KR20010053314A - Therapeutic system with addition of nacreous pigment - Google Patents

Abstract

A pharmaceutical release system for the continuous release of the active ingredient to the skin and / or mucous membranes contains pearl pigments in addition to the active ingredient.

Description

Pharmaceutical release system with pearl pigments {THERAPEUTIC SYSTEM WITH ADDITION OF NACREOUS PIGMENT}

Systems for controlling the release of active ingredients into the skin of humans or animals are particularly well known as so-called transdermal absorption therapy systems (TTS) or transdermal absorption transport systems (TDS). Depending on the structure and nature of the active ingredient release, there are differences between the pouch or storage system and the matrix system. The former system consists of a flat pouch or sachet containing the active ingredient, one side of the pouch or sachet being impermeable and the other side being a control membrane coated with an adhesive to adhere to the skin. . Due to this complex structure, it is very uneconomical to manufacture individual parts individually and then assemble them into a system. In addition, the required thickness of the system adversely affects the adhesion. In such pouch systems there is a risk of sudden complete release of the active ingredient into the skin as a result of physical breakdown of the membrane and / or pouch, so-called drug dumping.

The matrix system is usually composed of a backing layer which is separated from the skin and does not transmit the active ingredient, and an adhesive layer in which the active ingredient is dispersed. In order to protect the said adhesive layer, the adhesive protective film which removes before use is provided. Pressure-sensitive adhesive matrix layers are pressure-sensitive adhesive systems of acrylates, polyisobutylenes, resins, styrene-hydrocarbon copolymers or silicone-based pressure sensitive adhesives, which are well known to those skilled in the art. It is a system. Low molecular weight components such as plasticizers, solubilizers and permeation enhancers may be added to the system.

The pressure-sensitive adhesive may be a solvent adhesive modified by adding a crosslinking agent to an adhesive solution formed by polymerization in a suitable solvent. By adding one active ingredient or a combination of other active ingredients, a pressure sensitive adhesive solution containing the active ingredient can be prepared that can be used to prepare a transdermal absorption therapy system.

Dispersible adhesives are also suitable as the pressure-sensitive adhesive. To prepare this dispersible adhesive, monomers must be polymerized in aqueous solution.

The pressure-sensitive adhesive may be a hot melt adhesive. They are prepared by bulk polymerization with an apparatus such as an extruder, or are obtained by evaporating the solvent from a solvent-based lubricant. The solvent-free pressure-sensitive adhesive thus produced may be processed from the melt after adding the active ingredient or other ingredients. Thus, by adding an active ingredient for release and combining a water-soluble or at least water-expandable polymer with a water-soluble and meltable adhesive resin, a pressure-sensitive hot melt adhesive can be prepared that meets the requirements; The water-soluble and tacky components, which have low self-viscosity and form strings, when combined with hydrophilic polymers, form an excellent adhesive layer having a bonding strength that is nearly comparable to conventional adhesives obtained from solvent or dispersion forms. This method is cost effective because it can be made faster than when coating with a solvent pressure sensitive adhesive or a dispersion pressure sensitive adhesive.

The pressure-sensitive adhesive contains 0.5 to 50% by weight, preferably 1 to 20% by weight of the adhesive resin. These resins are well known to those skilled in the art and are also described in US Pat. No. 5,126,144.

The pressure-sensitive adhesive containing the active ingredient may include at least one auxiliary agent selected from the group consisting of anti-aging agents, plasticizers, antioxidants and absorption accelerators. Suitable plasticizers for use are well known to those skilled in the art and are also described in DE37 43 946.

According to patent document information, the pressure-sensitive adhesive agent (matrix) containing the above-mentioned active ingredient may contain an insoluble inorganic component which acts as a bonding strength enhancer. For example, US 5,686,099 describes the addition of hydrated aluminum silicates, kaolinite, montmorillonite, attapulgite, illite, bentonite and halosite. JP9099050 describes magnesium silicate and JP 7196481 describes the effects of kaolin and titanium dioxide type inorganic pigments. WO 95/05138 describes the addition of silica gels, calcium silicates and magnesium silicates.

The pressure-sensitive adhesive containing the active ingredient may be a single layer or may be a plurality of layers. The thickness of the pressure-sensitive adhesive containing the active ingredient is 0.02 to 1.0 mm. For example, EP0 275 716 discloses a two-layer transdermal absorption system for the simultaneous administration of one or more estrogens in solution or undispersed state in the polymer layer. In this case, the adhesive layer contains not only the active ingredient but also a component that promotes transdermal absorption administration. The polymer layer and the adhesive layer may be made of polyacrylate, silicone or polyisobutylene.

The materials of the impermeable thick layer, the peelable protective layer and the peelable inner layer are well known to those skilled in the art (for example DE 38 43 239).

The treatment system is not limited to TTS and includes, for example, an active ingredient containing polymer capable of releasing the active ingredient to the environment.

In the present invention, "active ingredient" refers to chemical elements, organic and inorganic compounds capable of exerting the desired effect by moving away from the components of the integrated body containing them. Among the fields of use of the present invention, application to human and livestock drugs, cosmetics and plants is particularly important.

The released active ingredient is preferably used for the treatment of local skin diseases, endothelial and percutaneous treatment of skin diseases, wound treatment, or skin protection in the manufacture of cosmetics. In the treatment of local skin diseases, local anesthetics, antibiotics, antiseptics, antifungals, antihistamines and anti-inflammatory agents, keratinicides and caustics, antiviral agents, anti-ohms, steroids can be used, and acne, psoriasis, light skin disease or Various ingredients for the precancer treatment are also used. Examples of active ingredients administered endothelially include steroidal and nonsteroidal antirheumatic agents, local anesthetics, circulatory accelerators, or vasoprotectants and vasoconstrictors for the treatment of vascular diseases, and also processes in subcutaneous fat tissue. The active ingredient which affects is also mentioned. Examples of active ingredients administered percutaneously include analgesics, antiarrhythmics, anesthetics and their antagonists, neurosuppressants, hormones and hormone substituents, antidepressants, sedatives, hypnotics, stimulants, antipachysons, ganglion blocking agents, sympathomimetic agents, alpha- Sympathetic nerve inhibitors, beta-sympathetic nerve inhibitors, anti-sympathetic nerve tonics, anti-asthmatic agents, antiemetic drugs, appetite suppressants, diuretics or active ingredients for weight loss. Preferred active ingredients include estradiol, estriol, progesterone, noestysterone, noethine drone, levonorgestrel and derivatives thereof, and ethinodiodiacetate, norgestamate, gestaden, desogestrel, deme Steroids such as guestrone, promegestrone, testosterone, hydrocortisone and derivatives thereof; Nitro compounds such as amyl nitrate, nitroglycerin and isosorbide nitrate; Amine compounds such as nicotine, chlorpheniramine, terpenadine, and triproridine; Oxychem derivatives such as pyroxycam; Mucopolysaccharides such as thiomucase; Opiates such as muprenorphine, fentanyl and salts, derivatives or analogs thereof, naloxone, codeine, dihydroergotamine, regergic acid derivatives, pizotyrin, salbutamol and terbutarin; Prostagladins such as PGA, PGB, PGE and PGF series, omeprazole and imipramine such as microprostol and enprosteel; Benzamide such as metoclopramine and scopolamine; Peptides and growth elements such as EGF, TGF, PDGF; Somatostatin; Clonidine; Dihydropyridine, such as nifedipine, nirenedipine, verapamil, diltiazem, ephedrine, propanolol, metoprolol, and spironolactone; And thiazides such as hydrochlorothiazine and flunarizine. In the treatment of wounds, for example, active hemostatic components such as enzymes, preservatives, anti-infective agents and antibiotics and wound toxic components, analgesics and active anesthetic components, and wound healing, promote granulation, blood vessels, Active substances are used that induce production or promote epithelialization.

The pressure-sensitive adhesive layer containing the pharmaceutically active ingredient or other active ingredient is formed by solution coating or dispersion coating, and then evaporating the solvent and the dispersion medium. If the amount of active ingredient in the patch is greater than the amount corresponding to the adsorption capacity of the film forming patch constituents, the active ingredient is very finely and randomly distributed in the adhesive matrix, resulting in rapid recomposition over the service period. It is possible to sufficiently maintain the saturation of the pressure sensitive adhesive and in this way to maintain the level of reduction in the release rate of the active ingredient from the patch as much as possible. Usually, a patch film is prepared by dissolving an adhesive component and an active component together in an organic solvent, spreading this solution on a web having a large surface area, and drying them.

However, it has been discovered that pressure sensitive transdermal absorption therapy systems containing the active ingredient in part or in whole in solution have the potential risk of recrystallization of the active ingredient with time. Once recrystallized, the active ingredient is not released, so the patch can no longer meet the therapeutic requirements. If moisture penetrates into the matrix, recrystallization can be further promoted.

In transdermal absorption systems, the problem of recrystallization of the active ingredient is particularly evident in systems in which the active ingredient contains estradiol, and certain gestagens.

Trials for suitable systems are found in the following patents.

EP0 275 716 describes a transdermal absorption system which simultaneously administers one or more estrogens present in solution or in microdispersion in the polymer layer. Apart from the active ingredient, the adhesive layer contains a component that improves transdermal absorption. The polymer layer and the adhesive layer may contain polyacrylate, silicone or polyisobutylene. However, this document does not show the effect of improving the penetration of the water-expandable polymer or the beneficial effect of the component preventing or retarding the recrystallization of the active ingredient.

EP 0186 019 also describes active ingredient patches in which a water expandable polymer is added to the rubber / adhesive resin composition, which patches may release estradiol. However, it has been found that the release of estradiol from these active ingredient patches is too slow to satisfy the therapeutic requirements.

DE-A 20 06 969 describes a patch or adhesive dressing that acts systematically, wherein the adhesive component or adhesive film contains a contraceptive component. Although the adhesive film is made of acrylate in this document, there is no suggestion that the combination of acrylate and water-expandable polymer has an effect of improving the penetration into estradiol. There is also no mention of using ingredients that prevent or delay formation of active ingredients.

DE-A 39 33 640 describes an active ingredient patch containing estrogen, which, in combination with the water-expandable component, is based on homopolymers and / or copolymers of at least one derivative of acrylic acid or methacrylic acid. Doing.

DE 0 364 211 states that copolymers based on vinylpyrrolidone and acrylates are particularly suitable for TTS from which estradiol is released. When 2-ethylhexyl acrylate is used, the fraction of vinylpyrrolidone is 13 to 42% by weight. Since the adhesive prepared according to this composition does not have the adhesive force suitable for a percutaneous absorption use, it is necessary to copolymerize and co-exist hexamethylene glycol dimethacrylate as an adhesive improvement component. As a result, the adhesive was too viscous and produced by a complex polymerization process. In addition, due to the high concentration of N-vinylpyrrolidone, solubility of estradiol is increased, but only about 0.2% can be usefully applied to humans. Unacceptable high concentrations of estradiol are necessary to obtain a transdermal absorption therapy system that produces sufficient blood levels.

DE 39 10 543 describes transdermal absorption systems with increased active ingredient flux. In order to avoid recrystallization, systems have been disclosed in islands in which island-like hydrophilic regions in which the active ingredient is present in supersaturated form.

Many patent documents describe the advantage of adding an inorganic filler to the pressure sensitive adhesive matrix.

For example, US Pat. No. 5,686,099 (Gentile) mentions only about 0.5 to 3% of aluminum silicate, montmorillonite and bentonite in estradiol TTS, and only mentions the bond strength enhancement properties resulting from this addition.

Accordingly, it is an object of the present invention to provide a stable (ie not recrystallized) active ingredient patch in which the release of the active substance does not change even after storage and the concentration of the active substance is satisfactory both economically and pharmacologically.

It has been found that addition of pearl pigments can substantially prevent recrystallization of estradiol and gestagen. They also allow to control the release of the active ingredient from the matrix. This is because they can reliably exert a blocking effect on skin moisture at the time of skin adhesion. Pearl pigments are additives used in partial color cosmetics for lipsticks, compact powders and manicures. These produce known pearlescent or mother of pearl effects. Based on this effect, they may be used in automotive finishes. It is also known to block moisture and oxygen in the sheath of the wire. Mica is also known to non-experts as insulation in the electrical industry. In addition, its fire resistance is very excellent.

The shape of the pearl pigment is a sheet-like structure. This sheet-like length is 5 micrometers-1000 micrometers, and thickness is 0.5 micrometer. Commercially available pearl pigments used in cosmetics have a sheet shape of 5 to 50 µm in length and 0.5 µm in thickness.

When they are used at concentrations of 0.1% to 20% (based on the dry mass) in the active ingredient matrix, they form a layered structure in the matrix, which creates a layered structure for water (moisture) and oxygen. Exhibits a blocking effect. Due to the layered orientation of the pearl pigment in the matrix layer and the large sheet-like volume compared to the matrix layer thickness caused by the coating process, they directly affect the diffusion of the active ingredient dissolved in the matrix. The space between the layered, sheet-like inert particles has a property comparable to thin capillaries. One skilled in the art recognizes that capillary phenomena have a strong effect on the crystallization of supersaturated solutions.

Pearl pigments here include mica pigments which may be coated with TiO ₂ and / or Fe ₂ O ₃ , guanine known as fish silver, and bismuthoxychloride.

The present invention relates to a system for controlling the release of active ingredient into the skin of a human or animal.

1 is a typical structural diagram of a TTS of a thick layer 1 having a pearl pigment present in a matrix 2 on a protective film 3;

Fig. 2 is a structural diagram of a matrix layer made of a laminate comprising an active ingredient matrix layer 2a having no pearl pigment and a pearl pigment containing layer 2b which may or may not contain an active ingredient at the time of manufacture.

The pearl pigment-containing layer 2b functions to control the release of the active ingredient.

The present invention will be described in more detail with reference to the following examples.

7 g of mica (e.g., Timimiron®) was added to the solution with 2 g propanediol, 2 g estradiol, 15 g ethyl acetate and 30 g ethanol with stirring. This dispersion was added to 150 g of acrylate adhesive solution (Durotak®) with stirring to homogenize. Knife-coated this composition on a polyester film having a thickness of 100 μm on one side of which was coated with aluminum and on both sides with a siliconizing agent, and the coated film was dried in a blowing oven for 10 minutes to contain the active substance and further weight per area. The adhesive film which is this 80g / m <2> was manufactured. Subsequently, this laminated body was bonded with the 15-micrometer-thick polyester film (thick layer). Thereafter, they were punched into individual patches having a surface area of 16 cm 2.

It has been found that this patch prevents or retards crystallization, in contrast to patches that have added, for example, bentonite or silica (aerosol) instead of pearl pigments, or have not added fine particles.

Claims (13)

In a pharmaceutical release system for the continuous release of the active ingredient to the skin and / or mucosa, A drug release system, characterized in that the system contains pearl pigments in addition to the active ingredient. The method of claim 1, The drug release system, characterized in that the pearl pigment present in the system has a layered orientation. The method of claim 1, Pharmaceutical release system, characterized in that the concentration of the pearl pigment is 0.1 to 30% by weight, preferably 1 to 10% by weight relative to the polymer matrix. The method according to any one of claims 1 to 3, A pharmaceutical release system, wherein the pearl pigment belongs to the group of mica pigments. The method according to any one of claims 1 to 4, A pharmaceutical release system characterized in that the pearl pigment is a mica pigment coated with titanium oxide and / or iron (III) oxide. The method according to any one of claims 1 to 5, A pharmaceutical release system, characterized in that the pearl pigment is dolomite (chrome mica), biotite, gold mica or lepidolite. The method according to any one of claims 1 to 6, A pharmaceutical release system, wherein the pearl pigment is bismuthoxychloride (BiOCl). The method according to any one of claims 1 to 7, A pharmaceutical release system, wherein the pearl pigment is guanine. The method according to any one of claims 1 to 8, The pearl pigment has a length of 5 µm to 100 µm, preferably 5 µm to 40 µm, particularly preferably 5 µm to 25 µm, and a sheet shape having a thickness of 0.5 µm to 1 µm. The method according to any one of claims 1 to 9, Pharmaceutical release system, characterized in that the system contains estradiol as the active ingredient. The method according to any one of claims 1 to 10, Pharmaceutical release system, characterized in that the system contains a combination of estradiol and estrogen as the active ingredient. The method according to any one of claims 1 to 11, The system is a plurality of layers, and wherein the layer facing the receptor substrate contains a pearl pigment. The method of claim 12, A pharmaceutical release system, wherein the pearl pigment modulates the release of the active ingredient.