JP2006022057A - Base for percutaneous absorption preparation and skin patch preparation using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a base for percutaneous absorption preparation having excellent percutaneous absorption of medicine and a skin patch preparation, in detail a base for percutaneous absorption preparation and a skin patch preparation in which the main component of the base and the kind of the medicine are widely selected. <P>SOLUTION: The base for percutaneous absorption preparation comprises a chain alcohol that is a branched alcohol and has 10-30 total carbon atoms and 5-20 carbons of the longest straight chain. The amount of the chain alcohol contained in the base for the percutaneous absorption preparation is 15-50 wt.%. The chain alcohol is preferably a monofunctional primary chain alcohol, concretely isostearyl alcohol, hexyldecanol, octyldodecanol, etc., may be cited as the chain alcohol. Preferably an adhesive is used as the main component of the base for the percutaneous absorption preparation and the layer of the base is formed on one side of a sheetlike substrate to form the skin patch preparation. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a base for a transdermally absorbable preparation excellent in transdermal absorbability of a drug. More specifically, the present invention relates to a base for a percutaneous absorption preparation capable of widely selecting a main component of the base and a kind of drug.

  2. Description of the Related Art Conventionally, transdermal absorption preparations that can administer drugs from the skin have been developed. As the pharmaceutical forms, for example, many ointments, plasters, liquids, patches and the like have been developed. In recent years, these transdermally absorbable preparations have been widely applied not only to local drug therapy but also to systemic drug therapy. The reason why such a percutaneous absorption-type drug therapy has attracted attention is because of its unique advantages.

  More specifically, for example, a method of injecting a drug directly into the body or blood vessel such as an injection exhibits a large pharmacological effect immediately, but its sustainability is inferior, so frequent administration is required. In addition, methods that absorb drugs from the digestive tract, such as oral administration, are safe and economical, but the efficacy of the drug decreases due to variations in absorption and retention in the digestive tract and metabolism in the first pass through the liver. Resulting in.

  On the other hand, the percutaneous absorption-type drug administration method can be expected to maintain the long-term efficacy of the drug and to achieve uniform absorption into the body. Thus, overdose of the drug can be avoided, thereby reducing side effects. Furthermore, since the administration site is on the surface of the body, the size and concentration of the preparation can be easily adapted to individual differences and administration purposes. Thus, the transdermally absorbable preparation has many advantages compared to other pharmaceutical forms.

  However, percutaneously absorbable preparations such as those described above generally have low percutaneous absorbability of drugs due to the barrier function of the skin, and it may be extremely difficult to absorb the required amount of drug from the skin. Therefore, in order to effectively release the drug and efficiently absorb it from the skin into the living body, a proposal has been made to contain a percutaneous absorption enhancer in the base. This percutaneous absorption enhancer improves the solubility and diffusibility of the drug in the base, and functions to change the state of the skin surface such as keratin softening, keratin permeability, and pore opening. Can be improved. As such a transdermal absorption enhancer, higher fatty acids such as oleic acid, caprylic acid, isopropyl myristate (IPM), octyl palmitate, or esters thereof are used.

  However, the percutaneous absorption preparation using the percutaneous absorption enhancer as described above has several problems. For example, in order to expect a desired pharmacological effect in a percutaneous absorption preparation, it may be necessary to contain a certain amount of a percutaneous absorption enhancer in the base. However, if the base contains a large amount of a percutaneous absorption enhancer, if the main component of the base is not compatible with the percutaneous absorption enhancer, the percutaneous absorption is promoted on the surface of the base during storage. So-called blooming that the agent exudes may occur, and the percutaneous absorption promoting action of the drug may be reduced. In addition, depending on the type of drug, it may react with a transdermal absorption enhancer, leading to a decrease in drug content, or may cause a reaction with a particularly basic drug to produce a degradation product. For this reason, from the viewpoint of drug stability, the drugs that can be contained in the base are limited, and many types of drugs cannot be formulated as transdermal absorption preparations.

  In view of the above problems in conventional percutaneous absorption preparations, the present invention provides a base for percutaneous absorption preparations that is safe and excellent in drug administration effect by using a percutaneous absorption enhancer that allows a wide selection of drugs to be used. And it aims at providing a skin patch preparation.

  Therefore, as a result of intensive studies to solve the above problems, the present inventors have percutaneously absorbed preparations of branched alcohols having the longest straight chain carbon number of 5 to 20 and total carbon numbers of 10 to 30. It has been found that by including it in a base for use, excellent transdermal absorbability of the drug is exhibited without causing the above-mentioned problems.

  That is, the present invention is a base for a transdermal preparation containing a drug, a branched saturated alcohol having a total carbon number of 10 to 30 and a longest linear carbon number of 5 to 20, The present invention provides a base for a percutaneous absorption preparation, which is contained in a proportion of 15 to 50% by weight of the base for a percutaneous absorption preparation.

  The present invention also provides a skin patch preparation comprising the above-mentioned base for a percutaneously absorbable preparation formed on one side of a sheet-like support.

  A branched saturated alcohol having a total carbon number of 10 to 30 and a longest linear carbon number of 5 to 20 used as a transdermal absorption enhancer in the present invention reacts with a drug. Neither does it cause blooming from the base. Therefore, in the base for transdermally absorbable preparations of the present invention, a wide variety of drugs and bases that can be used can be selected. Furthermore, in the base for transdermal absorption preparations of the present invention, the effect of promoting percutaneous absorption can be sufficiently exhibited by containing 15 to 50% by weight of the above transdermal absorption promoter.

  The main component of the base for percutaneous absorption preparation of the present invention (hereinafter simply referred to as “base”) is liquid as long as it is less irritating to the skin and can contain a drug, a percutaneous absorption enhancer, etc. during storage. , Semi-solid and solid forms may be used, and the material is not limited. Specifically, water, ethanol, glycerin, propylene glycol, polyethylene glycol, vegetable oil, liquid paraffin, lanolin, petrolatum, cetanol, solid paraffin, wax, wax, resin, gelatin, cellulose, dextrin, polyvinyl alcohol, polyvinyl ether, polyvinyl Pyrrolidone, acrylic adhesive obtained by polymerizing (meth) acrylic acid alkyl ester and copolymerizable monomer, natural rubber, synthetic polyisoprene rubber, block copolymer, rubber adhesive such as polyisobutylene, silicone An adhesive, a vinyl ester adhesive, a vinyl ether adhesive, or the like can be used. Among these, when used as a skin patch preparation to be applied to the skin surface, adhesives such as acrylic adhesives, rubber adhesives, silicone adhesives and the like having cohesiveness and adhesiveness that can be applied to the skin. It is preferable to use an agent. Among these pressure-sensitive adhesives, it is particularly preferable to use an acrylic pressure-sensitive adhesive because it is easy to control skin irritation and skin adhesion.

  In addition, the base for transdermal absorption preparation of the present invention contains a branched alcohol having a total carbon number of 10 to 30 and a longest linear carbon number of 5 to 20. This chain alcohol is a so-called percutaneous absorption enhancer (hereinafter, referred to as “percutaneous absorption enhancer”), which improves the diffusibility of the drug in the base or affects the state of the skin surface to improve the transdermal absorbability of the drug. The chain alcohol may be referred to as a transdermal absorption enhancer). As described above, since higher fatty acids and esters that have been conventionally used as percutaneous absorption accelerators have many reactive drugs, there is a possibility that a decrease in their pharmacological effects may be a problem. The higher fatty acids and esters may not react with the drug if they are in trace amounts, but it is necessary to add a certain amount or more in order to exert a transdermal absorption promoting action.

  However, since alcohols are used as transdermal absorption enhancers in the present invention, they do not react with drugs that react with fatty acids and esters, and a wide variety of drugs that can be contained in the base can be selected. Moreover, the percutaneous absorption enhancer in the present invention does not volatilize from the base during storage and does not cause blooming from the base. Thus, it is thought that it does not volatilize from a base because the total carbon number of the percutaneous absorption enhancer in this invention is 10 or more. Also, blooming from the base does not occur because the structure of the transdermal absorption enhancer in the present invention is a branched chain having a total carbon number of 30 or less and the longest straight chain carbon number of 5 to 20. Since it is a formula alcohol, it is considered that the molecular structure is large in molecular weight and is well compatible or dispersed in the main component of the base.

  Further, the percutaneous absorption enhancer in the present invention is contained in a proportion of 15 to 50% by weight, preferably 30 to 50% by weight, based on the base. If the amount is less than 15% by weight, the percutaneous absorption action cannot be sufficiently exhibited. If the amount exceeds 50% by weight, the amount of the drug contained in the base is limited, or depending on the type of the main component of the base, the coagulability May decrease.

  Such a percutaneous absorption enhancer is not particularly limited as long as it satisfies the above conditions. Specifically, isostearyl alcohol, hexyldecanol, and octyldodecanol are particularly preferably used.

  The drug contained in the base of the present invention is absorbed from the skin, and the onset of local and systemic effects is observed. Specifically, general anesthetics, hypnotics / sedatives, antiepileptics, detoxifying sedative / anti-inflammatory drugs, antipruritics, psychoneurotics, local anesthetics, skeletal muscle relaxants, autonomic nerves, antispasmodics, Parkinson Drugs, antihistamines, cardiotonic drugs, arrhythmic drugs, diuretics, antihypertensive drugs, vasoconstrictors, coronary vasodilators, peripheral vasodilators, arteriosclerotic drugs, cardiovascular drugs, respiratory stimulants, antitussive expectorant , Hormonal drugs, topical suppurative drugs, analgesic / astringent / anti-inflammatory drugs, parasitic skin disease drugs, hemostatic drugs, gout treatment drugs, antineoplastic drugs, antibiotics, chemotherapy drugs, asthma drugs Etc. can be used. The proportion of such a drug can be appropriately determined depending on the blending amount of the transdermal absorption enhancer, the main component of the base, the type of the drug, the purpose of administration, etc. 1 to 70% by weight, preferably 1 to 60% by weight.

  In addition to the above alcohols and drugs, other additives can be blended with the base of the present invention as necessary. The function of this additive varies depending on the main component of the base, the type of drug, the method of use of the percutaneous absorption preparation, etc., for example, stabilizers, antiseptic / disinfectants, pH adjusters, suspending agents, interfaces An activator, a filler, a deterioration inhibitor, a tackifier, a plasticizer, and the like can be blended within a range that does not affect the pharmacological effect.

  The base of the present invention is preferably used after being applied or applied to a site to be protected and fixed with an adhesive sheet or bandage, because it can be used without soiling clothes and fingers. In addition, as an effective method of use, when the transdermal absorption base of the present invention is used as a skin patch preparation formed on one side of a sheet-like support in advance, the amount of drug to be applied can be easily adjusted and the sticking operation is simple. Therefore, it is preferable. When the base for transdermal absorption preparation of the present invention is used as such a skin patch preparation, as described above, an adhesive is used as the main component so that the base itself has adhesiveness. It is preferable to use it.

  As a support when the base of the present invention is used as a skin patch preparation as described above, a support having flexibility to follow bent skin and having a good anchoring property with the base is used. Is good. Specific examples include polyester films, nonwoven fabrics, woven fabrics, and laminated films of polyester films and polyester nonwoven fabrics. Among these, it is suitable to use a laminated film of a polyester film and a polyester non-woven fabric from the viewpoints of the stability of the tan evening drug, the anchoring property with the adhesive layer, the ODT effect, and the like. The above skin patch preparation may be produced by a conventionally used method. For example, when an adhesive is used as the main component, a method of applying the adhesive to the support and drying, A base layer can be produced, and this adhesive layer can be produced by a method of adhering to a support. Such a skin patch preparation is preferably covered with a release liner or the like until use, since contamination of the pressure-sensitive adhesive layer surface during storage can be prevented.

  Examples of the present invention will be described below and will be described in more detail. However, the present invention is not limited to these examples, and various applications are possible without departing from the technical idea of the present invention. In the following, parts and% mean parts by weight and% by weight, respectively.

<Example 1>
An ethyl acetate solution is prepared by adding 25 parts of methoxamine base and 20 parts of isostearyl alcohol to 55 parts of an acrylic pressure-sensitive adhesive obtained by copolymerizing 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid. did. This ethyl acetate solution is applied to the polyester nonwoven fabric side of a laminated film of a polyester film (thickness 6 μm) and a polyester nonwoven fabric (basis weight 8 g / m ² ), dried by heating at 100 ° C. for 5 minutes, and a base having a thickness of 40 μm A layer was formed. Next, a polyester film (thickness: 75 μm) having a surface treated as a release liner was bonded to the base layer side to obtain a skin patch preparation of the present invention.

<Example 2>
An ethyl acetate solution is prepared by adding 25 parts of methoxamine base and 40 parts of isostearyl alcohol to 35 parts of solid content of an acrylic adhesive obtained by copolymerizing 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid. did. This ethyl acetate solution is applied to the polyester nonwoven fabric side of a laminated film of a polyester film (thickness 6 μm) and a polyester nonwoven fabric (basis weight 8 g / m ² ), dried by heating at 100 ° C. for 5 minutes, and a base having a thickness of 40 μm A layer was formed. Next, a polyester film (thickness: 75 μm) having a surface treated as a release liner was bonded to the base layer side to obtain a skin patch preparation of the present invention.

<Example 3>
Ethyl acetate solution in which 25 parts of methoxamine base and 40 parts of hexyldecanol are added to solid parts of acrylic adhesive obtained by copolymerizing 75 parts of 2-ethylhexyl acrylate ester, 22 parts of vinylpyrrolidone and 3 parts of acrylic acid Was made. This ethyl acetate solution is applied to the polyester nonwoven fabric side of a laminated film of a polyester film (thickness 6 μm) and a polyester nonwoven fabric (basis weight 8 g / m ² ), dried by heating at 100 ° C. for 5 minutes, and a base having a thickness of 80 μm. A layer was formed. Next, a polyester film (thickness: 75 μm) having a surface treated as a release liner was bonded to the base layer side to obtain a skin patch preparation of the present invention.

<Example 4>
Acetic acid in which 10 parts of biperidene base and 40 parts of octyldodecanol are added to 50 parts of an acrylic pressure-sensitive adhesive obtained by copolymerizing 75 parts of 2-ethylhexyl acrylate, 22 parts of vinylpyrrolidone and 3 parts of acrylic acid. An ethyl solution was made. This ethyl acetate solution is applied to the polyester nonwoven fabric side of a laminated film of a polyester film (thickness 6 μm) and a polyester nonwoven fabric (basis weight 8 g / m ² ), dried by heating at 100 ° C. for 5 minutes, and a base having a thickness of 60 μm A layer was formed. Next, a polyester film (thickness: 75 μm) having a surface treated as a release liner was bonded to the base layer side to obtain a skin patch preparation of the present invention.

<Example 6>
A hexane solution was prepared by adding 10 parts of piberidene base and 40 parts of isostearyl alcohol to 50 parts of a solid content of a rubber-based pressure-sensitive adhesive mainly composed of polyisobutylene. This hexane solution is applied to the polyester nonwoven fabric side of a laminated film of a polyester film (thickness 6 μm) and a polyester nonwoven fabric (basis weight 8 g / m ² ), heated and dried at 100 ° C. for 5 minutes, and a base layer 60 μm thick Formed. Next, a polyester film (thickness: 75 μm) having a surface treated as a release liner was bonded to the base layer side to obtain a skin patch preparation of the present invention.

<Comparative Example 1>
An ethyl acetate solution was prepared by adding 25 parts of methoxamine base to 75 parts of the solid content of an acrylic adhesive obtained by copolymerizing 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid. This ethyl acetate solution is applied to the polyester nonwoven fabric side of a laminated film of a polyester film (thickness 6 μm) and a polyester nonwoven fabric (basis weight 8 g / m ² ), dried by heating at 100 ° C. for 5 minutes, and a base having a thickness of 40 μm A layer was formed. Next, a polyester film (thickness 75 μm) having a release treatment applied as a release liner to the base layer side was bonded to obtain a skin patch preparation.

<Comparative example 2>
An ethyl acetate solution was prepared by adding 25 parts of methoxamine base and 10 parts of isostearyl alcohol to 65 parts of an acrylic pressure-sensitive adhesive obtained by copolymerizing 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid. . This ethyl acetate solution was applied to the polyester nonwoven fabric side of a laminated film of a polyester film (thickness 6 μm) and a polyester nonwoven fabric (basis weight 8 g / m ² ), dried by heating at 100 ° C. for 5 minutes, and a base of 40 μm thickness A layer was formed. Next, a polyester film (thickness 75 μm) having a release treatment applied as a release liner to the base layer side was bonded to obtain a skin patch preparation.

<Comparative Example 3>
A skin patch preparation was obtained in the same manner as in Example 1 except that stearyl alcohol was used instead of isostearyl alcohol.

<Comparative example 4>
A skin patch preparation was obtained in the same manner as in Example 1 except that isopropyl alcohol was used instead of isostearyl alcohol.

<Comparative Example 5>
A skin patch preparation was obtained in the same manner as in Example 1 except that isostearic acid was used in place of isostearyl alcohol.

<Comparative Example 6>
A hexane solution was prepared by adding 10 parts of piberidene base and 40 parts of lauryl alcohol to 50 parts of solid content of a rubber-based pressure-sensitive adhesive mainly composed of polyisobutylene. This hexane solution is applied to the polyester nonwoven fabric side of a laminated film of a polyester film (thickness 6 μm) and a polyester nonwoven fabric (basis weight 8 g / m ² ), heated and dried at 100 ° C. for 5 minutes, and a base layer 60 μm thick Formed. Next, a polyester film (thickness 75 μm) having a release treatment applied as a release liner to the base layer side was bonded to obtain a skin patch preparation.

  Table 1 summarizes the main components of the bases of Examples 1 to 5 and Comparative Examples 1 to 6, the alcohols contained, and the blending amount (% by weight) of alcohols with respect to the bases.

＜薬物吸収促進効果評価試験（透過性試験）＞
実施例１〜３および比較例１〜５にて作製したメトキサミン塩基を含有する皮膚貼付製剤を６ｍｍφ（０．２８２６ｃｍ²）に打抜き、ヘビ皮に貼付した。これを透過面積が同じである拡散セルに装着し、ヘビ皮透過性を測定した。透過した薬剤量は高速液体クロマトグラフィー（ＨＰＬＣ）で測定し、単位面積あたり２４時間累計の透過速度を算出し、アルコール類を配合していない比較例１品の透過速度との比を表２に記載した。
＜ブルーミング性評価試験＞
実施例１〜５および比較例１〜６にて作製した皮膚貼付製剤の物性について以下の判定基準で評価し、その結果を表２に記載した。

<Drug absorption promotion effect evaluation test (permeability test)>
The skin patch preparation containing methoxamine base prepared in Examples 1 to 3 and Comparative Examples 1 to 5 was punched into 6 mmφ (0.2826 cm ² ) and stuck on a snake skin. This was attached to a diffusion cell having the same transmission area, and snake skin permeability was measured. The amount of drug permeated was measured by high performance liquid chromatography (HPLC), and the permeation rate for 24 hours per unit area was calculated. Described.
<Blooming property evaluation test>
The physical properties of the skin patch preparations prepared in Examples 1 to 5 and Comparative Examples 1 to 6 were evaluated according to the following criteria, and the results are shown in Table 2.

  ○: Blooming of the percutaneous absorption enhancer from the base is not observed, and it can be used as a preparation.

  Δ: Some blooming of the percutaneous absorption enhancer from the base is observed, but can be used as a preparation because it can be applied to the skin surface.

  ×: Percutaneous absorption enhancer blooming from the base is observed, and it cannot be applied to the skin surface and cannot be used as a preparation.

表２の結果から、最長の直鎖炭素数が５〜２０の分岐型で全炭素数が１０〜３０のアルコール類を、１５〜５０重量％含有する基剤を用いた実施例１〜５にて得られる皮膚貼付製剤では、薬物の良好な経皮吸収促進作用が認められた。さらに、上記アルコール類を用いるとブルーミングが起こらず、基剤の粘着性も低下しないことは明らかである。

From the results in Table 2, Examples 1 to 5 using a base containing 15 to 50% by weight of a branched type alcohol having a longest straight chain carbon number of 5 to 20 and a total carbon number of 10 to 30%. In the obtained skin patch preparation, a good percutaneous absorption promoting action of the drug was observed. Furthermore, when the above alcohols are used, it is clear that blooming does not occur and the adhesiveness of the base does not decrease.

Claims (5)

In a base for a transdermal preparation containing a drug, a branched alcohol having a total carbon number of 10 to 30 and a longest linear carbon number of 5 to 20 is used for the transdermal preparation. A base for a percutaneous absorption preparation, which is contained in a proportion of 15 to 50% by weight of the base. The base for transdermal absorption preparation according to claim 1, wherein the chain alcohol is a monovalent and primary chain alcohol. The base for transdermal absorption preparation according to claim 1 or 2, wherein the chain alcohol is selected from at least one of isostearyl alcohol, hexyldecanol, and octyldodecanol. The base for a transdermal absorption preparation according to any one of claims 1 to 3, wherein the main component of the base for the transdermal absorption preparation is an adhesive. A skin patch preparation comprising the base for transdermal preparation according to claim 4 formed on one side of a sheet-like support.