JPH07304673A - Percutaneously absorbable cataplasm - Google Patents

Abstract

PURPOSE:To obtain a percutaneously absorbable cataplasm excellent in efficacy sustainability, percutaneous permeability of the medicinal ingredients, side effect suppression and low skin irritancy, thus useful as e.g. an analgesic, by providing one side of a substrate with a medicine-contg. tack agent layer consisting of a specific composition. CONSTITUTION:This percutaneously absorbable cataplasm is such that one side of a substrate is provided with a medicine-contg. tack agent layer which comprises 100 pts.wt. of a tack base, 0.1-40 pts.wt. of a morphinic acid-added salt, 0.1-30 pts.wt. of a morphine antagonist) acid-added salt and 0.1-15 pts.wt. of a percutaneous absorption promoter. The percutaneous absorption promoter, in turn, comprises (A) a compound with logP (P is the partition coefficient in octanol/water system) standing at -0.5 to 2, (B) a 2-8C oxycarboxylic acid or 2-8C bifunctional carboxylic acid, and (C) a fatty acid amide, a reaction product of a 10-14C aliphatic monocarboxylic acid and mono- or diethanolamine.

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 are narcotics having drug effects such as analgesia, antitussive and antidiarrheal action, and have been conventionally administered to patients in the dosage forms such as oral preparations, injections and suppositories. However, oral drugs do not last long and the injection itself causes a great deal of pain to the patient, and the suppository has a short duration, resulting in great pain to the patient.

Therefore, in recent years, in order to improve the above-mentioned drawbacks, researches on transdermal preparations of morphine acid addition salt have been actively conducted. While morphine acid addition salt has a medicinal effect such as analgesia, it has side effects such as dependence and respiratory depression, and it is necessary to administer a morphine antagonist at the same time in order to reduce such side effects. Examples of a combination system of a morphine acid addition salt and a morphine antagonist include, for example, Japanese Patent Publication No. Hei 4-501414, in which ethanol is added to enhance the absorption promoting effect of a narcotic analgesic. Has been done. However, since ethanol is highly volatile,
In industrialization, it was difficult to maintain the content uniformity, and there was a drawback that the skin irritation was high.

[0004]

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned drawbacks, and an object thereof is to continuously administer a morphine acid addition salt for a long time to reduce side effects. It is intended to provide a percutaneous absorption patch which is a skin absorption patch and has less skin irritation.

[0005]

As the support used in the present invention, a support that is usually used for patches can be used, and a support having flexibility and drug impermeability is preferable. preferable. For example, cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-
Examples thereof include vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyethylene, polyurethane, polyvinylidene chloride, and aluminum. These may be used as a single-layer sheet (film) or a laminated body of two or more kinds.

The adhesive base used in the present invention may be any adhesive as long as it has adhesiveness to the skin at room temperature, and examples thereof include an acrylic adhesive base and a rubber adhesive base.

As the acrylic adhesive base, a (co) polymer of (meth) acrylic acid alkyl ester obtained from an aliphatic alcohol having 2 to 18 carbon atoms and (meth) acrylic acid and / or the above (meth) ) A copolymer of alkyl acrylate and other functional monomer or copolymerizable monomer is preferably used.

As the above-mentioned (meth) acrylic acid alkyl ester, for example, methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate,
Isobutyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate , Lauryl (meth) acrylate, stearyl (meth) acrylate, dodecyl (meth) acrylate and the like.

Examples of the functional monomer include a monomer having a hydroxyl group and a monomer having a carboxyl group. As the monomer having a hydroxyl group, for example,
2-Hydroxyethyl (meth) acrylate, (meth)
Examples thereof include hydroxyalkyl (meth) acrylates such as hydroxypropyl acrylate. Examples of the monomer having a carboxyl group include α-β unsaturated carboxylic acids such as acrylic acid and methacrylic acid; maleic acid monoalkyl esters such as butyl maleate; (anhydrous) maleic acid; fumaric acid; crotonic acid and the like. Can be mentioned.

Examples of the copolymerizable monomer include, for example,
N-vinyl-2-pyrrolidone, vinyl acetate, styrene,
α-methylstyrene, vinyl chloride, acrylonitrile,
Examples thereof include ethylene, propylene and butadiene, which may be copolymerized.

A polyfunctional monomer may be added to the above copolymer. As the polyfunctional monomer,
For example, 1,6-hexane glycol dimethacrylate, 1,6-hexamethylene glycol dimethacrylate, tetraethylene glycol diacrylate, trimethylolpropane triacrylate, divinylbenzene, divinyltoluene, diallyl phthalate, diallyl malate, diallyl adipate, diallyl. Examples thereof include glycolate, triallyl isocyanurate, and diethylene glycol bisallyl carbonate.

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

A tackifier, a filler and the like may be added to the acrylic pressure-sensitive adhesive base within the pharmaceutically acceptable range.

The rubber-based pressure-sensitive adhesive base is a pressure-sensitive adhesive mainly composed of a rubber elastic body, and if necessary, a tackifying resin, a modifier such as a softening agent, and an antiaging agent may be added. Good. Examples of the rubber elastic body include natural rubber (cis-1,4-isoprene) and synthetic rubber (trans-1,4).
-Isoprene), styrene-isoprene-styrene block copolymer, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-butylene block copolymer, silicone rubber Etc.

Examples of the tackifying resin include rosin and rosin-based resins such as hydrogenated, disproportionated, polymerized or esterified rosin derivatives; phenolic resins such as α-pinene and β-pinene; terpene phenolic resins. An aliphatic, aromatic, alicyclic or copolymer petroleum resin; an alkyl-phenol resin; a xylene resin and the like. The amount of the tackifying resin used is the rubber elastic body 10
20 to 200 parts by weight is preferable with respect to 0 parts by weight.

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

As the above-mentioned pressure-sensitive adhesive base, an acrylic pressure-sensitive adhesive base is preferably used because the saturated solubility of the drug is high, and among them, (meth) acrylic acid alkyl ester and N are used.
A copolymer with -vinyl-2-pyrrolidone is preferably used.

The morphine acid addition salt used in the present invention is
It is a drug having analgesic, antitussive, antidiarrheal action, and the like, and examples thereof include morphine hydrochloride, morphine sulfate, and the like. When the addition amount of the morphine acid addition salt is small, the application area is large in order to administer the required amount, and as a result, the application property is poor,
It is difficult to apply the product for a long time and is inconvenient to use, and when the amount is too large, the adhesiveness is lowered and the applicability becomes poor, and the application for a long time becomes difficult.
It is limited to 1 to 40 parts by weight.

The morphine antagonist acid addition salt used in the present invention includes, for example, naloxone hydrochloride, nalorphine hydrochloride, levallorphan tartrate and the like, with naloxone hydrochloride being particularly preferred. When the amount of the morphine antagonist acid addition salt added is small, the application area is large in order to administer the required amount, and as a result, the adhesiveness is poor and the formulation is difficult to use because it is difficult to apply for a long time,
If the amount is too large, the adhesiveness is lowered and the sticking property is deteriorated, making it difficult to stick for a long time. Therefore, the amount is limited to 0.1 to 30 parts by weight with respect to 100 parts by weight of the adhesive base.

The transdermal absorption enhancer used in the present invention is at least one selected from the group consisting of compound (A), oxycarboxylic acid or divalent carboxylic acid (B) and fatty acid amide (C). .

The above compound (A) has a sufficient transdermal absorption effect even if its log P value (value showing hydrophobicity, where P is a partition coefficient in octanol / water system) is small or large. Is not obtained, it is limited to -0.5 to 2. The above logP value indicates hydrophilicity when it is small and lipophilicity when it is large, and is calculated (EUR.J.CHEM.-CHIMICA.THERAPEUTICA, JULY-AU).
See GUST, 1974-9, No4, p361-375).

Examples of the compound (A) include polyoxyethylene lauryl ether having 6 to 12 oxyethylene chains and aliphatic alcohol having 4 to 6 carbon atoms. Among them, polyoxyethylene (9) lauryl ether is preferable. preferable.

When the addition amount of the above compound (A) is small, the application area is large because the required amount is administered. As a result, the application property is poor, and it is difficult to apply for a long time, resulting in a formulation which is not easy to use. If this happens, the adhesiveness will decrease and it will be difficult to apply, so 0.1 to 1 to 100 parts by weight of the adhesive base is used.
Limited to 5 parts by weight.

The above-mentioned oxycarboxylic acid or divalent carboxylic acid (B) is limited to 2 to 8 carbon atoms because the transdermal absorption effect of the drug decreases as the carbon number increases. Examples of the oxycarboxylic acid include lactic acid, glyceric acid,
Examples thereof include tartaric acid and citric acid. Examples of the divalent carboxylic acid include oxalic acid, malonic acid, fumaric acid, maleic acid, malic acid, succinic acid, glutaric acid, adipic acid, phthalic acid and isophthalic acid. , Terephthalic acid, etc., among which lactic acid is preferred.

If the amount of the above-mentioned oxycarboxylic acid or divalent carboxylic acid (B) added is small, the amount of the necessary amount is administered, and the application area becomes large. As a result, the application property is poor and it is difficult to apply for a long time. It becomes a formulation that is not easy to use,
If the amount increases, the cohesive force of the pressure-sensitive adhesive base decreases, which causes adhesive residue and stringing during sticking and peeling. Therefore, the amount is limited to 0.1 to 15 parts by weight per 100 parts by weight of the pressure-sensitive adhesive base.

The fatty acid amide (C) has 10 to 10 carbon atoms.
14 is a reaction product of an aliphatic monocarboxylic acid with mono- or diethanolamine, and examples thereof include capric acid di (mono) ethanolamide, lauric acid di (mono) ethanolamide, palmitic acid di (mono) ethanolamide, and the like. Of these, lauric acid di (mono) ethanolamide is preferable.

When the amount of the above fatty acid amide (C) added is small, the required amount is administered and the application area is large. As a result, the application property is poor and it is difficult to apply for a long time, resulting in a formulation with poor usability. When the amount increases, the tackiness decreases,
Sticking becomes difficult. Furthermore, since it causes skin irritation and toxicity because it excessively migrates to the skin and strongly peels together with the stratum corneum, which is the outermost layer of the skin during peeling,
It is limited to 0.1 to 15 parts by weight with respect to 100 parts by weight of the adhesive base.

The constitution of the transdermal absorption patch of the present invention is as described above, and the production method thereof can be the conventionally known production method of an adhesive tape. A typical example thereof is a solvent coating method, and other examples include a hot melt coating method and an emulsion coating method.

[0029]

EXAMPLES The present invention will be described with reference to examples. Below "part"
“Parts by weight” means “parts by weight”. Preparation of transdermal patch (Example 1) 2-ethylhexyl acrylate 302.0
g (65 mol%), N-vinyl-2-pyrrolidone 9
8.0 g (35 mol%) and 1,6-hexamethylene glycol dimethacrylate 40.0 mg were charged into a separable flask, and 400.0 g of ethyl acetate was further added to adjust the monomer concentration to 50% by weight. This solution was heated to a temperature of 60 ° C. under a nitrogen atmosphere, 240 g of ethyl acetate and a polymerization initiator solution prepared by dissolving 2 g of lauroyl peroxide in 100 g of cyclohexane were added little by little.
The polymerization reaction was carried out over time to obtain an ethyl acetate solution of an acrylic pressure-sensitive adhesive base (hereinafter referred to as pressure-sensitive adhesive base A) having a solid content of 35% by weight.

100 parts of the adhesive base A as a solid content, 33 parts of morphine hydrochloride, 10 parts of naloxone hydrochloride, 8 parts of polyoxyethylene (9) lauryl ether, 1.6 parts of lactic acid and 4.9 parts of lauric acid diethanolamide. Blended in proportions,
Further, ethyl acetate was added so as to have a solid content concentration of 30% by weight, and mixed so that the whole was uniform to obtain a coating liquid.
This coating solution was applied onto a release paper, which was treated with polyethylene terephthalate (hereinafter referred to as PET) having a thickness of 48 μm, to give a thickness of 80 μm after drying, and then 60
Dry in a gear oven at ℃ for 30 minutes to form an adhesive layer, and then transferred to an EVA surface of a laminated film of polyethylene terephthalate and ethylene-vinyl acetate copolymer having a thickness of 38 μm (hereinafter referred to as PET-EVA), The transdermal patch of the present invention was obtained.

(Example 2) Adhesive base A as solid content 1
00 parts, 31 parts morphine hydrochloride, 16 parts naloxone hydrochloride,
7.8 parts of polyoxyethylene (9) lauryl ether,
Same as Example 1 except that 1.6 parts by weight of lactic acid was added, ethyl acetate was added so that the solid content concentration was 30% by weight, and the mixture was mixed so as to be uniform throughout, to obtain a coating liquid. Thus, the transdermal patch of the present invention was obtained.

(Example 3) Adhesive base A as solid content 1
00 parts, morphine hydrochloride 29 parts, naloxone hydrochloride 15 parts,
Same as Example 1 except that 1.5 parts by weight of lactic acid was added, ethyl acetate was added so that the solid content concentration was 30% by weight, and the mixture was mixed so as to be uniform throughout, to obtain a coating liquid. Thus, the transdermal patch of the present invention was obtained.

(Example 4) Adhesive base A as solid content 1
00 parts, morphine hydrochloride 31 parts, naloxone hydrochloride 15 parts,
Blended in a proportion of 7.7 parts of polyoxyethylene (9) lauryl ether, and further added ethyl acetate so as to have a solid content concentration of 30% by weight, and mixed so that the whole becomes uniform,
A transdermal patch of the present invention was obtained in the same manner as in Example 1 except that the coating liquid was used.

(Example 5) 2-ethylhexyl acrylate 36.4 g (10 mol%), 2-ethylhexyl methacrylate 313.3 g (80 mol%), dodecyl methacrylate 50.2 g (10 mol%), 1,6-hexa Charge 52.0 mg of methylene glycol dimethacrylate into a separable flask, and add ethyl acetate 40
0.0 g was added to make the monomer concentration 50% by weight.
This solution was heated to a temperature of 60 ° C. under a nitrogen atmosphere, a polymerization initiator solution prepared by dissolving 2 g of lauroyl peroxide in 100 g of cyclohexane and 240 g of ethyl acetate were added little by little, and a polymerization reaction was carried out for 12 hours. Solid content 3
A solution of 5% by weight of an acrylic adhesive base (hereinafter referred to as adhesive base B) in ethyl acetate was obtained.

100 parts of the adhesive base B as a solid content, 3.5 parts of morphine hydrochloride, 3.5 parts of naloxone hydrochloride, 3.5 parts of polyoxyethylene (9) lauryl ether, lactic acid.
5 parts and 3.5 parts of lauric acid diethanolamide were mixed, and ethyl acetate was further added so as to have a solid content concentration of 30% by weight, and the mixture was mixed so as to be uniform as a whole, thereby obtaining a coating liquid. In the same manner as in Example 1, the transdermal patch of the present invention was obtained.

Comparative Example 1 A transdermal patch was obtained in the same manner as in Example 1 except that polyoxyethylene (9) lauryl ether, lactic acid and lauric acid diethanolamide were not added.

Comparative Example 2 A transdermal patch was obtained in the same manner as in Example 5, except that polyoxyethylene (9) lauryl ether, lactic acid and lauric acid diethanolamide were not added.

Hairless Mouse Skin Permeation Test With respect to the transdermal patches prepared in the above Examples 1 to 5 and Comparative Examples 1 to 2, the skin permeation amounts of morphine hydrochloride and naloxone hydrochloride were measured by the following procedure. The Franz-type diffusion cell 1 shown in FIG. 1 has a bottomed cylindrical receptor tank 2 and a bottomed cylindrical donor tank 3 arranged thereon.
Consists of. An opening 4 is provided at the center of the bottom wall of the donor tank 3, and an upper flange 5 and a lower flange 6 are provided at the lower end of the donor tank 3 and the upper end of the receptor tank 2, respectively. Further, the receptor tank 2 is provided with a laterally projecting sampling port 7 on its side.

A hairless mouse (6 weeks old, male) was slaughtered by cervical dislocation, and the skin was immediately peeled off, and a 5 cm × 5 cm skin piece 8 from which subcutaneous fat was removed was placed on the upper flange 5 and the lower side of the diffusion cell 1. It was sandwiched between the flanges 6 so that the opening 4 of the donor tank 3 was completely closed by the skin piece 8. The receptor tank 2 is filled with a receptor liquid, and a magnetic stirrer 9 is placed inside.

The receptor liquid is NaH ₂ PO ₄ 5 × 10 ^-4
mol, Na ₂ HPO ₄ 2 × 10 ⁻⁴ mol, NaCl 1.
5 × 10 ^-2 mol, gentamicin 10 mg, distilled water 5
Dissolve in 00 ml and pH with 0.1N-NaOH aqueous solution.
After adjusting to 7.2, the volume was adjusted to 1000 ml with distilled water.

A test piece 10 obtained by punching out the percutaneous absorption patch prepared in Examples 1 to 5 and Comparative Examples 1 to 2 into a circular shape having a radius of 1 cm was applied to the upper surface of a skin piece 8, and then the diffusion cell 1 was applied to 3 pieces.
It was placed in a constant temperature bath at 7 ° C., and the receptor liquid was stirred by a magnetic stirrer. 24 hours after the start of the test,
The receptor liquid was sampled from the sampling port 7, and the amounts of morphine hydrochloride and naloxone hydrochloride in the sampled receptor liquid were measured by high performance liquid chromatography. The test was performed 3 times, and the average value is shown in Table 1.

[0042]

[Table 1]

[0043]

INDUSTRIAL APPLICABILITY The percutaneous absorption patch of the present invention comprises an adhesive base, a morphine acid addition salt and a morphine antagonist acid addition salt as a drug, and (A) logP as a percutaneous absorption promoter.
Value (a value showing hydrophobicity, where P is a partition coefficient in an octanol / water system) is a compound having a value of -0.5 to 2, (B) an oxycarboxylic acid having 2 to 8 carbon atoms or 2
Valency carboxylic acid, and (C) at least one selected from the group consisting of fatty acid amides, which are reaction products of aliphatic monocarboxylic acids having 10 to 14 carbon atoms and mono- or diethanolamine, are added, and thus the preparation is applied to the skin. When applied to the skin, the percutaneous absorption enhancer acts on the skin to enhance the skin permeability of morphine acid addition salt and morphine antagonist acid addition salt, and as a result, side effects can be suppressed without diminishing the analgesic effect. . Further, since the absorption enhancer of the present invention is a compound having low volatility, it can be easily industrialized.

[Brief description of drawings]

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

[Explanation of symbols]

 1 Diffusion Cell 2 Receptor Tank 3 Donor Tank 4 Opening 5 Upper Flange 6 Lower Flange 7 Sampling Port 8 Skin Piece 9 Magnet Stirrer 10 Test Piece

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area A61K 47/16 E

Claims (1)

[Claims] 1. A percutaneous absorption patch in which a drug-containing pressure-sensitive adhesive layer is formed on one surface of a support, wherein the drug-containing pressure-sensitive adhesive layer is 100 parts by weight of an adhesive base, and a morphine acid addition salt of 0.1-40. Parts by weight, 0.1 to 30 parts by weight of a morphine antagonist acid addition salt, and 0.1 to 15 parts by weight of a percutaneous absorption enhancer, wherein the percutaneous absorption enhancer has a (A) log P value (a value showing hydrophobicity). In the formula, P is a compound having a partition coefficient in an octanol / water system of −0.5 to 2, and (B) has 2 carbon atoms.
At least 1 selected from the group consisting of an oxycarboxylic acid or a divalent carboxylic acid, and (C) a fatty acid amide which is a reaction product of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms with a mono- or diethanolamine. A transdermal patch, characterized by being a seed.