TW201043208A - Vaginal delivery system - Google Patents

Abstract

The present invention is related to an intravaginal delivery system for the controlled release of drospirenone or drospirenone and an estrogen. The delivery system consists of one or more compartments, said one or each compartment comprising a core and a membrane encasing the core, said core and membrane essentially consisting of a same or different polymer composition, wherein at least one compartment comprises drospirenone or a mixture of drospirenone and an estrogen.

Description

201043208 VI. Description of the Invention: [Technical Field] The present invention relates to an intravaginal delivery system for long-term controlled release of one or more therapeutic lacquers or prodrugs thereof. In particular, the delivery system comprises at least one chamber comprising a core and a membrane surrounding the core, the core and membrane consisting essentially of the same or different polymer composition, at least one of which contains drospirenone or Precursor of drospirenone. Optionally, at least one chamber which may be the same or different from the chamber containing drospirenone may comprise a mixture of estrogen or 0 drospirenone and estrogen. [Prior Art] A vaginal delivery system capable of releasing a therapeutically active substance at a substantially constant rate to each other for a long period of time is extremely suitable for certain applications (e.g., contraception and hormone replacement therapy). Agents having progesterone activity and agents having estrogenic activity are preferably used at the same time, preferably at a substantially constant ratio. Contraceptive reliability is mainly provided by the progestin component, and the estrogen component is used to increase the ovulation inhibition of the progestin and to ensure cycle stability. A number of different structures of the vaginal ring are known in the literature, see for example 卯 4,596,576 and still 4,237,885. In a basic solution, the delivery system is simply formed by a closed loop containing drug-containing polymer core. A modified version thereof is a closed loop comprising a drug-free core surrounded by a drug matrix containing a plurality of different drugs as appropriate, and, optionally, an outermost polymeric film. E P 8 7 6 8 1 5 is a two-ring vaginal delivery system for a progestin steroid compound and an estrogen steroid compound for releasing a fixed physiological ratio for a long period of time. The delivery system comprises at least one, to the 'Tanghai 3 201043208 cavity to a thermoplastic polymer core comprising a mixture of progestin and an estrogenic compound and a thermoplastic polymer skin layer, the progestin compound initially having a relatively low supersaturation Degree is dissolved in the polymer core material. The drug delivery device is physically stable only when stored below room temperature. As indicated in the Ep 8768丨5 order, progesterone crystallizes on the surface of the vaginal ring. Crystallization of the progestogen on the surface of the device may result in uncontrolled, high explosive release. EP 836473 relates to a ring-shaped device comprising a first chamber having an ethylene-vinyl acetate copolymer drug-free core surrounded by a layer of ethylene-vinyl acetate copolymer loaded with steroid hormones, and a vinyl-vinyl acetate copolymer having no drug outer layer; a second chamber comprising an ethylene-vinyl acetate copolymer core loaded with a steroid hormone and a drug-free outer layer of an ethylene-vinyl acetate polymer; and optionally There is a thermoplastic material placebo chamber separating the first chamber from the second chamber. In a preferred embodiment, the invention relates to a two-chamber vaginal ring, wherein the first chamber comprises an etonogestrel and the second chamber contains etoposide and ethinyl estradiol (Asian Saturated mixture, two chambers as appropriate: separated from each other by a high density polyethylene placebo chamber. WO 1995000199 relates to an intravaginal delivery system, ... a flexible support member and a support member carrying a carrier containing the active agent. The support member is composed of a core member that is substantially open π-ring, and

The member is composed of at least one sleeve-like polymer body group V. The haul transport member surrounds the core member along a length of a portion of the core member in a stripped manner. WO 2005089723 relates to a drug delivery system. a plurality of chambers comprising and comprising a progestin compound dissolved in thermoplastic polyethylene vinyl acetate::: 4, 201043208, wherein if the delivery system consists of a chamber, the chamber comprises (i) a progesterone A thermoplastic polyethylene glycolate copolymer core of a compound and an estrogenic compound dissolved in a polyethylene vinyl acetate copolymer until the concentration is less than 25. The saturated content of the underarm; and (ii) the surface of the thermoplastic polyethylene vinyl acetate copolymer covering the core 'the surface layer is permeable to both compounds; if the delivery system consists of more than one chamber' then only one chamber contains (iii a progestin compound and an estrogenic compound, the progestin compound is dissolved in a thermoplastic polyethylene terephthalate copolymer core until a concentration below a saturation of 25 ° C; and (iv) a thermoplastic covering the core A polyethylene vinyl acetate copolymer skin which is permeable to both compounds. EP 862 396 relates to a vaginal sputum which comprises a body made of a first polymeric material having at least one hollow internal passage defining a hole up to the exterior of the body and adapted to receive a drug through the hole a core; and a core comprising at least one intravaginally administrable drug dispersed in a second polymeric material disposed in the channel. The core is suitably placed in the vaginal ring body prior to use to substantially avoid the initial drug burst in the individual tissue and the resulting side effects (such as nausea and D-spit). The advantage of the vaginal ring is that women do not need to take tablets daily. The annular structure is easy to apply, it is well tolerated, and the female herself can easily remove and reinsert the device at any time. Accordingly, the present invention provides an intra-channel delivery system that can be used to vaginally administer a snail web alone or in combination with estrogen in a dose of Z that is high enough for contraception or hormone replacement therapy. SUMMARY OF THE INVENTION 5 201043208 It is an object of the present invention to provide an intravaginal delivery system for the controlled release of one or more therapeutically active substances or prodrugs thereof over a prolonged period of time. The delivery system comprises at least one chamber 'the chamber or chambers comprising a core and a membrane surrounding the core 'the core and the membrane consisting essentially of the same or different polymer composition' wherein at least one of the chambers comprises The snails _, and optionally at least one chamber that may be the same or different from the chamber containing drospirenone, comprise estrogen. It is known that the unadapted snails are used orally (the snail steel = 60,000, 7~15 phantom 16^ dimethylene I side oxy ♦ _pregnant -4-thin-21, 17 times vinegar) It is not fully absorbed in the stomach, partly because of its poor solubility in water and its low dissolution rate in water. In addition, it is known that snail acidity = (including the conditions provided by the gastric juice of the stomach) has poor chemical stability. About 50% of drospirenone degrades to its untreated active isomer within 3 minutes when contacted with a hydrochloric acid solution having a pH of about 1. The present invention provides a method for administering drospirenone in an amount sufficient to administer a sufficient amount of bismuth oxime alone or in combination with an engraving hormone (preferably glycerol, estradiol, estradiol or estradiol). Improved intravaginal delivery system. In addition, by making the m system provided herein, the high stability of the snails under the yin. When embedded in a core or membrane matrix, the hydrophobic polymer composition completely covers the surface of the snail, degrading or forming an inactive isomer during use in the vagina, vagina. Prevent it from: The invented drug delivery system is especially suitable for female contraception and := domain. The delivery system can also be used to treat female sputum, postmenopausal, gonadal dysfunction or primary "two: ..., conditions and symptoms, which make the amount of estrogen sufficient to treat the endogenous 3 deficiency of estrogen 201043208 The disease, condition and symptoms, and the amount of snails is sufficient to protect the endometrium from estrogen side effects. Delivery systems can be based on inhibition of endogenous steroid production and exogenous progesterone: additionally used to treat endometriosis and uterine fibroids. Further, the present invention also provides a convenient and highly suitable drug delivery system for female animals. Accordingly, the present invention is directed to the following delivery system in the scope of the independent patent application. [Embodiment] The present invention is further illustrated by the following examples which describe various structures of the intravaginal delivery system of the present invention. The advantages of the present invention are obtained by an intravaginal delivery system comprising a chamber comprising a core and a membrane surrounding the core, the core and the crucible consisting essentially of the same or different polymer compositions, at least one of which The chamber contains estrogen containing a snail or its prodrug, and optionally at least one chamber that may be the same or different from the chamber containing drospirenone or its prodrug. According to one embodiment of the invention, the intravaginal delivery system consists of a chamber comprising a core and a chamber surrounding the core, the core and membrane consisting essentially of the same or different polymer composition, wherein the core comprises snail According to another embodiment of the invention, the intravaginal delivery system consists of a chamber comprising a core and a membrane surrounding the core, the core and membrane consisting essentially of the same or different polymer composition, wherein the core comprises a mixture of snail and estrogen. According to another embodiment of the invention, the intravaginal delivery system consists of at least 7 201043208 two chambers comprising a core and a membrane surrounding the core, the core and membrane consisting essentially of the same or different polymer composition, &quot At least one of the cores comprises drospirenone and the cores comprise - estrogen or a mixture of snails and estrogen. The chamber comprising the core and the membrane surrounding the core may contain therapeutically active substances in the core, membrane or both. The drospirenone, estrogen or mixture thereof is preferably located in the core. It is of course possible and within the scope of the invention for any combination of conveyor systems, systems (4) suitable for design or construction. The core consists essentially of a polymer composition' that is, the core is a polymer matrix in which the therapeutically active substance is dispersed. The core polymer composition is preferably selected such that the film primarily modulates the release of the therapeutically active agent. The rate of release is typically controlled by a separate membrane or by a membrane and core. The rate of release may also be primarily controlled by the core. Thus, even if the membrane surrounding the core is damaged, the therapeutically active substance will not be released in a completely uncontrolled manner in the patient's line of production. The core can be solid or hollow. By using a hollow core, forming a cavity in the middle of the ring - a continuous cavity in the ring reduces the overall weight of the ring and advantageously affects the flexibility, flexibility and softness of the ring, all of which provide the user with good Wear comfort. Depending on the particular embodiment in which the delivery system consists of two or more chambers, the chambers can be placed adjacent to one another. The chambers can also be juxtaposed or stacked, for example as described in US 4,822,616 to Schering AG and US Pat. No. 4,012,496, the entire disclosure of which is incorporated herein by reference. The surface of the other chamber or the groove assembled on the surface of the other chamber is 4 » ψ The length of the chamber may be the same or different. The chambers may be separated from each other by a knife diaphragm or an inert placebo chamber. One advantage of using several membranes or inertia to assess the chamber is that the rate of release is easier to control because there is no interaction between the active substances. The rim may cover the entire delivery system or cover only a portion of the system, where the degree of extension may vary depending on a variety of factors, such as the material selected and the active agent selected. The thickness of the film depends on the materials used and the active agent and the desired release characteristics, but is generally less than the thickness of the core component. The Ο 膜 film may be composed of _ above layers, in which case each layer has a specific thickness, and the thicknesses of the layers may be the same or different. The combination of juice thickness or material or a combination of different layers provides an additional possibility to control the rate of release of the active agent. The polymeric composition used in the film allows for the desired release rate of the therapeutically active agent to be obtained. nuclear. The polymer of the membrane and possibly the separator membrane or the inert placebo chamber may be the same or different and may represent a single polymer, a polymer of the mouth, or a polymer of the polymer composition that may be blended with each other. Composition. In principle, any polymer that is biodegradable or non-biodegradable can be used as long as it is biocompatible. As is known in the art, the therapeutically active agent is released from the polymer-based delivery system by the kinetic molecular weight, solubility, diffusivity, and charge, and the polymer = the concentration of the bulk agent. The distance between its surface and the characteristics of any base f or film. Poly-stone oxygenation, especially poly(dimethyl oxalate) (pdms) (d), is a membrane or matrix that adjusts the rate of penetration of the drug. The polyoxic oxidum is physiologically inert, and a large number of drugs can penetrate the polyoxyalkylene membrane, and the polyoxyxene also has the required strength characteristics. The penetration rate of the drug can be used in a suitable manner 9 201043208

The polymeric material is adjusted to a desired level (e.g., by adjusting the hydrophilic or hydrophobic nature of the material). For example, it is known from the literature that the addition of a poly(ethylene oxide) group or a trifluoropropyl group to a PDMS compound changes the rate of penetration of the drug. Other examples of η suitable materials include, but are not limited to, copolymers of dimethyl methoxy oxane and methyl vinyl fluorene oxide, ethylene/vinyl acetate copolymer (EVA), polyethylene, polypropylene, ethylene/ Propylene copolymer, acrylic polymer 'ethylene/ethyl acrylate copolymer, polytetrafluoroethylene (pTFE), polyurethane, thermoplastic polyamino phthalate, polyamine phthalate elastomer, polybutylene Diene, polyisoprene, poly(methacrylate), poly(methyl methacrylate), stupid ethylene-butadiene-styrene block copolymer, poly(hydroxyethyl methacrylate) (PHEMA) ) 'Polyvinyl chloride, polyvinyl acetate, polyether, polyacrylonitrile, "ethylene glycol, polymethylpentene, polybutylene dimerization, poly-based sulphuric acid s 曰 曰 (glycolic acid), poly ( Glycolic acid), polyanhydrides, polyorthoesters, hydrophilic polymers (such as hydrophilic hydrogels), crosslinked polyvinyl alcohol, butyl rubber, butyl rubber, [milk-hardened type M-based capping Organic polyoxetane (which hardens into an elastomer after adding a crosslinking agent to /m in the presence of a curing catalyst) One or two component dimethyl polyoxyalkylene compositions and mixtures thereof are cured by hydrogenation at room temperature or elevated temperature. The structural integrity of the material can be enhanced by the addition of particulate materials such as cerium oxide or diatomaceous earth. The elastomer may also be mixed with other additives, for example to modulate the hydrophilic or hydrophobic character of the elastomer, but it should be noted that all additives must be biocompatible and not deleterious to the patient. The core or membrane may also comprise a rate of release of one or more of the other therapeutic substances, such as inclusion of a complex forming agent (such as a cyclodextrin derivative) to modulate the initial release of the substance until 2010. Accept or required level. Additives f (e.g., surfactants, antifoaming agents, solubilizers or absorption delaying agents or mixtures of any two or more of these) may also be added to impart the desired properties to the system. In addition, additives such as pigments, brighteners, matting agents, chromogens, mica or equivalents can be added to the delivery system body or membrane or both to provide the desired appearance to the delivery system. , according to the specific example, the core and the membrane are composed of a siloxane-based elastomer group

G. The composition comprises at least one elastomer and possibly a crosslinked polymer. The term "elastomer comp〇siti〇n" can mean - a single-elastic body, # becoming a reversible shape due to stress, so that the shape of the elastomer after stress is restored to a specific level. The elastomer composition is also composed of two or more elastomers blended with each other. It should be understood that the term 'silox x_-based elastomer' includes an elastomer made of poly(disubstituted oxime), wherein the substitution f is mainly a lower alkyl group. Preferably, the alkyl group having 1 to 6 carbon atoms or the phenyl group, 纟"Halylene or phenyl group may be substituted or unsubstituted. Such widely used and preferred polymers are poly(di-f-based fluorene (pDMs): elastomeric compositions may also be selected from the group consisting of: - comprising poly(dimethyl oxalate) (pDMS) Elastomeric composition, • an elastomeric composition comprising a siloxane-based elastomer comprising 3,3,3 trifluoropropyl groups attached to a die-cutting atom, _ comprising poly(oxyalkylene) a base elastomer composition, such a poly(oxyalkylene) group attached to the amphoteric oxygen-fired unit by an alkoxy-terminated graft or block form or a mixture of such forms Forms exist, and 201043208 • a combination of at least two of them. According to the present invention - a specific example of a drospirenone core or a = 7 oxy-fired elastomer used in a film comprising a poly(oxidized) group, such that poly(oxidation) The Erguangxi oxygen burning unit is used in the form of an alkoxy-terminated graft or in the elastomer. The graft or the desired segment is cut by a carbon bond. The above poly(oxyalkylene) group is preferably a poly(ethylene oxide) group. In the polymer composition of the core or membrane, comprising a ruthenium-negative bond to a poly-oxygenate-based oxy-terminated graft or a poly(oxyalkylene)-based polyfluorene The proportion of oxyalkylene (e.g., polydimethyloxazepine (PE0_b_PDMS copolymer) containing poly(ethylene oxide) groups) is from 80% to the total amount of the polymer, but may of course be higher. Other possible ranges for the proportion of polyoxyalkylene containing poly(oxyalkylene) groups are from 5% to 60% or from 10% to 50%, preferably from 10% to 45% 'and more preferably 20% of the amount of the polymer composition. % to 40%. The use of one or more stabilizers in the preparation of the polymer or the addition of the stabilizer to the elastomeric composition increases the stability of the product and allows for room temperature without any other precautions or special packaging. Store the product underneath. Tocoferol can be mentioned as an example of a stabilizer, especially 0: -d-tocopherol, suitable amount is 〇丨wt% to 3 总量 of the total amount of the delivery system

Wt% 〇 Methods for preparing elastomers are provided, for example, in International Patent Applications WO 00/00550, WO 00/29464, and WO 99/10412 (each assigned to Leiras Oy). In addition to drospirenone, any therapeutically active substance having progesterone activity sufficient to achieve contraception or for hormone replacement therapy can be used. Suitable for the help of pregnancy 12 201043208 Examples of the compounds include the following compounds, such as cyclohexade acetate acetate, deSpregnane (deS〇geStrel), etorgestrel, levonorgestrel (lev〇norgestrel), linneprogesterone (lynestren〇1 ), medroxyprogesterone acetate, linosterone, norethisterone acetate, norgestimate or gestrinone. The snail snail may be used in place of the drospirenone in the compositions of the present invention, such as the oxyimino-pregnition g disclosed in WO 98/24801. In the context of this application, the generic term "dr〇spiren〇ne" is used to mean drospirenone itself or a prodrug thereof or a combination thereof. The meaning of this term in its context is obvious to those skilled in the art. Despite a drunk hemihydrate, alcohol benzoate. The estrogen may be selected from the group consisting of estradiol, ethinyl estradiol, and diol (such as estradiol valerate, estradiol benzoate, and estradiol butyrate). , estradiol hemihydrate, estradiol amino sulfonate, estrone, estradiol, estriol succinate, and conjugated estrogens (including combined equine estrogens, such as estradiol) 17/3_estradiol sulfate, ~ diol sulphuric acid vinegar, estrogen sulphur _ _, 17/5_ dihydroequine sulphuric acid vinegar, 17 "dihydroequine sulphuric acid vinegar, esculine sulphuric acid vinegar, 17 /3-Dihydroolefin estrogen sulfate and 17α-dihydroolefin eumesulfate) or a mixture thereof. Particularly worthy of estrogen is an androgen selected from the group consisting of estradiol, estradiol valerate, estradiol succinate, estradiol benzoquinone monohydrate, Estradiol amine based acid vinegar, female _ and female _ sulphuric acid vinegar or mixtures thereof. The best compound is B-Estradiol, estradiol,

The amount of 'therapeutic agent' varies depending on the rate of release of the particular therapeutic activity and the system is expected to provide therapeutic treatment into the delivery system, the intended use of the substance, and the pre-turning 13 201043208: because it can be designed There are no critical upper limits for the amount of therapeutically active agent that can be incorporated into a device. The lower limit depends on the activity of the m-therapy agent and the expected release time. Those skilled in the art will be readily able to determine the therapeutic activity of the various components of the delivery process. Preferably, the amount of therapeutic active agent in the delivery system is between about 0 and 60 wt%. When mixed in the polymer, the preferred amount is between 1 〇: 4 〇 wt% of the weight of the delivery system. Other possible ranges for the amount of therapeutic active agent are 〇 ""η/. , 10-50 wt%^ 25-60 wt%' 40-50 wt%^ 15-35 wt% 〇 于 于 于 于 于 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲 欲In particular, by changing the matrix or film or the ruthenium composition, it is, for example, such that the polyoxoelastomer contains a poly(oxyalkylene) group of Optimum. These groups are concentrated in the elastomer and penetrate the drug. In addition to the shovel π ^ ^ ^ , in addition to the tunable elastomer, other parameters (such as the size of the device, the heart drug load, etc.) also affect the daily dose released from the device. Some (but not excessive) experiments are to find the most suitable parameters for each combination. If released by the intravaginal route, a significantly lower dose is sufficient compared to the dose required for systemic administration. These lower doses must be within the pharmacologically equivalent dose range of the target dose administered per ounce. The oral sputum dose (i.e., the rate of release per sputum required for contraception) is ranged from thioindamine to ketone, acetylene estrone is 0.005-0.050 mg and estradiol is 0.050 0.200 mg. For drospirenone, a preferred daily release rate is 2 〇 7 mg and a better release rate is 3 mg. For hormone therapy, for the snails. · ~ For Estradiol. Mg and 雌1〇_〇 for estradiol. 14 201043208 The expected release time of scrotonone and estrogen is from 12 weeks to 12 months, preferably from weeks to 6 depending on the device, ranging from one week to several months, for example - month, and more preferably 21 to 3 month. The vaginal drug delivery provided in this article is especially necessary for the replacement therapy and treatment of women: == = = or primary ovarian disease, illness:

Insufficient related conditions and symptoms. The round-robin system can be additionally used to treat decidual ectopic and uterine fibroids based on inhibition of endogenous steroid production and exogenous pregnancy. The preferred intravaginal delivery system of the present invention is intended for administration of estrogens (especially alcoholic estrones or ethinyl estradiol) and high enough for contraception or hormonal therapy and/or protection of the endometrium from females. Hormone side effects affect the dose of drospirenone. Preparation of the Device The drug delivery system of the present invention can be prepared by any known technique. The therapeutically active agent is mixed in the core or membrane material by molding, injection molding 'rotation/injection molding, casting, extrusion (such as co-extrusion), coating extrusion, and/or Blending or other suitable methods are processed into the desired shape. The film layer can be applied to the core according to known methods, such as mechanical stretching or expansion of a pre-manufactured tubular film by a pressurized gas such as air, in a suitable solvent (eg, cyclohexane, diethylene glycol dimethyl ether) , swelling in propanol, isopropanol or solvent mixtures), or by extrusion, molding, spraying or dipping. A method particularly suitable for the preparation is disclosed in the Finnish patent FI 97947. This patent discloses an extrusion technique in which a pre-manufactured rod containing the active ingredient 15 201043208 is coated with an outer film. The therapeutically active agent is mixed in the core matrix polymer composition and processed into the desired shape and size by using known extrusion methods. The film layer can then be applied to the pre-manufactured core by feeding the core to the extruder, followed by another core or core without any active ingredients (ie, a placebo chamber) or a space filled with air. Gap (which will be filled with a film material to form a separator film during the extrusion process). The core and membrane of the loaded drug can also be prepared by co-extrusion. The fibers or tape obtained by the above method and comprising a core or a core surrounded by a film can be cut into portions having a desired length, and the portions can be assembled in any suitable manner to have a shape, size and suitable for placement in the vagina. s installation. The dimensions and length of the chambers may be the same or different. When the delivery system consists of two or more chambers, the chambers can be placed adjacent to each other, juxtaposed or stacked. - The chamber can be mounted on the other chamber or on the surface of the other chamber, especially when the previous chamber is relatively small compared to the other chamber. The chamber may surround the surface of the other chamber or may be assembled in a chamber such as a chamber on the surface of the other chamber to or from each other may or may not be separated by a separator membrane. The device can have a variety of shapes, such as various continuous, curved shapes such as a toroid, a ring, a (four), a square ridge, an ellipse, a spiral mandrel, and the like. The k-section of the step device can have almost any shape, and it can be, for example, a circular, egg-like shape. Printing + plate shape, elliptical shape, star shape and fiber-like material conveying device, : = joint members are joined together to form a medicinal material. This technical towel is known for the material r 4 , , , α Construction bond or joint Λ - material. Any method, mechanism, device or material that is coupled to σ '°Solution of solvent bonding 'adhesive bonding, heat-shrinking, heat 16 201043208 Bonding, pressure and the like. When U Jr. . . . _W is used with an organic solvent to make the sheet & the end of the sheet makes the surface feel sticky, and then bonded in a fluid tight bond upon contact and (iv) joined together by: From directing the fragment to the small one, or the sealant and then contacting the ends, or by: placing the high density molten polyethylene between the fibers in the mold at: = about 4 (temperature of TC) And the cooling is made by joining the fiber ends together. 4 hunting by know

The tubular chamber can also be joined into a closed system by using a plug or plug that is made of any inert biocompatible material and does not allow for the transfer of active material. Examples of suitable impermeable materials are metals such as gold, silver or silver alloys, glass domain materials and suitable polymers. If desired, the plug or plug can be better sealed or better adhered to the chamber using a biocompatible adhesive.

The delivery system may also comprise a substantially inert slab member that is biocompatible and materially stable over a period of time sufficient under the primary conditions of the vagina. Under the brother, the term "su-b lnert" means that the active agent does not diffuse or is self-nuclear at any substantial extent. It migrates into the support member in any other way. Suitable support materials are, for example, crosslinked rubbers (such as natural rubber, butyl rubber and polydimethylidene siloxane elastomers), flexible thermoplastic resins (such as vinyl acetate, EVA), thermoplastics. Polymers (such as styrene copolymers, polyurethanes, thermoplastic polyolefins) and biocompatible inert metals. The support members can be prepared in a simple and known manner. Suitable polymeric materials can be pressed, for example, in a mold, or extruded to form a rod-like member having a suitable diameter, and then the extrudate is then cut into portions of suitable length and then hardened into the desired substantially annular shape of 17 201043208. The support member can be solid material or hollow. - or a plurality of ring portions, dies or cores may be assembled in the form of a layer or coating on a pre-manufactured closed continuous branch # member. The drug-containing core can be formed, for example, by forming a suspension in the polymer composition with a finely powdered or even micron-sized active material, followed by using known techniques such as spraying, dip coating or multi-color injection molding. The technique) is applied in a layer form on a support member and is hardened by a known method. The film can be assembled in a similar manner. The hollow sleeve-like core is preferably placed on the branch member by first expanding the diameter to some extent and then inserting the support member into the hollow core by simply sliding it onto the rod-shaped cutting member. When the nuclear. With a poly-based polymer or cross-linked rubber, the expansion can be carried out, for example, by expanding in a suitable organic solvent, followed by placing the expanded body on the support member. As the solvent evaporates, the core tightens on the support member. Alternatively, the tubular core may be passed through a suitable device or by using, for example, compression and stretching, and passing through the support member in a stretched state. When the tensile force is interrupted = the sleeve-like body is tightened on the support member. The membrane can be assembled by using, for example, swelling or mechanical stretching on individual cores or on a rod-shaped delivery system = polymer tube. Finally, by using known techniques: the end of the rod or belt that is passed. The delivery system of the present invention can be prepared in any size, depending on the application, and the particular application. In fact, it is usually 35 mm to 70 mm for a female person, preferably 35 mm 5 45 mm to a main 58 mm or 65, and more preferably 50 to 58 mm. The cross-sectional diameter is usually ',, in a specific specific (four), wearing blood 6mm 々 day between 2 mm, between the claws, in a specific example at about 3. 〇mm盥$ ς , , 3·5 mm Between 2010 and 201043208, and in another embodiment between about 3 5 mm and 45, and in the body example between 4. G coffee and 5. 〇 mm. The cavity (if present) in the delivery system has a diameter in the range of 0.5 mm to 3 mm. Ο 核心 The length of the core of the drug delivery system is selected to provide the desired performance. The ratio of core lengths depends on the particular therapeutic application' including the desired ratio and dose of each drug to be delivered. The length of the drug containing chamber can be, for example, from 3 mm to 16 mm' or at most the total length of the delivery system. The length of the chamber separating the drug-containing core can generally be between 2_U() mm and depending on the nature of the material, its ability to prevent penetration of the active substance. Most desirably, the placebo chamber completely prevents the active substance from mixing' otherwise it may interfere with the release pattern. The thickness of the diaphragm may be from about 匪·2匪 to 5_. The thickness of the layer containing the living layer may be from 0.1 mm to 5.0 mm, and preferably the thickness of the 〇2 sub-U.2 mm to 3 5 is the thickness of the test. The rate at which the drug is released from the device is measured as follows: The delivery system is attached to the unrecorded steel in a vertical position. The raging squad with the device is held in a medium containing 250 ml or less. Glass bottle order. At 37 〇Γ ^ glass bottle. At the time of booking = 震 Γ 玻 Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ Γ During the test, keep leaking and swearing] to make it with 捭... ndition). Select the sampling frequency to maintain the sag condition in the enamel. The present invention, as well as the measured release rate at the expected level, is further illustrated by the following non-limiting examples of 201043208. The delivery system of the examples was prepared according to standard techniques known in the art and described in the patent application. The therapeutically active agent is mixed in the polymer composition and processed into the desired shape by using known methods. Preparing the crucible and assembling it onto the core according to known methods, such as by expanding a pre-manufactured tubular film from a suitable solvent (eg, propanol, isopropanol), or by using a coating extrusion as described in Finnish patent FI 97947 Press or coextrusion method. According to this method, each core is fed into an extruder, followed by another space filled with a space gap of air or without any active ingredient. The ends of the manufactured rods comprising the core and the membrane are joined together by using a stopper or a sealant. Preferably, cerium oxide is used as a filler. Example 1 Delivery system for administration of drospirenone A delivery system comprising drospirenone having a target release rate of 2.0 mg/day was prepared. The core containing drospirenone (20 Wt%) consists of a composition containing PE〇_b_pDMS (28 wt% of the total amount of the polymer), PDMS (35 wt% of the total amount of the polymer), and cerium oxide, and The length of the core is 16〇mm. The core is surrounded by a membrane consisting of PE0_b, PDMS/PDMs at a ratio of 20:80. The membrane wall thickness is 0.35 mm and the outer diameter of the core surrounded by the membrane is 4.5 mm. The ends of the membrane-core system are joined together by the use of an adhesive to form a closed delivery system. Example 2 Delivery system for simultaneous administration of drospirenone and estradiol A device comprising drospirenone having a target release rate of 3.0 mg/stroke and estradiol having a target release rate of 100 μg/day was prepared. Contains drospirenone (35 20 201043208)

The first core of Wt%) consists of pE〇_b_PDMS (41 wt% of the total amount of polymer) and PDMS' and the length of the core is 13 〇 mm. The second core comprising estradiol (i8 wt%) consisted of pE〇_b_pDMs (25 wt% of total polymer) and PDMS and was 10 mm in length. The core has an outer diameter of 3.6 mm. An inert core consisting of PDMS was added to provide a total length of 165 melons. The core portion is enclosed in a stack of PEO-b-PDMS/PDMS with a ratio of 35:65. The film layer is applied to the pre-manufactured core by co-extrusion. The 3 mm void remaining between the drug-containing cores is filled with a film material during the process to form a separator film. The thickness of the membrane wall is 〇35 mm, the inner diameter of the membrane is 3 45 mm and the outer diameter is 4 15_4 2 . The end of the chamber stem is joined to the closure system by the use of an adhesive. Example 3 〇 A delivery system for simultaneous administration of spirulina I and acetylene estradiol to prepare a delivery system comprising drospirenone at a release rate of 2.5 mg/day and acetaminophen at a release rate of gram/day. . The first core containing the snail _(2 〇%) consists of PE〇_b_pDMs (the total amount of polymer and PDMS, and the length of the core is A 150 mm. The core is surrounded by pE〇-b-PDMS/ The film consists of PDMS. (4) The thickness is 〇3, and the outer diameter of the core surrounded by the film is 35. The ends of the chamber are joined together by Shishi gum to form a closed system. The second core of estradiol (1 〇 wt ° / 〇) consists of pdms fine 屮 n 且 and is surrounded by a POMS membrane. The length of this chamber is 6 mm, the outer plum rabbit 3 < two 5 mm. The thickness is 0.3 mm. The chamber is joined by using an adhesive. Although the invention has been described with respect to specific, concrete examples and applications, the general practitioner may not deviate from the spirit of the claimed month or exceed the claimed invention. In the case of the present invention, other specific examples and modifications are possible in accordance with the teachings of the present invention. It is to be understood that the description of the present invention is provided by way of example and is not intended to limit the scope of the invention. Brief description of the figure] Figure 2 is a schematic diagram of the intravaginal delivery system, the vagina The support ring of the system is not applied to the support ring of the active agent or the third chamber containing the therapeutic active agent, and is applied to the outer surface and contains the membrane layer 3 of the (4) therapeutic _ ^ ::: delivery system or part thereof. The chamber: has a concave portion suitable for cooperating with the corresponding chamber 2 on a part of the wide surface of the trough 2a is a two-chamber chamber containing a stacked arrangement of the intravaginal delivery system ... "the part of the intravaginal delivery system is suitable Surrounded by the same or different membranes 3 with the corresponding v on the 4th surface. 5 matching grooves. Each chamber can be further illustrated in Figure 2b. Figure 3a is a cross-section of the internal communication system of the intravaginal delivery system. Some examples of containing the two images that are surrounded by the membrane 3 'the intravaginal delivery system and 5' are adjacent to each other. Figure 4 is the intravaginal delivery system - the third contains the membrane 3 The cavity 4 is not conceived. The intravaginal delivery system separates the two chambers 5 and 6' chambers 4 from the other chambers by means of a separating membrane. Figure 5 is positioned adjacent to each other for the intravaginal wheel 6 . The second schematic diagram, the intravaginal delivery system separates the chambers 4 and 6, and the cavity 6 is fixed to 4, 5 And 6. The inert placebo chamber c chambers to 4 and 5 are placed adjacent to each other with a, A and 5 and 6. 22 201043208 In this design, chambers 4, 5 or 6 may contain the same or different therapeutically active substances Figure 6 is a schematic illustration of an intravaginal delivery system comprising two chambers 4 and 5 stacked in a stack, both chambers being surrounded by membranes 3 and 3 which may be the same or different. Figure 7 is a vagina Another general design of an internal delivery system comprising a core 8, a membrane 3 surrounding the core, and an inert support element 9.

Figure 8 is another generic design of an intravaginal delivery system comprising two chambers (4, 5). The chamber 5 surrounds the chamber 4. Each chamber may additionally be surrounded by the same or different membranes. [Main component symbol description] 1 First chamber 2 Second chamber 3 m 3, Membrane 4 Chamber 5 Chamber 6 Chamber 8 Core 9 Supporting components 23

Claims (1)

201043208 VII. Patent application scope: 1. An intravaginal delivery system for long-term controlled release of drospirenone or snail and estrogen 'The system contains at least one cavity to 'the one chamber or each chamber Including a core and a membrane surrounding the core, the core and the membrane consisting essentially of the same or different polymer composition, wherein at least one of the chambers comprises a) drospirenone or a prodrug thereof; or b) drospirenone or a mixture of its prodrug and estrogen. 2. The intravaginal delivery system of claim 1, wherein one chamber comprises a snail or a prodrug thereof, and a chamber different from the chamber containing drospirenone or a prodrug thereof comprises estrogen . 3. The intravaginal delivery system of claim 1 or 2, wherein the estrogen is selected from the group consisting of ethinyl estradiol, estradiol, although diol hemihydrate, estradiol Succinate, estradiol valerate and estradiol stearate. 4. The intravaginal delivery system of claim 1 or 2, wherein the drospirenone drospirenone prodrug, estrogen or a mixture thereof is in the core. 5. The intravaginal delivery system of claim 1 or 2, wherein the core or cores are hollow. 6. The intravaginal delivery system of claim 1 or 2, wherein the drospirenone or a prodrug thereof is completely embedded in the hydrophobic polymer composition of the core or membrane matrix. 7. The intravaginal delivery system of claim 1 or 2, wherein the core and the membrane are made of a siloxane-based elastomer composition, 24 201043208 the composition comprising at least one elastomer and Non-crosslinked polymers that may be present. Eight, schema. (such as the next page) 25