Composition containing at least one active substance, affecting the levels of lipids in the blood

 

(57) Abstract:

Proposed: percutaneous therapeutic plaster containing self-adhesive layer of the matrix on the basis of organosilicon or polyacrylate with at least one active ingredient, an inhibitor oxometalates-COA-reductase, with a layer of the matrix is covered with impermeable to the active substance substrate. As inhibitor oxymethylphenyl-COA reductase inhibitor is a substance with structural elements tetrahydro-4-hydroxy-6-oxo-2H-Piran (e.g., lovastatin). The invention provides a slow release of the active substance with an absolute bioavailability. 8 C.p. f-crystals.

The invention relates to a preparation containing at least one active substance, affecting the level of lipid in the blood. This active substance is among the group of active substances involved in the lipid metabolism of the body and used to treat related diseases.

The substances are preferably inhibitors oxymethylphenyl-COA-reductase(HMO-COA-reductase).

Common disorders of lipid metabolism, in particular, the so-called hyperlophus infarction, stroke and obstruction of the lumen of the artery. Because of the increased level of lipid in the blood increased risk of cardiovascular disease affected about 15% of the adult population in the U.S. and Europe. An important starting point for prevention, therapy and treatment of their effects is the reduction of high levels of lipids in plasma. The basis of any treatment of hyperlipoproteinemias is the appropriate diet. We need to ensure the normalization of body weight, diet, relevant content, fat content less than 3% of total consumed calories, adequate fiber intake, which is part of the food, and the reduced consumption of cholesterol, in particular less than 300 mg per day. In addition, it is recommended to increase the intake of unsaturated primarily monounsaturated fatty acids, because they contribute to the change of lipoproteins in the process of metabolism. If the level of lipid in the blood cannot be normalized only by diet and it is associated with an increased risk of atherosclerosis, is additionally shown to lower levels of lipid drugs, with which you can achieve sushestvovanie lipoproteins and atherosclerosis of the coronary arteries; LIPID Long-term effects of pravastatin on coronary heart disease; CARE Test for cholesterol and recurrent been proven that the drug therapy is effective in preventing arteriosclerotic disease even in those cases, when to start treatment, the level of lipid in the blood was only slightly elevated or even were within normal limits.

Long-term positive effect of bypass surgery is often limited by the occurrence of atherosclerosis in the shunt. The development of atherosclerosis can be slowed down due to the constant decrease in the level of blood low-density lipoprotein. It has been proven that postoperative treatment with lovastatin contributes to the fact that the gap in the shunt remains open for a longer time, allowing the prediction of bypass surgery is becoming more favourable.

Reducing the level of lipid drugs can be divided into substances that reduce the level of blood triglycerides and cholesterol and other substances, primarily reducing the level of blood cholesterol. Among the substances belonging to the first group includes, for example, aryloxyalkyl-carbó the new acid, nicotinebuy alcohol and acipimox. Examples of substances, principally affecting the level of cholesterol in the blood, are anion exchange resins such as cholestyramine or colestipol; inhibitors oxymethylphenyl-COA-reductase, HMG-CoA-reductase, such inhibitors as lovastatin, simvastatin, mevastatin, pravastatin, fluvastatin, tseriwastatina or atorvastatin, probucol, dextrothyroxine and sitosterol.

These substances inhibit the action of oxymethylphenyl-COA-reductase at an early stage of cholesterol synthesis. Such inhibitors are the most potent in the treatment of hyperlipoproteinemias.

Currently, they are industrially produced in the form of tablets and capsules from 5 to 40 mg of the Active substances in them is entered in the active form, i.e. in the form of sodium salts of oxyacids (e.g., pravastatin) or in the form of prodrugs (e.g., lovastatin). However, after oral administration of the gastrointestinal tract absorbs only about 30% of the dose. Then the absorbed part of the active substance is highly susceptible to the effect of the first passage. Absolute bioavailability is the limit of the Ah 1-2 hours with the exception of atorvastatin, the half-life is 14 hours.

From techniques known intended for local use preparations containing inhibitors oxymethylphenyl-COA-reductase. Substances of this type can be used in the treatment of skin diseases. In this case, the inhibitors oxymethylphenyl-COA-reductase serve as protivopsoriaticescoe means, for example, as the counter skin aging substances or the treatment of acne. This active compound is administered in the form of a classical dosage forms, such as a gel, ointment or cream. When non-use of substances of the type described is used to increase the rate of percutaneous absorption of substances that are normally penetrate the skin sufficiently.

Less common are the descriptions of the systems that are being considered for percutaneous application of this type of substances. In U.S. patent US 5629014 described system is applicable for the regulated release of lovastatin on the skin or mucous membrane. The system consists of a polyester with microacoustic structure or foamed polyester, which serves as a reservoir for the active substance. Because this foam floor is mo an additional tool. This foam system is relatively thick and inflexible, and therefore its use by the patient is not very practical because of its thickness it can be accidentally deleted and restricts movement.

Percutaneous application of substances that lower the lipid content as a group of substances referred to in German patent DE 3634016 C2. This system differs in that the component responsible for adhesion, is present separately from the tank to the non-adhesive active substance.

Based on the above-mentioned prototype, the aim of the present invention is to provide a preparation containing at least one active substance, affecting the level of lipid in the blood, while using this drug it is possible to achieve release of therapeutically active substance at a constant and sustained over a long period of time, speed and a clearly defined dosage, in particular, to ensure the absolute bioavailability of a substance at the convenience of its use, and to utilize the drug as a reservoir for the active substance.

To achieve this goal, declared the drug type Pomeroy percutaneous therapeutic patch in the adhesive layer of the matrix containing the active substance, the matrix surface not in contact with the skin may be covered with a backing material that is impermeable to the active substance.

Therapeutic system for percutaneous application according to the invention has extremely high efficiency of drug therapy, providing a virtually constant rate of release of the active substance over a long period of time and the ability to accurately manage, as well as a significant increase in absolute bioavailability of the substance.

Additional options for implementation are set out in accordance with the dependent claims. In particular, self-adhesive mass is different in that it contains at least one active substance, the vast activity oxymethylphenyl-Co-a-reductase. and the fact that it contains structural elements of beta-hydroxycarboxylic acid (I) or tetrahydro-4-hydroxy-6-oxo-2H-Neronov (II). The active substance may be present in the form of its salt or a complex ester.

In the patch according to the invention can be used self-adhesive mass based on polyacrylate, Krasnopyorov or melt the adhesive substance or the like.

Weight based on the polyacrylate differ in that for them making use of acrylic and/or alkylacrylate acid, especially methacrylic acid or its derivatives, in particular, complex alkalemia esters. Preferred complex alkylamino esters of acrylic and/or methacrylic acid are esters with 1 to 18 carbon atoms in the alkyl residue, in particular methyl, ethyl, n-butyl, isobutyl, pentyl, 2-ethylbutyl, n-hexyl, heptyl, n-octyl, isooctyl, 2-ethylhexyl, n-decyl, Isodecyl, n-dodecyl and stearylamine or methacrylate. In addition to the above, in the structure of the polymer/copolymer may include additional comonomers. Their examples are acrylic and/or methacrylic amide, complex alkalemia esters of oxyacids and complex polyalkylene glycol esters of acrylic and/or methacrylic acid, nitrogen-containing monomers of acrylic and/or methacrylic acid or their salts, ethylene, vinyl acetate, finalproject, vinylboronate, vinyl pyrrolidone, vinyl chloride, vinyltoluene, Acrylonitrile or styrene.

Mass on the basis of organosilicon compounds have a larger free volume, low temperature phase transition of liquid-gas, high flexibility and high gas permeability, Java chemically inert and have good adhesion, adhesion and cohesion. Usually mass on the basis of organosilicon compounds contain polycondensate consisting of polydimethylsiloxane and silicone resin with a low coefficient of viscosity and the three-dimensional structure. To improve the so-called aminoethanol terminal hydroxyl group of the polydimethylsiloxane can be sealed with trimethylsiloxy.

Examples kauchukopodobnoe synthetic Homo-, co - or block polymers which can be used according to the invention are polyisobutylene, polyisoprene, polystyrene, copolymers of butadiene-styrene and styrene, copolymers of isoprene-styrene and styrene, copolymers of ethylene and styrene/propylene and styrene, copolymers of ethylene and styrene/butylene and styrene, polymers of simple vinyl ester, polyurethane, polybutadiene, copolymers of butadiene and styrene, copolymers of isoprene and styrene or block copolymers of styrene, isoprene and butylene.

In addition, there may be provided a substrate connected with self-adhesive mass. Such a substrate may be impermeable to the active substance and possess obstructive properties. This can be any of the materials used in conventional drugs. Example the materials of vinyl acetate and vinyl chloride, nylon, copolymer of ethylene and vinyl acetate, plasticized polyvinyl chloride, polyurethane, grades, polypropylene, polyethylene, polyamide or aluminium.

The composition may further include substances that enhance adhesion, permeation enhancers, substances, softening skin irritation, ions of metals such as aluminum or titanium, and to improve the adhesion - plasticizers, waxes, cyclic hydrocarbons or vegetable oil.

As substances that increase the stickiness, can be used kanifolnye resin, polyterpene resin, coumaroneindene resin, decentralitralisation resin, hydrocarbon resin or liquid polybutene resin.

Examples of substances which improve the absorption of the active substance, are derivatives of pyrrolidone, fatty acids, fatty alcohols, esters of fatty alcohols, simple fatty esters, derivatives of paraffin, terpenes, simple monoalkyl ethers of ethylene glycol, simple alkalemia esters of polyoxyethylene, simple akrilovye esters of polyoxyethylene, complex alkalemia esters of polyoxyethylene, simple alkalemia esters of polyoxypropylene, derivatives of fatty acids propylene glycol, esters of fatty sour is in, natural oils, laurocapram, phospholipids, amides, amino acids, N,N-dimethylformamide, N-methylformamide, acetonide, thioglycollate calcium, propylene glycol, polyethylene glycol, alkylsulfate, nutriceuticals, tetrahydrofurfuryl alcohol, N,N-diethyl-m-toluamide, anticholinergics, macrocyclic compounds, polar solvents, such as isosorbide or panthenol.

The preparation according to the present invention may also contain substances that ease skin irritation, such as bisabolol, chamomile oil, allantoin, glycerin or dipentene.

Hereinafter the invention will be illustrated with examples.

Example 1

Were mixed 626 g of the solution of adhesive polymer based on organosilicon compounds (for example, BIO-PSA X7-4301, 70 wt.% in n-heptane) and 48 g of 2-pyrrolidone (lovastatin), using plates of the mixture in the form of a film thickness of 600 μm was put on terpolymerization polyester film (for example, Scotchpak® 1022). The wet film was dried for 30 min at 50C and then a thin layer was applied onto a polyester film (for example, Hostaphan RN 15). Unit weight per unit area of the adhesive film obtained in this way was about 300 anzania in vitro through the skin of the cow udder. The average rate of release was 0.3 µg/cm2/h for a period of 72 hours

Example 2.

Were mixed 459,2 g of the solution of adhesive polymer to 70 wt.% the basis of organosilicon compounds (for example, BIO-PSA X7-4301, % n-heptane) and 6.6 g of ethyloleate (lovastatin), using plates of the mixture in the form of a film thickness of 600 μm was put on terpolymerization polyester film (for example, Scotchpak®1022). The wet film was dried for 30 minutes at 50C and then a thin layer was applied onto a polyester film (for example, Hostaphan RN 15). Unit weight per unit area of the adhesive film obtained in this way amounted to about 300 g/m2. Laminate using an appropriate punch cut out what you want and measured their in vitro permeation through the skin of the cow udder. Over a period of 72 h entered active substances almost completely penetrated through the skin cow bimini.

Example 3

Were mixed 85,34 g self-adhesive polyacrylate (e.g., Durotak 387-2052, 48,1 wt.% in a mixture of ethyl acetate, n-heptane, 2-propanol and ethanol) containing a carboxyl group, 85,34 g hydrophilic adhesive mixture of acrylate-based (for example, Plastoid E 35 N, 60 wt.% in ethyl acetate), 12.5 g of etelaat the siliconized polyester film (for example, Hostaphan ® RN 100). The wet film was dried for 30 min at 50C and then a thin layer was applied onto a polyester film (for example, Hostaphan RN 15). Unit weight per unit area of the adhesive film obtained in this way was about 130 g/m2.

1. Percutaneous therapeutic plaster, self-adhesive layer of the matrix which contains at least one active substance, with the specified layer of the matrix is covered by the substrate, is not permeable to the active substance, characterized in that the active substance matrix contains the inhibitor oxymethylphenyl-COA-reductase, and the adhesive layer is a polymer-based polyacrylate, silicone, polyisobutylene, polyisoprene, polystyrene, ethylene vinyl acetate, rubber, kauchukopodobnoe synthetic Homo-, co - or blakolmer or fusible adhesive.

2. Percutaneous therapeutic patch under item 1, characterized in that the molecule inhibitor oxymethylphenyl-COA-reductase contain structural elements of the beta-hydroxy carboxylic acid or tetrahydro-4-hydroxy-6-oxo-2H-pyrans.

3. Percutaneous therapeutic patch under item 1 or 2, characterized in that the inhibitor oxymethylphenyl is one or more paragraphs.1-3, characterized in that the inhibitor oxymethylphenyl-COA reductase inhibitor is a lovastatin, simvastatin, mevastatin, pravastatin, fluvastatin, atorvastatin, attestation or tseriwastatina.

5. Percutaneous therapeutic patch for one or more paragraphs.1-4, characterized in that the adhesive layer contains at least one excipient that enhances the permeation of the active substance through the skin.

6. Percutaneous therapeutic patch for one or more paragraphs.1-5, characterized in that the adhesive layer contains an excipient that increases the stickiness.

7. Percutaneous therapeutic patch for one or more paragraphs.1-6, characterized in that the adhesive layer contains at least one plasticizer.

8. Percutaneous therapeutic patch for one or more paragraphs.1-7, characterized in that the adhesive mass contains at least one excipient, ease skin irritation.

9. Percutaneous therapeutic patch for one or more paragraphs.1-8, characterized in that the adhesive mass contains at least one substance, affecting grip.

 

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