JPH0733681A - Percutaneous patch - Google Patents

Abstract

PURPOSE:To obtain a percutaneous patch capable of uniformly supplying an acid adduct of morphine through the skin having a horny layer over a long period and excellent in sustained-release properties. CONSTITUTION:This percutaneous patch is made up by putting a pressure- sensitive adhesive layer composed of a pressure-sensitive adhesive agent, an acid adduct of morphine and a percutaneous absorption promoter [an organic compound having -0.5 to 2.0 log P value (It is an index representing hydrophobic properties. P in the formula denotes a partition coefficient in octanol/water system)] on one side of a substrate in layers.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a transdermal patch.

[0002]

2. Description of the Related Art Morphine acid addition salts, such as morphine hydrochloride, are drugs having medicinal properties such as analgesic, antitussive and antidiarrheal effects, and have been conventionally administered to patients in the dosage forms such as oral preparations, injection preparations and suppositories. Had been administered. However, the oral agent has a drawback that the drug effect does not last for a long time, and the injection agent has a drawback that the administration itself causes pain to the patient. On the other hand, while suppositories alleviate the above-mentioned drawbacks of oral preparations and injections, their improving effects are not sufficient. In addition, suppositories have the drawback that the discomfort of the patient due to the route of administration is great.

In recent years, various studies have been conducted to percutaneously absorb morphine hydrochloride for the purpose of eliminating the above-mentioned drawbacks. For example, morphine hydrochloride is used as a ternary solvent of l-menthol / ethanol / water. Dissolved percutaneous absorption preparations have been reported (Abstracts of the 6th Annual Meeting of the Pharmaceutical Society of Japan, Abstracts of the 7th Annual Meeting of the Japanese Society of Pharmaceutical Sciences, Abstracts of the 6th Symposium on Transdermal Absorptive Preparations). However, it was impossible to uniformly percutaneously absorb morphine for a long period of time and to supply it to the human body, because even if the above liquid agent was applied to the skin, it would dry out immediately.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above drawbacks, and its object is to:
It is an object of the present invention to provide a transdermal patch that can uniformly supply an acid addition salt of morphine for a long period of time.

[0005]

The support used in the present invention is preferably a flexible one which is impermeable or hardly permeable to the drug and is, for example, cellulose acetate, ethyl cellulose, polyethylene, polypropylene, Polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene-vinyl acetate copolymer, polyvinylidene chloride, polyurethane, nylon, polyethylene terephthalate, polybutylene terephthalate, ethylene-vinyl acetate-carbon monoxide copolymer, ethylene- A resin film such as a butyl acrylate-carbon monoxide copolymer, an aluminum sheet, or the like is used, and may be a laminated sheet of these and may be laminated with a woven fabric or a nonwoven fabric.

The pressure-sensitive adhesive layer used in the present invention is a pressure-sensitive adhesive,
It consists of acid addition salt of morphine (drug) and organic compound (transdermal absorption enhancer). The pressure-sensitive adhesive may be any one that is pharmaceutically acceptable, and for example, pressure-sensitive adhesives such as acrylic pressure-sensitive adhesives and rubber-based pressure-sensitive adhesives that are used at room temperature are preferably used.

The above-mentioned acrylic pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of a polymer of alkyl (meth) acrylate, and it is a functional monomer, a polyfunctional monomer or a vinyl compound copolymerizable with the alkyl (meth) acrylate. And the like.

As the above alkyl (meth) acrylate, when the carbon number of the alkyl group is reduced, 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. To 18 are preferable, and for example, methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, octyl (meth) ) Acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate and the like.

Examples of the functional monomer include, for example,
(Meth) acrylic acid, 2-hydroxyethyl (meth) acrylate, 2-hydroxypropyl (meth) acrylate, butyl maleate, maleic acid, maleic anhydride,
Fumaric acid, crotonic acid and the like are included, and when the content thereof is large, the cohesive force is improved but the adhesive force is reduced, so that the content is preferably 20% by weight or less in the adhesive, more preferably 1 to
It is 10% by weight.

Examples of the polyfunctional monomer include, 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 When the content is small, there is almost no effect of improving the cohesive strength, and when the content is large, the cohesive strength is improved but the adhesive strength is reduced.
5% by weight is preferred.

Examples of the vinyl compound include ethylene, vinyl chloride, propylene, acrylonitrile and N.
-Vinyl-2-pyrrolidone, vinyl acetate, styrene, α
-Methylstyrene, butadiene, etc. are included, and the content thereof is preferably 50% by weight or less, more preferably 40% by weight or less in the pressure-sensitive adhesive because the cohesive force is improved but the adhesive force is reduced.

As the above-mentioned acrylic adhesive, for example,
A copolymer of 55 to 89.5% by weight of 2-ethylhexyl acrylate, 10 to 45% by weight of N-vinyl-2-pyrrolidone and 0.005 to 0.5% by weight of a polyfunctional monomer is preferably used. Further, a tackifier, a filler and the like may be added to the acrylic pressure-sensitive adhesive within the pharmaceutically acceptable range.

The above-mentioned rubber-based pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of a rubber elastic body. Generally, a tackifier is added, and a softening agent or the like may be appropriately added. Examples of the rubber elastic body include cis-1,4-isoprene, trans-1,4-isoprene, polyisobutylene, polybutadiene, styrene-butadiene copolymer, styrene-
Isoprene copolymer, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-olefin-styrene block copolymer, styrene-isoprene-butylene block copolymer, polyvinyl ether, polyurethane, Silicon rubber etc. can be mentioned.

Examples of the tackifier include rosin, hydrogenated rosin, disproportionated rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, alkyl-phenol resin, xylene resin, coumarone resin,
Examples include coumarone-indene resin.

Examples of the softening agent include process oil, palm oil, almond oil, olive oil, camellia oil, persic oil, peanut oil, sesame oil, soybean oil, mink oil, cottonseed oil, corn oil, safflower oil, palm oil. Oil such as castor oil, polybutene, liquid isobutylene, liquid polyacrylate, beeswax, carnauba wax, and lanolin.

Examples of the acid addition salt of morphine (drug) include morphine hydrochloride, morphine sulfate, and the like. When the amount of addition is small, the drug effect is low, and when it is large, the adhesive strength of the adhesive is low. , The adhesive 100
0.1 to 40 parts by weight is preferable with respect to parts by weight.

The organic compound (transdermal absorption enhancer) has a large log P value (an index showing hydrophobicity, where P represents a partition coefficient in the octanole / water system), but is large. Even so, the effect of promoting percutaneous absorption of the drug is lowered, so the value is limited to -0.5 to 2.0. The log P value indicates hydrophilicity when it is small and lipophilicity when it is large, and can be calculated.
(EUR.J.MED.CHEM.-CHIMICA.THERAPEUTICA, JULY-AUGUS
See T, 1974-9, No4, p361-375. ) When the amount of the organic compound added is small, the effect of promoting percutaneous absorption of the drug decreases,
If it increases, the compatibility with the pressure-sensitive adhesive deteriorates and the pressure-sensitive adhesive strength of the pressure-sensitive adhesive decreases.
1 to 15 parts by weight is preferable.

In the transdermal absorption patch according to claim 2, the organic compound (transdermal absorption enhancer) is polyoxyethylene lauryl ether or polyoxyethylene cetyl ether.
Tellurium, at least one organic compound selected from the group consisting of aliphatic alcohols and aliphatic monocarboxylic acids is used, and these may be used alone or in combination. When the amount of addition is small, the effect of promoting percutaneous absorption of the drug is reduced, and when it is large, the compatibility with the adhesive is poor and the adhesive strength of the adhesive is reduced. -15 parts by weight is preferred.

The above polyoxyethylene lauryl ether has a oxyethylene chain number of 6 to 12 because the effect of promoting the percutaneous absorption of the drug decreases as the number of oxyethylene chains in the molecule decreases or increases. Limited.

As the above polyoxyethylene cetyl ether, the effect of promoting percutaneous absorption of the drug decreases as the number of oxyethylene chains in the molecule decreases or increases.
The number of oxyethylene chains is limited to 14 to 16.

The above-mentioned aliphatic alcohol is limited to 4 to 6 carbon atoms because the effect of promoting percutaneous absorption of the drug decreases as the carbon number decreases or increases. Examples thereof include butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol, hexyl alcohol and the like.

The above-mentioned aliphatic monocarboxylic acid is limited to have 2 to 5 carbon atoms, because the effect of promoting percutaneous absorption of the drug decreases as the carbon number decreases or increases. Examples thereof include acetic acid, propionic acid, butyric acid, valeric acid and the like.

In the transdermal absorption patch according to claim 3, the transdermal absorption enhancer of at least one of hydroxycarboxylic acid and dicarboxylic acid is further added to the pressure-sensitive adhesive layer according to claim 1. It is a thing. The hydroxycarboxylic acid and dicarboxylic acid are limited to have 2 to 8 carbon atoms because the effect of promoting percutaneous absorption of a drug decreases as the carbon number increases, and examples of the oxycarboxylic acid include lactic acid and glyceric acid. , Tartaric acid, citric acid and the like, and lactic acid is particularly preferably used.

Examples of the dicarboxylic acid include saturated aliphatic linear dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid and suberic acid, fumaric acid and maleic acid. Examples thereof include unsaturated aliphatic straight chain dicarboxylic acids, aromatic dicarboxylic acids such as phthalic acid, isophthalic acid and terephthalic acid, malic acid and the like.

If the added amount of the above-mentioned percutaneous absorption enhancer is small, the effect of promoting percutaneous absorption of the drug is lowered, and if it is increased, the compatibility with the adhesive is deteriorated and the adhesive strength of the adhesive is lowered. 0.1 to 15 parts by weight is preferable with respect to 100 parts by weight of the agent.

The thickness of the pressure-sensitive adhesive layer used in the present invention is not particularly limited, but if it becomes thin, the drug effect cannot be obtained unless a large amount of the drug is added, and the pressure-sensitive adhesive force of the pressure-sensitive adhesive decreases. When the thickness is increased, the drug in the pressure-sensitive adhesive layer is not effectively used, the cost is only increased and the performance is not improved. Therefore, the thickness is preferably 20 to 200 μm, more preferably 30 to 100 μm.

The composition of the percutaneous absorption 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 transdermal agent. Mixing an absorption promoter, coating on a support and drying, coating on release paper, drying and then transferring on a support, mixing hot-melt adhesive with drug and transdermal absorption promoter Then, a method of coating and drying on a support can be used.

The acid addition salt of morphine (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 preserved. In doing so, it is preferable to block oxygen or store it together with an oxygen scavenger. Therefore, a film having a low oxygen permeability, particularly an oxygen permeability of 100 cm ³ / m ³ · atm ·
24 hrs (25 ° C.) or less, more preferably 20 cm ³ /
It is preferable to wrap with a film of m ³ · atm · 24 hrs (25 ° C) or less, and as the film, for example, an aluminum sheet, an aluminum sheet whose surface is covered with polyethylene, polyethylene terephthalate, or the like is used.
, Polyvinylidene chloride film, polyvinylidene chloride-polyethylene laminated film, and the like. Barrieron-CX (manufactured by Asahi Kasei Kogyo Co., Ltd.), Pairflex (manufactured by Kureha Chemical Industry Co., Ltd.), Kayflex (manufactured by Kureha Chemical Industry Co., Ltd.), Bobron. (Manufactured by Nigo Film Co., Ltd.), Embra-OV (manufactured by Unitika Co., Ltd.), Rayfan NO (Toray Synthetic Film) and the like.

The above-mentioned oxygen scavenger is capable of adsorbing, absorbing or removing oxygen, and any conventionally known one can be used, and examples thereof include active iron oxide and hydrosulfite (sodium dithionite). ), Ascorbic acid, butylhydroxytoluene and the like powders, granules, tablets, etc., such as AGELESS Z-20 (manufactured by Mitsubishi Gas Chemical Co., Inc.), freshness-retaining agent F (manufactured by Toppan Printing Co., Ltd.), etc. Is marketed under the name of.

[0030]

EXAMPLES Next, examples of the present invention will be described. In the following, "parts" means "parts by weight". (Synthesis of Adhesives A and B) A predetermined amount of the monomer shown in Table 1 and 400.0 parts of ethyl acetate were supplied to a separable flask equipped with a stirrer and a cooling device, and heated to 60 ° C. while stirring and purging with nitrogen. did. A solution prepared by dissolving 2.0 parts of lauroyl peroxide in 100.0 parts of cyclohexane was divided into 10 parts, and 1 was added to a separable flask to initiate polymerization. Thereafter, the remaining 9 was added one by one every hour, and 240.0 parts of ethyl acetate was gradually added to carry out a polymerization reaction for 12 hours. After completion of the reaction, the mixture is cooled to a solid content concentration of 35.
Ethyl acetate was added so that it would be wt%.

[0031]

[Table 1]

Examples 1-28, Comparative Examples 1-10 100 parts of the pressure-sensitive adhesive shown in Table 2, Table 3 and Table 4, a predetermined amount of morphine hydrochloride and a percutaneous absorption enhancer were supplied to a dissolver to obtain a solid content. Ethyl acetate was added so that the concentration became 30% by weight, and the whole was uniformly mixed. The obtained mixed solution is applied on a polyethylene-treated polyethylene terephthalate film (thickness: 48 μm) and then dried to a thickness of 80 μm.
Of the polyethylene terephthalate-ethylene / vinyl acetate copolymer laminated film having a thickness of 38 μm was transferred onto the ethylene / vinyl acetate copolymer layer to obtain a transdermal patch.

[0033]

[Table 2]

[0034]

[Table 3]

[0035]

[Table 4]

Skin Permeation Test Using the patches obtained in Examples 1 to 28 and Comparative Examples 1 to 10, the skin permeation amount (μg) was measured by the diffusion cell 1 shown in FIG. The diffusion cell 1 is composed of a bottomed cylindrical receptor tank 2 and a bottomed cylindrical donor tank 3 arranged on the tank 2. An opening 4 is provided at the center of the bottom wall of the donor tank 3, and the bottom wall is provided with a flange 5 extending in the circumferential direction. A flange 6 is provided on the upper part of the receptor tank 2, and a sampling port 7 protruding laterally is attached to the side wall. The flange 5 and the flange 6 are overlapped facing each other, and the donor tank 3 and the receptor tank 2 are stacked in an airtight and concentric manner.
A magnetic stirring bar 9 is placed inside the receptor tank 2.

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.
The obtained skin piece 8 was sandwiched between the flange 5 and the flange 6 of the diffusion cell 1, and the opening 4 of the donor layer 3 was completely closed by the skin piece 8. The obtained transdermal patch 10 was cut into a circular shape (3.14 cm ² ) and attached to the center of the skin piece 8 so that the adhesive layer was in contact with the skin piece 8.

The receptor layer 2 was filled with a receptor solution and placed in a constant temperature bath maintained at a temperature of 37 ° C., and the magnetic stirrer 9 was rotated by a magnet stirrer to stir it. Twenty-four hours after the start of the test, 1 ml of the receptor solution was sampled from the sampling port 7, and the amount of the drug in the sampled receptor solution was measured by high performance chromatography. Upon collection of the receptor solution, the receptor solution was replenished after the collection. Further, the test was conducted with n = 2, and the average value was calculated.
The results are shown in Table 5.

The receptor liquid is NaH ₂ PO ₄ 5 × 10 ^-4.
Dissolve mol, Na ₂ HPO ₄ 2 × 10 ^-4 mol, NaCl 1.5 × 10 ^-1 mol and gentamicin 10 mg in 500 ml of distilled water.
After adjusting to pH 7.2 with 0.1N aqueous solution, add distilled water to 100
It was prepared by adjusting the volume to 0 ml.

[0040]

[Table 5]

Storability test Storage condition 1; Polyethylene terephthalate film (thickness 12 μm) on one surface of aluminum film (thickness 9 μm)
m) and a polyethylene film (thickness 12 μm) are laminated, and a polyethylene film (10 cm square) having a polyethylene film (thickness 40 μm) laminated on the other side is made to face each other, and transdermally by a heat seal. Absorption patch and oxygen absorber (Mitsubishi Gas Chemical Co., Ltd., Ageless Z-
20 、 Oxygen absorption capacity 20 cm ³ ) 1 piece is enclosed. Storage condition 2: As in the storage condition 1, only the transdermal patch is enclosed. Storage condition 3: In the same manner as in storage condition 1, a transdermal patch and 2.5 g of silica gel are enclosed. The 9 cm square patches obtained in Examples 1 to 28 were packaged under the above conditions, stored at 60 ° C. for 1 month, then taken out from the packaging material, and the degree of coloring of the adhesive layer in each patch was visually observed. Observed at. The results obtained were as shown below.

Storage condition 1; No coloration was observed for all patches obtained in Examples 1-28. Storage condition 2; Yellowing for all patches obtained in Examples 1-28. Storage condition 3; Example 1 Yellowing for all patches obtained in ~ 28

[0043]

The composition of the percutaneous absorption preparation of the present invention is as described above, and a specific organic compound [l
ogP value (an index showing hydrophobicity, where P represents a partition coefficient in an octanole / water system) -0.5 to 2.
[0] is used, the acid addition salt of morphine can be uniformly supplied for a long period of time through the skin having keratin.

Therefore, the percutaneously absorbable preparation of the present invention provides pain,
It can be effectively applied to patients presenting with symptoms such as cough and diarrhea.

[Brief description of drawings]

FIG. 1 is a perspective view showing a diffusion cell.

[Explanation of symbols]

 1 Diffusion Cell 2 Receptor Tank 3 Donor Tank 4 Openings 5, 6 Flange 7 Sampling Port 8 Skin Piece 9 Magnet Stirrer 10 Percutaneous Absorption Patch

Claims (3)

[Claims] 1. A percutaneous absorption patch comprising an adhesive layer comprising an adhesive, a drug and a transdermal absorption enhancer laminated on one surface of a support layer, wherein the drug is an acid addition salt of morphine. The transdermal absorption enhancer is an organic compound having a logP value (an index showing hydrophobicity, where P represents a partition coefficient in an octanole / water system) of −0.5 to 2.0. A percutaneous absorption patch characterized by being present. 2. The percutaneous absorption enhancer comprises polyoxyethylene lauryl ether having 6 to 12 oxyethylene chains, polyoxyethylene cetyl ether having 14 to 16 oxyethylene chains, and 4 to 6 carbon atoms. 2. The transdermal patch according to claim 1, which is at least one organic compound selected from the group consisting of the aliphatic alcohol and the aliphatic monocarboxylic acid having 2 to 5 carbon atoms. 3. The transdermal absorption patch according to claim 1, wherein the pressure-sensitive adhesive layer further contains a transdermal absorption promoter having at least one of hydroxycarboxylic acid and dicarboxylic acid having 2 to 8 carbon atoms. Agent.