AU770573B2 - Transdermal plaster containing at least one active ingredient which influences blood serum lipid levels - Google Patents

Description

Composition containing at least one active substance having an influence on the levels of lipids in the blood 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 hydroxymethylglutaryl-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 <30% of the total number of calories, a sufficient dietary fibre intake, and a reduced cholesterol intake, especially <300 mg per.day, must be ensured. Furthermore it is advisable to increase the intake of unsaturated above all monounsaturated fatty acids, since these improve the metabolisation of lipoproteins.

If by dietary measures alone it is not possible to achieve a sufficient normalisation of the lipid blood level and if this means a higher risk of atherosclerosis, lipid-lowering medicaments are indicated in addition. By treatment with lipid-lowering medicaments a marked reduction of these diseases can be achieved. Current studies, e.g. LCAS Lipoprotein and Coronary Arterosclerosis Study; LIPID Longterm 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 atherosclerosis 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 pravastatin) or as a prodrug, i.e in their lactone form 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 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 antipsoriatics, 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 userfriendly 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 or a tetrahydro-4-hydroxy-6-oxo-2H-pyrans The active substance may be present in the form of its salt or in the form of an ester.

HO O HO 0

H(II)

OH

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 methacrylate. 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, styrenebutadiene-styrene copolymers, styrene-isoprene-styrene copolymers, styrene-ethylene/propylene-styrene copolymers, styrene-ethylene/butylene-styrene copolymers, polyvinyl ethers, polyurethane, polybutadiene, styrene-butadiene copolymers, styrene-isoprene copolymers or styrene-isoprenebutylene 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 terephthalate, 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-mtoluamide, 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 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 um thickness onto a fluoropolymerized polyester film (e.g.

Scotchpak® 1022). The moist film was dried for 30 minutes at oC 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 2 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 pg/cm 2 /h over a period of 72 hours.

EXAMPLE 2 459.2 g of a solution of a self-adhesive polymer based on silicone BIO PSA X7-4301, 70%-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 pmu thickness onto a fluoropolymerized polyester film (e.g.

Scotchpak® 1022). The moist film was dried for 30 minutes at OC 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 2 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 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 um thickness to a siliconized polyester film Hostaphan® RN100). The moist film was dried for minutes at 50 oC and subsequently laminated with a polyester film Hostaphan RN 15). The weight per unit area of an adhesive film prepared in this manner was about 130 g/m 2

Claims (13)

1. A preparation in the form of a transdermal therapeutic patch for application to the skin of a patient, containing in a self-adhesive matrix layer which can be covered at the side facing away from the skin with an active substance-impermeable backing layer at least one active substance having an influence on the lipid blood levels of an organism and at least one auxiliary substance enhancing the permeation of the active substance through the skin, characterized in that said active substance is selected from the group of active substances inhibiting hydroxymethylglutaryl-CoA reductase; the self-adhesive matrix layer is a mass based on silicone; and said auxiliary substance 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, Spropylene glycol fatty acid derivatives, glycerol fatty acid esters, polysorbates, poloxamers, dialkyl sulfoxides, urea and urea derivatives, glycerol, native oils, laurocaprames, phospholipids, amides, amino acides, NIN-dimethyl formamide, N-methyl formamide, acetonides, calcium thioglycolate, propylene glycol, polyethylene glycol, alkyl sulfate, sodium lauryl sulfate, tetrahydrofurfuryl alcohol, macrocyclic compounds or polar solvents such as panthenol.

2. A preparation according to claim 1, characterised in that the active substance inhibiting hydroxymethylglutaryl-CoA reductase contains the structural features of a beta- hydroxcarboxylic acid or of a tetrahydro-4-hydroxy-6-oxo-2h-pyrans in its molecule.

3. A preparation according to claim 1 or claim 2, characterized in that the active substance inhibiting hydroxymethylglutaryl-CoA reductase is present in the form of a salt or in the form of an ester.

4. A preparation according to any one of claims 1 to 3, characterised in that the active substance inhibiting hydroxymethylglutaryl-CoA is lovastatin, simvastatin, mevastatin, pravastatin, fluvastatin, atorvastatin, eptastatin or cerivastatin. COMS ID No: SMBI-00562043 Received by IP Australia: Time 15:44 Date 2004-01-08 08/01 2004 15:-40 FAX +61 2 94080101HOJINN&Mc NE j00/0 HODGKINSON McINHES IA006/007 06 5* 0 5 5 0 0

5@ PI206SAUO4 A preparation according to any one of the preceding claims, characterised in that the self-adhesive layer of the matrix contains at least one homo-, co- or block polymer.

6. A preparation according to any one of the preceding claims, characterised in that the self-adhesive mass is a hot-melt adhesive.

7. A preparation according to any one of the preceding claims, characterised in that the self-adhesive mass contains an auxiliary substance which increases tack.

8. A preparation according to any one of the preceding claims, characterised in that the self-adhesive mass contains at least one plasticizer.

9. A preparation according to any one of the preceding claims, characterised in that the self-adhesive mass contains at least one auxiliary substance alleviating skin irritations,

10. A preparation according to any one of the preceding claims, characterised in that the self-adhesive mass contains at least one substance having an influence on cohesion.

11. The use of a preparation according to any one of the claims 1 to 10 for producing a means for lowering increased plasma lipid levels, especially in the case. of systemic lipid metabolism disturbances, so-called hyperlipoproteinemias. and vascular diseases such as cardiac infarction, as well as in the case of occlusive arterial disease.

12. A preparation according to any one of claims 1 to 10, substantially as hereinibefore described with reference to the Examples, COMS ID Na: SMBI-00562043 Received by IP Australia: Time 15:44 Date 2004-01-08 08/01 2004 15:41 FAX +61 2 94080101 HODGKINSON McINNES 0007/007 P12069AU04 12

13. The use of a preparation according to claim 11, substantially as hereinbefore described with reference to the Examples. Dated this 8 'h day of January 2004 LTS LOHMANN THERAPIE-SYSTEME AG r* *0 *4* oro0 6 C C *ooo HODOKINSON AND McINNES Patent Attorneys for the Applicant COMS ID No: SMBI-00562043 Received by IP Australia: Time 15:44 Date 2004-01-08