Title of Invention

A PREPARATION IN THE FORM OF A TRANSDERMAL THERAPEUTIC SYSTEM

Abstract

A preparation in the form of a transdermal therapeutic system A preparation in the form of a transdermal therapeutic system containing at least one active substance and at least one akin penetration enhancer in a self-adhesive matrix layer, which is covered at the side facing away from the skin with an active substance - impermeable backing layer, characterized in that - said active substance is selected from the group of hydroxymethylglutaryl- CoA reductase inhibitors, the self adhesive matrix layer is a mass based on polyacrylate, silicone, polyisobutylene, polyisoprene, polystyrene, ethylene vinyl acetate, rubber or similar synthetic homo-, co- or block polymers, and that - said skin penetration enhancer is selected from the group consisting of pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glycol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl, ethers, propylene glycol fatty acid derivatives, glycerol fatty acid esters, polysorbates, poloxamers, dialkyl sulfoxides, urea and urea derivatives, glycerol, native oils, laurocaprames, phospholipids, amides, amino acids, N,N-dimethyl formamide, N-methyl formamide, acetonides, calcium thioglycolate, propylene glycol, poly ethylene glycol, alkyl sulfate, sodium lauryl sulfate, tetrahydrofurfuryl alcohol, macrocyclic compounds and panthenol.

Full Text

The invention relates to a preparation containing at least one active substance which has an influence on the levels of lipids in the blood of an organism. This active substance is a member of a group of active substances which intervene in the lipid metabolism of the organism and which are used for treating diseases related thereto. Said substances are preferably inhibitors of hydroxymethyl- glutaryl-CoA reductase (HMG-CoA reductase). Systemic lipid metabolism disturbances, especially so-called hyperlipoproteinemias, are of great significance in the pathogenesis of arteriosclerotic vascular diseases and of their consequences, such as cardiac infarction, apoplectic insultus and occlusive arterial diseases. In the USA and Europe about 15 percent of adults have an increased risk of suffering cardiovascular incidents because of increased lipid levels in the blood. A sensible starting point for prophylaxis, therapy and the treatment of consequences consists in lowering increased plasma lipid levels. Basis for any treatment of hyperlipoproteinemia is an appropriate diet. A normalization of weight, appropriate diet composition, a proportion of fat lipid-lowering medicaments a marked reduction of these diseases can be achieved. Current studies, e.g. LCAS -Lipoprotein and Coronary Arterosclerosis Study; LIPID - Long-term Intervention with Pravastatin in Ischemic Disease; CARE - The Cholesterol and Recurrent Events Trial, were able to show that drug therapy for prevention of arteriosclerotic vascular diseases is effective even where the lipid blood levels prior to treatment are only slightly increased or even within the normal range. Long-term success of bypass operations is often restricted by atherosclerosis in the bypasses. The progression of athero¬sclerosis can be reduced by consistent lowering of the blood LDL level. It was possible to show that post-operative treatment with lovastatin keeps bypasses open longer and thereby leads to an improved prognosis of bypass operations. Lipid-lowering medicaments can be classified into substances lowering the triglyceride as well as the cholesterol blood levels, and substances which first of all lower the cholesterol blood level. Among the substances belonging to the first substance group are, for example, aryloxyalcane carboxylic acids, e.g. clofibrate, etofibrate, etofylline clofibrate, bezafibrate, fenofibrate, gemfibrozil, nicotinic acid, nicotinyl alcohol and acipimox. Examples for substances influencing mainly the cholesterol blood level are: anion exchange resins such as colestyramine or colestipol; inhibitors of hydroxymethylglutaryl-CoA reductase, HMG-CoA reductase, inhibitors such as lovastatin, simvastatin, mevastatin, pravastatin, fluvastatin, cerivastatin or atorvastatin, probucol, dextrothyroxine and sitosterol. These substances inhibit hydroxymethylglutaryl-CoA reductase - an early stage of cholesterol synthesis. These inhibitors are the most potent substances for treatment of hypercholesterolemia. Commercial administration forms are currently tablets and capsules with a dosage of 5 to 40 mg. The active substances are administered either in their active form, i.e. as the sodium salt of the hydroxy acid (e.g. pravastatin) or as a prodrug, i.e in their lactone form (e.g. lovastatin). After oral treatment, however, only about 30% of the dose applied are absorbed from the gastrointestinal tract. The active substance portion absorbed is then subject to a considerable first pass effect. Absolute bioavailability ranges from 10 to 30%. The average elimination half-time of the active substance form lies within the range of 1 2 hours; exception: atorvastatin with 14 h. Preparations containing HMG-CoA reductase inhibitors and intended for topical application are prior art. Substances of this class can be employed for the therapy of skin diseases. Here, the HMG-CoA reductase inhibitors serve as anti-psoriatics, for example as anti-aging agents for the skin, or for the treatment of acne. The active compound here is incorporated in a classical administration form such as gel, ointment or cream. A non-therapeutic use consists in employing the substance class described herein for raising the percutaneous absorption rate of substances which can normally only insufficiently be absorbed. Descriptions of systems considering a transdermal application of this class of substances are more scarce. US 5,629,014 describes a system suitable, inter alia, for controlled release of lovastatin to the skin or mucous membranes. The system comprises a microcellular polyester or polyether foam serving as active substance reservoir. Since this foam is not adhesive itself, an additional means is necessary for fixing the foam on the surface of application. This foam-like system turns out to be relatively thick and inflexible. Application by the patient is thus not very practicable since the system, being exposed because of its height, is prone to being removed unintentionally and does not yield to movements of the body. A transdermal application of lipid-lowering agents, indicated as the overall group, is mentioned in DE 36 34 016 C2. This system is characterized in that the component responsible for adhesion is present separately from the non-adhesive active substance reservoir. Starting from the above-mentioned prior art, the invention has the object of providing a preparation containing at least one active substance which has an influence on the lipid blood levels of an organism, by which preparation it is possible to achieve a release of the therapeutically active substance which takes place at a constantly low rate over prolonged periods of time and which can be accurately dosed, and which preparation, in particular, guarantees absolute bioavailability of the substance while affording a user-friendly mode of application, and with the said preparation serving as active substance reservoir. To achieve this object, in a preparation of the kind as mentioned in the introductory portion of Claim 1, it is proposed by the invention that the said preparation be present in the form of a transdermal therapeutic patch (TTS) containing the active Substance in a self-adhesive matrix layer which on the side facing away from the skin can be covered-with an active substance-impermeable backing layer. The transdermal therapeutic application system according to the invention ensures an extremely efficient drug therapy wherein the release of the active substance remains virtually constant over a long period and can be accurately controlled, with the absolute bioavailability of the substance being significantly increased. Further embodiments are provided according to the subclaims. In particular, the self-adhesive mass is characterized in that it contains at least one hydroxymethylglutaryl-CoA reductase-inhibiting active substance, and that it contains structural elements of a beta-hydroxycarboxylic acid (I) or a tetrahydro-4-hydroxy-6-oxo-2H-pyrans (ii). The active substance may be present in the form of its salt or in the form of an ester. For the inventive patch a self-adhesive mass based on polyacrylate, silicone, ethylene vinyl acetate, rubber, rubber-like synthetic homo-, co- or block polymers, or of a hot-melt adhesive or the like may be used. Masses based on polyacrylate are characterized in that acrylic acid and/or alkyl acrylic acid, especially methacrylic acid or its derivatives, especially the alkyl esters, are used-for their production. Among the alkyl esters of acrylic acid and/or methacrylic acid those are preferred which have 1 to 18 carbon atoms in the alkyl residue, especially methyl, ethyl, n-butyl, isobutyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, isooctyl, 2-ethylhexyl, n-decyl, isodecyl, n-dodecyl and stearyl acrylate or methacar/late. Apart from these, further comonomers can participate in the structure of the polymer/copolymer. Examples are acrylic and/or methacrylic amide, hydroxyalkyl esters and polyalkylene glycol esters of acrylic and/or methacrylic acid, nitrogen-containing monomers of acrylic and/or methacrylic acid or the salts thereof, ethylene, vinyl acetate, vinyl propionate, vinyl butyrate, vinylpyrrolidone, vinyl chloride, vinyl toluene, acrylonitril or styrene. Masses based on silicone are characterized in that they have a large free volume, a low gas transition temperature, high flexibility and high gas permeability, are biocompatible, have a low surface tension and good wettability, are thermostable as well as chemically inert, and have good tackiness, adhesion and cohesion. Typically, silicone-based masses contain a polycondensate, comprising a low-viscous polydimethyl siloxane and a silicate resin, characterized by a three-dimensional network. To increase the so-called amine resistance, it is possible for the terminal hydroxyl group of the polydimethyl siloxane to be condensed with trimethyl siloxane. Examples for rubber-like synthetic homo-, co- or block polymers which may be employed according to the invention are polyisobutylene, polyisoprene, polystyrene, styrene-butadiene-styrene copolymers, styrene-isoprene-styrene copolymers, styrene-ethylene/propylene-styrene copolymers, styrene-ethylene/butylene-styrene copolymers, polyvinyl ethers, polyurethane, polybutadiene, styrene-butadiene copolymers, styrene-isoprne copolymers or.styrene-isoprene-butylene block copolymers. Furthermore, a backing layer may be contained which is connected with the self-adhesive mass. This backing layer may be impermeable to the active substance and have occlusive character. Any materials may be used which are employed in common preparations. Examples for such materials are cellulose acetate, ethyl cellulose, polyethylene tereph-thalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene, polyamide or aluminium. The composition may further comprise: tackifiers, penetration enhancers, agents for alleviating skin irritations, metal ions such as aluminium or titanium, and for increasing cohesion: plasticizers, paraffins, cyclic hydrocarbons or vegetable oils. As agents increasing tack, colophony resins, polyterpene resins, petroleum resins, coumarone-indene resins, terpene phenol resins, hydrocarbon resins or liquid polybutene resins may be used. Examples for agents enhancing the penetration of the active substance are: pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glykol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl ethers, propylene glycol fatty acid derivatives, glycerol fatty acid esters, polysorbates, poloxamers, dialkyl sulfoxides, urea and urea derivatives, glycerol, native oils, laurocaprames, phospholipides, amides, amino acids, N,N-dimethyl formamide, N-methyl formamide, acetonides, calcium thioglycolate, propylene glycol, polyethylene glycol,. alkyl sulfate, Sodium lauryl sulfate, tetrahydrofurfuryl alcohol, N,N-diethyl-m-toluamide, anticholinergics, macrocyclic compounds or polar solvents such as isosorbitol and panthenol. The preparation according to the present invention may also contain agents for alleviating skin irritations, such as bisabolol, chamomile oil, allantoin, glycerol or dipanthenol The invention will be explained in the following by means of examples: EXAMPLE 1 626 g of a solution of a self-adhesive polymer based on silicone (e.g. BIO PSA X7-4301, 70%-wt. in n-heptane) and 48 g of 2-pyrrolidone (with lovastatin) were mixed and, with the aid of a doctor knife, applied as a film of 600 µm thickness onto a fluoropolymerized polyester film (e.g. Scotchpak® 1022). The moist film was dried for 30 minutes at 50 *C and subsequently laminated with a polyester film (e.g. Hostaphan RN 15). The weight per unit area of an adhesive film prepared in this manner was about 300 g/m. From the laminate, TTSs of the desired size were punched out by means of a suitable punch, and in vitro permeation through isolated cow udder skin was measured. The flow rate was on average 0.3 µg/cm/h over a period of 72 hours. EXAMPLE 2 459.2 g of a solution of a self-adhesive polymer based on silicone (e.g. BIO PSA X7-4301, 709s-wt. in n-heptane) and 6.6 g of ethyl oleate (with lovastatin) were mixed and, with the aid of a doctor knife, applied as a film of 600 µm thickness onto a fluoropolymerized polyester film (e.g. Scotchpak® 1022). The moist film was dried for 30 minutes at 50 'C and subsequently laminated with a polyester film (e.g. Hostaphan RN 15). The weight per unit area of an adhesive film prepared in this manner was about 300 g/m. From the laminate, TTSs of the desired size were punched out by means of a suitable punch, and in vitro permeation through isolated cow udder skin was measured. Over a period of 72 hours the incorporated active substance diffused almost quantitatively through the cow udder skin. EXAMPLE ,3 85.34 g of a self-adhesive, carboxyl group-containing polyacrylate (e.g. Durotak 387-2052, 48.1%-wt. in a mixture of ethyl acetate, n-heptane, 2-propanol and ethanol), 85.34 g of a hydrophile acrylate adhesive mixture (e.g. Plastoid E 35 H, 60%-wt. in ethyl acetate), 12.5 g ethyl acetate as well as 8.4 g of 2-pyrrolidone (with lovastatin) were mixed and, with the aid of a doctor knife, applied as a film of 400 µm thickness to a siliconized polyester film (e.g. Hostaphan® RN100). The moist film was dried for 30 minutes at 50 °C and subsequently laminated with a polyester film (e.g. Hostaphan RN 15). The weight per unit area of an adhesive film prepared in this manner was about 130 g/m. WE CLAIM: A preparation in the form of a transdermal therapeutic system containing at least one active substance and at least one akin penetration enhancer in a self-adhesive matrix layer, which is covered at the side facing away from the skin with an active substance - impermeable backing layer, characterized in that - said active substance is selected from the group of hydroxymethylglutaryl-CoA reductase inhibitors, the self adhesive matrix layer is a mass based on polyacrylate, silicone, polyisobutylene, polyisoprene, polystyrene, ethylene vinyl acetate, rubber or similar synthetic homo-, co- or block polymers, and that said skin penetration enhancer is selected from the group consisting of pyrrolidone derivatives, fatty acids, fatty alcohols, fatty acid esters, fatty ethers, paraffin derivatives, terpenes, ethylene glycol monoalkyl ethers, polyoxyethylene alkyl ethers, polyoxyethylene aryl ethers, polyoxyethylene alkyl esters, polyoxypropylene alkyl, ethers, propylene glycol fatty acid derivatives, glycerol fatty acid esters, polysorbates, poloxamers, dialkyl sulfoxides, urea and urea derivatives, glycerol, native oils, laurocaprames, phospholipids, amides, amino acids, N,N-dimethyl formamide, N-methyl formamide, acetonides, calcium thioglycolate, propylene glycol, poly ethylene glycol, alkyl sulfate, sodium lauryl sulfate, tetrahydrofurfuryl alcohol, macrocyclic compounds and panthenol. The preparation as claimed in claim 1, wherein the hydroxymethylglutaryl-CoA reductase inhibitor contains the structural features of a beta-hydroxcarboxylic acid or a tetrahydro-4-hydroxy-6-oxo-2H-pyrans in its molecule. 3. The preparation as claimed in any one of claims 1 to 2, wherein the hydroxymethylglutaryl-CoA reductase inhibitor is present in the form of a salt or in the form of an ester. 4. The preparation as claimed in any one of claims 1 to 3, wherein the hydroxymethylglutaryl-CoA reductase inhibitor is lovastatin, simvastatin, mevastatin, pravastatin, fluvastatin, atorvastatin, eptastatin or cerivastatin. 5. The preparation as claimed in any one of claims 1 to 4, wherein the self- adhesive mass is a hot-melt adhesive. 6. The preparation as claimed in any one of claims 1 to 5, wherein the self- adhesive mass wherein it contains a tackifier. 7. The preparation as claimed in any one of claims 1 to 6, wherein the self-adhesive mass wherein it contains at least one plasticizer. 8. The preparation as claimed in any one of claims 1 to 7, wherein the self-adhesive mass wherein it contains at least one auxiliary substance selected from the group of bisabolol, chamomile, oil, allantoin, glycerol or dipanthenol. 9. The preparation as claimed in any one of claims 1 to 8, wherein the self- adhesive mass wherein it contains at least one substance selected from the group of cyclic hydrocarbons and vegetable oils.

Documents:

in-pct-2001-0014-che abstract-duplicate.pdf

in-pct-2001-0014-che abstract.pdf

in-pct-2001-0014-che claims-duplicate.pdf

in-pct-2001-0014-che claims.pdf

in-pct-2001-0014-che correspondence-others.pdf

in-pct-2001-0014-che correspondence-po.pdf

in-pct-2001-0014-che description(complete)-duplicate.pdf

in-pct-2001-0014-che description(complete).pdf

in-pct-2001-0014-che form-1.pdf

in-pct-2001-0014-che form-19.pdf

in-pct-2001-0014-che form-26.pdf

in-pct-2001-0014-che form-3.pdf

in-pct-2001-0014-che form-5.pdf

in-pct-2001-0014-che pct.pdf

in-pct-2001-0014-che petition.pdf