Title of Invention	A NOVEL HORMONE RELEASING INTRAUTERINE DEVICE AND A PROCESS FOR THE PREPARATION THEREOF.
Abstract	A novel intrauterine device for releasing therapeutically active agents at a controlled rate for a prolonged period of time, wherein said device comprises polymeric matrix embedded with microspheres.

Full Text

Technical Field of the Invention The present invention relates a novel intrauterine device comprising a polymeric matrix embedded with microspheres for releasing therapeutically active agents at a controlled rate for a prolonged period of time wherein said polymeric matrix and microspheres consist essentially of contraceptive hormones. Background of the Invention Contraceptive methods involving the administration of hormone substances are widely practiced among women who desire to limit pregnancies. Such methods control fertility through various biological mechanisms. Among the presently used hormonal methods of , fertility control, the most important are those which act by means of the following: (a) suppression of ovulation through inhibition of gonadotropin release; (b) alteration of the female reproductive tract to prevent migration of sperm to the site of fertilization or, if fertilization occurs, to block implantation of the zygote (nidation); or (c) spermicidal action. The oral contraceptives are the most prominent hormonal contraceptive agents. These agents are of two types: (a) an estrogen combined with a progestin, and (b) a progestin alone. The contraceptives of the combined type act primarily by suppressing ovulation by negative feedback to prevent gonadotropin (LH and FSH) release by the hypothalamus, but alterations in the reproductive tract may also contribute to the antifertility effect. Such alterations include changes in the cervical mucus (which increase the difficulty of sperm migration) and in the endometrium (which decrease the likelihood of nidation). The action of a progestin alone in a very low oral dose (the "mini-pill") appears to involve primarily alterations in the female reproductive tract, but ovulation suppression may also occur. Although the oral contraceptives are highly effective, their use is associated with unpleasant side effects (such as nausea, depression, weight-gain, and headache) and an increased long-time risk of severe disease (such as thromboembolism, stroke, myocardial infarction, hepatic adenoma, gall bladder disease, and hypertension). Bleeding 2 irregularities (such as break-through bleeding, spotting, and amenorrhea) are also frequent. A progestin, when administered alone, causes an increased incidence of changes in menstrual patterns, especially a marked increase in the amount and duration of menstrual bleeding. Besides the oral route of administration a progestin alone may be administered systemically by various sustained-release dosage forms which include: (a) depo injection (IM) of an insoluble progestin (e.g medroxy progesterone acetate), 9b) a subdrmal implant, or (c) an intravaginal insert With these methods of administration, the progestin is absorbed into the body continuously at a very low daily dose, and the systemic effects are similar to those produced by oral administration of a progestin. However, as with the oral progestins, the sustained release methods may cause serious menstrual flow irregularities. Other hormonal methods of contraception include the post coital administration of estrogens (e.g. diethylstilbestrol or ethinylestradiol) to prevent nidation or of prostaglandins which act as abortifacients. Both of these methods, at present, are limited to emergency situations. Still in the very early stages of development are immunological methods (vaccination) and methods involving the direct control of LHRH secretion from the pituitary by LHRH agonists or antagonists. The intrauterine device (IUD) is the most common alternative to the oral contraceptives. The anti-fertility effect of the IUD is not caused by chemical activity. Instead the material forming the IUD induces a foreign body reaction (irritation) in the contiguous endomentrium which appears to interfere in some way with nidation. The use of the IUD is complicated, however, by serious problems including the possibility of intrauterine perforation, pelvic inflammation, discomfort, or aggravated menstrual periods. A recent development is the flexible IUD bearing metallic copper. The contraceptive action of this device results from the combined effects of the copper (which very slowly dissolves in the uterine fluids), which acts on the blastocyst and on the cervical mucus or 3 endometrium, and of theIUD itself, which causes a foreign body reaction in the endomentrium. Another recent method of contraception involves the sustained release of progesterone locally within the uterine lumen. In this method the progesterone is incorporated into a chamber within a flexible intra-uterine device (IUD) formed from a polymer which is capable of releasing progesterone continuously into the uterine fluids at a slow rate over a prolonged period of time. The progesterone acts primarily locally to produce progestational alterations in the cervical mucus and endometrium. However, the antifertility action may also be caused by the reaction of the endometrium to the device itself ("IUD effect") or by systemic absorption of progesterone through the uterine membrane. Medicated IUDs as described in U.S. Pat. No. 4,341,728 is useful but have several drawbacks. An IUD is designed to be inserted into the woman"s uterus which makes positioning of the IUD important and requires insertion and removal by a qualified health professional. Medicated intracervical devices (ICDs) which are introduced into the cervical canal just beyond the cervical os in order to prevent pregnancy are also known and have also been used to release contraceptive hormones". Medicated ICDs can be useful for the inhibition of fertility but are also useful in treating and medicating other conditions of the female reproductive system. The patent U.S. Pat. No. 5,496,557 presents a delivery system for controlled delivery of an active substance comprising a hollow space enclosed by a wall and filled with said active substance. The wall is made of a biodegradable polymer and only one example of the filling is given, namely dispersion of an active substance in castor oil. This system does thus not disclose a core made of an elastomer. The system is further coated with non-permeable biodegradable polymer and the rate of diffusion of the active substance is controlled by the surface of the wall not covered by said non-permeable polymer. A El Mahgoub, S., Contraception, 1982, Vol., 25, No. 4, p. 357-374. problem that could occur with this kind of system is that if the wall is broken, the active substance is released in a non-controlled manner. Such release could lead to serious problems due to the side effects of the active substances or an intoxication by the active substances. From the foregoing, it is evident that the presently available methods of contraception are inadequate for various reasons because they: (a) may produce unpleasant side effects or increase the risk of serious disease, (b) may be unreliable, or (c) may be inconvenient and intrude on sexual enjoyment. Although many women practice contraception in spite of these inadequacies, a need exists in medicine for improved methods which combine effectiveness with increased safety and convenience. Further there has been a consistently large demand for the development of new, long- acting contraceptives that require minimal medical guidance. This is particularly the case in less developed countries where medical and family planning organizations are inadequate. Such improvements are afforded by the present invention. Summary of the Invention It is one of the aspects to provide a novel intrauterine device for releasing therapeutically active agent at a controlled rate for a prolonged period of time, wherein said device comprises polymeric matrix embedded with microspheres. It is another aspect to provide a novel intrauterine device comprising polymeric matrix embedded with microspheres, to produce a local or systemic physiological or pharmacological effect. For more controlled and prolonged release rate, the device may be encased by a polymeric membrane. It is yet another aspect to provide a novel intrauterine device comprising a polymeric matrix embedded with microspheres wherein said polymeric matrix and microspheres consist essentially of a same or different therapeutically active agents. A further aspect to provide a novel intrauterine device comprising a polymeric matrix embedded with microspheres wherein the said therapeutically active agent is distributed between the polymeric matrix and microspheres in a weight ratio of about 20:80 to about 80:20, preferably about 60:40 to about 40:60 and more preferably about 50:50. Particularly, the therapeutically active agent is a hormone and more particularly, the hormone is Levonorgestrel. It is one of the aspects to provide a process for preparing the novel intrauterine device, comprising the steps of: a. preparing the microspheres comprising levonorgestrel, b. preparing a solution of polymer/levonorgestrel mixture in an organic solvent, c. removing the solvent from the solution of polymer/levonorgestrel mixture, thereby forming a solid polymer/levonorgestrel matrix, d. embedding the microspheres of step (a) in the polymer/levonorgestrel matrix by compression technique to form polymeric matrix embedded with microspheres. It is yet another aspect is to provide a novel hormone releasing intrauterine device which overcomes the known problems, difficulties and deficiencies associated with the current IUDs; wherein the novel intrauterine device comprises of polymeric matrix embedded with microspheres. It is yet another aspect is to provide a contraception effect to the female mammal in need thereof, by providing a novel intrauterine device comprising of polymeric matrix embedded with microspheres. The intrauterine device may include one or more other hormones. A further aspect is to provide a intrauterine device that, ever if damaged, would not cause any danger to the subject. Furthermore, the invention aims to provide a intrauterine device that is easy and cost- effective to produce. Detailed Description of the Invention The novel intrauterine device according to present invention comprises polymeric matrix embedded with microspheres, wherein said polymeric matrix and the microspheres comprise essentially of a same or different therapeutically active agents. Further the intrauterine system may be encased by a polymeric membrane for more controlled and prolonged release rate. Particularly, the therapeutically active agent is a hormone and more particularly, the hormone is Levonorgestrel. Levonorgestrel containing microspheres may be prepared by techniques known in the pharmaceutical arts, such as solvent evaporation, emulsification, interfacial polycondensation, pan coating, air suspension, spray drying and congealing. Suitable polymers for preparing microspheres may be selected from any polymer which is biocompatible. A biocompatible polymer and its degradation products are non-toxic toward the recipient. Examples of bioerodable polymers include, but are not limited to, ethyl cellulose, poly(lactic acid), poly(glycolic acid), poly(lactide), poly(glycolide), poly(lactide-co-glycolide)s, poly(caprolactone), polycarbonates, poly acetals, polyamides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polyacetals, polycyanoacrylates, poly(ether ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of poly(ethylene glycol) and poly(ortho ester), degradable polyurethanes and copolymers and blends thereof. Also included are non-bioerodable polymers such as polyacrylates, ethylene-vinyl acetate copolymers, acyl-substituted cellulose acetates, non- degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulfonate polyolefins, and polyethylene oxide. Any suitable blends or copolymers of these materials can also be used. The diameter of the microspheres may be optimized to control the rate of release and the quantity of release. A further aspect of the present invention is to provide a process for preparing the novel intrauterine device, comprising the steps of: a. preparing the microspheres comprising levonorgestrel, b. preparing a solution of polymer/levonorgestrel mixture dissolved in an organic solvent, c. removing the solvent from the solution of polymer/levonorgestrel mixture, thereby forming a solid polymer/levonorgestrel matrix, d. embedding the microspheres of step (a) with the polymer/levonorgestrel matrix by compression technique to form polymeric matrix embedded with microspheres, For more controlled and prolonged release rate, the intrauterine device may be encased by a polymeric membrane. Suitable materials for preparing polymeric matrix may be selected from polyethylene, polypropylene, polymethylpentene ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, polycarbonate, polytetrafluoroethylene (PTFE), fluoroethylenepropylene (FEP), polyvinylidene fluoride (PVDF), polyvinylacetate, polystyrene, polyamides, polyurethane, polybutadiene, polyisoprene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, poly(methacrylate), polymethyl (meth)acrylate, poly(vinylidene) chloride, poly(vinylidene) ethylene, poly(vinylidene) propylene, polyethylene terephthalate, ethylene vinylacetate, a polyhydroxy alkoanate poly(lactic acid), poly(glycolic acid), poly(alkyl 2-cyanoacrylates), polyanhydrides, polyorthoesters, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer; ethylene/vinyloxyethanol copolymer, ethylene/vinyl/acetate copolymers, ethylene vinyl/alcohol copolymers, hydrophilic polymers such as the hydrophilic hydrogels of esters of acrylic and methacrylic acids, modified collagen, cross-linked polyvinyl alcohol, cross-linked, partially hydrolyzed polyvinyl acetate, silicone elastomers, especially the medical grade polydimethyl siloxanes, polyvinylmethylsiloxanes, other organopolysiloxanes, polysiloxane, neoprene rubber, butyl rubber, epichlorohydrin rubbers, hydroxyl-terminated organopolysiloxanes of the room temperature vulcanizing type which harden to elastomers at room temperature following the addition of cross- linking agents in the presence of curing catalysts, two-component dimethylpolysiloxane compositions which are platinum catalysed at room temperature or under elevated temperatures and capable of addition cross-linking as well as mixtures thereof. The polymeric matrix and the membrane encasing said polymeric matrix are thus essentially made of same or different elastomer composition that is described further below. In this application, the term "elastomer composition" may stand for one single elastomer, or the elastomer composition may be made up of two elastomers that are interlaced, one inside the other. Particularly, elastomer used is ethylene-vinyl acetate copolymer. The ethylene-vinyl acetate copolymer can be any commercially available ethylene-vinyl acetate copolymer, for instance as available under the trade names Elvax®, Evatane®, Lupolen V®, Movriton®, Ultrathene®, and Vestypar®. Suitable solvents may be selected from organic solvents such as methylene chloride, acetone, ethyl acetate, methyl acetate, tetrahydrofuran and chloroform. Suitable nonsolvents include alcohols, such as ethanol, nonpolar hydrocarbon solvents, such as isopentane. The solvent may be a single solvent or mixture of solvents. 9 The delivery device according to the invention may be an implant, an intrauterine system, an intracervical system or an intravaginal system. The manufacturing of such systems are done by techniques well known in the art. The shape and size of the system may also be freely chosen by the person skilled in the art. It is also evident that the systems according to the invention may be applied to humans as well as to animals. When the delivery system is for example an intrauterine system, it may further comprise a body forming the structure of the system. In this case, the microsphere-embedded polymeric matrix- membrane-structure of the system is hollow so that it can be positioned over the body of the system. The body may have the form of T, S or 7. According to an embodiment of the invention, the polymeric matrix consists of one or more of therapeutically active agents. According to another embodiment of the invention, the polymeric matrix further consists of microspheres with one or more of therapeutically active agents. Representative examples of therapeutically active agents that may be suitable for the present invention include (grouped by therapeutic class): Antihypertensives, Calcium channel blockers, Antiarrhyrthmics, Antiangina agents, Beta-adrenergic blocking agents, Cardiotonic glycosides, Adrenergic stimulants, Vasodilators, Antimigraine preparations, Anticoagulants and thrombolytic agents, Hemostatic agents, Analgesics and antipyretics, Neurotoxins, Neuroleptics, Hypnotics and sedatives, Antianxiety agents, Neuroleptic and antipsychotic drugs, Antidepressants, CNS stimulants, Anti-Alzheimer"s agents, Anti-Parkinson"s agents, Anticonvulsants, Antiemetics and antinauseants, Anti-inflammatory agents, Antirheumatoid agents, Muscle relaxants, Antigout agents, Hormones, Adrenal cortical hormones, Antiandrogens, Antiestrogens, Aromatase inhibitors, 5-.alpha, reductase inhibitors, Corticosteroids, Steroidal anti inflammatory agents,Pituitary hormones, Hypoglycemic agents and Thyroid hormones. 10 Other miscellaneous hormone agents such as octreotide; Pituitary inhibitors, Ovulation inducers, Diuretics, Antidiuretics, Obstetric drugs, Prostaglandins, Antimicrobials, Penicillins, Tetracyclines, Aminoglycosides, Antifungals, Quinolones, Sulphonamides, Sulphones. Other miscellaneous antibiotics such as chloramphenicol, clindamycin, erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, erythromycin lactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin, aztreonain, colistin IV, metronidazole, tinidazole, fusidic acid, trimethoprim, and 2-thiopyridine N-oxide; halogen compounds, particularly iodine and iodine compounds such as iodine-PVP complex and diiodohydroxyquin, hexachlorophene; chlorhexidine; chloroamine compounds; and benzoylperoxide; Antituberculosis drugs, Antimalarials, Antiviral agents, Anthelmintics, Cytotoxic agents, Anorectic and weight reducing agents, Hypercalcaemic agents, Antitussives, Expectorants, Decongestants, Bronchospasm, Antihistamines, Local anaesthetics, Stratum corneum lipids, Neuromuscular blocking agents, Smoking cessation agents, Dermatological agents, Allergens, Nutritional agents, Keratolytics, Anti-protozoal agents, Opiate antagonists and agonists, Bone active agents including bisphosphonates, Antihyperlipemic agents. Other pharmacologically active agents that may be used include anti-bacterial agents, anti-diabetics, anti-epileptics, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, .beta.- blockers, anti-parkinsonian agents, gastro-intestinal agents, lipid regulating agents, cox-2- inhibitors, leukotriene inhibitors, macrolides, protease inhibitors, anti-osteoporosis agents anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, anti-benign prostate hypertrophy agents, thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, 11 antisecretory agents, actin inhibitors, remodeling inhibitors, antisense nucleotides, antimetabolites, antiproliferatives, anticancer chemotherapeutic agents, growth hormone antagonists, growth factors, radiotherapeutic agents, peptides, proteins, enzymes, extracellular matrix components, free radical scavengers, chelators, antioxidants, antipolymerases, photodynamic therapy agents, gene therapy agents, drugs for vertigo, drugs for the central nervous system, drugs for the autonomic nervous system, autonomic ganglionic blockers, drugs for the peripheral nervous system, ophthalmic drugs, drugs for sense-organs, cardiacs, diuretics, vasoreinforcements, vasoconstrictors, antiarteriosclerotics, circulatory drugs, respiratory stimulants, drugs for respiratory organs, peptic ulcer drugs, stomachic digestants, antacids, cathartics, cholagogues, digestive drugs, urinary tract disinfectants, uterotonics, urogenital drugs, drugs for anus diseases, nutritive roborants, drugs for blood or body fluid, drugs for hepatic diseases, antidotes, habitual intoxication drugs, antipodagrics, enzyme preparations, cell activation drugs, antitumor agents, .alpha.-adrenergic blockers, cholinesterase inhibitors, anti- angiogenesis factors, anti-psoriatic agents, anti-diarrhoeals, anti-leukemic drugs, anti-aids drugs, drugs for dementia, angiotensin inhibitors, .alpha.- and .beta.-agonists, wound- healing promoters, calcium antagonists, pancreatic hormones, spasmolytics, cardiovascular agents, inotropic agents, gonadotropins, symphatomimetic agents, antifungals, neurotrophic factors, proton pump inhibitors, antipruritics, anti-addiction drugs, histamin-receptor antagonists, immunosuppressants and immunostimulants. In this specification, except where the context requires otherwise, the words "comprise", "comprises" and "comprising" means "include", "includes" and "including", respectively. That is, when the invention is described or defined as comprising specified features, various embodiments of the same invention may also include additional features. Also the reference signs should not be construed as limiting the claims. The invention is described below in greater detail by the following, non-limiting drawings and examples. 12 EXAMPLE I Preparation of Levonorgestrel containing microspheres: Microspheres were prepared by solvent evaporation technique. Ethyl cellulose was dissolved in methylene chloride to form a homogeneous polymer solution having a concentration of approximately 16%. To this known quantity (25mg) of Levonorgestrel was added and mixed thoroughly using vortex mixer for l0minutes, to completely mix with the polymer solution. The resultant polymer solution containing levonorgestrel was emulsified in 0.1% aqueous solution of poly vinyl alcohol, under stirring at 300 rpm using vortex mixer to form microspheres. The stirring was continued until the evaporation of methylene chloride complete. The microspheres were filtered using whatman paper washed 3 times with cold water and air-dried overnight at room temperature. The entrapment efficiency of the formulation was determined by solvent-extraction technique. l0mg of levonorgestrel loaded microspheres were dissolved in 10ml of methanol. After complete solubilization the samples were analyzed for Levonorgestrel in the UV Spectrophotometer, The microspheres prepared were sieved to separate lmm sized microspheres for further usage. II Preparation of Levonorgestrel containing polymeric matrix: Ethylene vinyl acetate (Elvax® 40w) was dissolved in methylene chloride to give 10% solution (w/v). To this polymeric solution accurately weighed quantity of Levonorgestrel 13 was added and mixed thoroughly. The polymer/levonorgestrel mixture was poured into the glass mold, which is previously cooled by placing it on dry ice for 5 minutes. After pouring, the mold remained dry ice for 10-15 minutes, to freeze the mixture. The frozen slab was pried loose with a cold spatula, transferred onto a wire screen (steel mesh) and kept at -20°C for 2 days in a freezer. The slabs were further dried for 2 more days at room temperature in a desiccator kept under a mild, house-line vacuum. The drug content of the prepared polymeric slabs were determined by solvent extraction technique. 100mg of levonorgestrel loaded polymeric slab was dissolved in 10 ml methylene chloride. After complete solubilization the samples were analyzed for levonorgestrel contents in the UV Spectrophotometer. III Preparation of novel intrauterine device: The intrauterine devices were prepared in the size of 2mm diameter X 20mm length according to the uterine dimension of rats. The levonorgestrel containing polymeric matrix prepared in step II were placed over the stainless mold (internal diameter size 2mm and length 20mm), which was preheated to 40 C. Calculated quantity of microspheres were carefully placed between the polymeric sheets in the mold. The mold was compressed in mild heat (40°C) and held in oven for 10 minutes at 40°C. The mold was then cooled and the cylindrical shaped, microspheres embedded intrauterine device was removed. The total levonorgestrel content in a single device was limited to 500mg, where the levonorgestrel was distributed equally in a weight ratio of 50:50 between the " -microspheres and polymeric matrix system. Intrauterine devices devoid of microspheres with the same quantity of levonorgestrel were also prepared for comparative study. 14 Fig. 1 shows the schematic diagram of novel intrauterine device containing microspheres; Fig. 2 shows the schematic diagram of plain intrauterine device. IV In-vitro drug release study: The intrauterine device prepared in step III were placed in a test tube containing 10ml of 10% methanolic phosphate buffer saline (Phosphate buffer saline pH 7.4 containing 10% methanol). The tubes were incubated at 37+l°C and shaken at 70±5 rpm. At designated times, the device was removed and transferred to the fresh buffer. The solution was measured for levonorgestrel content and the whole medium was changed after each sampling. In-vitro results About 94% of drug release was seen up to 143 days (Fig. 3) in plain device (device without microspheres), whereas microspheres embedded device released 91% of drug in more controlled manner upto 297 days (Fig. 4). In vivo studies Cyclic female adult Sprague Dawley rats were selected in the proestrus stage. Animals were anaesthetized under ether and the entire surgical area was wiped with disinfectant. A small incision was made in the dorsolateral side and the uterus was exposed. A small stab wound was made in the antimesometrial wall (near the cervix), through which the polymeric device (size 2mm diameter and 20mm length) was inserted. Care was taken throughout the procedure to avoid excess bleeding. The uterine horn was closed with a single stitch of 6-0 silk suture. The skin was closed with cotton suture. After allowing 2 weeks of rest period the animals were checked for their cyclicity. 15 The animals in proestrus stage were allowed to mate with males of proven fertility. On day 3 of pregnancy, the animals were sacrificed and their fallopian tubes were flushed out with phosphate buffer saline and checked for fertilized ova. Results expressed as mean ± S.E.M. of data from 10 animals. While there has \been shown and described what are the preferred emboliments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the invention as it is defined by the appended claims. 16 WE CLAIM: 1. A novel intrauterine device for releasing therapeutically active agents at a controlled rate for a prolonged period of time, wherein said device comprises polymeric matrix embedded with microspheres. 2. The novel intrauterine device as claimed in claim 1 wherein the therapeutically active agent is distributed between the polymeric matrix and microspheres in a weight ratio of 20:80 to 80:20. 3. The novel intrauterine device as claimed in claim 1 wherein the therapeutically active agent is levonorgestrel. 4. The novel intrauterine device as claimed in claim 1 wherein the polymer for polymeric matrix is selected from polyethylene, polypropylene, polymethylpentene ethylene/propylene copolymers, ethylene/ethyl acrylate copolymes, ethylene/vinyl acetate copolymers, polycarbonate,polytetrafluoroethylene(PTFE) , fluoroethylenepropylene (FEP), polyvinylidene fluoride (PVDF), polyvinylacetate, polystyrene, polyamides, polyurethane, polybutadiene, polyisoprene, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymers with vinyl acetate, poly(methacrylate), polymethyl (meth) acrylate, 17 poly(vinylidene)chloride, poly(vinylidene) ethylene, poly(vinylidene) propylene, polyethylene terephthalate, ethylene vinylacetate, a polyhydroxy alkoanate poly (lactic acid), poly(glycolic acid), poly(alkyl 2-cyanoacrylates), polyanhydrides, polyorthoesters, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer; ethylene/vinyloxyethanol copolymer, ethylehe/vinyl/acetate copolymers, ethylene vinyl/alcohol copolymers, hydrophilic polymers such as the hydrophilic hydrogels of esters of acrylic and methacrylic acids, modified collagen, cross-linked polyvinyl alcohol, cross-linked, partially hydrolyzed polyvinyl acetate, silicone elastomers, especially the medical grade polydimethyl siloxanes, polyvinylmethylsiloxanes, other organopolysiloxanes, polysiloxane, neoprene rubber, butyl rubber, epichlorohydrin rubbers, hydroxyl-terminated organopolysiloxanes of the room temperature vulcanizing type which harden to elastomers at room temperature following the addition of cross-linking agents in the presence of curing catalysts, two- component dimethylpolysiloxane compositions which are platinum catalysed at room temperatures or under elevated temperature and capable of addition cross-linking as well as mixtures thereof. 18 5. The novel intrauterine device as claimed in claim 1 wherein the polymer for microsphere is selected from ethyl cellulose, poly(lactic acid), poly(glycolic acid), poly(lactide), poly(glycolide), poly(lactide-co- glycolide)s, poly(caprolactone), polycarbonates, poly acetals, polyamides, polyanhydrides, poly(amino acid)s, poly(ortho ester)s, polyacetals, polycyanoacrylates, poly(ether ester)s, poly(dioxanone)s, poly(alkylene alkylate)s, copolymers of poly(ethylene glycol) and poly(ortho ester), degradable polyurethanes and copolymers and blends thereof. 6. The novel intrauterine device as claimed in claim 1 wherein the device may be encased by a polymeric membrane for more controlled and prolonged release rate. 7. The novel intrauterine device as claimed in claim 6 wherein the polymeric membrane encasing the device are thus essentially made of same or different elastomer composition. 8. The process for preparing the novel intrauterine device, comprising the steps of: 19 a. preparing the microspheres comprising levonorgestrel, b. preparing a solution of polymer/levonorgestrel mixture in an organic solvent, c. removing the solvent from the solution of polymer/levonorjestre! mixture, thereby forming a solid polymer/levonorgestrel mixture, d. embedding the microspheres of step (a) in the polymer/levonorgestrel matrix by compression technique to form polymeric matrix embedded with microspheres. 9. A process as claimed in claim 8 wherein microspheres are prepared by solvent evaporation, emulsification, interfacial polycondensation, pan coating, air suspension, spray drying or congealing. 10. A process as claimed in claim 8 wherein the solvent is selected from methylene chloride, acetone, ethyl acetate, methyl acetate, tetrahydrofuran, chloroform, ethanol, isopentane. 20 11. A method to provide a novel hormone releasing IUD which overcomes the known problems, difficulties and deficiencies associated with current IUD; wherein the novel intrauterine device comprises of polymeric matrix embedded with microspheres. A novel intrauterine device for releasing therapeutically active agents at a controlled rate for a prolonged period of time, wherein said device comprises polymeric matrix embedded with microspheres.

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180-kol-2004-granted-abstract.pdf

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180-kol-2004-granted-correspondence.pdf

180-kol-2004-granted-description (complete).pdf

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180-kol-2004-granted-specification.pdf