US 20040O86552A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0086552 A1 Klokkers et al. (43) Pub. Date: May 6, 2004

(54) TRANSDERMAL THERAPEUTIC SYSTEM (30) Foreign Application Priority Data FOR HIGHLY DSPERSED SILICON DOXDE Jul. 12, 2000 (DE)...... 1OO 33 853.4 (76) Inventors: Karin Klokkers, F (DE); Kai-Thomas Publication Classification Kramer, Bad job (DE); Martina Wilhelm, Holzkirchen (DE) (51) Int. Cl." ...... A61K 9/70 (52) U.S. Cl...... 424/449 Correspondence Address: Mr. Scott A. McCollister (57) ABSTRACT Fay, Sharpe, Fagan, Minich & McKee LLP The invention relates to a transdermal therapeutic System 1100 Superior Ave 7th Floor comprising a Surface layer which is impervious with respect Suite 700 to an active ingredient; a Self-adherent matrix layer or a Cleveland, OH 44114-2518 (US) plurality of matrix layers, wherein the exposed matrix layer is, at least Self-adherent when the System is applied. Said (21) Appl. No.: 10,332,864 System also comrises a pull-off protective coating, whereby the matrix layer(s) contains one or more active ingredients (22) PCT Filed: Jul. 12, 2001 and/or one or more biologically active Substances and highly dispersed Silicon dioxide. Said System contains Silicon diox (86) PCT No.: PCT/EPO1/08070 ide in order to increase skin permeation. US 2004/0O86552 A1 May 6, 2004

TRANSIDERMAL THERAPEUTIC SYSTEM FOR 0025 2.2 Cationic tensides (e.g., cetylpyridinium HIGHLY DISPERSED SILICON DOXDE chloride) and amines 0001. The invention relates to highly disperse silica as a 0026 3. Saturated and unsaturated fatty acids penetration promoting Substance in transdermal therapeutic 0027 4. AZones and derivatives (1-alkyl azacyclohep Systems containing an active agent. tan-2-one, 1-alkyl azacycloalkanone) 0002 Transdermal administration offers a number of advantages for a number of pharmaceutical agents or other 0028) 5. Amides such as N,N-diethyl-3-methylbenza biologically active Substances: mide (DEET), N,N-diethyl-m-toluamides 0003) The skin is completely available 0029. 6. Alkyl-N,N-dialkylaminoacetate 0004. There is no change in milieu as in oral application 0030) 7. Macrocyclic ketones and lactones 0005 Handling is easy and convenient 0031) 8. Pyrrollidones 0032) 9. Esters such as ethyl acetate, isopropyl 0006 Normally a single dose is sufficient instead of myristate, glycerin monolaurate, diethyl Sebacate, pro repeated daily doses pylene glycol esters of Saturated fatty acids 0007 Patient compliance is much better 0033 10. Terpenes such as limonene, menthol, cineol 0008 Long-term treatment is possible 0034 11. Phospholipids 0009. The release of the medication takes place approxi 0035 12. Organic acids such as citric acid, salicylic mately with a Zero order kinetic acid, etc. 0.010 Treatment can be discontinued more quickly 0036) The great number of different substances of various 0.011) A constant plasma level is assured for a long time chemical Structure with known penetration promoting action makes a single mechanism of action appear improbable. So 0012 Any initially excessively high plasma level as in then various mechanisms and combinations of mechanisms intravenous administration is avoided and in Some cases a will also be discussed. lower dose is possible than in oral administration by obvi ating the initial dose, So that a lower rate of Side effects 0037) 1. Solvent effects with respect to medication and OCCS. skin lipids 0013 The danger of overdosing or underdosing is 0038 2. Effects on the three-dimensional lipid struc reduced. ture of the membrane 0.014) A controlled release of medication is assured espe 0039) 3. effects on keratin and the protein structure of cially with a lower therapeutic indication. the skin 0.015. In many cases medications which, despite low 0040. Due to the great number of interactions within the dosage and high potency, are an ideal choice, have Such a skin and the differing chemical nature of the medication, it low skin permeation that it is impossible to achieve thera is difficult to predict the penetration promoting properties of peutic plasma levels with Simple transdermal therapeutic all these enhancers with respect to an active agent. Systems. With all these drugs it is necessary to add So-called 0041 Experience shows that it is very rare that a pen permeation promoters to the System in order to increase their etration promoting Substance or a particular mixture of absorption into the circulatory System. Several active agents or groups thereof provide the required 0016 Penetration promoting Substances must have the properties. following ideal properties in addition to their Specific pur 0042. The problem to which the invention is addressed is pOSe: the preparation of a penetration promoting Substance which 0.017. Both under occlusive and under nonocclusive con is compatible with the Skin and the active agent, and has no ditions they must be compatible with the skin even when left allergenic potential. Furthermore, it should be easily acces a relatively long time thereon, they must have no allergenic Sible and economical and at the same time have a penetration potential and must be compatible with the medication. promoting action on more than one active agent. 0.018. The enhancers referred to in the literature can be 0043 Surprisingly it has now been found that highly asSociated with various chemical classes: disperse Silica has the property of Substantially increasing the penetration of active agents and/or other biologically 0019 1. Primary and secondary alcohols active Substances through the skin. 0020 1.1 Short-chain primary alcohols C to Cs 0044) Highly dispersed silica, also known under the name Aerosil(R) of the firm of Degussa-Hüls, is commonly used for 0021) 1.2 Long-chain primary alcohols C to C thickening, thixotropication and Strengthening. Aerosil brings about a considerable improvement of the mechanical 0022) 1.3 Secondary alcohols C to Co properties of all elastomers, Such as tensile Strength, rip 0023 2. Tensides propagation or tear resistance. In liquids containing Solids, e.g., pigmented varnishes, Aerosil prevents or retards Set 0024. 2.1 Anionic tensides such as Na-dodecylsul tling. The agglomeration and caking of Solid particles of fate, for example Substances in powder form is prevented by Aerosil as a flow US 2004/0O86552 A1 May 6, 2004 adjuvant, So that packing, Storage and handling as assured nylidene chloride and/or Styrene-acrylonitrile, which if nec even in high humidity and pressure conditions. essary can be metallized or pigmented. 004.5 FR 5381 describes Aerosil as a thickener for topical 0055. The removable protective layer can be made of ointments. DE 3416248 describes the addition of colloidal polyester, polyethylene, polypropylene, polysiloxane, poly silica to a plaster matrix to improve viscosity. FR 2547502 acrylate, ethylene Vinyl acetate, polyurethane, polyisobutene describes a matrix for transdermal therapeutic Systems in or paper, usually coated with Silicone and/or polyethylene, which colloidal Silica is added as a thixotropic agent. or a mixture thereof. 0046) JP 2512565 B2 (Database Chemical Abstracts, AN 0056. A matrix plaster consists of a cover layer imper 115:263477) meable to the active agent, of one or more Self-adhesive matrix layer or layers containing the active agent, or one or 0047 JP 2503095 B2 (Database Chemical Abstracts, AN more matrix layers which are coated with a contact adhesive, 116:262553) and a removable protective layer. 0048 JP 06065066 (Database Chemical Abstracts, AN 0057 The medically common matrix formers, such as 121:42787) and polyacrylate, Silicone, polyisobutylene, rubber, rubber-like 0049 JP 04368323 (Database Chemical Abstracts, AN Synthetic homo-, co- or block polymers, butyl rubber, Sty 118:175811) describe plasters in which Aerosil(R) used asta renefisoprene copolymer, polyurethanes, copolymers of eth tin. ylene, polysiloxanes, Styrene/butadiene copolymer or a mix ture thereof, as they are provided in the state of the art. The 0050 JP 09 169636 Chemical Abstracts, AN 127:86139) adhesives can be polydimethylsiloxane, polyacrylates, poly describes Silica in a plaster to reduce skin irritation. isobutylene, polyacrylate with alkylalcohol esters with 4 to 0051 Transdermal therapeutic systems are also to be 10 carbon atoms, amine-resistant Silicone in ethylacetate or found in the following documents: DE 19827 732, DE 44 n-heptane, polyisobutylene/mineral oil or a mixture thereof. 05898, DE 43 09 830, DE 4230 588, WO92/20 339; WO 91/05 529, U.S. Pat. No. 5,939,090 and U.S. Pat. No. 0058 Another embodiment of the invention is a mem 5,676,968. This state of the art, however, gives no sugges brane System. This consists of a cover layer impermeable to tion of adjusting skin permeation with Silica. The problem is the active agent, a reservoir or reservoir layer containing Solved according to the invention by highly disperse Silica active Substance, a Semipermeable membrane, a contact which acts as a penetration promoting Substance in trans adhesive layer, and a removable protective layer. The matrix dermal therapeutic Systems containing active agents or other (the matrices) or the reservoir contains the active agent or biologically active Substances. agents and in Some cases Stabilizers, emulsifiers, thickeners, permeation promoters and/or common matrix adjuvants, 0.052 Aerosil(R90, Aerosil(R130, Aerosil(R150, Aero membrane System adjuvants or reservoir plaster adjuvants. sil(R200, Aerosil(E300, Aerosil(R380, Aerosil(ROX50, If necessary, cellulose derivatives, Such as, e.g., methylcel Aerosil(RTT600, Aerosil(RMOX80, Aerosil(ECOK84, lulose, hydroxy-propyl cellulose, hydroxyethylcellulose or Aerosil(ER202, Aerosil(ER805, Aerosil(ER812, carboxymethylcellulose, and/or carboxyvinyl polymer, Aerosil(R812S, Aerosil(ER972, and/or Aerosil(R) R974 or any polyacrylates, Sodium-plyOXilate or a mixture thereof can be other highly disperse silica, especially Aerosil(R200 and/or used as gel formers. Aerosil(RR972 can be used according to the invention as highly disperse Silica. 0059. The membrane, which usually consists of inert polymers, especially those based on polyethylene, polypro 0053. The transdermal therapeutic system which contains pylene, polyvinylacetate, polyamide, ethylene-Vinyl-acetate the permeation promoter Silica according to the invention is copolymers and/or Silicone, can have a controlling action on a plaster. This plaster can be a matrix or membrane System the release of the active agent on the basis of their pore size. which has an impermeable cover layer and a removable protective layer. In a membrane System the reservoir or 0060 A pressure-sensitive adhesive based, for example, reservoir layer lies between the cover layer and the mem on polyurethanes, polyisobutylenes, polyvinyl ethers, sili brane. cones, polyacrylate or a mixture of these, can be Selected as a pressure-Sensitive adhesive coating. 0.054 An impermeable cover layer can consist of films of acetal, acrylate, acrylonitrile-butadiene-styrene, acryloni 0061 The silicone-based adhesive may be a pressure trile (methyl methacrylate) copolymer, acrylonitrile copoly Sensitive Silicone adhesive, which is based on two main mer, ethylene ethyl acrylate, ethylene methyl acrylate, eth components, namely a polymer or adhesive, especially pol ylene Vinyl acetate, ethylene Vinyl acetate copolymer, ySiloxane and a resin, which increases the adhesiveness. The ethylene Vinylalcohol polymer, ionomers, nylon (polya polysiloxane adhesive usually is prepared with a croSS mide), nylon (polyamide) copolymer, polybutylene, poly linking agent for the adhesive, typically with a high molecu carbonate, polyester, polyethylene terephthalate, thermo lar weight polydiorganosiloxane, and with the resin, in order plastic polyester copolymer, polyethylene copolymer (high to form a three-dimensional Silicate Structure with an appro density), polyethylene (high-molecular-weight, high-den priate organic Solvent. The admixture of the resin to the sity), polyethylene (intermediate-molecular-weight, high polymer is the most important factor for changing the density), polyethylene (linear low density), polyethylene physical properties of the polysiloxane adhesive (see, for (low density), polyethylene (medium density), polyethylene example, Sobieski, et al., “Silicone Pressure Sensitive Adhe oxide, polyimide, polypropylene, polypropylene (coated), Sives”, Handbook of Pressure Sensitive Adhesive Technol polypropylene (oriented) polypropylene polystyrene, poly ogy, 2" ed., pp. 508-517 (D. Satas, ed.), Van Nostrand urethane, polyvinyl acetate, polyvinyl chloride, polyvi Reinhold, New York, (1989) US 2004/0O86552 A1 May 6, 2004

0.062 Trimethylated silica, which has been treated with Parkinsonism agents, antidementia drugs/cholinesterase polydimethylsiloxane with terminal trimethylsiloxy groups, inhibitors, ACE inhibitors, antihistaminics, ulcer therapeu is a further example of a pressure-Sensitive adhesive. ticS/H-receptor blockers, angiotensin-II-antagonists, neuro 0.063. In the case of the adhesives based on polyacrylates, leptics, antidepressives, local anesthetics and/or lipid low they can be any homopolymer, copolymer or terpolymer, ering agents. consisting of various acrylic acid derivatives. 0071. The transdermal therapeutic system can contain 0064. Thus, the polyacrylates can be polymers of one or one or more representatives of the group of the androgenics, more monomers of acrylic acid and other copolymerizable e.g., testosterone, testosterone undecanoate, androsterone monomers. Moreover, the acrylate polymers can include and/or their derivatives and/or their pharmaceutically unob copolymers of alkyl acrylates and/or methacrylates and/or jectionable Salts as active agent components. copolymerizable Secondary monomers or monomers with 0072 The transdermal therapeutic system can contain as functional groups. If the amount of any kind that is added as active components one or more representatives of the group monomer is varied, the cohesive properties of the resulting of the estrogens, e.g., eStradiol, estradiol benzoate, estradiol acrylate polymer are changed. In general the acrylate poly Valerate, estradiol dipropionate, ethinylestradiol and/or their mer consists of at least 50 wt.% of an acrylate, methacrylate, derivatives and/or their other pharmaceutically unobjection alkylacrylate or alkylmethacrylate monomer, 0 to 20% of a able Salts. functional monomer copolymerizable with acrylate, and 0 to 0073. The transdermal therapeutic system can contain as 50% of another monomer. active components one or more representatives of the group 0065. The following is a list of examples of various of the gestagens, e.g., progesterone, cyproterone acetate, acrylate monomers, Such as acrylic acid, methacrylic acid, cyproterone, chlormadinone, chlormadinone acetate, butylacrylate, butylmethacrylate, hexylacrylate, hexyl medroxyprogesterone acetate, levonorgestrel, norgestrel, methacrylate, isooctylacrylate, isooctylmethacrylate, gly norgestimate, norethiestrone acetate and/or their derivatives cidylmethacrylate, 2-hydroxyethylacrylate, methylacrylate, and/or their other pharmaceutically unobjectionable Salts. methyl methacrylate, 2-ethylhexylacrylate, 2-ethyl hexyl 0074 The transdermal therapeutic system can contain as methacrylate, decylacrylate, decylmethacrylate, dodecy active components one or more representatives of the group lacrylate, dodecylmethacrylate, tridecylacrylate and tride of the proton pumping inhibitors, e.g., omeprazole, esome cylmethacrylate, which can be polymerized alone or in prazole, lanSoprazole, leminoprazole, pantoprazole, mixture. rabeprazole, polapreZinc and/or their derivatives and/or their 0.066. In addition, functional monomers can be used for pharmaceutically unobjectionable Salts. the copolymerization which are copolymerizable with the 0075. The transdermal therapeutic system can contain as above-named acrylates, Such as acrylic acid, methacrylic active components one or more representatives of the group acid, maleic acid, maleic anhydride, hydroxyethylacrylate, of the migraine treatment agents and 5-HT-antagonists, hydroxypropylacrylate, acrylamide, dimethylacrylamide, e.g., lisuride, Sumatriptan, Sumatriptanhydrogen Succinate, acrylonitrile, dimethylaminoethylacrylate, dimethylamino rizatriptan, rizatriptan benzoate, almotriptan, avitriptan, elet ethylmethacrylate tert.-butylaminoethylacrylate, tert-buty riptan, froVatriptan, Naratriptan, Zolmitriptan and/or their laminoethylmethacrylate, methoxyethylacrylate, Vinyl derivatives and/or their their other pharmaceutically unob acetate and methoxyethylmethacrylate. jectionable Salts. 0067. Additional details and examples of pressure-sensi 0076. The transdermal therapeutic system can contain as tive acrylates which are suitable for the invention are active components one or more representatives of the group described in Satas Handbook of Pressure Sensitive Adhesive of the Sympatholytic and Sympathomimetic agents, e.g., Technology “Acrylic Adhesives", 2" ed., pp. 396-456 (D. adimolol, albuterol, alpenolol, amoSulalol, arotinolol, Satas, ed.), VanNostrand Reinhold, New York (1989). atenolol, bambuterol, betaxolol, bevantolol, bisoprolol, 0068 The penetration promoting highly disperse silica bitolterol, bopindolol, broxaterol, bucindolol, bucumolol, according to the invention is incorporated in the adhesive bufuralol, bunitrolol, bupranolol, butofilolol, carazolol, car layer. It is uniformly distributed in the latter. To achieve a buterol, carteolol, carvedilol, cetamolol, cicloprolol, clen uniform distribution the silica must generally Swell with the buterol, cloranolol, crateolol, dihydroargotamine, dihidroer adhesive upon incorporation. During the Swelling phase the gotamine tartrate, dihydroergotamine meSylate, dilevalol, adhesive and Silica mixture must be mixed for a long time doxazosin, etillefrin, epanolol, eSatenolol, fenoterol, for with a Suitable apparatus, e.g., an UltraturaX. molterol, ibuterol, isoprenalin, labetalol, landiolol, levobe taxolol, levosalbutamol, mabuterol, mepindolol, metipra 0069. The content of highly dispersed silica with respect nolol, metoprolol, morazon, nebivolol, nipradillol, to the matrix weight of the adhesive layer of the transdermal norfenefrin, noradrenalin, OXprenolol, picumeterol, pimolol, therapeutic System can amount to 0.1-10 wt.%, especially pindolol, pirbuterol, phenmetrazin, phenylephetric, phento 2-5 wt.% and preferably 2, 4 or 5 wt.%. lamine, phenoxybenzamine, praZosin, procaterol, pro 0070 The active agent contained in the transdermal panolol, rimiterol, reproterol, Salbutamol, Salmeterol, Sul therapeutic System can be a representative, for example, fonterol, teraZosin, terbutalin, tertatolol, tienoXolol, tilisolol, from the group of the androgens, estrogens, gestagens, timolol, tolaZolin, toliprolol, tolubuterol, tamsulosin, cloni proton pumping inhibitor, 5-HT, antagonists, Sym din, moXonidin and/or their derivatives and/or their phar patholytica, Sympathomimetica, anticholinergica, tranquil maceutically unobjectionable Salts. izers and anxiolytica, antiaddictives, analgesics, calcium 0077. The transdermal therapeutic system can contain as antagonists, antiemetics, vasodilators, anticoagulants, anti active components one or more representatives of the group US 2004/0O86552 A1 May 6, 2004

of the anticholinergics, e.g., OXitropium, atropine, Scopola 0084. The transdermal therapeutic system can contain mine base, atropine methyl bromide, atropine methyl nitrate, one or more representatives of the group of the anticoagul Scopolamine hydrobromide, Scopolamine hydrochloride, lants, e.g., certoparin, dalteparin, danaparoid, enoxaparin, Scopolamine hydroiodide, tropicamide, Oxobutinin and/or nedroparin, reviparin, tinzaparin and/or their derivatives their derivatives and/or their other pharmaceutically unob and/or their pharmaceutically unobjectionable Salts as active jectionable Salts. components. 0078. The transdermal therapeutic system can contain as 0085. The transdermal therapeutic system can contain active agent components one or more representatives of the one or more representatives of the group of the antiparkin group of the tranquilizer/anxiolytics, e.g., alprazolam, ben Sonism agents, e.g., aptiganel, biperiden, budipin, caber tazepam, bromazepam, camazepam, cloraZepate, clon golin, etacapon, idaZOXan, lazabernid, millacermid, moregi azepam, diazepam, etiracetam, etiolam, fludiazepam, fluni lin, pergolid (pergolidmeSylat, pergolidhydrochloride) trazepam, flutazolam, flutoprazepam, halazepam, pramipexol, quineloran, rasagelin, remacemide, ropinorol, ketazolam, loprazolam, lorazepam, lormetazepam, Selegilin, talipexol, tolcapon and/or their derivatives and/or medazepam, metaclazapam, meXaZolam, midazolam, their other pharmaceutically unobjectionable Salts as active nitrazepam, nordazepam, oxazolam, prazepam, temazepam, components. triazolam and/or their derivatives and/or their pharmaceuti 0086 The transdermal therapeutic system can contain cally unobjectionable Salts. one or more representatives of the group of the antidementia 0079 The transdermal therapeutic system can contain as agents/cholinesterase inhibitors, e.g., rivastigmin, pyri active components one or more representatives from the doStigmin, donepezil, tacrin and/or their derivatives and/or group of the antiaddictives, e.g., nicotine, methadone, dis their other pharmaceutically unobjectionable Salts as active ulfiram, lobelin and/or their derivatives and/or their phar components. maceutically unobjectionable Salts. 0087. The transdermal therapeutic system can contain 0080. The transdermal therapeutic system can contain one or more representatives of the group of the ACE one or more representatives from the group of the analge inhibitors, e.g., alaceprin, benazepril, ceronapril, cilaZapril, Sics, e.g., alminoprofen, bermoprofen, carprofen, fenopro denapril, fosinopril, imidapril, moexipril, moveltipril, per fen, flobufen, flunoxaprofen, loxoprofen, pelobiprofen, pra indopril, quinapril, ramipril, ramiprilat, rentiapril, Spirepril, noprofen, pentazocin, tilnoprofen, Ximoprofen, temocapril, trandolapril, utibapril, Zofenopril and their esters Zaltroprofen, diclofenac, amfenac, bromfenac, clidanac, and/or their derivatives and/or their other pharmaceutically etodolac, felbinac, fentiazac, mofeZolac, OXindanac, tifurac, unobjectionable Salts as active components. indomethacin, piroXicam, ampiroXicam, meloxicam, isoxi 0088. The transdermal therapeutic system can contain cam, lornoxicam, tenoxicam, butorphanol, buprenorphine, one or more representatives of the group of the antihista morphine, hydromorphone, dihydrocodeine, piritramide, minics, e.g., acrivastin, carebastin, cetirizin, clenbutaerol, levomethadone, fentanyl, amfenac Sodium, bromfenac deScarbethoxyloratadin, dimetinden, ebastin, epinastin, Sodium, clidanac Sodium, etodolac Sodium, felbinac Sodium, levocabastin, meguitazin, mizolastin, nafamoStat, fentiaZac Sodium, mofeZolac Sodium, OXindanec Sodium, tifurac Sodium, indomethacin Sodium, buprenorphine hydro norastemizol, olopatidin, Oxatomid rupatadin, tazifyllin, chloride, morphine acetate, hydromorphone hydrochloride, temelastin, traXanoX and/or their derivatives and/or their Oxycodone hydrochloride, piritramide hydrogen tartrate, other pharmaceutically unobjectionable Salts as active com levomethadone hydrochloride, fentanyl dihydrogen citrate ponents. and/or their derivatives and/or their other pharmaceutically 0089. The transdermal therapeutic system can contain unobjectionable Salts as active components. one or more representatives of the group of the ulcerothera 0081. The transdermal therapeutic system can contain peuticS/H-receptor blockers, e.g., dalcotidin, famotidin, one or more representatives of the group of the calcium lafutidin, niperdidin, nizatridin, OSutidin, pibutidin, piren antagonists, e.g., amlodipine, arandipine, azelmidipine, Zepin, ramixotidin, misoprostol and/or their derivatives and/ bamidipine, benidipine, cilnidipine, efonidipine, felodipine, or their other pharmaceutically unobjectionable Salts as flordipine, iganidipine, isradipine, lacidipine, lercanidipine, active components. manidipine, nilvadipine, niSoldipine, nitrendipine, palonid 0090 The transdermal therapeutic system can contain ipine, pranidipine, Vatanidipine, clentiazem and/or their one or more representatives of the group of the angiotensin derivatives and/or their pharmaceutically unobjectional Salts II-antagonists, e.g., candesartan, candesartan-cileXetil, losa as active components. rtan, tasoSartan and/or their derivatives and/or their other 0082 The transdermal therapeutic system can contain pharmaceutically unobjectionable Salts as active compo one or more representatives from the group of the antiemet nentS. ics, e.g., aZasetron, batanoprid, cleboprid, dazoprid, dolas 0091. The transdermal therapeutic system can contain etron, domperidon, granisetron, itasetron, levoSulpirid, one or more representatives of the group of the neuroleptics, nabilon, Ondansetron, pancoprid, ramosetron, tropisetron, e.g., benperidol, haloperidol, clozapin, flupentiXol, Zatosetron and/or their derivatives and/or pharmaceutically fluphenazin, droperidol, melperon, flupentiXoldecanoate, unobjectionable Salts as active components. fluspirilen, bromperidol, pimozid, trifluprometazin, risperi 0.083. The transdermal therapeutic system can contain don, Sertindol, trifluoperidol, olanzapin and/or their deriva one or more representatives of the group of the vasodilators, tives and/or their other pharmaceutically unobjectionable e.g., glycerin trinitrate (nitroglycerin), molsidomin and/or Salts as active components. their derivatives and/or their other pharmaceutically unob 0092. The transdermal therapeutic system can contain jectionable Salts as active components. one or more representatives of the group of the antidepres US 2004/0O86552 A1 May 6, 2004

Sives, e.g., citalopram, reboxetin, alprazolam, fluoxetin and/ atoms, and their esters and Salts, natural Vitamin E, Synthetic or their derivatives and/or their other pharmaceutically vitamin E and/or vitamin E derivatives; sorbitan fatty acid unobjectionable Salts as active components. ester and ethoxylated Sorbitan fatty acid ester; azone (lau rocapram); aZone mixed with alcohols; urea; 1-alkylpyrroli 0093. The transdermal therapeutic system can contain done, block copolymers of polyethylene glycol and dimethyl one or more representatives of the group of the local Siloxane with cationic group at one end; isoprpyl myristate, anesthetic drugs, e.g., lidocaine, benzocaine, procaine, tet isopropyl palmitate, folate-polyethyleneglycol-liposome, racaine, bupivacaine, cinchocaine, etidocaine, mepivacaine, proliposome, polyoxyethylene-10-Stearyl ether, mixture of butanilicaine, levobupivacaine, ropivacaine and/or their polyoxyethylene-10-Stearyl ether and glyceryl dilaurate; derivatives and/or their other pharmaceutically unobjection dodecyl-2-(N,N-dimethylamino)-propanoltetradecanoate able Salts as active components. and/or dodecyl-2-(N,N-dimethylamino)-propianate; 0094. The transdermal therapeutic system can contain N-acetylprolinate ester with more than 8 carbon atoms, one or more representatives of the group of the lipid low nonionic tensides, e.g., lauryl ether, esters of polyoxyethyl ering drugs, e.g., Simvastatin, atorvastatin, pravastatin, ene; ethoSome (phospholipid vesicle); dimethyl(arylimino cerivastatin, dalvastatin, itavastatin lovastatin, dextrothy )Sulfuran, mixture of oleic acid analogs and propylene roxime Sodium and/or their derivatives and/or their other glycol, mixture of padimate 0, octylsalicylate, octyl pharmaceutically unobjectionable Salts as active compo methoxycinnimate, laurocapram; Cetiolf HE, butanole G nentS. or a mixture of individual components can be used as additional permeation aids. 0.095 The active substance contained in the transdermal therapeutic System can also, however, be leflunomide, inda 0099] The invention is explained by the following pamide, hydroxytamoxifen, finasterid, tirofiban, roSiglita examples, but without limiting the Scope of the invention Zone, poglitaZone, montelukast and/or their derivatives and/ thereby. or their other pharmaceutically unobjectionable Salts. EXAMPLE 1. 0.096 “Pharmaceutically unobjectionable salts of the named basic active Substances” is to be understood to mean 0100 Comparison of the permeation values of a trans acid addition salts. These are obtained by the reation of the dermal therapeutic system (TTS) with and without silica. A active Substance in its free base form with pharmaceutically polyisobutylene adhesive (MA24A(E) of AdhesiveResearch unobjectionable acids. Pharmaceutically unobjectionable USA) was used, and trandolapril as active Substance. acids are inorganic acids (e.g., hydrochloric acid, hydrobro 0101) Apparatus for skin permeation: mic acid, Sulfuric acid, nitric acid, phosphoric acid) or organic acids (e.g., acetic, propionic, hydroxy acetic acid, 0102) Cells: Modified flow-through cell lactic acid, pyruvic acid, oxalic acid, maleic, malonic, Suc cinic, fumaric, malic, tartaric, citric, methaneSulfonic, 0.103 Skin: Hairless mouse from female mice ethaneSulfonic, benzeneSulfonic, p-toluenesulfonic, cyclo 0104. Acceptor medium: 0.9% sodium chloride-- hexanesulfaminic, Salicylic, p-aminoSalicylic and pamoaic 0.05% sodium azide, 60 ml per cell acid). Solvates with the active Substance are also designated as acid addition Salts. Such Solvates are, e.g., hydrates, 0105 Permeation temperature: 32° C.-0.5° C. alcoholates and the like. Possible pharmaceutically unob jectionable Salts of the Said acid active Substances are chiefly 0106 The active agent concentrations are then deter alkali metal Salts and/or alkali metal Salts as well as the mined after sampling with HPLC. ammonium Salt, Such as the potassium, Sodium, lithium, calcium, magnesium and ammonium Salt. 0097 Active substances, their derivatives and/or their Permeation (ug/cm) pharmaceutically unobjectionable Salts that are easily TTS without silica in the matrix Soluble in water are used as active components in the transdermal therapeutic System. Trandolapril 10 wt.% 24 h 4.9-14.4 Eutanol (E) G10 wt.% 48 h 11.9-26.6 0098. In addition to the active agent, the reservoir and the MA24A (E) 80 wt.% matrix layer can contain other known penetration aids TTS with silica in the matrix known in the State of the art if the penetration of the agent Trandolapril 10 wt.% 24 h. 37.6-58.0 through the skin is not Sufficiently high in the absence of the Eutanol (E) G 10 wt.% 48 h 82.6-118.1 Silica of the invention in the transdermal therapeutic System. MA24A (E) 76 wt.% Monovalent or polyvalent aliphatic, cycloaliphatic and/or Aerosit (E) 2004 wt.% aromatic-aliphatic alcohols with up to eight carbon atoms each, e.g., ethanol, 1,2-propanediol, dexpanthenol and/or polyethylene glycol, alcohol and water mixtures, Saturated 0107 The weight-percentages relate to the matrix weight. and/or unsaturated fatty alcohols with 8-18 carbon atoms, terpenes, e.g., cineol, carveol, menthone, terpineol, Ver EXAMPLE 2 benone, menthol, limonene, thymol, cymene, terpinen-4-ol, 0.108 Comparison of the permeation of a transdermal neomenthol, geraniol, fenchon; mixtures of terpenes and therapeutic system (TTS) with and without silica. A poly ethanol and/or propylene glycol, tea tree oil; Saturated isobutylene adhesive (MA24A(E) and the methanesulfonic and/or unsaturated cyclic ketones, alkyl-methyl Sulfoxides, acid Salt of Trandolapril was used as material, the trandola Saturated and/or unsaturated fatty acids with 8-18 carbon pril mesylate being formed in situ in the TTS. US 2004/0O86552 A1 May 6, 2004

0109) Apparatus for the skin permeation: 0123 Apparatus for skin permeation: 0110 Cells: modified flow-through cell 0.124 Cells: modified flow-through cells 0111 Skin: hairless mouse from female mice 0.125 Skin: hairless mouse from female mice 0112 Acceptor medium: 0.9% sodium chloride-- 0126. Acceptor medium: 0.9% sodium chloride-- 0.05% sodium azide, 60 ml per cell 0.05% sodium azide, 60 ml per cell. 0113 Permeation temperature: 32 C.E.0.5° C. 0127 Permeation temp.: 32 C+0.5 C

Permeation Lug/cm Permeation Lug/cm TTS without silica in the matrix TTS without silica in the matrix Trandolapril 10 wt % 24 h 10.9-13.8 Methanesulfonic acid 2.26 wt % 48 h 19.2-24.6 Ramipril 15 wt % 24 h 6-29 Eutanol (E) G. 5 wt % Methanesulfonic acid 3.8 wt % 48 h 11-53 MA24A (E) 78.7 wt % Eutanol (E) G 10 wt % TTS with silica in the matrix Durotak (E) 387-2353 71.2 wt % TTS with silica in the matrix Trandolapril 10 wt % 24h 36.1-74.4 Methanesulfonic acid 2.26 wt % 48 h 1'46.2-204.6 Ramipril 15 wt % 24 h 122-248 Eutanol (E) G. 5 wt % Methanesulfonic acid 3.5 wt % 48 h. 366-533 MA24A (E) 78.74 wt % Eutanol (E) G 10 wt % Aerosi (E) 2004 wt-% Durotak (E) 387-2353 66.5 wt.-% Aerosi (E) 2005 wt-%

0114. The weight-percentages refer to the matrix weight. 0128. The weight-percentages refer to the matrix weight. EXAMPLE 3 EXAMPLE 5 0115 Comparison of the permeation values of a trans dermal therapeutic system (TTS) with and without silica. A 0.129 Comparison of the permeation of a transdermal polyiobutylene adhesive (MA24A(R) and ramipril mesylate therapeutic system (TTS) with and without silica. An acry as the active Substance were used. late adhesive (DurotakCE)) was used and ramipril meSylate as active agent, the ramipril meSylate being formed in situ. 0116 Apparatus for skin permeation: 0.130 Apparatus for skin permeation: 0117 Cells: modified flow-through cells 0131 Cells: modified flow-through cells 0118 Skin: hairless mouse from female mice 0119) Acceptor medium: 0.9% sodium chloride-- 0132) Skin: hairless mouse from female mice 0.05% sodium azide, 60 ml per cell. 0.133 Acceptor medium: 0.9% sodium chloride-- 0120 Permeation temp.: 32 C+0.5 C 0.05% sodium azide, 60 ml per cell. 0134) Permeation temp.: 32 C+0.5 C

Permeation Lug/cm TTS without silica in the matrix Permeation Lug/cm Ramipril mesylate 15 wt % 24 h 111-156 TTS without silica in the matrix Eutanol (E) G 10 wt % 48 h 184-219 MA24A (E) 75 wt % Ramipril 10 wt % 24 h 19-24 TTS with silica in the matrix Methanesulfonic acid 2.4 wt.-% 48 h 41-48 Eutanol (E) G 10 wt % Ramipril mesylate 15 wt % 24 h 251-338 Durotak (R) 387-251O 77.6 wt % Eutanol (E) G 10 wt % 48 h 862-997 TTS with silica in the matrix MA24A (E) 70 wt % Aerosi (E) 2005 wt-% Ramipril 10 wt % 24 h 51-80 Methanesulfonic acid 2.4 wt % 48 h 205-253 Eutanol (E) G 10 wt % Durotak (E) 387-22510. 73.6 wt.-% 0121 The weight-percentages refer to the matrix weight. Aerosi (E) 2004 wt-% EXAMPLE 4 0.122 Comparison of the permeation of a transdermal 0.135 The weight-percentages refer to the matrix weight. therapeutic system (TTS) with and without silica. An acry late adhesive (Durotak(R) of National Starch/USA) and rami EXAMPLE 6 pril meSylate as active Substance were used, the ramipril 0.136 Comparison of the permeation of a transdermal meSylate being formed in situ. therapeutic system (TTS) with and without silica. A poly US 2004/0O86552 A1 May 6, 2004 isobutylene adhesive (MA24A(R) was used, and moxonidine more active agents and/or one or more other biologically base as active agent and oleic acid as enhancer. active Substances and highly disperse Silica, the System containing Silica to increase skin permeation. 0.137 Apparatus for skin permeation: 2. Transdermal therapeutic System with a cover coating 0138 Cells: modified flow-through cell impermeable to the active Substance, with one or more matrix coatings with a content of active Substance and/or 0.139 Skin: hairless mouse from female mice other biologically active matter, the matrix layer or layers 0140. Acceptor medium: 0.9% sodium chloride-- being coated with an adhesive (adhesive layer) and with a 0.05% sodium azide, 60 ml per cell. removable protective layer, the adhesive layer containing a highly disperse Silica. 0141 Permeation temp.: 32 C+0.5 C 3. Transdermal therapeutic System according to claim 2, characterized in that the System contains Silica to increase the skin permeation. Permeation Lug/cm 4. Transdermal therapeutic System with a cover coating impermeable to active Substance, a reservoir or a reservoir TTS without silica in the matrix layer with a content of the active Substance and/or other Moxonidin 10 wt.% 24 h 23.0-42.6 biologically active Substances, with a Semipermeable mem Oleic acid 10 wt.% 48 h 45.3-8.2.1 brane, with an adhesive coating and with a removable MA24A (R) 80 WT.9% protective layer, the adhesive coating containing highly TTS with silica in the matrix disperse Silica to increase the skin permeation. Moxonidin 10 wt.% 24 h 58.6-84.8 5. Transdermal therapeutic System according to any of the Oleic acid 10 wt % 48 h 107.8-159.0 foregoing claims, characterized in that the System contains Aerosi (E) 2003 wt % Silica in an amount which in a given System (disregarding MA24A (E) 77 wt.% Silica) corresponds to a given permeation value or is adjusted to a given permeation value. 6. Transdermal therapeutic System according to claim 5, 0142. The weight-percentages refer to the matrix weight. characterized by a Silica content which corresponds to a maximum permeation value. EXAMPLES 7 AND 8 7. Transdermal therapeutic System according to any of the 0143 For Ramipril mesilate a skin permeation with foregoing claims, characterized in that the highly disperse Eutanol G should be about 920 ug/cm/48 h (Example 7) and Silica has been incorporated uniformly into the Self-adhesive with Eutanol G/c-tocopherol acetate, about 680 ug/cm/48 matrix layer(s) or into the adhesive layer. h (Example 8). These specifications are achieved by increas 8. Transdermal therapeutic System according to claim 7, ing the content of Aerosil 200; cf. the following table. characterized in that the highly disperse Silica has been incorporated by causing a mixture of Self-adhesive matrix/ Silica or a mixture of preSSure-Sensitive adhesive/silica to Swell in the presence of a fluid medium and then forming it Skin permeation into matrix layer(s) or adhesive layer. Charge (Ramipril-TTS) Composition Lug/cm 9. Transdermal therapeutic System according to any of the RAMOOf6 TTS Ramipril Mesilate 15% 24 h: 294, 202 foregoing claims, characterized by a content of highly Eutanol G 10% disperse silica of 0.1 to 10 wt-%, especially 2 to 5 wt-% and Aerosil 2002% 48 h: 509, 394 MA. 24.73% preferably about 2, about 3, about 4 or about 5 wt-% with RAMOO81 TTS Ramipril Mesilate 15% 24 h; 251,338 respect to the weight of the Self-adhesive matrix layer(s) or Eutanol G 10% of the adhesive layer. Aerosil 2005% 48 h997, 862: 10. Transdermal therapeutic System according to any of MA. 24.70% RAMOOf7 TTS Ramipril Mesilate 15% 24 h: 148, 99 the foregoing claims, characterized by AerosilB90, Aero Eutanol G 10% sil(R) 130, Aerosil(R)150, Aerosil(R200, Aerosil(E300, Aero C-tocopherol acetate 10%. 48 h: 313, 272 sil(R380, Aerosil(ROX50, Aerosil(RTT600, Aerosil 2002% Aerosil(RMOX80, Aerosil(ECOK84, Aerosil(ER202, MA 24 63% RAMOO83 TTS Ramipril Mesilate 15% 24 h: 187, 190 Aerosil(ER805, Aerosil(ER812, Aerosil(E812S, Eutanol G 10% Aerosil(RR972 and/or Aerosil(ER974 as highly disperse C-tocopherol acetate 10%. 48 h: 653, 708 Silica. Aerosil 2005% 11. Transdermal therapeutic System according to claim 10, MA 24 60% characterized by Aerosil(R200 and/or Aerosil(ER972 as highly disperse Silica. 12. Transdermal therapeutic System according to any of 1. Transdermal therapeutic System with a cover coating the foregoing claims, characterized by a content of Stabiliz impermeable to the active Substance, with a Self-adhesive ers, emulsifiers, thickening agents, permeation promoting matrix coating or with a plurality of matrix coatings, of agents and/or conventional membrane System adjuvants or which at least the matrix coat exposed in the application of reservoir plaster adjuvants. the System is Self-adhesive, and with a removable protective coating, the matrix coating or coatings containing one or