JPH08143458A - Transdermal patch - Google Patents

Abstract

(57) [Summary] [Structure] The transdermal absorption patch of the present invention comprises an adhesive layer comprising an adhesive, a drug, a tackifier and a transdermal absorption enhancer on one surface of a support. In the skin absorption patch, the drug is an acid addition salt of morphine, the tackifier is a glycerin ester of hydrogenated rosin, and the transdermal absorption promoter is (A) 1 ogP value (P is an octanol / water system). Which has a partition coefficient of -0.5 to 2.0, and / or (B) an oxycarboxylic acid having 2 to 8 carbon atoms and / or a dicarboxylic acid having 2 to 8 carbon atoms. . [Effect] The action of the above specific percutaneous absorption enhancer can improve the transdermal absorbability of a drug, and the action of the above specific tackifier can ensure the required adhesive force even if the content of the drug is increased. Thus, this formulation provides stable, uniform transdermal penetration of acid addition salts of morphine over extended periods of time, resulting in pain, cough,
It can be effectively applied to patients with symptoms such as diarrhea.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transdermal patch, and more particularly to a transdermal patch capable of stably releasing a pharmaceutically acceptable acid addition salt of morphine over a long period of time.

[0002]

2. Description of the Related Art Morphine acid addition salts such as morphine hydrochloride are drugs having medicinal effects such as analgesia, antitussive, and emetic action, and have been conventionally used in the form of oral preparations, injection preparations, suppositories, etc. It has been administered to patients. However, the oral agent cannot maintain the drug effect for a long time, and the injection agent has a drawback that the administration itself causes pain to the patient. Although suppositories alleviate the above-mentioned drawbacks of oral preparations and injectable preparations, they have the drawbacks that their improving effects are not sufficient and that discomfort due to the administration route is great.

In recent years, for the purpose of eliminating these drawbacks,
Various studies have been conducted on the percutaneous absorption of morphine hydrochloride. For example, a percutaneous absorption preparation obtained by dissolving morphine hydrochloride in a ternary solvent of 1-menthol / ethanol / water has been reported (Japan The 6th Annual Meeting of the Pharmaceutical Society of Japan, the 7th Annual Meeting of the Pharmaceutical Society of Japan, and the 6th Symposium on Transdermal Formulations. However, since the above transdermal absorption preparation has a high volatility of ethanol, it is difficult to maintain a uniform content of the drug in the percutaneous absorption preparation during storage. There is a problem that the drug cannot be uniformly percutaneously absorbed over a period of time.

[0004] Japanese Patent Publication No. 2-500471 discloses a percutaneous absorption patch in which a pressure sensitive adhesive layer comprising a silicone pressure sensitive adhesive, a morphine narcotic analgesic and a percutaneous absorption enhancer is provided on one surface of a support. It is disclosed that the percutaneous absorption enhancer may be saturated or unsaturated fatty acids and their esters, alcohols, monoglycerides, acetates, diethanolamides and N, N-dimethylamides.

Further, Japanese Patent Laid-Open No. 61-83116 discloses a percutaneous absorption preparation comprising an opioid such as morphine, a percutaneous absorption enhancer and a carrier. The percutaneous absorption enhancer is saturated with 8 to 15 carbon atoms. It may be an aliphatic alcohol or fatty acid, or an unsaturated aliphatic alcohol or fatty acid having 8 to 15 carbon atoms.

[0006] However, all of these transdermal preparations have drawbacks in percutaneous absorption of the drug, and again, the drug cannot be uniformly percutaneously absorbed over a long period of time.

The present invention has been made in view of the above-mentioned drawbacks, and an object of the present invention is to enable the acid addition salt of morphine to be stably and uniformly released over a long period of time, and the morphine It is to provide a percutaneous absorption patch having excellent skin permeability.

[0008]

The transdermal patch according to the present invention comprises an adhesive layer comprising a pressure sensitive adhesive, a drug, a tackifier and a transdermal absorption enhancer on one surface of a support. In the skin absorption patch, the drug is an acid addition salt of morphine, the tackifier is a glycerin ester of hydrogenated rosin, and the transdermal absorption enhancer is (A) logP.
Value (P represents partition coefficient in octanol / water system)
An organic compound having -0.5 to 2.0, and / or
(B) It is characterized by comprising an oxycarboxylic acid having 2 to 8 carbon atoms and / or a dicarboxylic acid having 2 to 8 carbon atoms.

Each component of the transdermal absorption patch according to the present invention will be described in detail below.

The support is preferably flexible and drug-impermeable. For example, cellulose acetate, ethyl cellulose, polyethylene terephthalate, polybutylene terephthalate, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, plasticized vinyl acetate-vinyl chloride copolymer, nylon. Single-layer sheets of materials such as ethylene, vinyl acetate copolymer, ethylene-methyl acrylate copolymer, plasticized polyvinyl chloride, polyethylene, polyurethane, polyvinylidene chloride, and aluminum, or a laminate of two or more of these single-layer sheets. A laminate of a body or a single layer sheet and a woven or non-woven fabric is used.

The pressure-sensitive adhesive may be any pharmaceutically acceptable one, and acrylic pressure-sensitive adhesives, rubber pressure-sensitive adhesives and the like having pressure sensitivity at room temperature are preferably used.

As the acrylic pressure-sensitive adhesive, for example, a polymer mainly containing (meth) acrylic acid alkyl ester is preferably used. This may be a copolymer with a functional monomer, a polyfunctional monomer, a vinyl compound or the like which is copolymerizable with an alkyl (meth) acrylate.

As the (meth) acrylic acid alkyl ester, when the number of carbon atoms in the alkyl group is small, the cohesive force is improved, but the adhesive force is decreased, and when the alkyl group is increased, the adhesive force is improved but the cohesive force is decreased. 2-18 are preferable, for example, ethyl (meth) acrylate, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, (meth) Octyl acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate,
Examples thereof include isodecyl (meth) acrylate, lauryl (meth) acrylate, and stearyl (meth) acrylate.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and the like.

As the monomer having a hydroxyl group, for example, hydroxyalkyl (meth) acrylate such as 2-hydroxyethyl (meth) acrylate and 2-hydroxypropyl (meth) acrylate are preferably used.

As the monomer having a carboxyl group, for example, α, β-unsaturated carboxylic acid such as (meth) acrylic acid; maleic acid monoalkyl ester such as butyl maleate; maleic acid, maleic anhydride, fumaric acid. Acids and crotonic acid are preferably used.

Examples of the amide group-containing monomer include alkyl (meth) acrylamides such as acrylamide, dimethyl acrylamide and diethyl acrylamide; alkyl ether methylol (meth) acrylamides such as butoxymethyl acrylamide and ethoxymethyl acrylamide; and diacetone acrylamide. It is preferably used.

As the monomer having an amino group, for example, dimethylaminoethyl acrylate is preferably used.

When the content of the functional monomer increases, the cohesive force of the pressure-sensitive adhesive increases, but the pressure-sensitive adhesive force decreases, so the content of the pressure-sensitive adhesive is preferably 20% by weight or less, more preferably 1 to 1%.
0% by weight.

As the polyfunctional monomer, for example, 1,
6-hexane glycol dimethacrylate, tetraethylene glycol diacrylate, trimethylolpropane triacrylate, divinylbenzene, divinyltoluene, diallyl phthalate, diallylmaleate, diallyl adipate, diallyl glycolate, triallyl isocyanurate, diethylene glycol bisallyl carbonate, etc. Can be mentioned.

When the content of the polyfunctional monomer is small, there is almost no effect of improving the cohesive strength, and when it is large, the cohesive strength is improved but the adhesive strength is lowered.
It is 005 to 0.5% by weight.

Examples of the vinyl compound include vinyl acetate, styrene, α-methylstyrene, N-vinyl-2-pyrrolidone, vinyl chloride, acrylonitrile, ethylene, propylene and butadiene.

When the content of the vinyl compound is large, the cohesive strength is improved but the adhesive strength is lowered. Therefore, the content of the vinyl compound in the adhesive is preferably 50% by weight or less, more preferably 40% by weight or less.

Glycerin ester of hydrogenated rosin is added to the acrylic pressure-sensitive adhesive as a tackifier for adjusting the tackiness.

The content of the glycerol ester of hydrogenated rosin is preferably 1 to 100 parts by weight, more preferably 25 to 100 parts by weight, based on 100 parts by weight of the acrylic pressure-sensitive adhesive. If the content is too large or too small, the adhesive strength will not be improved.

If necessary, other tackifiers, fillers and the like may be added to the acrylic pressure-sensitive adhesive within the pharmaceutically acceptable range.

Other tackifiers include, for example, rosin-based resins, terpene-based resins such as α-pinene and β-pinene, terpene-phenolic resins, petroleum-based resins and the like.

Examples of the filler include hydrophobic silica, hydrophilic silica, calcium carbonate, titanium oxide, polyvinylpyrrolidone and the like.

The acrylic pressure-sensitive adhesive is prepared, for example, by blending the above-mentioned monomers and carrying out solution polymerization in the presence of a polymerization initiator.

The rubber-based pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of a rubber elastic body.

As the rubber elastic body, for example, cis-1,
4-isoprene (natural rubber), trans-1,4-isoprene, polyisobutylene, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene Examples thereof include block copolymers, styrene-olefin-styrene block copolymers, styrene-isoprene-butylene block copolymers, polyvinyl ethers, polyurethanes and silicone rubbers.

In the rubber-based pressure-sensitive adhesive, a glycerol ester of hydrogenated rosin is used as a tackifier for adjusting the tackiness. The content of the glycerol ester of hydrogenated rosin in the rubber adhesive is the same as that in the acrylic adhesive.

If necessary, the rubber-based pressure-sensitive adhesive may contain
Other tackifiers, softeners, anti-aging agents, etc. may be added.

Other tackifiers include, for example, rosin, hydrogenated rosin, disproportionated rosin, rosin ester, α
-Terpene resins such as pinene and β-pinene, terpenes-
Phenol resin, petroleum resin, alkyl-phenol resin, xylene resin, coumarone resin, coumarone-indene resin and the like can be mentioned.

Examples of the softening agent include oils such as process oil, palm oil, cottonseed oil, coconut oil and castor oil; polybutene, liquid isobutylene, liquid polyacrylate, beeswax, carnauba wax, lanolin and the like.

As the pressure-sensitive adhesive, an acrylic pressure-sensitive adhesive is preferable because it has a high saturated solubility of the drug, and in particular, (a) a (meth) acrylic acid alkyl ester and N-vinyl-2-pyrrolidone are used as monomer units. Copolymers containing, for example (meth) acrylic acid alkyl ester and N-vinyl-2
-Copolymer of pyrrolidone and polyfunctional monomer (weight ratio is, for example, (meth) acrylic acid alkyl ester 65-
99 parts: N-vinyl-2-pyrrolidone 1 to 35 parts: polyfunctional monomer 0 to 0.5 parts), b) a copolymer containing a plurality of (meth) acrylic acid alkyl esters as monomer units, for example, Copolymer of plural (meth) acrylic acid alkyl esters and polyfunctional monomer, more specifically, copolymerization of 2-ethylhexyl methacrylate, 2-ethylhexyl acrylate, dodecyl methacrylate and polyfunctional monomer A combination (weight ratio is, for example, 100 parts of 2-ethylhexyl methacrylate: 5 to 30 parts of 2-ethylhexyl acrylate: 5 to 30 parts of dodecyl methacrylate: 0 to 0.5 parts of a polyfunctional monomer) is preferably used. It

The acid addition salt of morphine which is a drug can be, for example, morphine hydrochloride, morphine sulfate and the like. When the content is low, the drug efficacy decreases, and when trying to secure the required drug efficacy, the application area becomes large and it becomes difficult to apply for a long time, and when it increases, the adhesive strength of the adhesive decreases and it is difficult to apply for a long time. Therefore, it is preferably 0.1 to 65 parts by weight, and more preferably 3 to 100 parts by weight of the adhesive.
60 parts by weight.

Next, the transdermal absorption enhancer will be described.

The log P value of the compound (A) is a value indicating the hydrophobicity (where P is the partition coefficient in the octanol / water system), and the transcutaneous release of the drug can be achieved regardless of whether the value is small or large. Since the absorption promoting effect decreases, -0.5 to
It is selected in the range of 2.0. A more preferable range of this value is -0.3 to 1.8.

The log P value indicates hydrophilicity when it is small and lipophilicity when it is large, and is calculated (EUR.J.MED.CHEM.-CHIMICA THERAPEUTICA, JUL
See Y-AUGUST, 1974-9, No4, p361-375).

Examples of the compound (A) include polyoxyethylene lauryl ether having 6 to 12 oxyethylene chains, which is a repeating unit, and 14 to 1 oxyethylene chains.
6 polyoxyethylene cetyl ether, carbon number 4-6
And aliphatic monocarboxylic acids having 2 to 5 carbon atoms, and these may be used alone or in combination.

Examples of the aliphatic alcohol having 4 to 6 carbon atoms include butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol and hexyl alcohol.

Examples of the aliphatic monocarboxylic acid having 2 to 5 carbon atoms include acetic acid, propionic acid, butyric acid and valeric acid.

When the content of the compound (A) is small, the effect of promoting the percutaneous absorption of the drug is lowered, and when it is attempted to secure the necessary drug effect, the sticking area becomes large and sticking for a long time becomes difficult. Since the compatibility with the adhesive becomes poor and the adhesive strength of the pressure-sensitive adhesive decreases, preferably 0.1 to 15 parts by weight, more preferably 1 to 100 parts by weight of the pressure-sensitive adhesive.
12 parts by weight.

As the oxycarboxylic acid and dicarboxylic acid (B), those having 2 to 8 carbon atoms are preferable because the effect of promoting percutaneous absorption of the drug decreases as the carbon number increases.

Examples of the oxycarboxylic acid include lactic acid, glyceric acid, tartaric acid and citric acid,
Examples of the dicarboxylic acid include oxalic acid, malonic acid,
Saturated aliphatic dicarboxylic acids such as succinic acid, glutaric acid, adipic acid, pimelic acid and suberic acid; unsaturated aliphatic dicarboxylic acids such as fumaric acid and maleic acid; aromatic dicarboxylic acids such as phthalic acid, isophthalic acid and terephthalic acid ;
Examples include malic acid. Lactic acid is particularly preferable as the oxycarboxylic acid and the dicarboxylic acid (B). When the content of oxycarboxylic acid or dicarboxylic acid (B) decreases, the effect of promoting percutaneous absorption of the drug decreases, and when trying to secure the necessary drug effect, the application area becomes large and it becomes difficult to apply for a long time. If so, the compatibility with the pressure-sensitive adhesive becomes poor and the adhesive strength of the pressure-sensitive adhesive decreases, so that it is preferably 0.1 to 15 parts by weight, and more preferably 1 to 12 parts by weight with respect to 100 parts by weight of the pressure-sensitive adhesive.

When the percutaneous absorption enhancer comprises the organic compound (A) and the oxycarboxylic acid and / or dicarboxylic acid (B), the organic compound (A) and the oxycarboxylic acid and / or dicarboxylic acid ( B)
The content of each is preferably 0.1 to 15 parts by weight, more preferably 1 to 12 parts by weight with respect to 100 parts by weight of the adhesive.

The preferred transdermal patch of the present invention has a compounding ratio of 0.1 to 6 parts by weight of the drug with respect to 100 parts by weight of the adhesive.
5 parts by weight, 1 to 100 parts by weight of tackifier and 0.5 to 15 parts by weight of percutaneous absorption enhancer.

A more preferable transdermal patch of the present invention is
The compounding ratio is 3 to 6 of the drug with respect to 100 parts by weight of the adhesive.
0 parts by weight, 25 to 100 parts by weight of tackifier and 1 to 12 parts by weight of percutaneous absorption enhancer.

The percutaneously absorbable patch of the present invention is usually provided with a release paper on the patch surface in order to protect the patch layer surface until use. As the release paper, polyethylene terephthalate film treated with silicon is often used, but the release paper is not limited thereto. The thickness of the release paper is 1000 μm or less, preferably 30 to 200 μm.

The thickness of the pressure-sensitive adhesive layer is not particularly limited, but if it becomes thin, the drug effect cannot be obtained unless a large amount of the drug is added, the adhesive force of the pressure-sensitive adhesive decreases, and if it becomes thick, The drug is not effectively used, and the cost does not increase, but the performance does not improve.
It is 0 μm, more preferably 30 to 100 μm.

The composition of the transdermal patch of the present invention is as described above, and any method may be adopted for its production.
For example, a solvent-based or emulsion-based adhesive, a drug and a percutaneous absorption enhancer are mixed, and the resulting mixture is applied onto a support and then dried. A method of laminating the obtained pressure-sensitive adhesive tank on a support, a method of mixing a hot-melt pressure-sensitive adhesive, a drug and a percutaneous absorption enhancer, coating the obtained mixture on a support and then drying can be applied. .

The acid addition salt of morphine, which is a drug, is a relatively unstable compound, and in particular, it decomposes with time in the presence of oxygen, so the transdermal patch of the present invention is used. When storing, it is preferable to block oxygen or store it together with an oxygen scavenger. The packaging material has a low oxygen permeability, preferably 100 cm ³ / m ² · atm · 24.
hrs (25 ° C.) or less, more preferably 20 cm ³ / m
A sheet or film having a temperature of ² · atm · 24 hrs (25 ° C) or less is used. Examples of such a film include an aluminum sheet, an aluminum sheet whose surface is covered with polyethylene, polyethylene terephthalate, etc., a polyvinylidene chloride film, a polyvinylidene chloride-polyethylene laminated film, and the like, Barrieron-CX (Asahi Kasei Corporation). Such as PAIRFLEX (made by Kureha Chemical Industry Co., Ltd.), K-Flex (made by Kureha Chemical Industry Co., Ltd.), Boblon (made by Nigo Film Co., Ltd.), Embra OV (made by Unitika Co., Ltd.), Rayfan NO (Toray Synthetic Film) It is marketed under the name.

As the oxygen scavenger, for example, active iron oxide,
Examples thereof include powdery materials such as hydrosulfite, ascorbic acid, butylhydroxytoluene, granules, tablets, etc., such as Ageless Z-20 (manufactured by Mitsubishi Gas Chemical Co., Inc.) and freshness-retaining agent F (manufactured by Toppan Printing Co., Ltd.). It is marketed under the name.

[0055]

Next, embodiments of the present invention will be described. Synthesis of acrylic pressure-sensitive adhesive (a) 2-ethylhexyl acrylate 302.0 g (65 mol%), N-vinyl-2-pyrrolidone 98.0 g (35 mol%) and 1,6-hexaneglycol dimethacrylate 40.0 mg Was charged into a separable flask equipped with a stirrer and a chiller, and ethyl acetate 400.0
g was added to adjust the monomer concentration to 50% by weight. The temperature of this solution was raised to 60 ° C. under a nitrogen atmosphere, and a solution of 2 g of lauroyl peroxide dissolved in 100 g of cyclohexane and 240 g of ethyl acetate were added little by little to carry out a polymerization reaction for 12 hours to obtain a solid content of 35% by weight. An ethyl acetate solution of the acrylic pressure-sensitive adhesive (a) was obtained.

Synthesis of acrylic pressure-sensitive adhesive (b) The charge amount of the monomer was adjusted to 2-ethylhexyl acrylate 3
6.4 g (10 mol%), 2-ethylhexyl methacrylate 313.3 g (80 mol%), dodecyl methacrylate 50.2 g (10 mol%) and 1,6-hexane glycol dimethacrylate 52.0 mg Except for this, the same operation as the acrylic pressure-sensitive adhesive (a) was performed to obtain an ethyl acetate solution of the acrylic pressure-sensitive adhesive (b) having a solid content of 35% by weight.

The mixing ratio of the monomers in the pressure sensitive adhesive synthesis is shown in Table 1.

[0058]

[Table 1] Example 1 100 parts by weight of acrylic pressure-sensitive adhesive (a) (as solid content),
Morphine hydrochloride 40.6 parts by weight, hydrogenated rosin glycerin ester (ester gum H, manufactured by Arakawa Chemical Industry Co., Ltd.) 50 parts by weight, polyoxyethylene (9) lauryl ether 10.
After 1 part by weight and 2.0 parts by weight of lactic acid were placed in a container, ethyl acetate was further added so that the solid content concentration was 30% by weight, and the whole was uniformly mixed to obtain a coating solution. This coating solution was applied on a silicon-treated polyester terephthalate film (thickness 48 μm) and then dried at 60 ° C. for 30 minutes in a gear oven to form an adhesive layer having a thickness 80 μm. Then, the ethylene / vinyl acetate copolymer surface of a 38 μm-thick support (a laminated film of polyethylene terephthalate and an ethylene-vinyl acetate copolymer) is bonded to this pressure-sensitive adhesive layer to obtain the transdermal patch of the present invention. It was

Examples 2 to 4 The present invention was carried out in the same manner as in Example 1 except that the amounts of the adhesive, the drug, the tackifier and the transdermal absorption enhancer were changed to the values shown in Table 2. To obtain a transdermal patch.

Comparative Examples 1 and 2 Example 1 was repeated except that the amounts of the adhesive, the drug and the percutaneous absorption enhancer were changed to the values shown in Table 2 and the tackifier (ester gum H) was used. The same procedure was followed to obtain a transdermal patch.

[0061]

[Table 2] Skin Permeability Test A skin permeation test was performed on the transdermal patches obtained in the above Examples and Comparative Examples using the Franz diffusion cell (1) shown in FIG. μg) was measured. In FIG. 1, the diffusion cell (1) is composed of an inverted hat-shaped receptor tank (2) and a hat-shaped donor tank (3) arranged thereon. The side wall of the receptor tank (2) is fitted with a sampling port (7) protruding laterally, and a magnetic stirrer (9) is installed inside the receptor tank (2).
Is placed.

Above the receptor tank (2) is the donor tank (3)
Receptor tank (2) placed with each opening facing each other
By fitting the flange (5) of the donor tank (3) to the flange (6) of the container, the receptor tank (2) and the donor tank (3) are stacked in an airtight manner.

A hairless mouse (6 weeks old, male) was sacrificed by cervical dislocation, and immediately the back skin was peeled off to remove subcutaneous fat and muscle layer to obtain a skin piece (8) of about 5 cm × 5 cm.

This skin piece (8) is attached to the flange of the diffusion cell (1).
It was held between the (5) and the flange (6) so that the opening (4) of the donor tank (3) was completely closed by the skin piece (8).

The percutaneous absorption patches obtained in Examples and Comparative Examples were cut into a circle (3.14 cm ² ), and the pressure-sensitive adhesive layer of the obtained test piece (10) was opened in the donor tank (3). It was attached to the central part of the skin piece (8) in the part (4).

The receptor bath (2) was filled with the receptor solution, and the receptor bath was placed in a constant temperature bath maintained at a temperature of 37 ° C.
(2) was installed, and the magnetic stirrer (9) was rotated by a magnetic stirrer to stir the solution. Test start 24
After 1 hour, 1m of the receptor solution from the sampling port (7)
1 was sampled, and the amount of the drug in this sampling solution was measured by high performance chromatography to obtain a test piece 3.1.
The skin permeation amount per 4 cm ² was determined. Upon collection of the receptor solution, the receptor solution was replenished after the collection. The test was performed three times for each patch, and the average value of the obtained measured values was calculated. The values thus obtained are shown in Table 3.

The receptor solution was NaH ₂ PO ₄
5 × 10 ⁻⁴ mol, Na ₂ HPO ₄ 2 × 10 ⁻⁴ mo
1, NaCl 1.5 × 10 ⁻¹ mol and gentamicin 10 mg were dissolved in distilled water 500 ml, and a 0.1 N aqueous solution of NaOH was added to adjust the pH to 7.2.
It was prepared by adding distilled water to make 1000 ml.

Adhesion Test a) A rabbit whose back was shaved with an electric clipper and an electric shaver was subjected to a transdermal absorbability test. Transdermal patches (3.14 cm ² / sheet) obtained in Examples and Comparative Examples
When three patches were applied to the back of the shave and the applied state was visually observed 1 hour after the application, all of the patches of Examples 1 to 4 maintained a good applied state. On the other hand, the patch of Comparative Example 1 was attached to the back of the shave, but about 50
% Was peeled from the shaving back, and the patch of Comparative Example 2 was completely removed from the shaving back.

B) The adhesive strength of the percutaneous absorption patches obtained in Examples and Comparative Examples was measured. The measuring method is J
IS Z0237 "Adhesive tape / adhesive sheet test method"
The 180 ° peeling method specified in 1. However,
A test piece having a width of 15 mm was used. The test was performed three times for each patch, and the average value of the obtained measured values was calculated. The values thus obtained are shown in Table 3.

[0070]

[Table 3] Percutaneous Absorption Test Male hairless rats (body weight approximately 170 hours) whose back was shaved with an electric clipper and an electric shaver 24 hours before application.
g) was subjected to a transdermal absorbability test. Three percutaneous absorption patches (6.7 cm ² / sheet) obtained in Example 1 were applied to the back of the shave and fixed with gauze and a plaster. After pasting 1, 2,
0.2m from the jugular vein at 4, 6, 8, 10 and 24 hours
l After collecting blood and separating plasma, the morphine concentration in plasma was adjusted to H
It measured on the following conditions by PLC. The test was performed on 10 hairless rats. The results are shown in FIG. 2 (values are mean ± standard error).

<HPLC conditions> Column: YMC Pack ODS-A AM-31
2 Mobile phase: pH 2.1 Phosphate buffer / acetonitrile /
Methanol (74/24/2) Flow rate: 2.0 ml / min Detector: Electrochemical detector

[0072]

EFFECTS OF THE INVENTION According to the transdermal patch of the present invention,
It is possible to improve the transdermal absorbability of a drug by the action of the above specific transdermal absorption promoter, and ensure the required adhesive force even if the content of the drug is increased by the action of the above specific tackifier. can do.

Thus, this patch can stably and uniformly permeate the acid addition salt of morphine over a long period of time, and can be effectively applied to patients with symptoms such as pain, cough and diarrhea. You can

[Brief description of drawings]

FIG. 1 is a perspective view of a diffusion cell used in a skin permeability test.

FIG. 2 is a graph showing the time course of morphine concentration in plasma.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical display location A61K 47/08 E 47/10 E 47/12 E (72) Inventor Mikiya Kitamura Mishima-gun, Osaka Prefecture Honcho Hyakuzan 2-1 Sekisui Chemical Co., Ltd.

Claims (11)

[Claims] 1. A percutaneous absorption patch comprising an adhesive layer comprising an adhesive, a drug, a tackifier and a transdermal absorption enhancer on one surface of a support, wherein the drug is an acid addition salt of morphine. The tackifier is a glycerin ester of hydrogenated rosin, and the transdermal absorption enhancer is (A) 1
an organic compound having an ogP value (P represents a partition coefficient in an octanol / water system) of −0.5 to 2.0, and / or (B) an oxycarboxylic acid having 2 to 8 carbon atoms and / or
Alternatively, a transdermal absorption patch consisting of a dicarboxylic acid having 2 to 8 carbon atoms. 2. The organic compound (A) is a polyoxyethylene lauryl ether having 6 to 12 oxyethylene chains, a polyoxyethylene cetyl ether having 14 to 16 oxyethylene chains, and an aliphatic alcohol having 4 to 6 carbon atoms. And a compound selected from the group consisting of aliphatic monocarboxylic acids having 2 to 5 carbon atoms, or a combination thereof, according to claim 1. 3. The aliphatic alcohol having 4 to 6 carbon atoms is a compound selected from the group consisting of butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol and hexyl alcohol, or a combination thereof. The transdermal patch according to claim 2. 4. The transdermal patch according to claim 2, wherein the aliphatic monocarboxylic acid having 2 to 5 carbon atoms is a compound selected from the group consisting of acetic acid, propionic acid, butyric acid and valeric acid, or a combination thereof. . 5. The transdermal patch according to claim 1, wherein the logP value is -0.3 to 1.8. 6. The transdermal patch according to claim 1, wherein the oxycarboxylic acid is a compound selected from the group consisting of lactic acid, glyceric acid, tartaric acid and citric acid, or a combination thereof. 7. The dicarboxylic acid is oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid,
The percutaneous absorption patch according to claim 1, which is a compound selected from the group consisting of suberic acid, fumaric acid, maleic acid, phthalic acid, isophthalic acid, terephthalic acid and malic acid, or a combination thereof. 8. The transdermal patch according to claim 1, wherein the organic compound (A) is contained in an amount of 0.1 to 15 parts by weight based on 100 parts by weight of the adhesive. 9. The oxycarboxylic acid and / or dicarboxylic acid (B) is contained in an amount of 0.1 per 100 parts by weight of the adhesive.
The percutaneous absorption patch according to claim 1, which is contained in an amount of -15 parts by weight. 10. The transdermal patch according to claim 1, wherein the tackifier is contained in an amount of 1 to 100 parts by weight based on 100 parts by weight of the adhesive. 11. A compounding ratio of 0.1 to 65 parts by weight of a drug and 1 to 100 parts of a tackifier to 100 parts by weight of an adhesive.
The percutaneous absorption patch according to claim 1, which is 0.5 to 15 parts by weight of the percutaneous absorption enhancer.