JP5227535B2 - Patch - Google Patents

Description

  The present invention relates to a patch, and more particularly to a patch containing lidocaine and / or a pharmaceutically acceptable salt thereof as a drug.

  Lidocaine, which has a local anesthetic effect, is known to be effective in treating postoperative pain and pain due to neuropathy because it provides analgesic effects when administered at low doses. Administration with gels, patches, etc. Among these, the transdermal administration method using a patch is a useful administration method because of the advantages of ease of administration, improved compliance, and sustained effects.

The adhesive layer constituting the patch is usually formed from a mixture containing a drug and an adhesive base. Regarding the pressure-sensitive adhesive layer, researches have been conducted not only on lidocaine but also on various drugs for the purpose of improving transdermal absorbability of the drug and reducing skin irritation (Patent Documents 1 to 5).
JP 2000-178186 A JP 2002-363070 A JP-A-2005-170938 JP 2004-292379 A JP 2006-1859 A

  Since the patch is used after being applied to the skin, etc., of course, appropriate adhesion is required, but from the viewpoint of sustained effect, the stability of the drug content and the stability of the drug release rate are particularly It becomes important. However, it has not always been easy to stabilize the drug content and the drug release amount at the same time by applying conventionally known methods including the above publication. In particular, for lidocaine, which has recently become increasingly important for local anesthesia, no effective method is known.

  Accordingly, an object of the present invention is a patch containing lidocaine and / or a salt thereof as a drug, which has not only moderate adhesiveness but also excellent drug content stability and drug release rate stability. Is to provide.

  In order to achieve the above object, the present invention provides a patch comprising an adhesive layer on a support, wherein the adhesive layer is at least one selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof. A patch containing a drug and an alkyl alkanol is provided.

  In the present invention, since the alkyl alkanol is contained in the pressure-sensitive adhesive layer containing lidocaine and / or a pharmaceutically acceptable salt thereof, both the drug content and the stability of the drug release rate in the pressure-sensitive adhesive layer are improved. The reason why such an effect occurs is not necessarily clear, but the alkylalkanol functions effectively as a solubilizer for lidocaine and / or a pharmaceutically acceptable salt thereof, and other components constituting the pressure-sensitive adhesive layer. It is assumed that the compatibility and the affinity of are improved.

  The content of the alkyl alkanol is preferably 4 to 12% by mass based on the total mass of the pressure-sensitive adhesive layer. By setting the content of the alkyl alkanol within this range, not only can the drug content and drug release rate be stabilized, but also crystallization of lidocaine and / or a pharmaceutically acceptable salt thereof can be suppressed. Problems such as phase separation and decrease in the percutaneous absorption rate due to crystallization are solved.

  The alkyl group of the alkyl alkanol preferably has 1 to 8 carbon atoms, and is preferably at least one selected from the group consisting of octyldodecanol, isostearyl alcohol, hexyldodecanol and decyldodecanol. The alkyl alkanol is preferably a 2-alkyl alkanol. By using such an alkyl alkanol, the stabilization of the drug content and the drug release rate is further increased, and the adhesiveness is also improved.

  The ratio of alkyl alkanol to drug is preferably 0.8 to 2 by mass ratio. That is, the value of “mass of alkyl alkanol / mass of drug” is preferably 0.8 or more and 2 or less. By containing the alkyl alkanol at such a ratio, the drug content and the drug release rate can be stabilized over a long period of time.

  The pressure-sensitive adhesive layer preferably contains a thermoplastic elastomer, and a styrene-isoprene-styrene block copolymer can be applied as the thermoplastic elastomer. By constituting the adhesive layer with such an elastomer, compatibility with lidocaine and / or a pharmaceutically acceptable salt or alkylalkanol thereof is improved, and not only adhesion but also excellent percutaneous absorption ability. A patch can be provided.

  According to the present invention, there is provided a patch containing lidocaine and / or a salt thereof as a drug, which has not only moderate adhesion but also excellent drug content stability and drug release rate stability. Is done.

  Hereinafter, preferred embodiments of the patch of the present invention will be described in detail. In the present specification, “%” means “mass%” unless otherwise specified.

  The patch according to the embodiment includes a pressure-sensitive adhesive layer on a support, and the pressure-sensitive adhesive layer may be formed on both sides of the main surface of the support or on one side. The pressure-sensitive adhesive layer contains at least an adhesive base and a medicinal component in addition to the alkyl alkanol, and the medicinal component includes at least lidocaine and / or a pharmaceutically acceptable salt thereof. Even if the adhesive base itself is made of an adhesive polymer (acrylic polymer, etc.), it is a polymer (natural rubber, thermoplasticity) that produces adhesiveness when mixed with other components (tackifier, etc.). It may be made of an elastomer or the like.

  The adhesive layer of the patch may contain lidocaine or a pharmaceutically acceptable salt thereof (such as lidocaine hydrochloride) alone or as a mixture as a drug. In order to make it contain in an adhesive layer, it is preferable that lidocaine is contained alone.

  It is preferable that the compounding quantity of a lidocaine and / or its pharmaceutically acceptable salt is 1-10% with respect to the mass of the whole adhesive layer. By making the amount of lidocaine 1% or more, a sufficient anesthetic effect (analgesic effect) by lidocaine can be obtained as a patch, and by making it 10% or less, adverse effects on the physical properties of the patch itself due to crystal precipitation. Can be eliminated. Further, the blending amount of lidocaine is more preferably 4 to 6% with respect to the mass of the entire pressure-sensitive adhesive layer from the viewpoint of preventing the pressure-sensitive adhesive residue and drug crystallization.

  The adhesive layer of the patch contains an alkyl alkanol, which mainly functions as a solubilizer for lidocaine or a pharmaceutically acceptable salt thereof. As the alkyl alkanol, at least one selected from octyldodecanol, isostearyl alcohol, hexyl decanol, and decyldodecanol is preferable, and 2-alkylalkanol is preferable. Particularly preferred as the alkyl alkanol is octyldodecanol. Octyldodecanol may be a mixture of different isomers or only a specific structure. Examples of octyldodecanol include 2-octyldodecanol.

  The compounding ratio (mass ratio) of lidocaine and / or a pharmaceutically acceptable salt thereof and the alkyl alkanol in the pressure-sensitive adhesive layer is preferably the former: the latter = 1: 0.8 to 1: 2. In consideration of sufficiently maintaining the solubility of lidocaine contained in the pressure-sensitive adhesive layer and the adhesive strength to the skin, the alkyl alkanol is 4 to 12% (preferably 4 to 10%) is preferable.

  The pressure-sensitive adhesive layer contains a pressure-sensitive adhesive base in addition to the components shown above. Adhesive bases include styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-isoprene rubber, styrene-butadiene rubber, polyisoprene, polyisobutylene, polybutadiene rubber, silicone rubber, acrylic Polymers (butyl acrylate, 2-ethylhexyl acrylate, vinyl acetate, methacrylate, hydroxyethyl acrylate, glycidyl methacrylate, methoxyethyl acrylate, acrylic acid, etc.), natural rubber, polyurethane rubber, etc. It is done. As the adhesive base, a thermoplastic elastomer is preferable, and a styrene-based thermoplastic elastomer such as a styrene-isoprene-styrene block copolymer or a styrene-butadiene-styrene block copolymer is more preferable. Particularly preferred as the adhesive base is a styrene-isoprene-styrene block copolymer.

  5-40% of the whole adhesive layer is preferable, and, as for the compounding quantity of a styrene-isoprene-styrene block copolymer, 10-35% is especially preferable. If the blending amount is less than 5%, the cohesiveness and shape retention of the base tend to decrease, and if it exceeds 40%, the cohesiveness of the base increases and adhesive strength decreases and workability decreases. Etc. may be caused.

  The pressure-sensitive adhesive layer may contain a tackifier together with the pressure-sensitive adhesive base. Examples of tackifiers that can be used include alicyclic saturated hydrocarbon resins, rosin resins, terpene resins, maleic resins, etc., but alicyclic saturation from the viewpoint of adhesive strength and compatibility with adhesive bases. Hydrocarbon resins are preferred.

  40-60% of the whole adhesive layer is preferable, and, as for the compounding quantity of a tackifier, 45-55% is more preferable.

  The pressure-sensitive adhesive layer may contain a plasticizer. Such plasticizers include liquid paraffin, petroleum oil (paraffinic process oil, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, vegetable oil (olive oil, camellia oil, castor oil, tall oil). , Peanut oil, etc.), silicone oil, dibasic acid ester (dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (polybutene, liquid isoprene rubber, etc.), etc., and a mixture of two or more thereof may be used. However, a saturated hydrocarbon plasticizer is preferred, and liquid paraffin alone is particularly preferred.

  The blending amount of the plasticizer is preferably 5 to 40%, more preferably 10 to 30% with respect to the entire pressure-sensitive adhesive layer in consideration of sufficient permeability and maintenance of cohesiveness as a patch.

  You may mix | blend additional components, such as an antioxidant, a filler, a crosslinking agent, antiseptic | preservative, and an ultraviolet absorber, with an adhesive layer as needed. The additive component is appropriately blended within a range of preferably 10% or less, more preferably 5% or less, particularly preferably 2% or less, based on the total mass of the pressure-sensitive adhesive layer.

  The support on which the pressure-sensitive adhesive layer containing the above-described components is formed preferably does not affect the drug release, and can be stretchable or non-stretchable. Usable supports include polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester, nylon, polyurethane and other synthetic resin films, sheets, sheet porous bodies, sheet foams, Examples include woven or non-woven fabric, paper, and laminates or composites thereof. In consideration of irritation and followability to the skin, those having elasticity are preferable, and polyester woven fabric (knitted fabric) is particularly preferable.

  The thickness of the pressure-sensitive adhesive layer formed on the support is preferably 50 to 300 μm, more preferably 80 to 150 μm. In addition, when the thickness of the pressure-sensitive adhesive layer is less than 50 μm, the persistence of adhesiveness and adhesion tends to decrease, and when it exceeds 300 μm, the cohesive force and shape retention tend to decrease.

  The patch may be provided with a release liner on the adhesive layer in order to protect the adhesive layer. The release liner is not particularly limited as long as it has sufficient peelability from the pressure-sensitive adhesive layer, and a polyethylene terephthalate (PET) film, a polyethylene film, a polypropylene film, a polytetrafluoroethylene film, and the like can be used.

  The patch can be produced by a conventional method such as a solvent method or a hot melt method. For example, in the case of manufacturing by the solvent method, by adding other components to the organic solvent solution of the adhesive base to be blended, stirring, spreading on the support, drying to form an adhesive layer, A patch can be obtained. In addition, when the adhesive base to be blended can be applied by the hot melt method, after the adhesive base is dissolved at a high temperature, other components are added, and the mixture is stirred and spread on the support. By forming the agent layer, the patch of the present invention can be obtained. In addition, after forming a drug layer using a release liner instead of the support, the patch of the present invention can be obtained by pasting the support.

  EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example and a comparative example, this invention is not limited to a following example at all.

[Preparation of patch]
The components shown in Table 1 were mixed with toluene, and the mixture was stirred to obtain a uniform dissolved product. Next, this dissolved material is spread on a PET film, and after removing toluene by volatilization with a dryer, it is placed on a support (PET knitted fabric) and the adhesive layer is pressure-transferred onto the support to transfer the patch. Obtained. In addition, the numerical value of prescription shown in Table 1 points out "mass%". A styrene-isoprene-styrene block copolymer was used as an adhesive base, an alicyclic saturated hydrocarbon resin as a tackifier, and a saturated hydrocarbon plasticizer as a plasticizer.

[Drug content stability test]
The drug content stability of the patches of Example 3 and Comparative Example 1 was evaluated by the following method. That is, after the preparation was stored at 60 ° C. for 1 month, at 40 ° C. for 1 month and 3 months, and at 25 ° C. for 3 months, the content of lidocaine in the stored preparation was measured by liquid chromatography. The drug content (%) was calculated. The measurement was repeated three times, and the average value of the results obtained is shown in Table 2. As apparent from the results in Table 2, it was confirmed that the addition of 2-octyldodecanol as a solubilizer suppresses the decrease in drug content.

[Drug release rate stability test]
The stability of the drug release rate of the patches of Example 3 and Comparative Example 1 was evaluated by the following method. That is, after the preparation was stored at 60 ° C. for 1 month or 40 ° C. for 1 month, lidocaine was released from the stored preparation for 12 hours using a dissolution tester (with the eluate as purified water). The content of lidocaine in the collected eluate was measured by liquid chromatography, and the drug content (%) with respect to the prescribed amount was calculated. The measurement was repeated 5 times, and the average value of the obtained results is shown in FIGS. It was confirmed that addition of 2-octyldodecanol as a solubilizer suppresses a decrease in drug release rate.

[Adhesion test]
Using the patches of Examples 2 to 6, adhesion was evaluated by finger tack according to the following criteria. The obtained results are shown in Table 3.
○: Good △: Slightly weak ×: Weak

[Drug crystallization test]
The patches of Examples 1 to 7 and Comparative Example 1 prepared according to the formulations shown in Table 1 were stored at 4 ° C. for 7 days, and the crystallization of the drug in the adhesive layer was evaluated. The results are shown in Table 4.

[Evaluation of solubility and patch performance]
The solubility (25 ° C.) of lidocaine in the compounds shown in Table 5 was measured by the following method. That is, after adding lidocaine to each solubilizer so as to be saturated and sufficiently stirred, the mixture is filtered, and the lidocaine concentration in the filtrate is measured by liquid chromatography to calculate the saturation solubility (%). did. The measurement was repeated three times, and the average value of the results obtained is shown in Table 5.

Next, about the compound (No. 1-9) with the good solubility of lidocaine, 5 mass% lidocaine and base solution (5 mass% with respect to 5 mass% solubilizer with respect to the base composition whole quantity) Adhesive base, tackifying resin and plasticizer are mixed in toluene and stirred solution) to prepare a patch, and exudation from the base, skin irritation, and drug skin permeability are evaluated. This is shown in FIG. Note that the patch is a mixture of each component spread on a PET film, and the toluene is volatilized and removed by a dryer, and then covered with a support (PET knitted fabric), and the adhesive layer is pressure-transferred onto the support. And made.

It is a figure which shows the drug release stability of the patch of Example 3. It is a figure which shows the drug release stability of the patch of the comparative example 1.

Claims (5)

A patch comprising an adhesive layer on a support,
The pressure-sensitive adhesive layer contains at least one drug selected from the group consisting of lidocaine and pharmaceutically acceptable salts thereof and an alkyl alkanol ,
The said alkyl alkanol is at least 1 sort (s) selected from octyldodecanol and isostearyl alcohol, Comprising: The content is 4-12 mass% on the basis of the total mass of the said adhesive layer . The patch according to claim 1, wherein the alkyl alkanol is a 2-alkyl alkanol. The patch according to claim 1 or 2 , wherein the ratio of the alkyl alkanol to the drug is 0.8 to 2 in terms of mass ratio. The patch according to any one of claims 1 to 3 , wherein the pressure-sensitive adhesive layer contains a thermoplastic elastomer. The patch according to claim 4 , wherein the thermoplastic elastomer is a styrene-isoprene-styrene block copolymer.

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