NZ279226A

NZ279226A - Desogestrel-containing transdermal application

Info

Publication number: NZ279226A
Application number: NZ279226A
Authority: NZ
Inventors: Ralph Lipp; Clemens Gunther; Jutta Riedl; Ulrich Tauber
Original assignee: Schering Ag
Priority date: 1994-02-18
Filing date: 1995-02-09
Publication date: 1998-05-27
Also published as: HU9602286D0; NO963433L; AU1578695A; KR970701538A; DE4405899A1; JPH09508911A; CA2183544A1; WO1995022321A1; EP0744943A1; HUT74458A

Description

<div class="application article clearfix" id="description"> New Zealand No. International No. 279226 PCT/EP95/00481 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 18.02.1994; Complete Specification Filed: 09.02.1995 Classificatlon:(6) A01K31/565; A61K9/70; A61M37/00 Publication date: 27 May 1998 Journal No.: 1428 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Desogestrel-containing transdermal application agent Name, address and nationality of applicant(s) as in international application form: SCHERINQ AKTIENGESELLSCHAFT, a Body Coporate of D-13342 Berlin, Federal Republic of Germany \. 279226 Agent for Transdermal Administration That contains Desogestrel The invention relates to an agent for transdermal administration, characterized in that it contains desogestrel optionally in combination with one or more estrogen(s) and one or two penetration-enhancers that can be mixed with one another in a matrix system, but without the addition of crystallization inhibitors. Desogestrel (13-ethyl-ll-methylene-18,19-dinor-17a-pregnen-4-en-20-yn-17fi-ol) is a substance of formula • As is generally known, it is a pharmacologically effective compound with extraordinarily strong gestagenic effectiveness (J. of Steroid Biochem., 2A, 1981, 175 ff and Europ. J. Clin. Pharmakol. IS, 1979, 349 ff), which is used in combination with estrogenically effective compounds for the production of agents of contraceptive action that are to be administered orally (Marvelon(R>) . It has now been found that desogestrel optionally in combination with one or more estrogen (s) can be used very well OH H,C \ N.Z. PATENT OFFICE 16 AUG 1936 RECEIVED 279226 for the production of an agent for the transdermal administration of the active ingredient or active ingredient mixture. Quite general references to desogestrel-containing transdermal systems are already found in publications. Thus, WO 93/08795, which relates to transdermal therapeutic systems, which contain crystallization inhibitors, mentions that the systems, among others, could also contain desogestrel. WO 93/02669, which relates to transdermal therapeutic systems, which contain a polar penetration-enhancer and a penentration-enhancer that is insoluble in the latter, also mentions that the systems could contain desogestrel. In PCT/EP93/02224, which was ultimately not published as of the priority date of this application and which relates to 3-keto-desogestrel-containing transdermal systems, there is a quite general reference that it is possible to administer desogestrel transdermally, but that 3-keto-desogestrel is to be preferred because of its greater potency. There are no references in this application to matrix systems that contain desogestrel. As is generally known, pharmaceutical agents that are to be administered transdermally have the advantage that they make possible a more uniform release of the active ingredient over a longer period than is generally possible in other agents that are to be administered — such as, for example, perorally. These properties can generally be used advantageously in a number of endocrine diseases. For poorly water-soluble steroid hormones, such as, for example, the gestagens, however, it is generally quite problematical to provide transdermal systems that ensure a 2792 26 penetration of the active ingredient through the skin that is sufficient for treatment. It has now been found that it is possible, surprisingly enough, with the help of the agent according to the invention to achieve a therapeutically adequate, very uniform rate of penetration of the steroid hormones through the skin, while this is only conditionally possible in the known steroid hormones that contain agents that are to be administered transdermally (EP-A 137278 and EP-A 275716), which makes necessary the use of comparatively large systems. Suitable estrogens for the agent according to the invention are, for example, the estradiol, the eptriol, the ethinylestradiol, the mestranol, the 14a,l7a-ethanoestra-1,3,5(10)-triene-3,17B-diol (WO 88/01275), the 14a,17a-ethanoestra-1,3,5(10)-triene- 3,16a,176-triol (W091/08219) and their esters (EP-A 163596), such as the estradiol-dipropionate, the estradiol-dihexanoate and the estradiol-didecanoate. In addition to desogestrel, the combination preparations according to the invention preferably contain 1 to 3 — especially 1 to 2 — estrogen (s). According to the invention, the agent for transdermal administration is a transdermal therapeutic system (TTS) and here especially is embedded in a matrix system. Suitable matrix systems are those that are usually used for percutaneous administration of active ingredients (Yie W. Chien: "Transdermal Controlled Systemic Medications," Marcel Dekker, Inc., New York and Basel, 1987, Dr. Richard Baker: "Analysis of Transdermal intellectual property office of nz 0 3 APR 1998 RECEIVED 279226 Drug Delivery Patents 1934 to 1984" and "Analysis of Recent Transdermal Delivery Patents# 1984-1986 and Enhancers" Membrane Technology & Research 1030 Hamilton Court Menlo Park CA 94025 (415) 328-2228). Thus, for example, a transdermal therapeutic system can be used, which consists of a) an impermeable cover layer, one to three matrix layer (s) that adhere to the cover layer and that contain desogestrel, optionally estrogen(s) and optionally penetration-enhancing agents that are permeable and self-adhesive to these components or are covered or surrounded by a skin contact adhesive that optionally contains penetration-enhancing agents, a removable protective layer, or b) a cover that is provided with a contact adhesive that optionally contains penetration-enhancing agents, one to three matrix layer(s) (each) that leave uncovered a contact adhesive border and that are attached by means of a cover to the contact adhesive and that contain desogestrel, optionally estrogen(s) and penetration-enhancing agents; and a removable protective layer. A transdermal therapeutic system according to variant a) represents a simple matrix system. It can be, for example, of round, oval or rectangular shape and can be produced as follows. A solution or suspension of up to 25% by weight of active ingredient or active ingredient mixture, 0-40% by weight of a penetration-enhancing agent, 30-70% by weight of a medicinally usual adhesive filled up with a suitable volatile solvent to 100% 279226 by weight is coated with a plane, impermeable cover layer. After drying, a second and optionally later even a third layer, that optionally contains active ingredients, penetration-enhancing agents and adhesives, can be applied on this layer and dried. Then, the matrix system is provided with a removable protective layer. If a medicinally usual matrix former is used, which does not adhere or insufficiently adheres to the skin after the system is dried, the system can be covered or surrounded in addition with a skin contact adhesive before the removable protective layer is applied. Suitable volatile solvents are, for example, lower alcohols, ketones or lower carboxylic acid esters, such as ethanol, isopropanol, acetone or ethyl acetate, polar ethers, such as tetrahydrofuran, lower hydrocarbons, such as cyclohexane or benzine, ox* else halogenated hydrocarbons, such as dichloromethane, trichloromethane, trichlorotrifluoroethane and trichlorofluoromethane. There is no need for an explanation that mixtures of these solvents are also suitable. ;Suitable penetration-enhancing agents are, for example, monovalent or multivalent alcohols, such as ethanol, 1,2-propanediol or benzyl alcohol, saturated and unsaturated fatty alcohols with 8 to 18 carbon atoms, such as lauryl alcohol or cetyl alcohol, hydrocarbons, such as mineral oil, saturated and unsaturated fatty acids with 8 to 18 carbon atoms, such as stearic acid or oleic acid, fatty acid ester with up to 24 carbon atoms or dicarboxylic acid diesters with up to 24 carbon atoms. ;N.Z. PATENT OFFICE ;16 AUG 1988 ;279226 ;Fatty acid esters, which are suitable for the agent according to the invention, are, for example, those of acetic acid, caproic acid, lauric acid, myristic acid, stearic acid and palmitic acid, such as, for example, the methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, sec-butyl ester, isobutyl ester, tert-butyl ester or monoglyceric acid esters of these acids. Especially preferred esters are those of myristic acid or oleic acid, such as their methyl esters and especially their isopropyl esters. Suitable dicarboxylic acid diesters are, for example, the diisopropyl adipate, diisobutyl adipate and diisopropyl sebacate. ;Other penetration-enhancing agents are phosphatide derivatives, such as lecithin, terpenes, amides, ketones, urea and its derivatives or ethers, such as, for example, dimethyl isosorbide and diethylene glycol monoethyl ether. There is no need for a more detailed explanation that also mixtures of these penetration-enhancing agents are suitable for the production of the agent according to the invention. ;As medicinally usual adhesives, for example, silicones, polyurethanes, block polymers, styrene-butadiene copolymers as well as natural or synthetic rubbers, such as, e.g., polyisobutylenes and especially polyacrylates, are suitable. As additional matrix formers, cellulose ether, polyvinyl compounds or silicates are to be considered. To increase the stickiness, the usual additives, such as, for example, tackifying resins and oils, can be added to the matrix obtained. ;279226 ;As protective layers, all films are suitable that are usually used in transdermal therapeutic systems. Such films are, for example, siliconized or fluoropolymer-coated. ;As a cover layer, for example, 10 to 100 ^m-thick films made of polyethylene or polyester can be used selectively pigmented or metallized in this system. The pharmaceutical agent layer applied on it preferably has a thickness of 20 to 500 jxm. The release of the active ingredients takes place preferably over an area of 5 to 100 cm2. ;In the case of multilayer matrix systems, desogestrel and optionally penetration-enhancers can be introduced, for example, in the matrix applied on the impermeable cover layer, while the layer or layers below contain the estrogens and optionally also penetration-enhancers. In contrast, however, it is also possible in such a transdermal system to arrange several active ingredient-containing matrix systems side by side. ;A transdermal therapeutic matrix system according to variant b can be, for example, also round, oval or rectangular and can be produced as follows. ;A cover is coated with a skin contarft adhesive. Then, one to three punched-out areas of a matrix layer that is provided with an impermeable cover and that contains desogestrel, optionally estrogen(s) and penetration-enhancing agents, is bonded to the cover pro TTS, so that the cover has a sufficient edge for attaching to the skin and also sufficient interspaces in several areas and provides it with a removable protective layer. ;8 ;279226 ;The materials that are used in this matrix system can be the same as in those of variant a. ;In the production of transdermal therapeutic systems with two or three active ingredient-containing matrix layers or pharmaceutical agent reservoirs that are arranged side by side, it is often suitable to introduce desogestrel in one and estrogen or estrogens in the other. In such cases, the active ingredient-containing matrix systems or pharmaceutical agent reservoirs can contain not only different active ingredients, but in addition different penetration-enhancing agents. ;The concentration at which the active ingredient or the active ingredient mixture optimally is dissolved or suspended in the solvent is usually 0.01 to 25% by weight for desogestrel. In estrogens, the concentration depends, by the nature of things, on the type of active ingredient used and the single dose sought; it must be determined in individual cases by the preliminary tests familiar to one skilled in the art, such as, for example, the determination of the achievable plasma concentrations of active ingredient after dermal application, in the case of selected agents according to the invention. In general, active ingredient concentrations of 0.01 to 25% by weight of estrogen in agents according to the invention will be sufficient here, too. The weight ratio of desogestrel to estrogen or estrogens is approximately 5:1 to 1:10 in the combination preparations. ;For oral contraception, the gestagenic daily dose is 150 /ug of desogestrel, which is converted almost completely to the pharmacologically active 3-keto-desogestrel during absorption. ;In.Z. PATENT ;16 AUG 1995 ;279226 ;The contraceptive daily dose can be lowered to about 60 /xg of 3-keto-desogestrel by incorporation of 3-keto-desogestrel in a subcutaneous depot (Implanon*10) (Contraception AZ, 1993, 251-261), because of a relatively constant rate of release. To make this daily dose of 60 fj,g of desogestrel bioavailable by transdermal routes with a TTS of 10 cm2 area, a transdermal flow of about 250 M9/cm2/h is required. This transdermal flow is far exceeded with the agent according to the invention. In the case of the matrix systems according to variant a or b, care must be taken for a sufficient spacing of the areas to prevent a diffusion of the active ingredients in the respective other area. Other features of the transdermal systems according to the invention can be explained based on the attached drawings that are not true-to-scale. Fig. l shows a cross section through a simple round matrix system according to variant a without the removable protective layer. It consists of impermeable cover layer 1 and pharmaceutical agent-containing matrix layer 2. Fig. 2 shows a cross section through a matrix system according to variant b without the removable protective layer. Fig. 3 shows a longitudinal section through this system. The system consists of cover 3, which is provided with a contact adhesive layer 4. Two pharmaceutical agent-containing matrix layers 6 and 8 are attached to this contact adhesive layer by impermeable covers 5 and 7. 10 2? 9226 The desogestrel-containing agents for transdermal administration according to the invention can be used for treating the same diseases as the previously known agents, for example, agents to be administered orally, that contain highly effective gestagens. Moreover, the optionally estrogen-containing preparations according to the invention also can be used for contraception. The agents according to the invention have special advantages in the treatment of diseases that require a long-term treatment with relatively high dosage of the active ingredients. Here, the frequency of administration can be significantly reduced and an essentially uniform blood plasma level can be achieved. Further, it is advantageous that no gastrointestinal side effects are to be expected, and in estrogen-containing combination preparations, the first liver passage is avoided, and that the dose of estrogen can be reduced. These advantages make the estrogen-free monotherapeutic agents of this invention appear to be especially suitable to treat, for example, endometriosis, gestagen-dependent tumors, benign breast diseases or the premenstrual syndrome. The transdermal use of estrogens in sequential or continuous combination with desogestrel offers special advantages, for example, for treating menopausal symptoms, for the prevention of osteoporosis, for regulation of the menstrual cycle and for stabilization of the menstrual cycle. The following embodiments are used for a more detailed explanation of the invention. The following commercial, products were used in the embodiments: 11 279226 Polyester film of 0.074 mm thickness (Skotchpak00 1009) of the 3M manufacturer; polypropylene film (Celgard(R> 2500) of the Celanese manufacturer, Linerfolie Skotchpak [liner film Scotchpak](R> 1022 and 1360 of the 3M manufacturer; Transferkleber [transfer adhesive] 9871 of the 3M manufacturer, polyacrylester adhesive of Sichello<R) J 6610-21 type of the Henkel KG manufacturer, silicone adhesive of X-7-2960 type of the Dow Corning manufacturer and hydroxypropyl cellulose of the Klucel(R> HXF type of the Hercules manufacturer, polyisobutylene of Oppanol<R) B 15 SF type of the BASF AG company. ITT-;— • - 279226 Example 1 0.8 g of desogestrel 8.0 g of 1,2-propa.nediol are introduced in succession while being stirred in 62.4 g of a 50% solution of silicone adhesive in benzine. After the batch is degassed, the mixture is applied by a coating device to polyester film, so that after the volatile solvent is removed, a uniform film of 40 g/m2 of solid coating results. Then, it is laminated with a fluoropolymer-coated polyester liner. The thus obtained laminate is divided by a punching device into round individual plasters of 10 cm2 area and packaged in aluminum foil. Fig. 1 shows a cross section through this plaster without a polyester liner. After the liner film is removed, the plaster adheres to the skin. The determination of content yields a uniform active ingredient distribution of 0.08 mg/cm2 on average. Example 2 5.0 g of desogestrel and 10.0 g of isopropyl myristate are dissolved in succession while being stirred in 170 g of a 50% solution of polyacrylester adhesive in acetone/benzine. After the batch is degassed, the solution is applied by a coating device to polyester film, so that after the volatile solvent is removed, a uniform film of 100 g/m2 of solid coating results. Then, it is laminated with a siliconized active ingredient-free liner film. The thus obtained laminate is divided by a punching N.Z. PATENT OFFICE 16 AUS 1996 RECEiVilD 279226 device into individual plasters of 10 cm2 area and packaged in aluminum foil. After the liner film is removed, the plaster adheres to the skin. The content of desogestrel is 0.5 mg/cm2 on average. Example 3 3.5 g of estradiol 3.5 g of desogestrel and 7.0 g of 1,2-propanediol with 10% 1-dodecanol are dissolved or suspended in succession while being stirred in 112 g of a 50% solution of polyacrylester adhesive in acetone/benzine. After the batch is degassed, the mixture is applied by a coating device to polyester film, so that after the volatile solvent is removed, a uniform film of 70 g/m2 of solid coating results. Then, it is laminated with a siliconized active ingredient-free liner film. The thus obtained laminate is divided by a punching device into individual plasters of 10 cm2 area and packaged in aluminum foil. After the liner film is removed, the plaster adheres to the skin. In a like manner, the content of estradiol and desogestrel is about 0.35 mg/cm2 each. Example 4 Analogously to Example 1, two different segment-type matrix systems are produced, which have the design represented in Figs. 2 and 3. Matrix system I consists of matrix layer 8 — provided 279226 with a polyester film 7 — of the following composition: 1.0 mg of desogestrel 5.0 mg of isopropyl myristate 44 mg of acrylate adhesive solid and has an area of 5 cm2. Matrix system II consists of matrix layer 6 — provided with a polyester film 5 — of the following composition: 2.0 mg of l7fi-estradiol 10.0 mg of isopropyl myristate and 88 mg of acrylate adhesive solids and has an area of 10 cm2. Both matrix systems are bonded to a linen cloth that is coated with a skin contact adhesive, as Fig. 3 shows. After lamination and punching out, plasters of the type shown in Figs. 2 and 3 result. N.Z. PATENT OFFICE 16 AU61996 15 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> Claims

1. Agent for transdermal administration, characterized in that it contains desogestrel optionally in combination with one or more estrogen (s) and one or two penetration-enhancers that can be mixed with one another in a matrix system, but without the addition of crystallization inhibitors.

2. Agent for transdermal administration according to claim 1, wherein as estrogen(s), one or more of estradiol, estriol, 17a-ethinylestradiol, mestranol, 14a,17a-ethanoestra-l,3,5(i0)-triene-3,17fl-diol, 14a,17a-ethanoestra-l,3,5(10)-triene- 3,16a,176-triol or esters of these compounds are used.

3. Agent for transdermal administration according to claim 1 or 2, wherein the agent for transdermal administration is a transdermal therapeutic system which consists of a) an impermeable cover layer, one to three matrix layer (s) that adhere to the cover layer and that contain desogestrel, optionally estrogen(s) and optionally penetration-enhancing agents that are permeable and self-adhesive to these components, or are covered or surrounded by a skin contact adhesive that optionally contains penetration-enhancing agents, a removable protective layer, or b) a cover that is provided with a contact adhesive that optionally contains penetration-enhancing agents, one to three matrix layer(s) (each) that leave uncovered a contact adhesive border and that are attached by means of an impermeable cover to the contact adhesive and that contain desogestrel, optionally estrogen(s) and penetration-enhancing agents; and a removable protective layer. Intellectual property office of n.z. 0 3 APR 1098 RECEIVED 2?9?26

4. Agent for transdermal administration according to claim 4, wherein the active ingredient-containing matrix layer is a polyaerylate.

5. Use of desogestrel for the manufacture of an estrogen-free agent for transdermal administration according to any of claims 1 to 4 for transdermal contraception, for treating endometriosis, for treating gestagendependent tumors and/or for treating the premenstrual syndrome.

6. Use of desogestrel for the manufacture of an agent for transdermal administration according to any of claims 1 to 4 for use, optionally in combination with estrogen-containing agents, in treating menopausal symptoms, in the prevention of osteoporosis, in regulation of the menstrual cycle, in stabilization of the menstrual cycle and/or in transdermal contraception.

7. Agent for transdermal administration according to claim 1 substantially as herein described or exemplified.

8. Use according to claim 5 or 6 substantially as herein described or exemplify°J. END OF CLAIMS 0 3 APR E93 </div>