MXPA99006219A - Silicone core long term androgen delivery implant - Google Patents

Abstract

This invention features an implantable system for use as a male contraception and as a treatment of benign prostate hypertrophy and other conditions. The implant system includes an implant intended for subcutaneous or local administration having a core comprising a silicone elastomer and drug matrix which is encased in an ethyl vinyl acetate coating or membrane.

Description

IMPLANT OF DELIVERY OF LONG TERMI NON-DROGEN WITH NUCLEI SILICONE FIELD OF I NVENTION The present invention refers to the field of male contraception as well as to the treatment of benign prostatic hypertrophy, and other conditions which can be treated by androgen or hormonal therapy and methods and apparatuses to perform it. More particularly, this invention relates to an improved implant delivery system.

BACKGROUND OF THE INVENTION Implant delivery devices or subcutaneous devices have been known to deliver contraceptives to women for some time. In fact, a number of devices have been used in subcutaneous contraceptive systems for women, including the widely used NORPLANT® and NORPLANT I I® systems. These systems involve implants composed of a silicone elastomer, such as, for example, SILASTIC®, siloxane-containing material available from Dow Corning. See Patents of E. U. , Nos. 4,957, 1 19 and 5,088,505. The convenience and reliability of these systems make them desirable substitutes for other forms of chemical and mechanical contraception. Of course, if similar systems could be provided for men, their convenience could encourage a larger portion of the population already sexually active to engage in contraception. However, the production of a male subcutaneous contraceptive does not exist without difficulties. One can not simply administer compounds that block gonadotropin secretion and sperm production, such as LH RH and its analogs, without also decreasing the production of testosterone. This can depress male sexual function which could undermine the advantages of using this type of system. Therefore, androgens should be an essential part of a total male subcutaneous contraceptive strategy. One possible answer involves the production of an implant system to administer both an androgen and a sterilant. An implant would be administered to a patient and deliver an androgen such as testosterone or 7a-methyl-19-nortestosterone ("M ENT") or its derivatized acetate ("M ENT Ac") to provide normal male function. The same implant or another implant would administer a sterilant. The NORPLANT® system would seem a possible model for such implants. Unfortunately, when these silicone-based implants were investigated, considerable complications arose. In fact, a system that uses an implant based on silicone elastomer was found to be unsatisfactory. As noted in Sundaram et al., "7-Alpha-Methyl-Nortestosterone (MENT): The Optimal Androgen for Male Contraception", Annals of Medicine, (1993), 25, 199-205, implants based on SILASTIC® containing MENT had to be replaced at three-week intervals due to the rapid loss of androgen. Based on this discovery, it was concluded that androgen could not be administered from implants containing silicone elastomers in a highly repetitive, practical, long-term manner. It was subsequently discovered that androgen could be delivered alone, for androgen therapy when done as part of an implant system using an ethyl vinyl acetate core ("EVA") and a regime-limiting coating containing EVA. See Patent of E. U. , No. 5,733,565. Of course, although this discovery was a significant advance in male contraception, it is still desirable to identify other implant systems that could be useful for androgen delivery, either alone, as part of androgen replacement therapy or in combination with a sterilant to maintain the sexual function of male cells while providing contraceptive efficacy.

BRIEF DESCRIPTION OF THE I NVENTION Although it was previously concluded that SI LASTIC® and other silicone-based polymers should be avoided when subcutaneous implants are constructed to deliver androgen, it has now been discovered that silicone elastomers such as SILASTIC® may play a role in the production of male contraceptive implants after all. Indeed, there are advantages in constructing an androgen-containing implant from a core of a silicone elastomer as long as ethyl vinyl acetate or other suitable material is used as the limiting membrane of the regime surrounding the reservoir or core. These advantages include providing a sustained and constant release of a daily dose of a drug and having a release rate profile close to the order of zero. This result was particularly surprising in view of the original observation that silicone-based implants exclusively exhibited a profile of unsatisfactory release rate. In addition, the availability of silicone elastomers as core forming materials provides significant benefits since silicone elastomers can have increased compatibility with specific androgens and their analogues. Because the silicone elastomers can be modified to provide properties that are different from those of the vinyl acetate monomers, it may be possible to affect the properties of the core by using one or another specific material. Adding SILASTIC® or silicone elastomers to the arsenal of potential materials as sources of cores is, therefore, of great benefit. In accordance with one aspect of the present invention, a subcutaneous implant for androgen delivery is provided. The implant includes a core comprising a silicone elastomer and drug matrix enclosed in an EVA coating or membrane of a limiting regime. This device can be used alone, for hormone replacement therapy and to treat various conditions for which androgen therapy is recognized. In a particularly preferred embodiment according to the present invention, this silicone elastomeric core implant can be used in combination with an implant suitable for the delivery of a sterilant such as LH RH, its analogues or functionally related compounds. In this case, by using two implants, for example, both contraception and a male function retention can be performed. Packages that include one or more of these implants are also contemplated.

BRIEF DESCRIPTION OF THE DIAMETERS Figure 1 is a cross-sectional view of the implant of the present invention. Figure 2 is a graph showing the in vitro release profile of MENT Ac from 60% MENT Ac matrix-silicone elastomer cores covered with an EVA tube as illustrated in Figure 1.

Figure 3 is a graph showing the in vitro release regime profile of MENT Ac from 60% MENT Ac cores - EVA matrix with an EVA tube. Figure 4 is a graph showing the comparison of M ENT Ac release regimes from two implants, one with a SILASTIC core-matrix of MENT Ac and the other with a core of EVA. Both are enclosed in an EVA membrane. Figure 5 is a cross-sectional view of an implant designed for the administration of LHRH.

DETAILED DESCRIPTION OF PREFERRED MODALI DADES The term "androgen" as used in accordance with the present invention encompasses male sex hormones, both occurring naturally and synthetically. The androgenic hormones are steroids which are produced in the body by the testes, in the cortex of the adrenal gland or in the laboratory. These include testosterone and its esters, buciclate, cypionate, propionate, phenylpropionate, cyclopentylpropionate, isocarporate, enanthate and decanoate. Synthetic androgens such as M ENT and their esters such as MENT Ac are also encompassed by the term. The implant of the present invention can also be used to deliver functionally related compounds such as anabolic agents. These agents generally exhibit strong anabolic potency and relatively weak androgenic activity. These compounds include methandriol, oxymetholone, methandioneone, oxymesterone, nondrolone phenylpropionate and noretandrolone. The esters of all the above compounds are preferred. For the purposes of the present invention, these compounds can be considered androgens as well. Subcutaneous implants containing androgen according to the present invention can be used alone for therapeutic protocols involving the administration of androgens such as the treatment of hypogonadism, prostatic hyperplasia and weakening of muscles. The implant androgen delivery device according to the present invention is designed to include sufficient androgen to provide the subject or patient with a required daily dose of a pharmaceutically effective amount of the androgen over the functional lifetime of the implant. This should preferably be at least 7 days and more preferably 30 days or longer. Iplants capable of releasing androgen uniformly over 100 to 180 days are particularly preferred. Also, preferably, the regimen at which the androgen is provided to patients is relatively constant, i.e., a release profile of the zero order or pseudo-zero order. The core of these androgen-containing implants is composed of silicone elastomers and drugs. A wide class of silicone elastomers can be used to form the drug matrix of silicone elastomer. Suitable silicone elastomers according to the present invention include SILASTIC® and silicone elastomer R-2602 RTV available from N usil Sílicone Technology, 1040 Cindy Lane, Carpinteria, California 93013. Silicone elastomers can be catalyzed so that polymerization and formation of the core are carried out at room temperature. The core can also be formed by heat-curable core material. The membrane or coating is preferably made of an EVA polymer. The melt index of this membrane material is less than 10 g / 10 min. , preferably, less than or equal to 8 g / 1 0 min. More preferably, the melt index is less than about 5 g / 10 min. , and most preferably about 4 g / 1 0 min. The content of vinyl acetate ("VA") is generally less than 20% by weight. The EVA copolymer could have, for example, a composition of about 9-12% VA polymer content.

Suitable EVA polymers which can be used as a membrane are, for example, Evatane® with the designations 501/502 (melt index 2, content of vinyl acetate 7.55%), 554/555 4, (12.5%), 540 (10, 18%) and particularly 450, 460, 470, 550, 560, 650, 660, 750, 760 and 770, and Evatane® 1080 VN and in particular 1040 VN 4 supplied by Atochem. Although the EVA membrane or coating is regime limiting, the core material also has an effect on the drug release rate profile of the implant. Figure 2 illustrates the in vitro release profile of MENT Ac from an implant containing a silicone-drug elastomer matrix surrounded by an EVA tube according to the present invention. Figure 3, on the other hand, illustrates the in vitro release profile of MENT Ac from an implant containing it and EVA-drug matrix surrounded by an EVA tube. The implants of Figures 2 and 3 were manufactured in a similar manner. In both cases, the core matrices were made by extruding MENT Ac / matrix material into molds. The preparation of the silicone elastomeric core / EVA membrane implants according to Figure 2 was carried out as follows: 1.5 g of MENT Ac was mixed with 1 g of silicone elastomer R-2602 RTV (Nusil Silicone Technology, 1040 Cindy Lane, Carpinteria, CA 93013). 2-3 drops of stannous octoate were introduced and mixed intensely. The mixed paste was introduced into a metal syringe and injected into a brass mold with spaces of appropriate diameter, for example 2.38 mm. The paste mixture could be extruded directly (in an open atmosphere) through a nozzle of a certain diameter, but injecting into a mold ensures the uniformity of the diameter of the core bars obtained. The drug mixture was allowed to polymerize at room temperature and the mold was opened after curing at 80 ° C for 10 minutes. The bars obtained were cut into pieces of 4 cm. The EVA tube (content of VA 9%, approximately 2.55 mm in diameter) was cut into 5 cm lengths. The tube has wall thickness from about 0.14 mm to about 0.17 mm. The tube was soaked in methylene chloride for about 1 minute. Each of the 4 cm bars was introduced into the space of one of the 5 cm pieces of the soaked EVA tube, leaving approximately 0.5 cm without filling on both sides. The fi tube was left overnight at room temperature to allow evaporation of the methylene chloride. The two ends of the tube were then sealed by filling them with molten EVA (25% VA content). The sealed implants were heated at 70 ° C for 5-10 minutes to increase the sealing and adhesion between the external EVA tube and the end seals. The two ends of the fi tube were cut out, leaving approximately 2.5 mm as a sealing tip. The obtained implants could be properly sterilized and packed. In effect, these implants were made as described in Example 1.

The preparation of the EVA core / EVA membrane implants according to Figure 3 was carried out in the same way as the implants of Figure 2 except that the core material was constructed as follows: 1 g of EVA granules , 25% EVA content (Aldrich Chemical Company Inc., CRAFTSMEN IN CHEMISTRY MI LWAUKEE WIS 53233 USA) were soaked in 12 ml of methylene chloride (Fisher Scientific). The obtained solution was swirled before and after the addition of 1.5 g of M ENT Ac. The methylene chloride was evaporated under vacuum (at room temperature) for 2 hours. The solid dispersion obtained was placed in a metal syringe and heated at 1 10 ° C for 5 minutes and then extruded through the 0.254 cm nozzle of the metal syringe in appropriate molds. The bar obtained was cooled and cut into pieces of 4 cm. Each of the 4 cm bars was then introduced into the space of a 5 cm pieces of the soaked EVA tube, leaving approximately 0.5 cm without filling on both sides. The filled tube was left overnight at room temperature to allow evaporation of the methylene chloride. The two ends of the tube were then sealed by filling with molten EVA (25% VA content). The sealed implants were heated at 70 ° C for 5-10 minutes to improve the sealing and adhesion between the outer EVA tube and the end seals. The two ends of the filled tube were cut out, leaving approximately 2.5 mm as a sealing tip. The obtained implants could be properly sterilized and packed.

The measurement of the in vitro diffusion of MENT Ac implants of Figures 2 and 3 were carried out by: a. gumming each implant above the bottom of the individual glass bottles (approximately 25 ml capacity) using medical adhesive; b. quantitatively measure 20 ml of ZEPH I RAN® 1: 750 solution, available from Winthrope Labs, a division of Sterling (Benzalkonium chloride solution in a 17% aqueous solution) in each of the bottles; c. screw the lid of the bottle and place it in a horizontal position on the appropriate shelf in the water bath; d. adjust the temperature to 37 ± 1 ° C and agitation speed of 100 ± 2 strokes per minute; and. change solutions daily, and continue incubating; and f. assay samples daily using UV spectrophotometer at the appropriate wavelength (243 nm). The ZEPH I RAN® solution is used as a reference standard. As illustrated in Figure 2, following an initial drug start, the silicone elastomeric drug matrix implant exhibited a release rate profile of the order of pseudo zero over the entire 100 day period. In contrast, the profile of release rate of the implant based on EVA was less uniform during the period of 100 days (Figure 3). This comparison is further represented in Figure 4 which shows a side-by-side comparison of the profiles of release regimes of the elastomeric silicone-drug matrix and EVA-drug matrix implants. Without limitation, the best release rate profile of an implant having an elastomeric silicone-drug matrix compared to an EVA-drug copolymer matrix may be based on the solubility properties of the steroid in the drug matrices. In the EVA-drug copolymer matrix implant, the matrix is made of polyethylene and vinyl acetate. The steroid is soluble only in the vinyl acetate portion of the EVA polymer. The EVA drug matrix contains areas of crystallinity through which the steroid can not diffuse and amorphous areas through which the steroid can diffuse. In contrast, in implants containing an elastomeric silicone matrix, the steroid is soluble in the entire matrix and thus reaches more uniformly the external tubing limiting EVA regimen. This is particularly surprising in view of the advance that the EVA core implant / EVA-coated implant represented on silicone / silicone-coated core implants used in female contraceptives. See Patent of E. U. , No. 5,733, 565. Figure 1 illustrates a longitudinal cross-sectional view of a partially assembled implant 10 which contains a central core 1 1 extending in an axial direction and having an outer surface 12 and ends 13 and 14. opposites. The core 1 1 is a matrix of a pharmaceutically effective amount of androgen 15 for administration subcutaneously dispersed substantially uniformly in a base 16 of silicone elastomer to form a matrix. The membrane 17 overlaps the core 1 1. The membrane 17 is made of an EVA polymer. The membrane 17 has opposite ends 18 and 19 which extend axially beyond the opposite ends 13 and 14, respectively of the central core 1 1 to define cavities 20 and 21, respectively. By complete assembly of the device, the cavities 20 and 21 are substantially filled with ethylene vinyl acetate copolymer (EVA), with a content of vinyl acetate of 25%, forming the seals 22 and 23. The seals 22 and 23 arranged in cavities 20 and 21, respectively, cooperate with the overlapping ends 18 and 19, respectively, of the membrane 17 to completely encapsulate the central core 1 1. Seals 22 and 23 can be made of the same EVA material that forms the cavities and membrane of the implant. The EVA copolymer of the stamps could have, for example, a composition of approximately 9% -25% VA polymer content. Preferably the VA content of the stamps is 9%. The sealant minimizes the diffusion of the drug in the axial direction, that is, from the ends of the device. The potential for axially undesirable diffusion of the drug increases as the length of the implant decreases, v. g. , up to approximately 3.0 centimeters and less. Seals 22 and 23 also serve to more safely hold the device together, v. g. , maintain the structural integrity of the device, and avoid the infiltration of biological tissues to the open ends of the device in another way. An androgen-containing implant is preferably cylindrical with a maximum external diameter of approximately 3.0 millimeters and a maximum length of approximately 5.0 centimeters. More preferably, the implants will have an outer diameter that ranges from about 2.4 to about 2.7 millimeters and a length from about 4.4 to about 5.0 centimeters. The bar-shaped core, in this case, ranges from about 4.0 to about 4.5 cm in length. The bar diameter is obviously sufficient to fit inside the tube. Of course, depending on the circumstances, it may be necessary or desirable to increase the length or diameter of the device or to change it from a cylindrical configuration to a different geometry. In this regard, other geometric shapes, including, for example, rings, loops, and discs, are contemplated for the present invention. However, since it is necessary to produce the device in such a way that it does not cause an impediment or cause discomfort to the user, it is preferable to keep it as small and as unobtrusive as possible. The androgen delivery device of subcutaneous implant according to the present invention can be manufactured generally in accordance with standard techniques. The androgen or selection androgens are mixed with the silicone elastomer to form a homogeneous matrix. The mixing is continued until a substantially uniform dispersion is performed. The material is then processed to the desired shape by molding, casting, extrusion or other appropriate processes. An outer layer can then be applied to the central core in a variety of ways, such as by mechanical stretching, impregnation or immersion. See, for example, the Patents of E. U. Nos. 3,832,252, 3,854,480 and 4,957, 1 19, the texts of which are incorporated herein by reference. See also the discussion of the construction of androgen-containing implants in the Patent of E.

U. No. 5,733,565, the text of which is also incorporated herein by reference. In a preferred method the androgen is mixed with the silicone elastomer and uniformly mixed to give a paste. An appropriate amount of a catalyst such as, for example, Stannous Octoate is introduced and mixed rapidly and intensively throughout the material. The mixture is filled into a metal syringe or an extruder and injected through a suitable mold. The extruded core material could be allowed to cure at room temperature or it could be cured in a moderate temperature oven such as 80-90 ° C. The individual cores or bars can then be cut from the extruded material of any desired length. The dimensions of each bar or core are determined, at least in part, based on the method and location of the implant, the intended useful life, the composition of the SI LASTIC® material, the amount of androgen and its potency, etc.

The core is then covered with a limiting membrane of an EVA polymer regime. As noted previously, this can be done by a number of known processes including, for example, spraying or submerging the core in the coating material. However, one of the most convenient ways to do the same is to provide a piece of EVA tube of sufficient internal and external diameter composed of the desired regime-limiting material. This tube is cut into pieces that are slightly longer than the length of the bars or cores. The tube is then soaked in an organic solvent such as methane chloride for a short time (in the order of 60 seconds). The core is then introduced into the space of the EVA tube, leaving approximately 0.5 centimeters of unfilled tube at both ends. The tube preferably has an outer diameter of 2.39 to 2.55 millimeters and an inner diameter or space of 2.13 to 2.36 millimeters. The stuffed tube is then dried. The two ends of the tube are then sealed with filling of a molten EVA. The sealed implants can then be heated briefly to improve the seal and adhesion between the EVA tube and the end seals. This will also ensure the evaporation of any traces of organic solvent, if any. The two ends of the implant are then trimmed, leaving approximately 2.5 millimeters as a sealing tip. The ends of the device can also be sealed in a variety of other ways in accordance with recognized art techniques. For example, radio frequency can be used. The implants thus obtained can then be sterilized using, for example, ethylene oxide and packaged for use. The device could also be produced by coaxial extrusion as is well known in the art. The implant of the invention should contain an amount of androgen that is sufficient to provide the required daily dose of a pharmaceutically effective amount of that androgen for a desired period of time. This means that if the appropriate daily dose of androgen is 5 micrograms per day, then the implant must contain enough androgen to allow administration of 5 micrograms every day for as long as the implant is used. Preferably, the implant has a shelf life of at least 7 days. More preferably, the subcutaneous implant will deliver a reasonably constant amount of androgen for a period of at least 30 days. Implants that can release an amount of androgen daily in a stable manner for 100 to 180 days or more are preferable. As noted previously, the implant must be designed to ensure a release profile of the order of zero androgen during the lifespan as possible. A release profile of the order of pseudo zero (following the initial boot is illustrated in Figure 2). An amount of "pharmaceutically effective" androgen is that amount sufficient to support sexual function (when used in combination with a male infertility implant), vaccine or other drug that leads to the suppression of testosterone) for the predetermined period of time, v. g. , the life of the implant. The weight ratio of the silicone elastomer-based material to the androgen in the central core will generally range from about 1: 1 to about 1: 1.5. The implant of the present invention must contain a sufficient amount of androgen to provide a constant release substantially of a daily dose of between about 100 to about 1000 micrograms of androgen and more preferably between about 200 and about 500 micrograms of androgen each day during the implant life. Preferably, the core consists of between 50% to about 70% by weight of androgen and between about 50% to about 30% by weight of a silicone elastomer. Sterilants are drugs that kill sperm, interrupt sperm production, suppress sperm production or return sperm unable to fertilize an egg. The effects of these sterilants are generally reversible. That is, once they are removed, sperm production and / or viability returns. A preferred subclass of sterilants used in accordance with the present invention is LHR H peptides (luteinizing hormone-releasing hormone) as well as their analogues and functionally similar compounds. These compounds are active polypeptides that act on the anterior pituitary gland to effect the release of hormones that affect the activity of reproductive organs. The naturally occurring LH RH peptide is produced in the hypothalamus region of the brain and controls the reproductive cycle of mammals acting to effect the release of luteinizing hormone and funicular stimulation hormone which in turn acts on the gonads to stimulate the synthesis of steroid hormones and to stimulate the maturation of the gametes. LHRH can be used for hypogonadal and impotence conditions and to stimulate spermatogenesis, and androgen production in men. Large doses of highly potent and long-lasting LHRH analogues have the opposite effect; suppressing spermatogenesis in the male. Thus, this material can act as a chemical sterilant. See Patents of E. U. Nos. 4,234,571, 5,292,515 and 5,266,325. Other analogs of LH RH are known which also provide, in doses of lower levels, chemical sterilizing activity in males. According to the present invention, these sterilizing compounds can be administered through a second implant which differs significantly in structure and composition when compared to the first androgen delivery implant.

A group of delivery implants useful as the second implant according to the present invention is a hydrogel implant.

Hydrogel-based delivery systems for LH RH and its analogs are known and described in U.S. Patent Nos. 5,266,325 and ,292,515, the texts and drawings of which are incorporated herein by reference. In one embodiment, the second implant is formed from a homogeneous hydrophilic copolymer having a predetermined equilibrium water content or "EWC" value. This material can be produced by polymerization by the addition of a mixture containing ethylenically unsaturated hydrophilic monomer A and an ethylenically unsaturated hydrophilic monomer B copolymerizable therewith. The copolymer is useful as a hydrogel membrane in the diffusion therethrough of a selected active compound, (sterilant), in an aqueous or non-aqueous medium, in a predetermined ratio. The second implant is preferably an article of cylindrical shape, water-swellable, water-soluble, homogenous, uniform copolymer with a concentric core having a predetermined equilibrium water content value. The implant is formed by the addition polymerization of a mixture containing ethylenically unsaturated hydrophilic monomer A and ethylenically unsaturated monomer B copolymerizable therewith. This may provide a device for implanting which is useful for the sustained release of an active agent therefrom from a patient. This modality involves: a. forming a polymerizable liquid mixture containing monomer A and monomer B in amounts sufficient to give a homogeneous copolymer AB having a predetermined value of equilibrium water content; b. introducing a predetermined quantity of said polymerizable liquid mixture into the open end of a polymerization column; c. rotating said polymerization column about its longitudinal axis maintained substantially parallel to the ground at a sufficient rate to cause radially outward displacement of said polymerizable liquid mixture to assume a predetermined hollow cylindrical liquid configuration with said column; d. maintaining the polymerization column under polymerization conditions to convert said polymerizable mixture of predetermined liquid configuration into a predetermined solid hollow cylindrical configuration; and e. recovering a cylindrically shaped copolymer article having the predetermined value of equilibrium water content and further characterized by a cylindrical core or reservoir and internal and external cylindrical surfaces of uniform thickness substantially between said surfaces. In a preferred embodiment, a homogeneous hydrophilic copolymer of 2-hydroxyethyl methacrylate ("HEMA") and hydroxylpropyl methacrylate ("HPMA") are produced and used. In one embodiment, the second implant is a cylindrical, uniformly shaped copolymer cartridge characterized by a predetermined EWC value, produced with a substantial uniformity of thickness between its external and internal cylindrical surfaces using a pore-forming agent evenly or uniformly distributed through of the whole cartridge. In this aspect of the invention, a mixture of uniform or homogeneous polymerizable liquid monomer A, monomer B, and a pore-forming agent, is prepared using sufficient amounts to result in a homogeneous copolymer having the pre-established EWC value. Another modality of the second implant involves the preparation of a delivery device for the delayed / sustained release of an active agent there, v. g. , a drug, which includes: a. introducing an active agent and, optionally, a pharmaceutically acceptable carrier into the core (reservoir) of the aforementioned cylindrical shaped copolymer body in an amount sufficient for sustained sustained release of said active agent into a delivery environment; b. further introducing liquid polymerizable material into said core in an amount sufficient to cover the active agent or to substantially or completely fill the core to the upper part of the cylindrical body, said liquid polymerizable material in its polymerized state having an equilibrium water content value which exceeds the equilibrium water content value of the cylindrical body; and c. polymerizing said polymerizable material to effectively seal the opening of the core with a water insoluble water-insoluble polymer plug (layer). The delayed / sustained release implant comprises a copolymer, hydrophilic xerogel or hydrogel cartridge (collectively referred to as a hydrogel herein). The implant further includes a hydrophilic sealing means for sealing the open end of the cartridge so that it defines an enclosed core, a sterilant and optionally, a pharmaceutically acceptable carrier, contained in the core in an amount sufficient to be continuously released for a period of time. extended time. The cartridge is characterized by internal and external cylindrical surfaces without strips, smooth, insoluble in water, capable of swelling by water, and a predetermined EWC value. The hydrophilic sealing means exhibits the ability to swell with water, insolubility to water, and an equilibrium water content value that exceeds that of the cartridge. Figure 5 illustrates a shape of the second implant 30 of the invention. The cartridge 31 is shown with a base 33 as an oval (after trimming and polishing) packed with drug such as analogues of LHRH 34 in its core. The external and internal cylindrical services of the cartridge 30 are smooth and without stripes. The covered Teflon 36 separates the drug 34 from hydrophilic plug 37, formed in situ from the liquid and polymerized material to a solid hydrophilic plug 37. The equilibrium water content of the plug 37 and thus its ability to build up are greater than the EWC of the cartridge 31. Therefore, an airtight seal will be formed by hydration. The outer surface 38 of the cap 37 that includes a portion of the adjoining wall 39 of the cartridge is oval shaped by cutting and polishing. The amount of LH RH or its analogues will depend on many factors. However, mainly, the amount will depend on the regimen and extension of release, the implant's useful life, the physical size and needs of the patient, the type of treatment for which the implants are prescribed and, of course, the need to complement the androgen administration from the first implant previously described. The treatment of infertility with synthetic LH RH peptides requires a low level of drug, while the reduction of fertility and relative effects requires a large dose in relation to the activity of LHRH that occurs in nature. For the control of LH RH agonist fertility, it is desired to release the drug at such a rate that the subject will receive between 0.05 and about 100 micrograms per kilogram of body weight per day, preferably between 0.1 and 5.0 micrograms per kilogram of body per day. The result is a second implant for sustained release of an active agent such as this sterilant thereof which includes a water-insoluble, water-insoluble, water-swellable, non-biodegradable, biocompatible AB hydrophilic copolymer cartridge, a sealant for closure of the open end of the cartridge which includes a water-insoluble, water-swellable, non-biodegradable, biocompatible hydrophilic polymer plug having an equilibrium water content value greater than that of the cartridge per se. The sterilant, either alone or in combination with other carriers, diluents or active ingredients, is contained in the container of the cartridge in an amount sufficient to provide the predetermined sustained release thereof over the lifetime of the implant. Most preferably, AB copolymer consists of from about 25 to 70 weight percent of 2-hydroxyethyl methacrylate units (monomer A) and from 75 to 30 weight percent of monomer units B. Units B possess EWC value predetermined in the range of 25 to about 75 weight percent. The monomer B can be hydroxypropyl methacrylate units. In a modalitypair. , the two implants can be provided to the physician in charge in a single package, ready to be used. The package would include two implants, one for the delivery of an androgen and one for delivering a sterilant. Preferably, at least one of the implants will already be loaded in a device capable of administering the implant directly to the patient. For example, each could be loaded setely into a syringe or trocar for subcutaneous administration. Most preferably, the second implant will be hydrated in saline and stored in hypertonic saline. The package may also include gauze, trocars, scalpels and the like, all in a sterilized container. The first implant can be sterilized by the use of ethylene oxide. However, the second implant is preferably sterilized by steam. However, it will often be beneficial to administer the first and second implants at different times. For example, the second implant would be implanted first, with the first implant containing the androgen being implanted when the testosterone levels are significantly depressed (approximately castration levels). This may happen weeks later. Of course, both implants may still have been provided in a single package. However, individual packages, designed to be mixed and matched can be provided for each implant. Of course, the present invention is not limited to a system using a hydrogel implant as described herein for the second implant. Any implant that is capable of delivering one or more sterilants in a manner that is complementary to the first implant previously described can be used. When provided as of an implant system comprising a first implant designed for the administration of androgen and a second implant intended for the administration of a sterilant, the first and second implants are preferably dimensioned and cooperatively formed and are designed such that each releases a pharmaceutically complementary amount of androgen and sterilant respectively. This means that the two implants can be administered in close proximity to one another. Therefore, they must be sized so that they will not cause any interference between them or discomfort to the patient. In addition, the two implants should be designed such that the amount of androgen and amount of sterilizer provided each day to the patient will be both, effective in terms of contraception and in terms of maintaining sexual function. The sterilant (LH RH agonist) is provided in an amount of about 50-120 mg / day. The androgen (MENT Ac) is provided in an amount of about 100-1000 mg / day and more preferably in amounts of about 200-800 mg / day. Even more preferable, the androgen is provided in an amount of 300-700 mg / day, and most preferably 400-600 mg / day. The in vitro diffusion of any androgen from the first implant or the diffusion of the sterilant from the second implant is an indication of the diffusion characteristics of the implants in vivo. The in vitro diffusion of the drug from either the first or the second implant can be determined, for example, by methods described in J. Pharm. Sci., 63,365 (1974), Chien et al., Or by methods described in the U.S. Patent. , No. 3,710,795. In vivo diffusion can be measured by, for example, the methods described in "7 Aipha-Methyl-19-Nortestosterone (MENT): The Optimal Androgen for Male Contraception", Annals of Medicine, (1993), 25, 199-205 , Sundaram and collaborators. The devices of the present invention can be implanted in a subject according to normal procedures. By the term "subject" is meant mammals, v. g. , human, valuable domestic family, sports or farm animals, laboratory animals. In the case of these implants, for example, this procedure is advantageously performed with a trocar and the device is preferably implanted under the skin of the upper arm of the patient. See Am. J. Obstet. Gynecol. , 160: 1286-92 (1989), Shoupe et al., And J. Reprod. Med. , 31: 898-905 (1986), Tikkanen et al.

EXAMPLES EXAMPLE 1 Preparation of Implant of M ENT Ac / Silicone Elastomer A. Preparation of Core Bars Containing MENT Ac at 60% w / w 1.5 g of MENT Ac was mixed with 1 g of R-2602 RTV Silicone Elastomer (Nusil Silicone Technology, 1040 Cindy Lane, Carpinteria, CA 93013). 2-3 drops of stannous octoate were introduced and mixed intensely. The mixed paste was placed in a metal syringe and injected into a brass mold with spaces of appropriate diameter, for example 2.38 mm. The paste mixture could be extruded directly (in an open atmosphere) through a nozzle of a certain diameter, but injecting into a mold ensures the uniformity of the diameter of the obtained core bars. The mold was opened after curing at 80 ° C for 10 minutes. The bars were either cut into 4 cm pieces or injected directly into a mold of the required diameter and length of 4 cm. B. Coating of the Cores with EVA Tube EVA tube (9% VA content, approximately 2.55 mm in diameter) was cut into 5 cm lengths. The tube has wall thickness from about 0.14 mm to about 0.17 mm. The tube was soaked in methylene chloride for about 1 minute. Each of the 4 cm cores was introduced into the space of one of the 5 cm pieces of the soaked EVA tube, leaving about 0.5 cm unfilled on both sides. The filled tube was left overnight at room temperature to allow evaporation of the methylene chloride. The two ends of the tube were then sealed by filling them with EVA (25% VA content). The sealed implants were heated at 70 ° C for 5-10 minutes to improve the sealing and adhesion between the outer EVA tube and the end seals. The two ends of the filled tube were cut out, leaving approximately 2.5 mm as a sealing tip. The obtained implants could be properly sterilized and packed. The implants used in Figures 2 and 4 were prepared according to the preceding example.

Claims (23)

1. REIVIN DICATIONS 1. An implant system, comprising: a first implant designed for subcutaneous or local administration of an androgen, said first implant including an androgen in an amount that is sufficient to provide the daily dose of a pharmaceutically effective amount of said androgen over a predetermined time in a core formed of a silicone elastomer, and a membrane covering said core, said membrane formed of ethyl vinyl acetate copolymer; and a second implant designed for subcutaneous or local administration of a sterilant, said second implant including said sterilant in an amount sufficient to provide the daily dose of a pharmaceutically effective amount of said sterilant at said predetermined time. The implant system of claim 1, wherein said first implant and said second implant are of a cooperative size and shape and are designed such that each releases a pharmaceutically complementary amount of said androgen and said sterilant, to provide treatment to a patient who needs it. 3. The implant system of claim 1, wherein said ethylene vinyl acetate copolymer of said first implant has a molecular weight such that the melt index is greater than 10 grams / 10 minutes, and a vinyl acetate content. less than 20% by weight. 4. The implant system of claim 1, wherein said androgen is selected from the group consisting of M ENT, M ENT Ac, testosterone, testosterone esters, methandroyl, oxymetholone, methandienone, oxymesterone, nondrolone phenylpropionate and noretandrolone. 5. The implant system of claim 4, wherein said androgen is MENT. 6. The implant system of claim 5, wherein said androgen is MENT Ac. The implant system of claim 1, wherein said pharmaceutically effective amount of said androgen is provided in an amount that is sufficient to provide the required daily dose of a pharmaceutically effective amount of said androgen for a predetermined time of at least approximately 7 days. 8. The implant system of claim 1, wherein said predetermined time is at least about 100 days. 9. The implant system of claim 8, wherein said predetermined time is at least about 180 days. The implant system of claim 1, wherein said androgen is provided in an amount that is sufficient to provide a daily dose of between about 1000 and about 1000 micrograms of androgen per day. The implant system of claim 10, wherein said androgen is provided in an amount that is sufficient to provide a daily dose of between about 200 and about 500 micrograms of androgen per day. The implant system of claim 1, wherein said core of said first implant consists of from about 50 to about 75% androgen and from about 50 to about 25% of said silicone elastomer. The implant system of claim 1, wherein said second implant includes a water-insoluble, water-swellable, non-biodegradable, biocompatible AB-hydrophilic AB-copolymer cartridge having from about 25 to about 70 percent in weight of 2-hydroxyethyl methacrylate units (monomer A) and from about 75 to about 30 weight percent of monomer units B and has a predetermined EWC value in the range of from about 25 to about 75 weight percent; a sealant for closing an open end of said cartridge comprising a plug of water-insoluble, water-insoluble, biocompatible, non-biodegradable, hydrophilic polymer plug having an equilibrium water content value greater than that of the cartridge; with said sterilant contained in a reservoir disposed within said cartridge. The implant system of claim 13, wherein said monomer B includes hydroxypropyl methacrylate units. 15. The implant system of claim 14, wherein said sterilant is provided in an amount of about 5 mg and about 50 mg. 16. The implant system of claim 1, wherein said sterilant is LH RH or an analogue of LH RH. 17. The implant system of claim 13, wherein said sterilant is LH RH or an analogue of LH RH. 18. An implant designated for subcutaneous or local administration comprising: (a) a drug-polymer matrix core that includes a silastic elastomer and an androgen in an amount sufficient to provide the required daily dose of a pharmaceutically effective amount of said androgen by a predetermined time; and (b) a membrane that covers said core of the drug and said androgen matrix and said membrane including ethylene vinyl acetate having a molecular weight which results in a melt index which is less than 10 grams / 10 minutes and a content of vinyl acetate of less than 20% by weight. The implant of claim 18, wherein said androgen is selected from the group consisting of MENT, MENT Ac, testosterone, testosterone esters, methandroyl, oxymetholone, methandienone, oxymesterone, nondrolone phenylpropionate and noretandrolone. 20. The implant of claim 19, wherein said androgen is MENT. twenty-one . The implant of claim 20, wherein said androgen is M ENT Ac. The implant of claim 19, wherein said pharmaceutically effective amount of said androgen is provided in an amount sufficient to provide the required daily dose of a pharmaceutically effective amount of said androgen for a predetermined time of at least 7 days. 23. The implant of claim 22, wherein said predetermined time is at least about 30 days.