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US 2004O241219A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0241219 A1 Hille et al. (43) Pub. Date: Dec. 2, 2004

(54) TRANSDERMAL THERAPEUTIC SYSTEM (86) PCT No.: PCT/EP02/09057 BASED ON POLYACRYLATE-CONTACT-BONDING (30) Foreign Application Priority Data ADHESIVES WITHOUT FUNCTIONAL GROUPS Aug. 24, 2001 (DE)...... 101.41652O (76) Inventors: Thomas Hille, Neuwied (DE); Frank Publication Classification Theobald, Bad Breisig (DE); Ursula Hildegard Klein, Neuwied (DE) (51) Int. Cl." ...... A61K 9/70 (52) U.S. Cl...... 424/449 Correspondence Address: William F Lawrence (57) ABSTRACT Frommer Lawrence & Haug The invention relates to a transdermal therapeutic System 745 Fifth Avenue (TTS) consisting of a rear layer, a protective layer and an New York, NY 10151 (US) active-Substance-containing polymer layer. The polymer matrix comprises a polyacrylate which contains an (21) Appl. No.: 10/487,380 extremely reduced number of functional groups. In one particular embodiment, the polyacrylate is free from (22) PCT Filed: Aug. 13, 2002 hydroxyl groups and/or carboxyl groups. US 2004/0241219 A1 Dec. 2, 2004

TRANSIDERMAL THERAPEUTIC SYSTEM BASED are both produced by National Starch. These polyacrylates ON POLYACRYLATE-CONTACT-BONDING have proven to be stable and highly tolerable contact ADHESIVES WITHOUT FUNCTIONAL GROUPS adhesive polymers for the production of transdermal thera peutic Systems which contain hormones as active 0001 Transdermal therapeutic systems (TTS) are flat compounds. pharmaceutical products built up in layers, in which one or more active compounds are embedded in an optionally 0007. A disadvantage in the case of the transdermal contact-adhesive polymer matrix with or without excipients therapeutic Systems whose polymer matrices contain poly (e.g. penetration accelerators). As a rule, this polymer matrix acrylates which contain the functional groups mentioned is prepared by coating a Support film with the polymer (hydroxyl group, carboxyl group) is the low active com material containing the active compound and then providing pound utilization. This is to be observed in particular in it with a covering film, which also remains on the skin hormone-containing transdermal therapeutic Systems. In this during the application of the transdermal therapeutic System. case, a low active compound utilization is to be understood The Support film Serves as a protective layer for the polymer as meaning that, after expiry of the intended administration matrix during the Storage period and optionally as an appli period of the transdermal therapeutic System, a relatively cation aid for the later application of the transdermal thera large amount of the active compound remains unutilized in peutic System. the “used’ transdermal therapeutic System in comparison with the total amount of the active compound contained 0002 Transdermal therapeutic systems make possible a therein before the start of the administration of this trans continuous Supply of active compound over the entire appli dermal therapeutic System. cation period. They are therefore comparable with continu ous drip infusions with respect to their concentration-time 0008 Since in some cases very expensive active com profiles. Numerous transdermal therapeutic Systems con pounds are employed in transdermal therapeutic Systems, taining different active compounds and active compound the low active compound utilization is undesirable from combinations are found today on the pharmaceutical market. economic and from ecological points of view. Finally, in the One of the most important indication areas for transdermal case of pharmaceutical active compounds having a toxic therapeutic Systems is hormone Substitution therapy, in action in relatively high concentration, a high residual particular in the case of women in the menopause. In the content can also constitute a certain risk potential for the early years of transdermal hormone Substitution therapy, improper taking of a higher dose. -containing monopreparations were especially 0009. According to the invention, this disadvantage is employed therefor. Recently, however, transdermal thera Solved by means of a transdermal therapeutic System which, peutic Systems are being Supplied which contain a combi as the base polymer for the polymer matrix, contains a nation of (e.g. 17B-) and gestagens (e.g. contact-adhesive polyacrylate which contains an extremely ). , the male , like reduced content of hydroxyl groups and/or carboxyl groups, wise belongs to the group consisting of the Steroid hor so that this can be described as “essentially free of functional mones, which are used in the course of hormone Substitution groups”. This is all the more Surprising, Since among experts therapy, in particular in the treatment of . the presence of functional groups, in particular hydroxyl 0003) A number of commercially obtainable transdermal groupS and/or carboxyl groups, in the polyacrylates is con therapeutic Systems are constructed as "matrix Systems'. sidered as a prerequisite for a good cohesion and/or adhesion These are Systems in which the polymer matrix, which is of the polymer matrix. equipped to be contact-adhesive or non-contact-adhesive, 0010) Suitable polyacrylates which according to the contains the active compound in dissolved or Suspended invention are "essentially free of functional groups' are form. The polymer matrix in this case usually consists of polymers (homopolymers, copolymers and block copoly contact adhesives based on polyacrylates. mers) based on acrylic acid esters and/or methacrylic acid 0004. The polyacrylates used in this case are prepared eSterS. from monomers (acrylic acid and methacrylic acid, and in 0011 Suitable monomers for the preparation of the poly each case their esters, optionally with vinyl ), which acrylate according to the invention are in this case in contain functional groups. These functional groups can particular n-butyl acrylate, n-butyl meth-acrylate, ethyl Survive the polymerization of the monomers employed acrylate, 2-ethylhexyl acrylate, ethyl methacrylate, methyl unchanged and influence the properties of the resulting acrylate, methyl methacrylate, tert-butyl acrylate, Sec-butyl polyacrylate-in particular the tackineSS and the adhesive acrylate, tert-butyl methacrylate, cyclohexyl methacrylate, power-crucially. 2-ethylhexyl methacrylate, isobornyl methacrylate, isobutyl methacrylate, isopropyl acrylate, isopropyl methacrylate and 0005 Thus, adhesive formulations based on polyacrylate mixtures of these monomers. These monomers are esters of are disclosed in EP 614356, in which the content of the total acrylic and methacrylic acid which contain linear, branched of acrylic acid, glycidyl methacrylate and hydroxyethyl or cyclic aliphatic C-C Substituents without other func acrylate is between 4.8 and 5.5% by weight (cf. table 3 of tional groups. this document). 0012 Vinyl acetate can also be used as a comonomer for 0006 The person skilled in the art distinguishes poly the preparation of the polyacrylate together with at least one acrylates having -OH groups (hydroxyl groups) and those of these monomers. The content of vinyl acetate in the having -COOH groups (carboxyl groups) as functional monomer mixture used for the preparation of the polyacry groups. The polyacrylates containing hydroxyl groups late should be below 20% by weight, preferably below 5% include, for example, Durotak 2287, the polyacrylates con by weight. A vinyl acetate content of below 1.5% by weight taining carboxyl groups, for example, Durotak 2051, which is particularly preferred. US 2004/0241219 A1 Dec. 2, 2004

0013 The esters of acrylic acid or methacrylic acid which 0021 f-adrenoreceptor Such as, for example, carry functional groups and can be contained in the mono formoterol, terbuterol, ritodrine, mer mixture used for the preparation of the polyacrylate are primarily to be understood as meaning esters containing 0022 C.-adrenoreceptor blockerS Such as, for example, hydroxyl groups, that is 2-hydroxy-ethyl acrylate, 2-hy dapiperazole, doxazosine, praZosine, yohimbine, trima droxyethyl methacrylate, 3-hydroxy-propyl acrylate and Zosine, 3-hydroxypropyl methacrylate. However, Substances Such 0023 B-adrenoreceptor blockers such as, for example, as acrylonitrile, methacrylonitrile, acrylamide, dimethylami acebutolol, atenolol, bisoprolol, bopindolol, bupra noethyl acrylate etc can also be be considered within the nolol, propanolol, metoprolol, nadolol, pindolol, meaning of this description as “esters of acrylic acid or timolol, methacrylic acid containing functional groups”. 0024 anabolics such as, for example, , 0.014. However, the proportion of the total of acrylic acid, , , 4-hydroxy-19-nortestosterone, methacrylic acid, 2-hydroxyethyl acrylate, 2-hydroxyethyl methenolone, methacrylate, 3-hydroxypropyl acrylate and/or 3-hydrox 0025 analgesics (narcotics) Such as, for example, ypropyl methacrylate in the monomer mixture used for the alfentanil, buprenorphine, , dimenoxadol, fen preparation of the polyacrylate is below 2% by weight, tanyl, , lofentanil, , , preferably below 1.5% by weight and particularly preferably morphine derivatives, , normorphine, below 0.2% by weight. propiram, Sufentanil, tilidine, 0.015 “Essentially free of functional groups” within the 0026 analgesics (non-narcotics) Such as, for example, meaning of the present description is thus to be understood aminopyrine, antipyrine, aspirin, benoxaprofen, buce as meaning that the total content of acrylic acid, methacrylic tin, clometacin, etodolac, felbinac, fenoprofen, flubi acid and esters of acrylic acid or methacrylic acid which profen, ibufenac, indomethacin, indoprofen, ketopro carry functional groups (in particular the esters containing fen, keterolac, miroprofen, hydroxyl groups) in the polyacrylate is below 2% by weight, preferably below 1.5% by weight. In a particular embodi 0027) such as, for example, , flu ment, the total content of these monomers is below 0.2% by , , , methandros weight. In a particular embodiment, none of these esters of tenolone, 17-, 17C.-methyltestoster acrylic acid or methacrylic acid which carry functional one 3-cyclopentyl enol ether, , groups are contained in the monomer mixture. , , , praster one, Stanolone, , testosterone, testosterone 0016. The monomer mixtures can be polymerized in 17- hemiacetal, testosterone 17B-cypionate, tes various ways, e.g. by ionic, free-radical or light-induced tosterone enanthate, testosterone nicotinate, testoster means etc., optionally using crosslinkerS Such as, for one phenylacetate, , tiomester example, aluminum acetylacetonate, allyl glycidyl ether OneS, and/or glycidyl methacrylate (which—if present-are con 0028 Such as, for example, amucaine, tained in the monomer mixture in a content of below 0.5% amylocalne, biphenamine, cocaine, diperodone, by weight) and optionally also using auxiliaries Such as ecgonidine, euprocine, fenalcomine, fomocaine, heX antioxidants, stabilizers and/or alkyl-mercaptains (which—if obarbital, hexylcaine, , hydroxyprocaine, present-are contained in the monomer mixture in a content hydroxytetracaine, , leucinocaine meSylate, of below 0.1% by weight). Water, optionally together with levoxadrol, , mepivacaine, meprylcaine, emulsifiers or organic Solvents, can be used as the reaction metabutoxycaine, , , naepaine, medium. Octacaine, Orthocaine, OXethazaine, parethoxycaine, 0017 Contact adhesives based on polyacrylates, which in phenacaine, piperocaine, polidocanol, pramoxine, our view come under this definition of “essentially free of prilocalne, procaine, propanocaine, , risocaine, functional groups” are the Elite adhesives from National , , , thiobutabarbital, Starch and GMS 3083 from Solutia. thiopental, tolycaine, trimecaine, , 0.018. In a particularly simple embodiment, the polymer 0029 antiallergics Such as, for example, amlexanox, matrix consists exclusively of the active compound (or an , , cromolyn, fenpipran, , active compound combination) and the polyacrylate accord repirinast, tiaramide, tranilast, traXanox, urushiol, keto ing to the invention. However, embodiments are also poS tifen, , , pentigetide, Sible in which a mixture of a polyacrylate without a func 0030 such as, for example, , tional group is used with a polyacrylate containing cyoctol, cyproterone, Oxendrolone, functional groups. 0031 antianginals Such as, for example, amlodipine, 0.019 Beside the preferred hormones, in particular the amyl nitrite, cinepaZet maleate, imolamine, isosorbide Steroid hormones, other pharmaceutically active Substances dinitrate, limaprost, molsidomine, nitroxyalkylamide can also be used as active compounds in the polymer derivatives, matrices based on polyacrylates without functional groups. 0032 antiarrhythmics Such as, for example, acecain The following Substances are suitable for this: ide, adenosine, ajmaline, alprenolol, amoproxan, aprin 0020 C-adrenoreceptor agonists Such as, for example, dine, bretylium tosylate, bubumolol, bunaftine, butid , adrenolone, , , tia rine, butobendine, meobentine, mexiletine, moricizine, menidine, pirmenol, pronethalol, propafenone, pyrinoline, US 2004/0241219 A1 Dec. 2, 2004

0033 penicillins such as, for example, amdinocillin, estradiol 17B-cypionate, , , ethinylestra pivoxil, amoxicillin, amplicillin, apalcillin, aspoxicillin, diol, , , mytatrienediol, polyestra azidocillin, azlocillin, bacampicillin, benzylpenicillin, diol phosphate., quineStradiol, , carbenicillin, carfecillin, carindacillin, clometocillin, cloxacillin, cyclacillin, dicloxacillin, diphenicillin, epi 0038 gestagens Such as, for example, , cillin, fenbenicillin, floxicillin, hetacillin, lenampicil , acetate, lin, metampicillin, methicillin, meZlocillin, nafcillin, acetate, , , , oxacillin, penamecillin, penethamate hydriodide, peni , ethinylestrenol, , ethyno cillin G benethamine, penicillin G benzathine, penicil diol, ethynodiol diacetate, flurogestone acetate, lin G benzhydrylamine, penicillin G calcium, penicillin , geston.orone caproate, , Ghydrabamine, penicillin N, penicillin O, penicillin V, 17-hydroxy-16-methyleneprogesterone, 17O-hydrox penicillin V benzathine, penicillin V hydrabamine, pen yprogesterOne, 17O-hydroxygesterone caproate, imepicycline, phenethicillin, piperacillin, pivapicillin, , , , medroX propicillin, quinacillin, Sulbenicillin, talampicillin, yprogesterone, acetate, , nore thindrone, norethindrone acetate, norethynodrel, norg temocillin, tiacarcillin, esterone, , , , 0034 antidiabetics such as, for example, sulfonylurea 19-norprogesterone, , , derivatives, acetohexamide, carbutamide, chlorpropa , , , trenge mide, glibornuride, gliclazide, glimepiride, glipizide, Stone, gliquidone, glisoxepide, glyburide, glybuthiazole, gly buZole, glyhexamide, glymidine, glypinamide, phenb 0039 vasodilators such as, for example, bencyclan, utamide, tolaZamide, tolbutamide, tolcyclamide, acar ciclonicate, , , diisopropylamine bose, benzylthiazolidine-2,4-dione, calcium dichloroacetate, eburnamonine, fenoxedil, ibudilast, meSOXalate, miglitol, ifenprodil, nafronyl, nicametate, nicergoline, nino dipine, papaverine, pentifylline, tinofedrine, Vincam 0035 antihistaminics such as, for example, acrivas ine, Vinpocetine, amotriphene, bendazole, benfurodil tine, , , chlorpheniramine, hemisuccinate, benziodarone, chloracy Zine, chromo dimethindene, metron S, , , nar, clobenfurol, clonitrate, dilaZep, dipyridamol, dro thenaldine, , , bietanautin, bro penilamine, efloxate, erythritol, erythrityl tetranitrate, mdiphenhydramine, , , diphe etafenone, floredil, ganglefen, bis(B-diethy nylpyraline, , , , laminoethyl ether), hexobendine, isosorbide dinitrate, mephenhydramine, p-methyldiphenhydramine, itramine tosylate, khellin, lidoflazine, hexani , , piprine hydrinate, trate, medibazine, nicorandil, nitroglycerine, pen , , , chlorothene, taerythritol tetranitrate, pentrinitrol, pimethylline, pre , methafurylene, , meth nylamine, propatyl nitrate, pyridofylline, trapidil, apyrilene, , pyrilamine, tallastine, the tricromyl, trimetazidine, troInitrate phosphate, Visna nyldiamine, , tripelennamihe, Zolamine, dine, bamethane, , bradykinin, brovincam , , ., hydroxy Zine, ine, bufoniod, buflomedil, butalamine, cetiedil, cicloni , cate, cinepazide, cyclandelate, eledoisine, hepronicate, 0036 antimigraine agents, hydrogenated ergot alka inositol niacinate, isoxSuprine, kallidine, kallikrein, loids, adrenoreceptor blockers, Ca antagonists, Seroto moxisylyt, nicofuranose, nylidrine, piribedil, Suloctidil, nin antagonists, platelet aggregation inhibitors, antide Xanthinal and niacinate, and also . preSSants Such as, for example, alpiropride, , ergocornine, ergocorninine, ergoc EXAMPLE ryptine, ergot, ergotamine, acetate, fona 0040 Four transdermal therapeutic systems (formula Zine, methySergide, , pizotyline, Sumatriptan, tions nos. 1 to 4) were prepared, which as active compounds anagrelide, argatroban, ciloStazole, daltroban, defi contained 17 B-estradiol or testosterone in the polymer brotide, enoxaparine, fraxiparine, indobufen, lamopa matrix. As a back layer, a polyethylene terephthalate film ran, OZagrel, picotamide, plafibride, tedelparine, ticlo was used; the area weight of the polymer matrix was 100 pidine, triflusal, g/m. (The thickness of the polymer matrix can preferably 0037 bronchodilators such as, for example, ephedrine be between 15 to 30 um.) derivatives Such as, for example, albuterol, bambuterol, 0041. For comparison of the behavior with respect to the bitolterol, carbuterol, clenbuterol, chlorprenaline, diox active compound utilization, on the one hand Durotak 2287 ethedrine, eproZinol, etafedrine, ethylnorepinephrine, was employed for the polymer matrix as a contact-adhesive fenoterol, hexoprenaline, isoetharine, isoproterenol, polyacrylate having a functional group, while in the trans mabuterol, metaproterenol, N-methylephedrine, pir dermal therapeutic Systems according to the invention the buterol, procaterol, protokylol, reproterol, rimiterol, adhesive GMS 3083 from Solutia was used as a contact Soterenol, terbutaline, tulobuterol, estrogens Such as, adhesive polyacrylate without a functional group within the for example, , broparoestrol, chlorotria meaning of this description. nisene, , , diethylstilbestrol dipropionate, , , hexestrol, methal 0042 Tables 1 and 2 show the cumulated amounts of lenestril, , colpormone, , , active compound for the respective polymer matrices which conjugated estrogenic hormones, estrogen esters, were measured in a Franz's cell which was equipped with an , 17B-estradiol, estradiol, , EVA membrane. US 2004/0241219 A1 Dec. 2, 2004

e) auxiliaries from the group consisting of the antioxi TABLE 1. dants, Stabilizers and/or alkylmercaptains in a content of below 0.1% by weight. Release behavior from estradiol-containing 2. The transdermal therapeutic System as claimed in claim polymer matrices 1, characterized in that the polymerization of the monomer Cumulated amount of mixture is carried out by ionic, free-radical or light-induced active compound in means, in water which can contain emulsifiers or in organic No. Ingredients % content Lug/cm (after 3 days) Solvents as a reaction medium. 1. 17B-estradiol 1.OO 170.3 3. The transdermal therapeutic System as claimed in claim Durotak 2287 99.OO 1 or 2, characterized in that the monomer mixture contains 2 17B-estradiol 1.OO 24O6 vinyl acetate in a content of below 5% by weight. GMS 3O83 99.OO 4. The transdermal therapeutic System as claimed in one or more of claims 1 to 3, characterized in that aluminum acetylacetonate, allyl glycidyl ether and/or glycidyl meth 0043) acrylate is used in the monomer mixture as a crosslinker. 5. The transdermal therapeutic System as claimed in one TABLE 2 or more of claims 1 to 4, characterized in that the group of Release from testosterone-containing polymer esters of acrylic or methacrylic acid which contain linear, matrices branched and/or cyclic aliphatic C-C Substituents without Cumulated amount of another functional group consists of n-butyl acrylate, n-butyl active compound in methacrylate, ethyl acrylate, 2-ethylhexyl acrylate, ethyl No. Ingredients % content Lug/cm (after 3 days) methacrylate, methyl acrylate, methyl methacrylate, tert butyl acrylate, Sec-butyl acrylate, tert-butyl methacrylate, 1. testOsterOne 2.OO 575.3 Durotak 2287 98.00 cyclohexyl methacrylate, 2-ethylhexyl methacrylate, 2 testOsterOne 2.OO 675.5 isobornyl methacrylate, isobutyl methacrylate, isopropyl GMS 3O83 98.00 acrylate, isopropyl methacrylate and mixtures of these OOCS. 6. The transdermal therapeutic System as claimed in one 0044) The active compound utilization results from the or more of claims 1 to 5, characterized in that the monomer cumulated amount of active compound divided by the mixture is free of acrylic acid, methacrylic acid, 2-hydroxy amount of active compound contained in the TTS. ethyl acrylate, 2-hydroxyethyl methacrylate, 3-hydroxypro 0.045 AS is seen, in the case of estradiol it was possible pyl acrylate and/or 3-hydroxypropyl methacrylate. by use of the polyacrylate adhesive without functional 7. The transdermal therapeutic System as claimed in one groups to achieve a 40% better active compound utilization, or more of claims 1 to 6, characterized in that the active in the case of testosterone a 17% better active compound compound is a pharmaceutically active Substance from the utilization. In other words: The cumulative flux is higher by group consisting of the C.-adrenoreceptor agonists, the the factor 40% and 17% respectively. Thus with the same B-adrenoreceptor agonists, the O.-adrenoreceptor blockers, active compound loading a better active compound utiliza the f-adrenoreceptor blockers, the analgesics (narcotics), tion can be achieved. the analgesics (non-narcotics), the androgens, the anesthet ics, the antiallergics, the antiandrogens, the antianginals, the 1. A transdermal therapeutic System comprising back antiarrhythmics, the penicillins, the antidiabetics, the anti layer, protective layer and at least one active-compound histaminics, the antimigraine agents, the hydrogenated ergot containing polymer matrix comprising a polyacrylate, the alkaloids, the Caantagonists, the Serotonin antagonists, the polyacrylate being a homopolymer, copolymer or block platelet aggregation inhibitors, the anti-depressants, the copolymer which can be prepared by polymerization of a bronchodilators, the estrogens, the gestagens, the vasodila monomer mixture consisting of tors and nicotine. 8. The transdermal therapeutic System as claimed in one a) a monomer or a mixture of monomers from the group or more of claims 1 to 7, characterized in that the active consisting of the esters of acrylic or methacrylic acid, compound is a hormone or a combination of hormones. which carry linear, branched and/or cyclic aliphatic 9. The transdermal therapeutic System as claimed in claim C-C2 substituents without another functional group, 8, characterized in that the hormone is 17 B-estradiol, ethi b) acrylic acid, methacrylic acid, 2-hydroxyethyl acrylate, nylestradiol, , levonorgestrel, norethin 2-hydroxyethyl methacrylate, 3-hydroxypropyl acry drone, norethindrone acetate or testosterone. late and/or 3-hydroxypropyl methacrylate, the content 10. The use of a transdermal therapeutic system as of these monomers in the total being below 2% by claimed in one of claims 1 to 9 for the treatment of weight, hypogonadism, for hormone Substitution therapy or for c) vinyl acetate in a content of below 20% by weight, contraception. d) crosslinkers in a content of below 0.5% by weight