JP2003073263A - Cataplasm with improved stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new substrate for cataplasm for the purpose of comprehensively satisfying such requirements as adhesion to the skin and no sense of incompatibility in the adhesion, impermeability of cutaneously valuable substances including a medicament, ODT and stretchability, and to provide a cataplasm for the skin using such a substrate. SOLUTION: This cataplasm for the skin is obtained by coating the substrate with an adhesive including a cutaneously valuable substance and, as necessary, incorporated with a plasticizer, absorption promoter, crosslinking agent, etc.; wherein the substrate consists of a flexible polymer film at least one side of which is provided with a thin film of aluminum, silica, alumina, or the like by a film-forming means such as physical vapor deposition, chemical vapor deposition or electroplating.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a transdermal patch, and more specifically, a pressure-sensitive adhesive layer containing a drug for transdermal absorption has excellent adhesion to the skin, and the drug can be efficiently absorbed in vivo. The present invention relates to a transdermal patch, which can prevent or treat various diseases by transdermal administration.

[0002]

2. Description of the Related Art In recent years, various percutaneous absorption preparations have been proposed for use by sticking to the skin surface as means for administering drugs into the body, and patch preparations containing various drugs in an adhesive have been developed and put on the market. Has reached. These transdermal patch preparations are acrylic or synthetic rubber adhesives mixed with various skin value substances, and the drug can be absorbed into the body continuously through the skin surface just by applying it to the skin surface. And exhibits an excellent pharmacological action.

However, the studies on these patch preparations focus on the composition of the adhesive containing and releasing the drug for percutaneous absorption, the absorption enhancer, and the like. The support also plays an important role from the viewpoints of the stability of the drug in the patch, the adhesion and discomfort to the skin surface, the ODT (occlusive bandage therapy), etc. Is extremely small.

The most important property required for the support is low solubility in the drug. If the drug migrates from the drug-containing adhesive to the support, the long-term stability of the drug is impaired. Polyethylene terephthalate (PET) film is used in most of the percutaneous absorption preparations currently on the market because PET has extremely low solubility for most drugs, low molecular weight additives, and the like. However, PET has the above-mentioned advantages, but on the other hand, it has drawbacks such as (1) the film has a hard feel and a poor sticking feeling, and (2) because it has no elasticity, the adhesion to the skin flexion is poor.

To date, a laminate with a non-woven fabric has been studied in order to alleviate the hard feel of PET. Japanese Patent Application Laid-Open No. 10-167955 discloses a patch support in which a non-woven fabric made of PET fiber and a polyester film are adhered to each other via a PET resin.
A non-woven fabric having a basis weight of / m ² or more is used, and it is devised so as to give a soft feeling to the support and not to cool it.
In Japanese Patent Laid-Open No. 11-20548, a basis weight of 5 to 19 g
/ M ² PET non-woven fabric and 5 to 25 μm thick PET
There has been reported a medical patch, which is characterized in that an adhesive layer for skin application is laminated on the PET film surface of a support having a laminated structure with the film production. However, P
There is no report yet on a support having stretchability which enables good skin contact feeling and adhesion to the skin flexion part by using a film instead of ET.

[0006]

DISCLOSURE OF THE INVENTION The present invention comprehensively provides adhesion and no discomfort to the skin surface, impermeability of valuable skin substances such as drugs, ODT (occlusive bandage therapy) and elasticity. The present invention relates to a novel adhesive patch support, and further to a skin patch using such a support.

[0007]

The present invention provides a thin film forming means such as physical vapor deposition, chemical vapor deposition, and electroplating for forming aluminum,
Silica, alumina, a valuable substance for skin on a support made of a soft polymer film, characterized in that a thin film such as alumina is formed on at least one surface, and, if necessary, a plasticizer,
It is a patch for skin coated with a pressure-sensitive adhesive containing an absorption promoter, a cross-linking agent and the like. By using the support according to the present invention, polyurethane which has been impossible until now,
A soft polymer film such as ethylene vinyl acetate can be used, and there is no need for adhesion or discomfort to the skin surface, impermeability of the drug to the support, ODT (occlusive bandage therapy), elasticity, etc. It becomes possible to manufacture a percutaneous absorption preparation satisfying the quality. Further, by adopting such a support, it is not limited to a patch preparation but is useful for a patch in which the transdermal drug is not contained in the adhesive layer, for example, as a dressing agent.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The thin film forming means used in the present invention is not particularly specified, and the already established technique can be used. For example, physical vapor deposition (PVD) using vacuum vapor deposition, sputtering, etc., chemical vapor deposition (CVD) under normal pressure and reduced pressure, plasma CVD, (PCV)
D), electroplating, etc. Although there are many kinds of substances to be vapor-deposited, aluminum, inorganic oxides and the like are preferable in consideration of reactivity with drugs, toxicity and the like. Among these, silicon oxide is particularly desirable because it can obtain a particularly high barrier.

The vapor deposition method is not particularly specified, but PCVD is particularly desirable. In the PCVD method, since silicon atoms plasmatized on the surface of the base material are vapor-deposited on the film in the form of silicon oxide while being oxidized with oxygen, a dense and extremely small gap is formed, and a higher vapor deposition layer is formed with the same film thickness.
In addition, PCVD enables vapor deposition at a lower temperature than physical vapor deposition, and causes less damage to the base film. In the present invention, the vapor-deposited layer formed by the PCVD method can obtain a vapor-deposited film having higher transparency as compared with the conventional physical vapor deposition method. Transparency is also a desirable property as a support for percutaneous absorption preparations. A specific thin film can be formed by the PCVD method by using the following materials and processes. Evaporate silicon chloride, hydride, etc. and oxygen gas,
A raw material gas mixed with an inert gas such as helium and / or argon is introduced into a plasma chemical vapor deposition machine provided with a soft plastic film to form a silicon oxide layer of 50 to 500 angstrom.

The thickness of the thin film produced is preferably in the range of 50 angstroms to 2.0 nanometers. If the thickness is less than 50 angstroms, the rate of pinholes increases, and the valuable substance for skin or the like tends to be transferred to the support. If it is thicker than 2.0 nanometers, the advantage of supporting it is small and there are drawbacks such as prolongation of processing time.

In the skin patch of the present invention, valuable substances for skin contained in the adhesive layer include drugs for percutaneous absorption, raw materials for cosmetics, etc., which may be arbitrarily selected according to the purpose. Steroids such as estradiol, analgesic and anti-inflammatory agents such as ketoprofen, hypnotics, tranquilizers, antihypertensives, antihypertensives, antihypertensive diuretics, antibiotics, anesthetics, antibacterial agents, antifungal agents, vitamin agents. , Coronary vasodilators, antihistamines, antitussives, sex hormones, antidepressants, cerebral circulation improvers, antiemetics, antitumor agents, biopharmaceuticals and other types of drugs, and various vitamins, whitening agents, skin wetting agents, etc. However, a substance that stays on the skin surface, or a transdermally absorbable substance that penetrates subcutaneously or into blood and exerts a local action or a systemic action can be used. Two or more kinds of these valuable substances for skin can be used in combination, if necessary.

The content of these drugs for percutaneous absorption can be appropriately set according to the drug species and the purpose of administration, but it is usually 0.1 to 40% by weight, preferably 1 to 3% by weight in the adhesive.
It is contained in the range of about 0% by weight. If the content is less than 0.1% by weight, it may not be possible to expect a therapeutically or prophylactically effective amount to be released, and if it exceeds 40% by weight, the effect cannot be expected to increase due to an increase in the amount, so economically Is not only disadvantageous, but also tends to have poor adhesion to the skin. In the present invention, the above-mentioned skin valuable substance does not need to be completely dissolved in the pressure-sensitive adhesive, and the drug in the undissolved state may be contained by containing the drug having the solubility or higher in the pressure-sensitive adhesive. Is. In this case, the undissolved drug needs to be uniformly dispersed in the transdermal preparation so that the content does not vary.

As the pressure-sensitive adhesive for forming the pressure-sensitive adhesive layer for sticking to the skin, an acrylic pressure-sensitive adhesive or synthetic rubber pressure-sensitive adhesive which has been conventionally used so as not to cause rash when contacted with the skin surface. Medical adhesives such as (synthetic isoprene rubber, polyisobutylene rubber, styrene / butadiene rubber, styrene / isoprene / styrene rubber, styrene / butadiene / styrene rubber) can be used.

Examples of the acrylic adhesive include (meth)
A polymer obtained by polymerizing an acrylic acid alkyl ester in a proportion of 30% by weight or more is preferable, and one or two or more (meth) acrylic acid alkyl ester and one or two or more copolymerizable monomers 2 to 50% by weight. A copolymer obtained by copolymerizing 100% is used. The copolymerizable monomer has at least one unsaturated double bond involved in the copolymerization reaction in the molecule, and also has a carboxyl group (eg (meth) acrylic acid, maleic acid, maleic anhydride, etc.) or a hydroxyl group. (For example, (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester, etc.), amide group (for example, (meth) acrylamide, etc.), alkoxyl group (for example, (meth) acrylic acid methoxyethyl ester, (meth)) Acrylic acid ethoxyethyl ester) and the like having a functional group in the side chain can be used. Other than these, copolymerizable monomers include, for example, (meth) acrylonitrile, vinyl acetate, N-vinyl-2-pyrrolidone, methylvinylpyrrolidone, and various macromonomers.

These copolymerizable monomers can be copolymerized with one kind or two or more kinds, but the adhesive property is adhesiveness or cohesiveness, and the release property of the drug for transdermal absorption contained in the adhesive layer. In view of the above, at least one of a carboxyl group-containing monomer and a hydroxyl group-containing monomer is copolymerized as an essential component in the range of 0.5 to 20% by weight, preferably 1 to 15% by weight, and if necessary, Other monomers exemplified above,
For example, a vinyl-based monomer such as vinyl acetate or N-vinyl-2-pyrrolidone, a macromonomer of 60% by weight or less,
It is preferable to copolymerize in the range of 50% by weight or less.

Examples of the rubber adhesive include polyisobutylene, butyl rubber, styrene-isoprene block copolymer, and the like. When using these rubber-based pressure-sensitive adhesives, it is preferable to contain a tackifier. The inclusion of tackifier in the rubber-based adhesive not only improves the skin adhesiveness, but also when the transdermal patch containing the drug for transdermal absorption is used, the drug is sustained and effective. Drug release may be achieved. As such a tackifier, specifically, one having a crystalline state at room temperature and a softening point of 50 to 250 ° C. is preferable, and for example, rosin or its derivative, terpene resin, terpene / phenol resin, petroleum resin, Examples thereof include tackifying resins such as alkyl-phenolic resins and xylene-based resins. These resins may be used alone or in combination of two or more in an amount of 30% by weight or less, preferably 5 to 20% by weight.

The support to which the present invention is extremely effective is PE.
It is not a polymer film in which migration of a drug or the like to a support is small even if a vapor-deposited thin film such as T is not formed thereon, but a soft polymer film having high flexibility such as polyurethane or silicon. These soft polymer films have excellent adhesion to the skin, adhesiveness to the flexion, etc., but until now they were not used as a support for percutaneous absorption preparations because they are drugs and low molecular weight additives. , Etc. are generally high in solubility, and therefore drugs, low-molecular-weight additives, etc. migrate from the adhesive to the support, and the stability of the drug over time cannot be maintained. Extremely useful transdermal by preventing migration from adhesives such as drugs and low molecular weight additives to the support while maintaining adhesion to the skin and sticking to the bent part by forming a vapor-deposited thin film on the support. It is possible to provide a support for an absorption preparation.

Examples of soft polymers to which the present invention is effective are rubber-based polymers such as silicone elastomer, polybutadiene and ethylene propylene rubber, olefin-based polymers such as polyethylene and polybutene, ethylene-vinyl acetate, ethylene-acrylic. There are vinyl copolymer polymers such as ethyl acidate, polyurethane, and the like. These soft polymers have a common physicochemical property that they have a glass transition temperature of 30 ° C. or lower and are amorphous polymers.

In general, the above-mentioned soft polymer has a large water vapor permeability, and therefore has a disadvantage as a support from the viewpoint of ODT (occlusive dressing therapy) as compared with PET. By forming a vapor-deposited thin film according to the present invention, not only the permeation of drugs, low-molecular-weight additives, etc. to the support can be prevented but also the water vapor permeability can be markedly reduced. ) The effect can be remarkably increased and the transdermal absorption of the drug can be increased. In the present invention, the thickness of the support is 10 to 200 μm, preferably 20.
The thickness is about 100 μm. If the thickness is less than 10 μm, sufficient mechanical strength cannot be imparted, and if the thickness exceeds 200 μm, the transdermal absorption preparation may be a soft polymer film due to the rigidity of the film itself. The overall softness becomes uncomfortable and the skin feels uncomfortable, or the skin following property during sticking to the skin surface becomes poor.

The low molecular weight additive contained in the pressure-sensitive adhesive layer in the present invention contains at least one organic liquid component selected from the group consisting of fats and oils and fatty acid esters. By including these components, effects such as improvement of skin adhesiveness and skin permeability of the drug for transdermal absorption and reduction of skin irritation can be obtained. As the oils and fats, olive oil, castor oil, squalene, orange oil, mineral oil and the like can be used. As the fatty acid ester, isopropyl myristate, diethyl sebacate, octyl palmitate, ethyl oleate, diisopropyl adipate, ethyl lactate, propylene glycol fatty acid ester, lauryl nicotinate, octyldodecyl myristate, cetyl isooctanoate,
Glyceryl tri-2-ethylhexanoate, neopentyl glycol dioctanoate, octyldodecyl lactate, diisostearyl malate, and the like having 6 to 20 carbon atoms can be used.

By plasticizing the pressure-sensitive adhesive layer by making these organic liquid components compatible with the pressure-sensitive adhesive layer, it is possible to give a soft feeling to the skin when applied to the skin surface, and further to carry out a crosslinking treatment. By giving a suitable cohesive force,
It is possible to reduce skin irritation that occurs when peeling off after use. A known substance can be used as the crosslinking agent in the crosslinking treatment. For example, polyfunctional isocyanate, organoaluminum complex, and the like. The content of the organic liquid component in the pressure-sensitive adhesive layer is 25 to 200 parts by weight, preferably 40 to 180 parts by weight, based on 100 parts by weight of the pressure-sensitive adhesive. If the content of the organic liquid component is too low, the effect due to the addition cannot be expected, and if it is too high, the adhesive layer is excessively plasticized and the cohesive force is reduced, and the adhesive is applied to the skin surface even after crosslinking treatment. A residual phenomenon is caused to increase skin irritation during peeling.

The adhesive layer of the present invention contains a surfactant,
A low molecular weight absorption promoter such as fatty acid and its ester or amide may be contained. Many of these low molecular weight absorption promoters easily migrate into a soft polymer, but the migration is inhibited by the formation of the vapor-deposited thin film of the present invention and remains in the pressure-sensitive adhesive layer, and therefore also exerts a strong absorption promoting action. .

[0023]

EFFECTS OF THE INVENTION Since the transdermal absorption and absorption preparation of the present invention has the constitution as described above, since it uses a soft polymer film, it has excellent adhesion (adhesiveness) to the skin surface and good operability for application. There is no sense of discomfort during application. Further, since the vapor-deposited thin film is formed, the valuable substance for skin and the organic liquid component are not leaked to the support, and the long-term stability is excellent. Also, due to the decrease in the water vapor permeability of the support due to the formation of a vapor-deposited thin film
The T effect is surely obtained, and the transdermal absorbability of the drug is also improved.

[0024]

EXAMPLES Examples of the present invention will be shown below and will be described more specifically. In the following text, "parts" and "%" all mean weight conversion values.

[Example 1] (Production of vapor-deposited film A) A polyurethane film having a thickness of 40 μm was used as a base material, and aluminum was used as an evaporation source to evaporate it by heating in a vacuum chamber to provide a space between the polyurethane film and the evaporation source. Oxygen gas was supplied to the atmosphere to form an aluminum oxide vapor deposition layer having a film thickness of 200 Å on the film.

Example 2 (Preparation of Evaporated Film B) Silane gas was evaporated and turned into plasma under a pressure of 2 × 10 −2 Torr using a PCVD apparatus using microwave discharge, and a 300 Å film was formed on a silicon film having a thickness of 80 μm. A thick silicon oxide vapor deposition layer was formed.

Example 3 (Preparation of Adhesive Base A) 200 g of 2-ethylhexyl acrylate, 100 g of methoxyethyl acrylate and 15 g of acrylic acid were placed in a separable flask, 500 g of ethyl acetate was further added, and the temperature was raised under a nitrogen atmosphere. Heat to 70 ° C and add 1 g of benzoyl peroxide.
Was gradually added to 100 ml of ethyl acetate, and polymerization was carried out for 24 hours to obtain an acrylic adhesive base solution A.

Example 4 (Preparation of Adhesive Base B) 300 g of 2-ethylhexyl acrylate, 100 g of N-vinyl-2-pyrrolidone, and 30 g of hydroxyethyl methacrylate were placed in a separable flask, and 400 ml of ethyl acetate was further added. Then, this solution was heated to a temperature of 80 ° C. under a nitrogen atmosphere, 1 g of azobisisobutyronitrile was added, and polymerization was carried out for 24 hours to obtain an acrylic adhesive base solution B.

Example 5 (Preparation of Adhesive Base C) 10.0 g of a styrene / isoprene triblock copolymer (styrene content 30%), 20 g of rosin ester and 20.0 g of paraffin were added to 100 g of cyclohexane. A rubber-based adhesive base solution C was obtained by dissolving.

Examples 6, 7, 8, 9, 10 and Comparative Example 1,
2,3,4,5,6 (Various films, various adhesives, various transdermal preparations using two kinds of drugs) Urethane film, silicon film, aluminum oxide vapor deposition layer forming urethane film, silicon oxide layer forming silicon film Using the adhesives prepared in Examples 3, 4, and 5 as a support, transdermal preparations containing ketoprofen and estradiol as drugs were prepared. More specifically, a composition solution comprising an adhesive solution, a drug, and other additives is applied onto PET release paper using an applicator so as to have a thickness of about 50 μm after drying, and then 8
After heating at 0 ° C for 10 minutes to distill off the solvent, the release paper covered with the composition was transferred to various films to obtain a percutaneous absorption preparation sheet. The transfer to the vapor deposition layer forming film was performed on the vapor deposition layer surface. Table 1 shows the composition of the various transdermal preparation sheets prepared.

[Table 1]

Test Example 1 (Stability test of drugs and plasticizers using various percutaneous absorption and absorption preparations) Examples 6, 7, 8, 9, 1 prepared by the above method.
0, various preparation sheets of Comparative Examples 1, 2, 3, 4, 5, 6 were punched out to obtain a percutaneously absorbable preparation patch (diameter 3.0 cm). The weight of the obtained patch was weighed and the theoretical drug content and theoretical plasticizer content were calculated. Next, each patch was sealed in an aluminum bag (innermost layer, polyethylene) by heat sealing and stored at 40 ° C for 1 month. One month later, the adhesive was removed from each patch, the drug and the plasticizer were extracted by immersing them in 50 cc of ethanol at room temperature for 24 hours, and the resulting extract was subjected to high performance liquid chromatography to quantify the drug and organic liquid components. The stability was evaluated in comparison with the theoretical content. The test results are shown in Table 2.

[Table 2] From the results shown in Table 2, it is clear that the vapor deposition thin film treatment according to the present invention can prevent the transfer of the drug and the organic liquid component to the support. Further, these transdermal preparation patches exhibited an excellent ODT effect and were also excellent in drug release to the skin surface.

Claims (4)

[Claims] 1. A skin valuable substance is provided on a support made of an amorphous polymer film having a glass transition temperature of 30 ° C. or lower and a thin film of aluminum or an inorganic oxide formed on at least one surface by vapor deposition. A patch for skin to which the adhesive composition containing is applied. 2. The method according to claim 1, wherein the vapor deposition process is vacuum vapor deposition.
A skin patch, which is selected from atmospheric pressure chemical vapor deposition, reduced pressure chemical vapor deposition, and plasma chemical vapor deposition. 3. The patch for skin according to claim 1, wherein the inorganic oxide is silicon oxide or alumina. 4. The amorphous polymer having a glass transition temperature of 30 ° C. or lower according to any one of claims 1, 2 and 3, wherein the polymer is a rubber-based polymer such as silicone elastomer, polybutadiene or ethylene propylene rubber, or polyethylene. A patch for skin characterized by being selected from olefin polymers such as polybutene, vinyl acetate copolymers such as ethylene-vinyl acetate and ethylene-ethyl acrylate, and polyurethane.