(12) Patent Application Publication (10) Pub. No.: US 2004/0241219 A1 Hille Et Al
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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 Steroid 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. estrogen-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 estrogens (e.g. 17B-estradiol) and gestagens (e.g. contact-adhesive polyacrylate which contains an extremely norethisterone). Testosterone, the male Sex hormone, 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 hypogonadism. 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 acetate), 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 agonists 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, androstenediol, 0.014. However, the proportion of the total of acrylic acid, bolandiol, clostebol, 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, codeine, dimenoxadol, fen preparation of the polyacrylate is below 2% by weight, tanyl, isomethadone, lofentanil, methadone, morphine, preferably below 1.5% by weight and particularly preferably morphine derivatives, normethadone, normorphine, below 0.2% by weight. propiram,