JP2008101029A - Percutaneous absorption type preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a percutaneous absorption type preparation which prevents a coloration phenomenon caused to the medical field, when a percutaneous absorption type medicine is compounded in an adhesive, has an acceptable preparation appearance, and is also excellent in the stability of a medicine content. <P>SOLUTION: This percutaneous absorption type preparation is obtained by forming on at least one side of a support a medicine-containing adhesive layer containing 2-mercapto benzimidazole and/or propyl gallate, and a percutaneously absorbable medicine such as azelastine in an acrylic copolymer adhesive using a functional monomer as an essential component and an azo compound such as azobisisobutyronitrile as a polymerization initiator. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a transdermally absorbable preparation, and more particularly, to a transdermally absorbable preparation that allows a percutaneously absorbable drug to exist stably in the preparation, particularly suppresses coloring of the preparation and is excellent in drug content stability.

  In recent years, various skin-applied external preparations such as poultices and tapes have been developed as percutaneous absorption preparations for administering drugs into the living body through the skin surface. Tapes containing drugs that exert their effects have attracted attention. Under such circumstances, a tape-type transdermal preparation containing nitroglycerin, isosorbide nitrate, various steroids, non-steroids, anesthetics, antihypertensives, etc. as a pharmacologically active substance in a pressure sensitive adhesive. Proposed, developed, and some have been launched. These transdermally absorbable preparations are prepared by mixing various transdermally absorbable drugs with acrylic or synthetic rubber adhesives, and the drugs can be absorbed into the body continuously through the skin surface simply by applying to the skin surface. And exhibits excellent pharmacological action.

  However, since these preparations have a transdermally absorbable drug mixed in the adhesive, the percutaneously absorbable preparation is colored due to the interaction of various trace components in the adhesive and the drug, and the storage period There are many of them that tend to enhance their coloration.

  In general, when a drug reacts with an adhesive component, a decomposition product is generated, and the structure of the decomposition product is clarified in order to prevent it, and this is prevented by adding a decomposition inhibitor (antioxidant, stabilizer), etc. Is given. However, in the case of the above coloring phenomenon, even a reaction product of an extremely small amount of component often causes coloring exceeding the limit acceptable in appearance of the preparation, and it is very difficult to examine means for preventing it. Is almost. Therefore, screening is usually performed in the form of adding a large number of compounds to a formulation that causes coloration, and it is unavoidable to examine it by a very large and inefficient means of selecting effective ones. It is a fact.

  The present invention relates to a transdermal absorption-type preparation that prevents coloring phenomenon that occurs when a transdermally absorbable drug is blended in an adhesive, is acceptable in appearance of the preparation, and has excellent drug content stability. It is intended to be provided to.

  As a result of intensive studies to solve the above problems, the present inventors have been synthesized using a transdermal drug, a functional monomer as an essential component, and an azo compound as a polymerization initiator. By incorporating 2-mercaptobenzimidazole and / or propyl gallate in the acrylic copolymer pressure-sensitive adhesive, a coloring phenomenon or the like due to the interaction between the transdermally absorbable drug and various trace components in the pressure-sensitive adhesive layer, or the like The inventors have found that a coloring enhancement phenomenon during the storage period is suppressed, and that a stable transdermal preparation that is acceptable in appearance of the preparation can be obtained, and the present invention has been completed.

  That is, the present invention relates to an acrylic copolymer pressure-sensitive adhesive synthesized by using a functional monomer as an essential component and an azo compound as a polymerization initiator, a transdermally absorbable drug, and 2-mercaptobenzimidazole. And / or a percutaneous absorption-type preparation comprising a pressure-sensitive adhesive layer containing propyl gallate formed on at least one side of a support.

  The transdermally absorbable preparation of the present invention comprises an acrylic copolymer pressure-sensitive adhesive synthesized by using a functional monomer as an essential component and an azo compound as a polymerization initiator, a transdermally absorbable drug, 2 A pressure-sensitive adhesive layer containing mercaptobenzimidazole and / or propyl gallate is formed on at least one side of a support, and the transdermally absorbable drug is contained in the acrylic copolymer pressure-sensitive adhesive. Prevents coloring phenomenon that occurs when blended. Therefore, the preparation of the present invention suppresses the coloring phenomenon due to the interaction between the transdermally absorbable drug and various trace components in the acrylic copolymer adhesive or the coloring enhancement phenomenon during the storage period, and the appearance of the preparation It becomes a stable percutaneously absorbable preparation which is well tolerated. Furthermore, the transdermally absorbable preparation of the present invention is also excellent in the stability of the transdermally absorbable drug content.

  The transdermal preparation of the present invention has an adhesive layer formed on at least one side of a support, and the adhesive layer comprises a transdermal drug, 2-mercaptobenzimidazole and / or propyl gallate. And an acrylic copolymer pressure-sensitive adhesive. The acrylic copolymer pressure-sensitive adhesive is prepared using a functional monomer as an essential component and an azo compound as a polymerization initiator. Hereinafter, the components of the transdermally absorbable preparation of the present invention will be described.

(1) Support The support used in the transdermal preparation of the present invention is not particularly limited, but transdermal drug contained in the adhesive layer, 2-mercaptobenzimidazole and / or propyl gallate, etc. It is preferable that the additive such as a plasticizer or an absorption accelerator is lost from the back through the support and does not cause a decrease in content, that is, a material which does not allow these components to permeate.

  Specifically, polyesters such as polyethylene terephthalate, polyamides such as nylon, polyolefins such as polyethylene and polypropylene, polyvinylidene chloride, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, Examples thereof include single films such as polyvinyl chloride, ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, plasticized polyvinyl chloride, polyurethane, ionomer resin, and metal foil such as aluminum foil, or laminate films thereof.

  As these supports, those having a thickness that does not impair the soft feeling of the percutaneous absorption preparation, specifically 1 to 25 μm, preferably about 1 to 15 μm are used. Further, in the percutaneous absorption type preparation containing additives such as a plasticizer and an absorption accelerator, when a laminate of a porous film is used on the support, the adhesive layer is improved due to improved anchoring properties. This is preferable because the adhesive force between the substrate and the support is improved.

Specific examples of the porous film include paper, woven fabric, non-woven fabric, and mechanically perforated film or sheet. The thickness of the porous film is 10 to 500 μm considering the improvement of the anchoring property and the flexibility of the entire transdermal preparation, and 10 to 200 μm in the case of a thin preparation such as a plaster type or an adhesive tape type. It is preferable to be in the range. When using a woven fabric or a nonwoven fabric as a porous film, it is preferable that the basis weight of the pressure-sensitive adhesive layer is 5 to 30 g / m ² , preferably 8 to 20 g / m ² , because the anchoring property is improved. Further, in order to control the drug release property of the transdermally absorbable preparation, the support can be made relatively breathable.

(2) Acrylic copolymer pressure-sensitive adhesive The acrylic copolymer pressure-sensitive adhesive used in the present invention releases a percutaneously absorbable drug contained on the skin surface by closely fixing the transdermal preparation on the skin surface. It has a function. Such an adhesive includes a functional monomer as an essential component and a polymerization initiator from the viewpoints of stability of the transdermally absorbable drug, releasability, and reactivity when the adhesive is subjected to a crosslinking treatment. It is preferable to use an acrylic copolymer pressure-sensitive adhesive synthesized using an azo compound. Functional monomers are advantageous in terms of drug release and reactivity during cross-linking treatment, and acrylic copolymer adhesives are prepared by polymerization reaction. This is advantageous.

  The acrylic copolymer pressure-sensitive adhesive can be obtained by copolymerizing a functional monomer with (meth) acrylic acid alkyl ester used for a normal acrylic pressure-sensitive adhesive as a main component monomer. .

i) Main Component Monomer As the above (meth) acrylic acid alkyl ester, specifically, the alkyl group has 4 to carbon atoms such as butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl and the like. (Meth) acrylic acid alkyl ester having 13 straight chain alkyl groups or branched alkyl groups can be used, and these can be used alone or in combination of two or more.

  Moreover, the said (meth) acrylic-acid alkylester is not limited to the thing of the said illustration, If it is the range which does not change the characteristic of this invention, the (meth) acryl which has a C1-C3 alkyl group. An acid alkyl ester or a (meth) acrylic acid alkyl ester having an alkyl group having 14 or more carbon atoms may be used in combination.

ii) Functional monomer As the functional monomer that can be copolymerized with the above (meth) acrylic acid alkyl ester, it has at least one unsaturated double bond involved in the copolymerization reaction in the molecule, What has a functional group in a side chain can be used. Such functional monomers include carboxyl group-containing monomers such as (meth) acrylic acid, itaconic acid, maleic acid, maleic anhydride, (meth) acrylic acid hydroxyethyl ester, (meth) acrylic acid hydroxypropyl ester Hydroxyl group-containing monomers such as styrene sulfonic acid, allyl sulfonic acid, sulfopropyl (meth) acrylate, (meth) acryloyloxynaphthalene sulfonic acid, acrylamidomethylpropane sulfonic acid-containing monomers, (meth) Amino group-containing monomers such as acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic acid tert-butylaminoethyl ester, (meth) acrylamide, dimethyl (meth) acrylamide, N-butyl alcohol Amyl group-containing monomers such as rilamide, N-methylol (meth) acrylamide, N-methylolpropane (meth) acrylamide, (meth) acrylic acid methoxyethyl ester, (meth) acrylic acid ethoxyethyl ester, (meth) acrylic acid Alkoxyl group-containing single amount such as methoxyethylene glycol ester, (meth) acrylic acid methoxydiethylene glycol ester, (meth) acrylic acid methoxypolyethylene glycol ester, (meth) acrylic acid methoxypolypropylene glycol ester, (meth) acrylic acid tetrahydrofurfuryl ester The body is mentioned.

  Other monomers that can be copolymerized include, for example, (meth) acrylonitrile, vinyl acetate, vinyl propionate, N-vinyl-2-pyrrolidone, methyl vinyl pyrrolidone, vinyl pyridine, vinyl piperidone, vinyl pyrimidine, vinyl piperazine, vinyl pyrazine. , Vinyl pyrrole, vinyl imidazole, vinyl caprolactam, vinyl oxazole, vinyl morpholine and the like.

  One or more of these monomers can be copolymerized, but adhesion and cohesiveness as adhesive properties, release of percutaneous absorbable drugs contained in the adhesive layer, and crosslinking treatment of the adhesive From the standpoint of reactivity, etc., at least one of a carboxyl group-containing monomer and a hydroxyl group-containing monomer is an essential component, and other monomers exemplified above are copolymerized as necessary. Is particularly preferred. The copolymerization amount of the functional monomer can be arbitrarily set so as to be in the range of 2 to 40% by weight, preferably 3 to 35% by weight in the total monomer amount depending on the purpose.

iii) Polymerization initiator As the polymerization initiator for polymerizing the acrylic copolymer pressure-sensitive adhesive used in the present invention, an azo compound is used in view of ease of polymerization reaction and physical properties of the resulting acrylic copolymer pressure-sensitive adhesive. It is preferable to use a compound. Specific examples of the azo compound include azobisnitrile compounds such as azobisisobutyronitrile, azobispropionitrile, azobisvaleronitrile, diazoaminobenzene, nitrosoacylallylamines, azothioethers, p- Examples include azo and diazo compounds such as nitrobenzenediazonium salts. The amount of these polymerization initiators is arbitrarily set so as to be in the range of 0.01 to 2 parts by weight, preferably 0.05 to 2 parts by weight, with respect to 100 parts by weight of the total monomers to be subjected to polymerization. be able to.

iv) Polymerization The acrylic copolymer pressure-sensitive adhesive used in the present invention is obtained by synthesizing by the method known per se in the presence of the polymerization initiator using the main component monomer and the functional monomer. Can do. For example, a polymerization method such as a solution polymerization method, an emulsion polymerization method, a bulk polymerization method or a suspension polymerization method can be employed. In addition, the pressure-sensitive adhesive may be subjected to a crosslinking treatment by a method known per se as necessary.

(3) Transdermally absorbable drug In the transdermally absorbable preparation of the present invention, a transdermally absorbable drug [provided that 6-amino-5-chloro-1-isopropyl-2- ( Except 4-methyl-1-piperazinyl) benzimidazole and pharmacologically acceptable salts thereof. ] In a dissolved or dispersed state, it can be used as a patch for the treatment and / or prevention of various diseases.

  The drug to be contained is not particularly limited as long as it is a transdermal drug, and examples thereof include fat-soluble drugs having a molecular weight of 400 or less, a melting point of 300 ° C. or less, and a solubility in water of 4 mg / ml or less. The transdermally absorbable drugs include corticosteroids, analgesic / anti-inflammatory agents, hypnotic sedatives, tranquilizers, antihypertensive agents, antihypertensive diuretics, antibiotics, anesthetics, antibacterial agents, antifungal agents, vitamins, coronary drugs They are vasodilators, antihistamines, antitussives, sex hormones, antidepressants, cerebral circulation improving agents, antiemetics, antitumor agents, biopharmaceuticals, and other types of drugs.

  Specifically, at least one heteroatom selected from carboxylic acid derivatives, amino acid derivatives, amine derivatives, amide acid derivatives, steroid derivatives, alcohol derivatives, aromatic amine derivatives, naphthalene derivatives, oxygen atoms, sulfur atoms and nitrogen atoms. And the like. Preferred is a heterocyclic derivative containing at least one heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom.

  More specifically, azelastine, verapamil, metoprolol, sodium valproate, L-methionine, meprobamate, estradiol, propranolol, pilocarpine, indomethacin, pindolol, nifedipine, ifenprodil, diazepam, clemizole, allopurinol and the like can be mentioned. Two or more kinds of these drugs can be used in combination as required.

  The content of these drugs can be appropriately set according to the type of drug and the purpose of administration, but is usually 1 to 40% by weight, preferably about 2 to 30% by weight in the acrylic copolymer pressure-sensitive adhesive. Let When the content is less than 1% by weight, it is not possible to expect the release of a drug effective for treatment or prevention. On the other hand, when the content exceeds 40% by weight, the therapeutic and preventive effects are limited and economically disadvantageous. is there.

(4) 2-mercaptobenzimidazole and propyl gallate The 2-mercaptobenzimidazole and propyl gallate contained together with the transdermally absorbable drug in the adhesive layer in the transdermal preparation of the present invention are transdermally absorbed. It acts on a minor component in the acrylic copolymer pressure-sensitive adhesive that causes a coloring phenomenon due to interaction with a sex drug, and exhibits an action of inhibiting the reaction between the transdermally absorbable drug and the minor component in the pressure-sensitive adhesive. In the present invention, a coloring phenomenon that occurs when the transdermal absorbable drug is blended in the adhesive by inhibiting the reaction between the transdermal absorbable drug and the trace component in the acrylic copolymer adhesive. Alternatively, the coloring enhancement phenomenon during the storage period can be suppressed.

  In order to exert such an action, the content of these 2-mercaptobenzimidazole and propyl gallate can be appropriately set according to the type of pressure-sensitive adhesive, the type of drug, and the intensity of coloring. As 0.01 to 5% by weight, preferably 0.02 to 3% by weight, more preferably 0.03 to 2% by weight in the pressure-sensitive adhesive. These may be used alone or in combination. It can mix | blend in an adhesive.

  If the contents of these 2-mercaptobenzimidazole and propyl gallate are too small, a sufficient inhibitory action cannot be exhibited, and the effect of suppressing the coloring phenomenon cannot be expected. On the other hand, if the content of these 2-mercaptobenzimidazole and propyl gallate is too large, interaction with other components in the pressure-sensitive adhesive such as a cross-linking agent or a transdermally absorbable drug may occur. The product tends to form and again reduce the stability of the formulation.

  Next, production examples of the transdermally absorbable preparation of the present invention are shown. The transdermal preparation of the present invention is dissolved or dispersed in a solvent in the order of the acrylic copolymer pressure-sensitive adhesive, 2-mercaptobenzimidazole and / or propyl gallate, and transdermal drug, and is known if necessary. A tackifier, a plasticizer, an absorption accelerator, a surfactant, a filler and the like are appropriately added, and the obtained solution or dispersion is applied to at least one side of the support and dried, usually with a thickness of 10 to 10%. It can be produced by forming an adhesive layer having a thickness of 200 μm, preferably 15 to 150 μm, on at least one side of the support.

  In addition, the above solution or dispersion is applied onto a protective release sheet, dried, and a pressure-sensitive adhesive layer having a thickness of 10 to 200 μm, preferably 15 to 150 μm is usually formed on the release sheet, and then supported. It can also be produced by bringing the body into close contact with the adhesive layer.

  In order to prevent the adhesive from adhering to devices, containers, etc. during manufacture, transportation or storage, and to prevent deterioration of the formulation, the transdermal absorption type preparation of the present invention is usually applied to the surface. A release sheet is laminated. And it peels at the time of use, the surface of an adhesive layer is exposed, affixed on skin, and administers. As the release sheet, since it is necessary to be easily peeled off from the pressure-sensitive adhesive layer at the time of use, polyester, polyvinyl chloride, polyvinylidene chloride, which is usually subjected to silicone treatment on the contact surface with the pressure-sensitive adhesive layer, A film such as polyethylene terephthalate, or a laminate film of high-quality paper or glassine paper and polyolefin is used. The thickness of the release sheet is 1000 μm or less, preferably 30 to 200 μm.

The dose of the transdermally absorbable preparation of the present invention varies depending on the type of transdermally absorbable drug used, the age, weight, symptoms, etc. of the patient. The preparation containing ˜500 mg is applied to skin 1 to 100 cm ² once a day to about once every 7 days.

  EXAMPLES Hereinafter, although this invention is described in detail with an Example, a comparative example, and an experiment example, this invention is not limited at all by these. In the following description, parts and% mean parts by weight and% by weight, respectively.

[Preparation of adhesive solution A]
Under an inert gas atmosphere, 72 parts of 2-ethylhexyl acrylate, 25 parts of N-vinyl-2-pyrrolidone and 3 parts of acrylic acid were charged into the flask, and 0.3 part of azobisisobutyronitrile was used as a polymerization initiator. Polymerization was initiated by addition. The inner bath temperature was controlled to 58 to 62 ° C. by adjusting the stirring speed and outer bath temperature, and dropwise addition of ethyl acetate, and a polymerization reaction was carried out to prepare an adhesive solution A.

[Preparation of adhesive solution B]
Under an inert gas atmosphere, 93 parts of 2-ethylhexyl acrylate and 7 parts of acrylic acid were charged into the flask, and 0.3 parts of azobisisobutyronitrile was added as a polymerization initiator to initiate polymerization. The inner bath temperature was controlled to 58 to 62 ° C. by adjusting the stirring speed and outer bath temperature, and dropwise addition of ethyl acetate, and a polymerization reaction was performed to prepare an adhesive solution B.

[Preparation of adhesive solution C]
In an inert gas atmosphere, 50 parts of 2-ethylhexyl acrylate, 15 parts of 2-hydroxyethyl acrylate and 35 parts of vinyl acetate are charged into the flask, and 0.3 part of azobisisobutyronitrile is used as a polymerization initiator. Polymerization was initiated by addition. The inner bath temperature was controlled to 58 to 62 ° C. by adjusting the stirring speed and the outer bath temperature, and dropwise addition of ethyl acetate, and a polymerization reaction was performed to prepare an adhesive solution C.

[Preparation of adhesive solution D]
In an inert gas atmosphere, 75 parts of 2-ethylhexyl acrylate, 20 parts of butyl acrylate, and 5 parts of acrylic acid were charged into the flask, and 0.3 parts of azobisisobutyronitrile was added as a polymerization initiator to conduct polymerization. Started. The inner bath temperature was controlled to 58 to 62 ° C. by adjusting the stirring speed and the outer bath temperature, and dropwise addition of ethyl acetate, and a polymerization reaction was performed to prepare an adhesive solution D.

[Preparation of adhesive solution E]
In an inert gas atmosphere, 95 parts of acrylic acid 2-ethylhexyl ester and 5 parts of acrylic acid 2-hydroxyethyl ester were charged into the flask, and 0.3 parts of azobisisobutyronitrile was added as a polymerization initiator to initiate polymerization. I let you. The inner bath temperature was controlled to 58 to 62 ° C. by adjusting the stirring speed and outer bath temperature, and dropwise addition of ethyl acetate, and a polymerization reaction was performed to prepare an adhesive solution E.

[Preparation of adhesive solution F]
Under an inert gas atmosphere, 98 parts of 2-ethylhexyl acrylate and 2 parts of acrylic acid were charged into the flask, and 0.3 part of azobisisobutyronitrile was added as a polymerization initiator to initiate polymerization. The inner bath temperature was controlled at 58 to 62 ° C. by adjusting the stirring speed and the outer bath temperature, and dropwise addition of ethyl acetate, and a polymerization reaction was performed to prepare an adhesive solution F.

[Preparation of adhesive solution G]
Under an inert gas atmosphere, 75 parts of 2-ethylhexyl acrylate ester, 23 parts of butyl acrylate and 2 parts of acrylic acid were charged into the flask, and 0.3 parts of azobisisobutyronitrile was added as a polymerization initiator to conduct polymerization. Started. The inner bath temperature was controlled to 58 to 62 ° C. by adjusting the stirring speed and the outer bath temperature, and dropwise addition of ethyl acetate, and a polymerization reaction was performed to prepare an adhesive solution G.

[Preparation of adhesive solution H]
Under an inert gas atmosphere, 80 parts of 2-ethylhexyl acrylate, 19 parts of N-vinyl-2-pyrrolidone, and 1 part of acrylic acid are charged in a flask, and 0.3 part of azobisisobutyronitrile is used as a polymerization initiator. Polymerization was initiated by addition. The inner bath temperature was controlled to 58 to 62 ° C. by adjusting the stirring speed and outer bath temperature, and dropwise addition of ethyl acetate, and a polymerization reaction was performed to prepare an adhesive solution H.

[Experimental example]
A pressure-sensitive adhesive solution containing various drugs was prepared according to the blending ratio shown in Table 1, and the obtained solution was applied onto a polyester separator (thickness 75 μm) and dried so that the thickness after drying was about 60 μm. An adhesive layer was formed.

  Next, this pressure-sensitive adhesive layer was bonded to a polyester film (12 μm thick) to produce Example products and Comparative product. In the table, 2-MBI represents 2-mercaptobenzimidazole, PGa represents propyl gallate, and IPM represents isopropyl myristate. The content is expressed as the content in the pressure-sensitive adhesive layer after drying.

  With respect to the percutaneous absorption preparations prepared in the above Examples and Comparative Examples, the coloration degree of each preparation and the drug content stability in each preparation were tested by the following methods.

[Preparation color test]
For each transdermal preparation, the degree of coloration of the preparation was examined immediately after preparation and after storage for 2 months in a sealed state at 50 ° C. Each formulation was punched out to an appropriate size, and the coloring degree Δb of each formulation was measured using a color difference meter CR-200 (manufactured by Minolta). Further, for each preparation, the coloring degree Δb _{0 of a} tape containing no transdermally absorbable drug, 2-mercaptobenzimidazole and propyl gallate at all was measured, and this was used as a blank value and subtracted from the coloring degree Δb of each preparation. The formulation coloring degree (Δb−Δb ₀ ) was calculated. Furthermore, the coloring intensity was obtained by subtracting the coloring degree of the preparation immediately after preparation preparation from the coloring degree of the preparation after storage for 2 months in a sealed state at 50 ° C.

[Drug content stability test in the preparation]
Each transdermal preparation was examined for the stability of the drug content in each preparation after storage for 2 months in a sealed state at 50 ° C. Each preparation was punched out to an appropriate size, extracted by shaking with an organic solvent, and the amount of drug in the extracted solution was measured by high performance liquid chromatography. These results are shown in Table 2.

Claims (1)

An acrylic copolymer pressure-sensitive adhesive synthesized using an azo compound as a polymerization initiator and a functional monomer as an essential component; and a transdermally absorbable drug [provided that 6-amino-5-chloro-1- Except for isopropyl-2- (4-methyl-1-piperazinyl) benzimidazole and pharmacologically acceptable salts thereof] and 2-mercaptobenzimidazole and / or propyl gallate Is a transdermally absorbable preparation formed on at least one side of a support.