaft. A plurality of engagement elements disposed at the slide plate are engageable with and disengageable from the respective gears which are fixed to the above-mentioned shaft. The memory system by the key system can be stored in the gear train or reset. However, the lock taught by the above U.S. patent has the following problems. Since each control button can set only a single memory information, a combination of memory information achievable through each control button is limited, and selection of password numbers and safety performance are limited. Moreover, since the number setting of the control buttons is linked to the number setting of the adjacent control buttons and the password number is stored in order of the setting input, the number setting lacks in versatility and the smooth execution of the locking and unlocking procedure is jeopardized. Moreover, since the turning force of the door handle acts on the slide plate, it can easily be perceived whether or not memory setting has been made through the respective control buttons. This, together with the above-mentioned disadvantage in limitation of the memory capacity, tends to create such a fear that repeated evil attempt should be made on the control buttons, the lock could be unlocked comparatively easily. On the other hand, a long time use of a same password number leads gives a chance to a third party to perceive and decode the number. This is not desirable in view of protection of the password number. Therefore, it is desirable that the password number is altered frequently. However, since the alternation mechanism and operation thereof requires a time-consuming troublesome work in view of its structure, the simplification and easiness are demanded. For example, the lock proposed by the present applicant in Japanese Patent Publication No. S62-54951 is designed such that at the time for altering the password number, a case frame and a packing plate, which are arranged at the inside and the outside of the door, is removed therefrom, the corresponding control buttons are pulled out in their exposed states, and inserted into a slit in their erected or inverted states and then reassembled. However, this method has such problems that since the case frame and the backing plate are required to be detached from the door and the buttons are required to be detached or replaced, complicated and time-consuming work is required. In the lock of the above-mentioned U.S. Pat. No. 3,115,765, at the time for altering the password, the control buttons are operated to set or input the current password number and thereafter, the slide plate is moved to release the engagement between the engagement element and the groove. After the current password number is canceled, the control buttons are operated to set or input a new password number. This method, when compared with the above-mentioned method, has such advantages that the troublesome work for removing the related parts from the door is no more required and thus, this operation can be made in a simple and convenient manner. However, it has such a problem that since the password number can be altered from the outside of the door, the third party can make a falsification relatively easily. Therefore, uneasiness in relation to protection and security occurs. It is, therefore, a main object of the present invention, to provide a button-operated lock which is capable of solving the above-mentioned problems and in which the amount of information to be set to the control buttons is increased, a large setting amount of information and its wide selection can be obtained, and safety performance can be enhanced. Another object of the present invention is to provide a button-operated lock, in which the structure can be simplified and made compact and light-weight, and the manufacturing cost can be reduced. A further object of the present invention is to provide a button-operated lock, in which the setting or inputting of information to the control buttons, as well as an altering operation thereof, can be made correctly, safely, easily and rationally. A still further object of the present invention is to provided a button-operated lock, in which decoding or perceiving of information, which would otherwise be made by the third party relatively easily, is prohibited so that the third party is prevented from making a falsification and/or conversion of such information. A yet further object of the present invention is to provide a button-operated lock, in which a criminal unlocking procedure, which would otherwise be made by the third party comparatively easily through a control hole formed in a case, can be prevented from occurring. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a perspective view showing one embodiment of the present invention, in which a button-operated lock according to the present invention is mounted on an entrance door. FIG. 2 is a front view showing the button-operated lock according to the present invention, in which the lock is mounted on the entrance door. FIG. 3 is a left side view of FIG. 2 . FIG. 4 is a perspective view showing an essential part of the present invention in an exploded manner. FIG. 5 is a front view showing a case and a protection plate to which the present invention is applied. FIG. 6 is a sectional view taken on line A-A of FIG. 5 . FIG. 7 is a sectional view taken on line B-B of FIG. 5 . FIG. 8 is a sectional view taken on line C-C of FIG. 5 , additionally showing an attaching state of a control button to the button-operated lock. FIG. 9 is a sectional view taken on line D-D of FIG. 5 . FIG. 10 is a perspective view showing a control button to which the present invention is applied, in an exploded manner. FIG. 11 is a perspective view showing an assembling state of a block assembly to which the present invention is applied, in which a case is omitted. FIG. 12 is a sectional view taken on line E-E of FIG. 11 , in which a part of a back plate is omitted. FIG. 13 is a sectional view taken on line F-F of FIG. 11 , in which a part of the back plate is omitted. FIG. 14 is a sectional view taken on line G-G of FIG. 11 , in which a part of the back plate is omitted. FIG. 15 is an enlarged sectional view taken on line H-H of FIG. 11 . FIG. 16 is an enlarged sectional view taken on line I-I of FIG. 11 . FIG. 17 is a front view showing an assembling state of the present invention, in a simplified manner. FIG. 18 is an enlarged sectional view taken on line J-J of FIG. 17 , showing a state in which a control tool is not yet inserted. FIG. 19 is an enlarged sectional view showing a state in which the control tool is inserted and a crutch shaft is depressed in FIG. 18 and in which the control buttons are not yet depressed. FIG. 20 is an enlarged sectional view showing a state in which the control tool is inserted and a crutch shaft is depressed in FIG. 19 and in which the control buttons are already depressed. FIG. 21 is a perspective view showing the block assembly to which the present invention is applied, in an exploded manner. FIG. 22 is a sectional view taken on line K-K of FIG. 21 . FIG. 23 is an enlarged sectional view taken on line L-L of FIG. 21 . FIG. 24 is a front view showing a terminal gear to which the present invention is applied. FIG. 25 is a sectional view taken on line M-M of FIG. 24 . FIG. 26 is an explanatory view showing a relation between a control cam to which the present invention is applied and a cutout groove thereof, and a cam shaft and memory information in sequential order. FIG. 27 is a perspective view showing a state of a driving cam to which the present invention is applied. FIG. 28 is a perspective view showing a state of the driving cam to which the present invention is applied, but when view from the opposite side of FIG. 27 . FIG. 29 is a sectional view taken on line N-N of FIG. 27 , showing an assembling state of the driving cam to which the present invention is applied and a door handle on the outdoor side. FIG. 30 is a sectional view taken on line O-O of FIG. 27 . FIG. 31 is a perspective view showing a memory releasing link to which the present invention is applied. FIG. 32 is a perspective view showing a changeover shaft to which the present invention is applied. FIG. 33 is a front view showing an assembling state of the memory releasing line to which the present invention is applied and a control plate. FIG. 34 is a perspective view showing a control plate to which the present invention is applied and a lock plate, in which an assembling state thereof is shown. FIG. 35 is an enlarged sectional view taken on line P-P of FIG. 34 . FIG. 36 is a front view showing an assembling state of the control plate to which the present invention is applied and a block main body. FIG. 37 is a perspective view showing a button-operated lock according to the second embodiment of the present invention, in which the button-operated lock is mounted on the entrance door. FIG. 38 is a perspective view showing an essential part of the button-operated lock according to the second embodiment in an exploded manner, in which a back plate is omitted. FIG. 39 is a perspective view showing the button-operated lock according to the second embodiment in an exploded manner, in which a case is omitted. FIG. 40 is a perspective view showing, in an exploded manner, a block assembly which is applied to the button-operated lock according to the second embodiment. FIG. 41 is a sectional view showing an essential part of a safety mechanism of a door handle which is applied to the button-operated lock according to the second embodiment. FIG. 42 is a sectional view showing an essential part of a ball retainer which is applied to the safety mechanism of the door handle according to the second embodiment. FIG. 43 is a front view showing an essential part of the safety mechanism which is applied to a block main body according to the second embodiment, in which a guide groove and a pin are in engagement relation. FIG. 44 is a front view showing an essential part of FIG. 43 on an enlarged basis. FIG. 45 is a sectional view showing an assembling state of an information altering unit which is applied to the second embodiment. FIG. 46 is a sectional view taken on line Q-Q of FIG. 45 . FIG. 47 is a perspective view showing a control cam which is applied to the second embodiment. FIG. 48 is a sectional view of a terminal gear which is applied to the second embodiment. FIG. 49 is a front view showing a crutch shaft which is applied to the second embodiment. FIG. 50 is a plan view of FIG. 49 . FIG. 51 is a perspective view showing a button-operated lock according to the third embodiment of the present invention, in which the button-operated lock is attached to a kitchen door. detailed-description description="Detailed Description" end="lead"? |
Tumor specific oligosaccharide sequences and use thereof |
The present invention describes oligosaccharide sequences, which are specifically expressed by human tumors. The present invention is related to a method of determining an oligosaccharide sequence, which comprises a tumor specific terminal N-acetylglucosamine residue, in a biological sample, the presence of said sequence in said sample being an indication of the presence of cancer. The present invention provides antigenic substances comprising said oligosaccharide sequences in a polyvalent form and it further provides diagnostic agents, pharmaceutical compositions and cancer vaccines comprising said oligosaccharide sequences or substances binding to said oligosaccharide sequences. The present invention is also related to methods for the treatment of cancer. |
1. Use of a substance binding to one or several of the terminal human tumor specific oligosaccharide sequences of a N-glycan type structure according to Formula [GNβ2Man]r1α3([GNβ2Man]r2α6){Man[β4GN[β4(Fucα6)r3GN]r4]r5}r6 (I) wherein r1, r2, r3, r4, r5, and r6 are either 0 or 1 with the proviso that at least r1 is 1 or r2 is 1; GN is GlcNAc, with the proviso that when both r1 and r2 are 1, one GNβMan can be further elongated with one or several other monosaccharide residues such as by galactose, and/or one GNβ2Man can be truncated to Man, and/or Manα6 residue and/or Manα3 residues can be further substituted by GNβ6 or GNβ4, and/or Manβ4 can be further substituted by GNβ4, in the preparation of a pharmaceutical or nutritional composition for the treatment of human cancer. 2. The use according to claim 1, wherein said terminal human tumor specific oligosaccharide sequence is according to Formula [GNβ2Man]r1α3([GNβ2Man]r2α6){Man[β4GN]r5}r6 (II) wherein r1, r2, r5, and r6 are either 0 or 1, with the proviso that at least r1 is 1 or r2 is 1; GN is GlcNAc, with the proviso that when both r1 and r2 are 1, one GNβMan can be further elongated with one or several other monosaccharide residues such as by galactose, and/or one GNβ2Man can be truncated to Man. 3. The use according to claim 2, wherein the substance binding to the terminal human tumor specific oligosaccharide sequence is a human antibody. 4. The use according to claim 3, wherein the human cancer is a human solid tumor. 5. The use according to claim 4, wherein the human tumor specific oligosaccharide sequence is expressed on cell surface or tissue surface of said human solid tumor. 6. The use according to claim 5, wherein the composition is for the treatment of a human tumor diagnosed to express or elevatedly express compared to normal tissue said human tumor specific oligosaccharide sequence. 7. The use according to claim 5, wherein said human solid tumor is hypernephroma, cancer of larynx, colon cancer, stomach cancer, lung cancer, ovarian cancer, or mucious carcinoma. 8. The use according to claim 7, wherein the patient suffering from the tumor is under immunosuppressive medication or suffering from immunodeficiency. 9. The use according to claim 1, wherein the human tumor specific oligosaccharide sequence is GlcNAcβ2Man, GlcNAcβ2Manα3(GlcNAcβ2Manα6)Man, GlcNAcβ2Manα3(GlcNAcβ2Manα6)Manβ4GlcNAc, GlcNAcβ2Manα3(GlcNAcβ2Manα6)Manβ4GlcNAcβ4GlcNAc, GlcNAcβ2Manα3(GlcNAcβ2Manα6)Manβ4GlcNAcβ4(Fucα6)GlcNAc, GlcNAcβ2Manα3(Manα6)Man, GlcNAcβ2Manα3(Manα6)Manβ4GlcNAc, GlcNAcβ2Manα3(Manα6)Manβ4GlcNAcβ4GlcNAc, GlcNAcβ2Manα3(Manα6)Manβ4GlcNAcβ4(Fucα6)GlcNAc, Manα3(GlcNAcβ2Manα6)Man, Manα3(GlcNAcβ2Manα6)Manβ4GlcNAc, Manα3 (GlcNAcβ2Manα6)Manβ4GlcNAcβ4GlcNAc, Manα3(GlcNAcβ2Manα6)Manβ4GlcNAcβ4(Fucα6)GlcNAc, GlcNAcβ2Manα3Man, GlcNAcβ2Manα3Manβ4GlcNAc, GlcNAcβ2Manα3Manβ4GlcNAcβ4GlcNAc, GlcNAcβ2Manα3Manβ4GlcNAcβ4(Fucα6)GlcNAc, GlcNAcβ2Manα6Man, GlcNAcβ2Manα6Manβ4GlcNAc, GlcNAcβ2Manα6Manβ4GlcNAcβ4GlcNAc, or GlcNAcβ2Manα6Manβ4GlcNAcβ4(Fucα6)GlcNAc 10. Use of a substance as defined in claim 2 in the preparation of a diagnostic agent for the diagnosis of a human tumor or human tumor type, wherein the diagnostic agent binds to a human tumor specific oligosaccharide sequence, which is expressed on cell surface or tissue surface of the human tumor. 11. The use according to claim 10, wherein a sample to be diagnosed is taken from a patient being under immunosuppressive medication or suffering from immunodeficiency. 12. The use according to claim 11, wherein said human tumor is a human solid tumor. 13. The use according to claim 12, wherein the tumor is hypernephroma. 14. The use according to claim 12, wherein the tumor is ovarian or lung cancer. 15. The use according to claim 12, wherein the tumor is cancer of larynx, colon cancer, stomach cancer, or mucious carcinoma. 16. The use according to claim 12, wherein the diagnostic agent is for the diagnosis of a human tumor which express or elevatedly express compared to normal tissue a human tumor specific oligosaccharide sequence as defined in claim 2. 17. Use of the terminal human tumor specific oligosaccharide sequence as defined in claim 2 in the preparation of a pharmaceutical or nutritional composition for the treatment of human cancer. 18. The use according to claim 17, wherein said human cancer is a human solid tumor. 19. The use according to claim 18, wherein the human tumor specific oligosaccharide sequence is expressed on cell surface or tissue surface of human tumor. 20. The use according to claim 19, wherein the tumor is hypernephroma. 21. The use according to claim 19, wherein the composition is for the treatment of a human tumor diagnosed to express or elevatedly express compared to normal tissue said human tumor specific oligosaccharide sequence. 22. The use according to claim 19, wherein the oligosaccharide sequence is in a polyvalent and/or antigenic form. 23. Use of the terminal human tumor specific oligosaccharide sequence as defined in claim 2 in the preparation of a human cancer vaccine. 24. A method for diagnosing cancer or tumor in a biological sample taken from a human patient, the method comprising determining the presence in said sample of an oligosaccharide sequence as defined in claim 2, so that the tumor specific terminal oligosaccharide structure is detected on the surface of the tumor. 25. Use of a substance binding to one or several of the human tumor specific terminal GlcNAcβ3/β6 oligosaccharide sequences of a following O-glycan type structure GlcNAcβ3Galβ3(Galβ4GlcNAcβ6)GalNAc, GlcNAcβ3Galβ3(GlcNAcβ6)GalNAc, GlcNAcβ3Galβ3GalNAc, Galβ3(GlcNAcβ6)GalNAc, or GlcNAcβ6GalNAc in the preparation of a pharmaceutical or nutritional composition for the treatment of human cancer. 26. The use according to claim 25, wherein said substance is a human antibody. 27. The use according to claim 26, wherein the human cancer is a human solid tumor. 28. The use according to claim 27, wherein the human tumor specific oligosaccharide sequence is expressed on cell surface or tissue surface of human tumor. 29. The use according to claim 28, wherein the composition is for the treatment of a human tumor diagnosed to express or elevatedly express compared to normal tissue said human tumor specific oligosaccharide sequence. 30. The use according to claim 28, wherein said human tumor is hypernephroma, cancer of larynx, colon cancer, stomach cancer, lung cancer, ovarian cancer, or mucious carcinoma. 31. The use according to claim 30, wherein the patient suffering from the tumor is under immunosuppressive medication or suffering from immunodeficiency. 32. The use according to claim 30, wherein the tumor specific oligosaccharide sequence is Galβ3(GlcNAcβ6)GalNAc or GlcNAcβ6GalNAc. 33. Use of a substance as defined in claim 25 in the preparation of a diagnostic agent for the diagnosis of human cancer or human cancer type. 34. The use according to claim 33, wherein the diagnostic agent binds to a human tumor specific oligosaccharide sequence, which is expressed on cell surface or tissue surface of the human cancer. 35. The use according to claim 34, wherein said human cancer is a human solid tumor. 36. The use according to claim 35, wherein the diagnostic agent is for the diagnosis of a human tumor which express or elevatedly express compared to normal tissue a human tumor specific oligosaccharide sequence as defined in claim 25. 37. Use of the terminal human tumor specific oligosaccharide sequence as defined in claim 25 in the preparation of a pharmaceutical or nutritional composition for the treatment of human cancer. 38. The use according to claim 37, wherein said human cancer is a human solid tumor. 39. The use according to claim 38, wherein said human tumor specific oligosaccharide sequence is expressed on cell surface or tissue surface of human tumor. 40. The use according to claim 39, wherein the composition is for the treatment of a human tumor diagnosed to express or elevatedly express compared to normal tissue said human tumor specific oligosaccharide sequence. 41. The use according to claim 39, wherein said oligosaccharide sequence is in a polyvalent and/or antigenic form. 42. Use of the terminal human tumor specific oligosaccharide sequence as defined in claim 25 in the preparation of a human cancer vaccine. 43. A method for diagnosing cancer or tumor in a biological sample taken from a human patient, the method comprising determining the presence in said sample of an oligosaccharide sequence as defined in claim 25, so that the tumor specific terminal oligosaccharide structure is detected on the surface of the tumor or cancer. 44. Use of a substance binding to one or several of the human tumor specific terminal GlcNAcβ3/6Gal oligosaccharide sequences of a following O-glycan type structure GlcNAcβ3Gal, GlcNAcβ3Galβ4Glc, GlcNAcβ3Galβ4GlcNAc, GlcNAcβ3Galβ4GlcNAcβ3Gal, GlcNAcβ3Galβ4GlcNAcβ3Galβ4Glc, GlcNAcβ6Gal, and GlcNAcβ6Galβ4GlcNAc in the preparation of a pharmaceutical or nutritional composition for the treatment of human cancer. 45. The use according to claim 44, wherein said substance is a human antibody and wherein said human cancer is hypernephroma, cancer of larynx, colon cancer, or lung cancer, and optionally wherein the patient is suffering from the tumor is under immunosuppressive medication or suffering from immunodeficiency 46. The use according to claim 44, wherein said substance is a human antibody and wherein the human cancer is a human solid tumor and the oligosaccharide sequence is selected from the group GlcNAcβ3Gal, GlcNAcβ3Galβ4Glc, GlcNAcβ3Galβ4GlcNAcβ3Gal, GlcNAcβ3Galβ4GlcNAcβ3Galβ4Glc, GlcNAcβ6Gal, and GlcNAcβ6Galβ4GlcNAc. 47. The use according to claim 46, wherein the human tumor specific oligosaccharide sequence is expressed on cell surface or tissue surface of human tumor. 48. The use according to claim 47, wherein the composition is for the treatment of a human tumor diagnosed to express or elevatedly express compared to normal tissue said human tumor specific oligosaccharide sequence. 49. The use according to claim 47, wherein said human tumor is hypernephroma, cancer of larynx, colon cancer, or lung cancer. 50. The use according to claim 48, wherein the patient suffering from the tumor is under immunosuppressive medication or suffering from immunodeficiency. 51. The use according to claim 48, wherein the tumor specific oligosaccharide sequence is GlcNAcβ3Galβ4GlcNAcβ3Gal or GlcNAcβ3Galβ4GlcNAcβ3Galβ4Glc. 52. Use of a substance as defined in claim 46 in the preparation of a diagnostic agent for the diagnosis of a human tumor or human tumor type, wherein the diagnostic agent binds to a human tumor specific oligosaccharide sequence, which is expressed on cell surface or tissue surface of the human tumor. 53. The use according to claim 52, wherein a sample to be diagnosed is taken from a patient being under immunosuppressive medication or suffering from immunodeficiency. 54. The use according to claim 53, wherein said human tumor is a human solid tumor. 55. The use according to claim 54, wherein the diagnostic agent is for the diagnosis of a human tumor which express or elevatedly express compared to normal tissue a human tumor specific oligosaccharide sequence as defined in claim 44. 56. Use of the terminal human tumor specific oligosaccharide sequence as defined in claim 44, wherein the sequence is selected from the group GlcNAcβ3Galβ4Glc, GlcNAcβ3Galβ4GlcNAcβ3Gal, GlcNAcβ3Galβ4GlcNAcβ3Galβ4Glc, GlcNAcβ6Gal, and GlcNAcβ6Galβ4GlcNAc in the preparation of a pharmaceutical or nutritional composition for the treatment of human cancer. 57. The use according to claim 56, wherein said human cancer is a human solid tumor. 58. The use according to claim 57, wherein said human tumor specific oligosaccharide sequence is expressed on cell surface or tissue surface of human tumor. 59. The use according to claim 58, wherein the composition is for the treatment of a human tumor diagnosed to express or elevatedly express compared to normal tissue said human tumor specific oligosaccharide sequence. 60. The use according to claim 58, wherein said oligosaccharide sequence is in a polyvalent and/or antigenic form. 61. The use according to claim 46, 54, or 57, wherein the tumor is hypernephroma, colon cancer or lung cancer. 62. Use of the terminal human tumor specific oligosaccharide sequence as defined in claim 46 in the preparation of a human cancer vaccine or use substance defined in claim 44 in the preparation of a human cancer vaccine for indication defined in claim 45. 63. A method for diagnosing cancer or tumor in a biological sample taken from a human patient, the method comprising determining the presence in said sample of an oligosaccharide sequence as defined in claim 46, so that the tumor specific terminal oligosaccharide structure is detected on the surface of the tumor. 64. Use of a substance binding to human tumor specific protein linked GlcNAc or a derivative thereof in the preparation of a pharmaceutical or nutritional composition for the treatment of human cancer. 65. The use according to claim 64, wherein said human cancer is a human solid tumor. 66. The use according to claim 65, wherein said human tumor specific protein linked GlcNAc is expressed on cell surface or tissue surface of human tumor. 67. The use according to claim 66, wherein the composition is for the treatment of a human tumor diagnosed to express or elevatedly express compared to normal tissue said human tumor specific protein linked GlcNAc. 68. The use according claim 66, wherein said human tumor or cancer is hypernephroma, cancer of larynx, colon cancer, stomach cancer, lung cancer, ovarian cancer, mucious carcinoma. 69. The use according claim 68, wherein the patient suffering from the tumor is under immunosuppressive medication or suffering from immunodeficiency. 70. Use of a substance as defined in claim 64 in the preparation of a diagnostic agent for the diagnosis of human cancer or human cancer type. 71. The use according to claim 70, wherein the diagnostic agent binds to a human tumor specific oligosaccharide sequence, which is expressed on cell surface or tissue surface of the human cancer. 72. The use according to claim 71, wherein said human cancer is a human solid tumor. 73. The use according to claim 72, wherein the diagnostic agent is for the diagnosis of a human tumor which express or elevatedly express compared to normal tissue a human tumor specific protein linked GlcNAc as defined in claim 64. 74. A method for diagnosing cancer or tumor in a biological sample taken from a human patient, the method comprising determining the presence in said sample of a protein linked GlcNAc as defined in claim 64, so that the tumor specific protein linked GlcNAc structure is detected on the surface of the tumor or cancer. 75. The use according to the claim 1, 25, 44 or 64, wherein said substance binding to said oligosaccharide sequence is an aptamer, a peptide or a protein. 76. The use according to claim 75, wherein said protein is an antibody, a lectin, or a fragment thereof 77. The use according to claim 76, wherein said protein is an enzyme recognizing the terminal GlcNAc-structures, preferably a glycosyltransferase enzyme or variant thereof. 78. The use according to claim 76, wherein said antibody is a human or humanized antibody. 79. The use according to claim 22, 41 or 60, wherin said polyvalent conjugate of the oligosaccharide sequence wherein position C1 of the reducing end terminal of the oligosaccharide sequence (OS) comprising the tumor specific terminal sequence is linked (-L-) to an oligovalent or a polyvalent carrier (Z), via a spacer group (Y) and optionally via a monosaccharide or oligosaccharide residue (X), forming the following structure [OS-(X)n-L-Y]m-Z where integer m have values m>1 and n is independently 0 or 1; L can be oxygen, nitrogen, sulfur or a carbon atom; X is preferably lactosyl-, galactosyl-, poly-N-acetyl-lactosaminyl, or part of an O-glycan or an N-glycan oligosaccharide sequence, Y is a spacer group or a terminal conjugate such as a ceramide lipid moiety or a linkage to Z. 80. The use according to claim 1, 25, 44, or 64, wherein said pharmaceutical composition further comprises a pharmaceutically acceptable carrier and optionally an adjuvant. 81. The method according to claim 43, wherein the determination comprises (a) contacting said biological sample with a substance binding to said oligosaccharide sequence, and determining the presence of a combination of said substance and said sample, the presence of said combination being an indication of cancer present in said sample, or (b) releasing the oligosaccharide structures of said biological sample by enzymatic or chemical methods to form a fraction containing free oligosaccharide structures from said sample, and determining the presence of said oligosaccharide sequence in said fraction, the presence of said oligosaccharide sequence in said fraction being an indication of cancer present in said sample. 82. The method according to claim 24 or 63, wherein the determination comprises (a) contacting said biological sample with a substance binding to said oligosaccharide sequence, and determining the presence of a combination of said substance and said sample, the presence of said combination being an indication of tumor present in said sample, or (b) releasing the oligosaccharide structures of said biological sample by enzymatic or chemical methods to form a fraction containing free oligosaccharide structures from said sample, and determining the presence of said oligosaccharide sequence in said fraction, the presence of said oligosaccharide sequence in said fraction being an indication of tumor present in said sample. 83. The method according to claim 81 or 82, wherein a cancer or tumor type is determined. 84. The method according to claim 81, 82 or 83, wherein normal glycosylation of the tissue containing the cancer is determined. 85. The method according to claim 84, wherein the glycosylations are determined on the surface of cancer and normal tissue 86. The use according to claim 23, 42 or 62, wherein said vaccine further comprises ad pharmaceutically acceptable carrier and optionally an adjuvant. 87. The use according to claim 1, 25, 44 or 64, wherein said nutritional composition is a functional food or food additive containing antibodies recognizing said tumor specific oligosaccharide sequences. 88. The use according to claim 87, wherein said antibodies are produced in milk or in hen eggs. 89. A pharmaceutical composition comprising a human antibody binding specifically to a oligosaccharide sequence with terminal GlcNAcβstructure for use in the treatment of human cancer. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Various tumors express oligosaccharide sequences which are different from the non-malignant glycosylation of the same cell or tissue type. Examples of the known or speculated cancer associated oligosaccharide structures include: glycolipid structures such as globo-H (Fucα2Galβ3GalNAcβ3Galα4LacβCer), gangliosides: GM1 Galβ3GalNAcβ4(NeuNAcα3)LacβCer or GD2 GalNAcβ4(NeuNAcα8NeuNAcα3)LacβCer; Lewis-type fucosylated structures such as Lewis a and x: Galβ3/4(Fucα4/3)GlcNAc, Lewis y: Fucα2Galβ4(Fucα3)GlcNAc, sialyl-Lewis x: NeuNAcα3Galβ4(Fucα3)GlcNAc, and some combinations of these on polylactosamine chains; O-glycan core structures, such as T-antigen Galβ3GalNAcαSer/Thr-Protein, Tn-antigen GalNAcαSer/Thr-Protein or sialyl Tn-antigen NeuNAcα6GalNAcαSer/Thr-Protein. Presence of non-human structures such as N-glycolyl-neuraminic acid in cancers has also been indicated. Association and specificity of oligosaccharide structures with regard to cancers have been well established only in few cases, some of the structures are present in normal cells and tissues and are possibly only more concentrated in cancers. One report has indicated that structures with terminal GlcNAcβ3Galβ4GlcNAc sequence are present in human leukaemia cells (Hu et al., 1994). The structures may also be equally present on normal leukocytes. Thus, the relation of the finding to glycosylation patterns generally present in solid tumors was not indicated. This type of saccharide structures may be a part of rare normal glycosylations of human tissues: GlcNAcβ3Galβ4GlcNAcβ6 sequence linked on O-glycans is probably present on human gastric mucin. A study shows that a monoclonal antibody recognizing GlcNAcβ3Galβ4GlcNAcβ6 sequence may possibly recognize similar structures on malignant tissues, such as mucinous ovarian neoplasms, pseudopyloric metaplasia of gallbladder and pancreatic epithelia, gastric differentiated carcinoma of stomach, gallbladder and pancreas, and on non-malignant tissues, such as human amniotic fluid, but, however, the structures from malignat tissues were not characterized (Hanisch et al., 1993). The antibody did not recognize neoglycolipid structure GlcNAcβ3Galβ4GlcNAcβ3Galβ4 nor carcinomas of lung, colorectum, endometrium or other organs. Another monoclonal antibody raised against testicular cells probably recognizes branched N-acetyllactosamines such as GlcNAcβ3(GlcNAcβ6)Galβ4GlcNAc- (Symington et al., 1984). Terminal GlcNAc has also been reported from mucins of human foetal mucin (Hounsell et al., 1989). In normal tissues terminal GlcNAc may be present in minor amounts as biosynthetic intermediates in the biosynthesis of poly-N-acetyllactosamines. Several monoclonal antibodies has been raised against a semisynthetic glycolipid GlcNAcβ3Galβ4GlcNAcβ3LacβCer, these antibodies were shown to recognize glycolipids from cultured colon cancer cell lines and tumors (Holmes et al., 1991). However, the antibodies recognized several structures and the binding data was contradictory. Moreover the glycolipids were not recognized by all of the antibodies and the glycolipid structures from cancer cells or tumors were not characterized. Therefore the presence of terminal GlcNAc structures on tumors were not established. Another study showed production of a monoclonal antibody against GlcNAcβ3LacβCer (Nakamura et al., 1993). This antibody also weakly recognized the pentasaccharide structure described above. Moreover, the antibody recognized a protease sensitive epitope on COS-1 cells, which cell line is not of human origin. The immunization protocols of these studies did not describe induced antibody responses against polyvalent conjugates of the saccharides, but immunization by glycolipids. Normally there are large amounts of antibodies recognizing terminal GlcNAc structures in human serum. There are also a class of natural antibodies recognizing terminal Galα3Galβ4GlcNAc- structures. The Galα antigen is not naturally present in man and recently it was also shown that the natural antibodies bind structures such as GalNAcα3Galβ4GlcNAc, GalNAcβ3Galβ4GlcNAc, and GlcNAcβ3Galβ4GlcNAc (Teneberg et al., 1996). The X2-structure, GalNAcβ3Galβ4GlcNAc, is a normal antigen on human tissues and structures GalNAcα3Galβ4GlcNAc and Galα3Galβ4GlcNAc have not been described from normal or cancer tissues. Thus, the present finding that the terminal GlcNAc structure is a tumor antigen indicates that the actual function of the natural antibodies might be the prevention of cancers having terminal GlcNAc structures. The following patents describe cancer antigens and their use for making antibodies for therapheutic and diagnostic uses and for cancer vaccines. The antigen structures are not related to saccharides of the present invention: Cancer vaccines: U.S. Pat. Nos. 5,102,663; 5,660,834; 5,747,048; 5,229,289 and 6,083,929. Therapeutic antibodies: U.S. Pat. Nos. 4,851,511; 4,904,596; 5,874,060; 6,025,481 and 5,795,961. Diagnostics: U.S. Pat. Nos. 4,725,557; 5,059,520; 5,171,667; 5,173,292; 6,090,789; 5,708,163; 5,679,769; 5,543,505; 5,902,725 and 6,203,999. In the prior art tumor diagnostic and therapheutic antibodies recognizing chitobiose-mannose trisaccharides has been described in DE 38 07 594 A1. The application also describes other N-glycans with numerous varying terminal structures some of which may also comprise non-reducing terminal N-acetyl glucosamine. Several of the desired structures have been later characterized as normal glycans and not cancer specific structures. The application claims to describe structures useful for cancer applications. However, it is not quite clear from the application what the structures of desired glycan are. It is indicated that the GlcNAc residues can be α2, α4, or α6-linked. The present invention is not directed to such unusual structures. Another patent application WO 00/21552 claims several unusual O-glycan structures isolated from bovine submaxillary mucin. Some of the structures such as GlcNAcβ6GalNAcα6GalNAc and GalNAcβ3(GlcNAcβ6)GalNAc comprise terminal GlcNAc-residues. Present invention is not directed to these structures comprising two GalNAc-residues. The application contains speculation about potential therapheutic use of the structures as antigens related to cancer. It has not been shown that the structures are related to bovine cancer but the structures are present in bovine normal submaxillary secretion. Moreover, it is even less probable that the structures would be present in human tissues, as the glycosylations are species specific and vary between human and bovine, so that glycosyltransferase and glycosylation profiles are different in bovine and human. The human genome is also known and glycosyltransferases which could be related to synthesis of the claimed bovine structures has not been produced and characterized. So far none of the six novel glycosyltransferases claimed has been described from human, or human cancer (nor from bovine cancer). Moreover, any bovine glycosylations has not been found from human salivary mucins which have been carefully characterized. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention describes oligosaccharide sequences, which are specifically expressed by human tumors. The present invention is related to a method of determining an oligosaccharide sequence, which comprises a tumor specific terminal N-acetylglucosamine residue, in a biological sample, the presence of said sequence in said sample being an indication of the presence of cancer. The present invention provides antigenic substances comprising said oligosaccharide sequences in a polyvalent form and it further provides diagnostic agents, pharmaceutical compositions and cancer vaccines comprising said oligosaccharide sequences or substances binding to said oligosaccharide sequences. The present invention is also related to methods for the treatment of cancer. |
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