JP2596539B2 - Transdermal and transmucosal preparations - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to transdermal dosage forms, such as cataplasms and tapes, and / or transmucosal dosage forms, such as oral preparations, containing a drug. The present invention particularly relates to a transdermal / transmucosal preparation having enhanced transdermal absorbability of the drug.

(Prior art) In order to obtain systemic or local drug efficacy, transdermal and / or transmucosal formulations are used to absorb drugs (bioactive substances) through the skin or mucous membranes. Have been done. This transdermal / transmucosal administration method has many advantages over the conventional oral administration method. For example, when a drug is orally administered, the drug absorbed in the intestine circulates to the liver and is metabolized, so that a considerable amount of the drug is degraded before exerting its medicinal effect. In contrast, transdermal and transmucosal administration methods
The absorbed drug does not pass through the liver during the first circulation in the body. Therefore, the metabolism in the liver does not significantly reduce the efficacy. Oral administration of non-steroidal anti-inflammatory drugs tends to cause gastrointestinal disorders, but transdermal and transmucosal administration is unlikely to cause such gastrointestinal disorders. Controlling the absorption of a drug can reduce the side effects caused by the absorption of a large amount of the drug in a short time. If a constant blood concentration can be maintained over a long period of time, the number of drug administrations can be reduced.

However, even when a drug is administered using a transdermal / transmucosal preparation, the drug is less likely to penetrate the skin or mucous membrane, and the bioavailability often decreases. Especially,
There is a stratum corneum on the skin surface, and since this stratum corneum has a barrier function for preventing invasion of foreign substances into the body, a sufficient amount of a drug capable of exerting a pharmacological effect is often not absorbed through the skin.

Preparations containing an absorption enhancer to reduce the barrier function of the stratum corneum and absorb a sufficient amount of the drug have been manufactured. For example, JP-A-57-9714, JP-B-58-43368, JP-A-58-52216, JP-A-58-79918,
JP-A-60-13720 and JP-A-60-11431 disclose patches and the like in which an absorption enhancer is contained in an adhesive layer.

Among the above-mentioned absorption promoters, for example, salicylic acid, urea,
Dimethyl sulfoxide is known to dissolve keratin, but the percutaneous absorption of the drug is not always good even if it is added. Propylene glycol, glycerin,
Sodium pyrrolidonecarboxylate can retain moisture in the stratum corneum, but has little effect on promoting drug absorption. Dimethyl sulfoxide and the like tend to irritate the skin and mucous membranes and cause erythema and rash. When a tape preparation is prepared by adding a dicarboxylic acid ester such as diisopropyl adipate or a fatty acid ester to the adhesive layer, the compatibility between the adhesive and the drug is reduced, so that the drug is easily precipitated from the adhesive. Adhesion may decrease. Sulfur-containing compounds such as calcium thioglycolate also cause asthma. In addition to the above compounds, myristic acid esters, adipic acid esters, lauryl sulfate esters, polyoxyethylene alkyl ethers, and the like have also been disclosed. Not enough. As described above, at present, a transdermal / transmucosal preparation capable of effectively absorbing a drug has not yet been obtained.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional disadvantages, and aims at providing a preparation capable of effectively absorbing the contained drug through the skin and mucous membranes. It is in. Another object of the present invention is to provide a transdermal / transmucosal preparation which enhances the percutaneous / transmucosal absorbability of a drug contained therein and contains an absorption enhancer which is non-irritating to the skin and mucous membranes and is safe for the living body Is to provide. Still another object of the present invention is to provide a transdermal preparation containing an absorption enhancer which does not change the properties of the base, does not precipitate the drug, and does not cause the drug to be denatured. -To provide a transmucosal preparation.

(Means for Solving the Problems) The transdermal / transmucosal preparation of the present invention is a preparation in which a pressure-sensitive adhesive layer containing a drug and an absorption enhancer for the drug is provided on one surface of a support, Is isosorbide dinitrate or hydrocortisone acetate, and the absorption enhancer is a fatty acid monoalkylolamide and / or an alkylene oxide adduct of a fatty acid monoalkylolamide, wherein the fatty acid has 6 to 18 carbon atoms. The above object is achieved.

The absorption promoter used in the present invention is a fatty acid monoalkylolamide (1) and / or an alkylene oxide adduct of a fatty acid monoalkylolamide (II) represented by the following formula: R ₁ CONH—R ₂ —OH _{(I) R 3 CONH-R} 4 O- (R 5 O) n -H (II) wherein R _1, R ₃ is an aliphatic hydrocarbon group having 5 to 17 carbon atoms; R _2,
R ₄ is a saturated hydrocarbon group having 2 to 6 carbon atoms; R ₅ is a saturated hydrocarbon group having 2 to 4 carbon atoms
And n is an integer of 1 to 40.

Fatty acids capable of forming the above compounds have 6 to 6 carbon atoms.
18 (corresponding R ₁ and R ₃ have 5 to 17 carbon atoms), preferably 8 to 16. When the number of carbon atoms is out of the range of 6 to 18, the absorbability of the drug contained in the preparation decreases. Fatty acids include caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, margaric acid, stearic acid, hexadecenoic acid,
Oleic acid, linoleic acid and the like can be mentioned. These are 2
They may be used as a mixture of more than two species. For example, a coconut oil fatty acid which is a mixture thereof is suitably used.

When the monoalkylolamine is condensed with these fatty acids, the above-mentioned compound (I) is obtained. The monoalkylolamine used has 2 to 6 carbon atoms (corresponding to the carbon numbers of R ₂ and R ₄ ). When the carbon number is within this range,
The smaller the carbon number, the better the drug absorption. Examples of the monoalkylolamine include monoethanolamine, monoisopropanolamine, monobutanolamine, and monohexanolamine.

When an alkylene oxide is further added to the fatty acid monoalkylolamide (I), an alkylene oxide adduct of the fatty acid monoalkylolamide (polyoxyalkylene fatty acid monoalkylolamide) (II) is obtained. The addition of the alkylene oxide increases the stability and improves the hydrolysis resistance. This improves the stability of the drug. This effect is remarkable especially when the drug is alkaline and unstable. The addition mole number of the alkylene oxide is 1 to 40, preferably 1 to 20.
It is. When the number of added moles exceeds 40, the absorbability of the drug decreases. Two or more absorption promoters may be used in combination. The alkylene group of the alkylene oxide has 2 carbon atoms.
To 4, and ethylene oxide, propylene oxide, and butylene oxide are used.

The absorption enhancer is contained in the preparation at a ratio of 0.5 to 50% by weight. This ratio indicates the content of the whole preparation, for example, in the case of patches such as tape preparations and cataplasms.
It shows the content relative to the portion excluding the support. The same applies to the drug content described below. If the amount of the absorption promoter is too small, the effect of promoting absorption of the drug cannot be obtained. Even if the amount is excessive, not only does the absorption of the drug not improve any more, but also, for example, in the case of a tape preparation, the adhesive properties are reduced, and the compatibility with the adhesive may be deteriorated.

The drug (bioactive substance) used is limited to isosorbide dinitrate or hydrocortisone acetate. The amount of these drugs varies depending on the type of drug, the purpose of use of the preparation, and the like, but usually the drug is contained in the preparation at a ratio of 0.1 to 30% by weight.

Among the transdermal / transmucosal preparations of the present invention containing these drugs and the above-mentioned absorption enhancers, transdermal preparations include tape preparations, patches and cataplasms. Transmucosal preparations include oral preparations.

Among the above-mentioned preparations, a tape preparation and a patch have a pressure-sensitive adhesive layer containing a drug and an absorption enhancer formed on one surface of a support. The base (adhesive) of the tape preparation or the patch is not particularly limited as long as it has an adhesive force capable of fixing the base to the skin surface for a long time at normal temperature. For example, pressure-sensitive adhesives such as acrylic, rubber-based, and silicone resin-based pressure-sensitive adhesives can be used. Usually, acrylic-based and rubber-based pressure-sensitive adhesives are used.

In the case of acrylic pressure-sensitive adhesives, the (co) polymer of alkyl (meth) acrylate obtained from an aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid, and / or A copolymer of an alkyl (meth) acrylate and another functional monomer is preferably used.

Examples of the above (meth) acrylate include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, and stearyl acrylate. , Methyl methacrylate, ethyl methacrylate,
Butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate,
Examples include decyl methacrylate, isodecyl methacrylate, lauryl methacrylate, and stearyl methacrylate.

The functional monomer includes a monomer having a hydroxyl group,
Examples thereof include a monomer having a carboxyl group, a monomer having an amide group, and a monomer having an amino group.
Examples of the monomer having a hydroxyl group include hydroxyalkyl (meth) acrylates such as 2-hydroxyethyl (meth) acrylate and hydroxypropyl (meth) acrylate. Examples of the monomer having a carboxyl group include α-β unsaturated carboxylic acids such as acrylic acid and methacrylic acid; monoalkyl maleates such as butyl maleate; maleic acid; coumaric acid; and crotonic acid. Maleic anhydride also provides the same (co) polymerization component as maleic acid. Examples of the monomer having an amide group include alkyl (meth) acrylamide such as acrylamide, dimethylacrylamide, and diethylacrylamide; and alkyl ether methylol (meth) acrylamide such as butoxymethylacrylamide and ethoxymethylacrylamide. Examples of the monomer having an amino group include dimethylaminoacrylate.

Examples of copolymerizable monomers other than the above include vinyl acetate, styrene, α-methylstyrene, vinyl chloride, acrylotrile, ethylene, propylene, butadiene, and the like, and these may be copolymerized. The pressure-sensitive adhesive preferably contains 50% by weight or more of a (meth) acrylic acid alkyl ester as a (co) polymerization component.

As the rubber-based adhesive, natural rubber, synthetic isoprene rubber, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, styrene-butadiene copolymer, styrene-isoprene copolymer and the like are used.
Silicone rubber such as polyorganosiloxane is used as the silicone resin-based pressure-sensitive adhesive.

In the above-mentioned pressure-sensitive adhesive, if necessary, various compounding agents such as rosin resin, polyterpene resin, cumarone-indene resin, petroleum resin, terpene phenol resin, etc .; liquid polybutene, mineral oil, lanolin, liquid poly Plasticizers such as isoprene and liquid polyacrylate; fillers; antioxidants;

As a support for a tape preparation, a patch, and a cataplasm described later, a support usually used for a patch is used. Such support materials include cellulose acetate, ethyl cellulose, polyethylene terephthalate,
Examples include vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, and aluminum. These are used, for example, as a single-layer sheet (film) or a laminate of two or more sheets (laminate). Materials other than aluminum may be used as a woven or nonwoven fabric.

A base (adhesive) layer containing a drug and an absorption promoter is formed on the surface of the support to obtain a tape preparation or a patch. To form the base layer, various coating methods such as a solvent coating method, a hot melt coating method, and an electron beam curing emulsion coating method can be used. Among them, a solvent coating method is suitably used. To form a base layer by solvent coating, for example,
The base is diluted with a suitable solvent and the drug, absorption enhancer,
Further, if necessary, a compounding agent is added and uniformly mixed, and the obtained solution is applied to the surface of the support and dried. Instead of applying the solution directly to the surface of the support, the solution may be applied to a release paper coated with a silicone resin or the like, and then dried and then brought into close contact with the support. Such a release paper is used to protect the surface of the base layer of the patch until use. In coating methods other than the solvent coating method, it is recommended to arrange a release paper after the base layer is formed to protect the base layer surface. The thickness of the base layer also varies depending on the purpose of use, but is usually 30 to 200 μm. 30μ
If it is less than m, it cannot contain the required amount of drug,
The tackiness is also insufficient. When the thickness exceeds 200 μm, the drug contained in the base layer near the support is not sufficiently diffused, and the drug release property is reduced.

The cataplasm also has a drug-containing layer containing a drug and an absorption promoter formed on one surface of the support. Usually, they are less adherent than tape preparations and patches, so they are fixed to the skin surface with a bandage. Examples of bases for cataplasms include natural polymers such as sodium alginate, gelatin, corn starch and tragacanth; cellulose polymers such as methyl cellulose, hydroxyethyl cellulose and carboxymethyl cellulose; starch polymers such as dextrin and carboxymethyl starch; polyvinyl alcohol; Synthetic polymers such as sodium polyacrylate, methoxyethylene-maleic anhydride copolymer, polyvinyl ether, and polyvinylpyrrolidone are used.

The base, the drug and the absorption enhancer are uniformly mixed, and a drug-containing layer is formed on the surface of the support to obtain a desired poultice. The drug-containing layer further includes purified water; a humectant such as a polyhydric alcohol (eg, glycerin, propylene glycol); kaolin, bentonite, zinc white,
Inorganic fillers such as titanium dioxide; viscosity modifiers; crosslinking agents;
Antioxidants; and the like.

(Action) When the transdermal / transmucosal preparation of the present invention is brought into close contact with the skin or mucosal surface, the contained drug is easily absorbed through the skin or mucous membrane. Although the detailed mechanism is unknown,
It is considered that the absorption enhancer acts on the skin or mucous membrane to denature the protein, increase the water content and soften the protein. Therefore, it is considered that the stratum corneum on the skin surface, which is usually hard to penetrate the drug, is also softened and the contained drug is easily absorbed through the skin.

Since a sufficient amount of the drug is easily absorbed to obtain the required medicinal effect, it is not necessary to incorporate a large amount of the drug into the preparation as in the related art. In other words, the bioavailability of the drug is high. Such a transdermal / transmucosal absorption promoting effect is much higher than when a conventional absorption enhancer is used. further,
The absorption enhancer used in the present invention has no irritation to the skin and has high safety. It does not denature the contained drug. Excellent compatibility with base. Since the compatibility between the drug and the base does not change, the drug does not precipitate from the prepared preparation. When used as a tape or patch,
The absorption promoter itself does not adversely affect the physical properties of the pressure-sensitive adhesive, such as reducing the pressure-sensitive adhesive function of the pressure-sensitive adhesive.

(Example) Hereinafter, the present invention will be described with reference to examples.

Example 1 (A) Preparation of patch (tape preparation): An ethyl acetate solution containing 22% by weight of a copolymer consisting of 97% by weight of 2-ethylhexyl acrylate and 3% by weight of acrylic acid was prepared. To 100 parts by weight of this solution, 1.7 parts by weight of isosorbide dinitrate as a drug and 1.1 parts by weight of polyoxyethylene (2) coconut oil fatty acid monoethanolamide as an absorption promoter were added, followed by sufficient stirring. This was applied on a polyamide film and dried in a gear oven at 70 ° C. for 20 minutes to obtain a patch having a pressure-sensitive adhesive layer thickness of 50 μm.

(B) Performance evaluation of patch: The patch obtained in section (A)
It was cut into a size of 50 cm ² , and this was affixed to the skin surface of the depilated back of a Japanese white rabbit. 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 10 hours and 24 hours later, blood was collected from the auricular vein of rabbits and centrifuged to obtain plasma.
This was extracted with hexane and subjected to Ni ⁶³ ECD gas chromatography to measure the drug concentration. Table 1 shows the results. After 24 hours, the patch was peeled off, but redness appeared on the skin surface.
No rash or other disorders were observed.

Comparative Example 1 (A) Preparation of Patch (Tape Preparation): Same as Example 1 (A) except that no absorption promoter was added.

(B) Performance evaluation of patch: Using the patch obtained in this comparative example (A), the same procedure as in Example 1 (B) was carried out. Table 1 shows the results. The patch was peeled off 24 hours later, but no redness or rash was observed on the skin surface.

Example 2 (A) Preparation of patch (tape preparation): Acetic acid was added to 100 parts by weight of an ethyl acetate solution containing 20% by weight of a copolymer consisting of 60 parts by weight of 2-ethylhexyl acrylate and 40 parts by weight of vinyl acetate. An acetone solution of 0.12 parts by weight of hydrocortisone and 0.5 part by weight of polyoxyethylene (2) coconut oil fatty acid monoethanolamide (absorption promoter) were uniformly mixed. This is applied on a polyethylene film and
After drying for 5 minutes, a patch having a pressure-sensitive adhesive layer thickness of 50 μm was obtained.

(B) Performance evaluation of patch: Using the patch obtained in the section (A) of this example, a drug permeability test was performed using an in vitro diffusion cell. Table 2 shows the drug permeability (%) after 24 hours.
The test method is as follows.

Drug permeability test method using in vitro diffusion cell:
Prepare a 25 cm Franz diffusion cell. Physiological saline adjusted to pH 7.2 is put in the receptor part of the Franz diffusion cell, and warm water of 37 ° C is circulated on the outer wall part to keep the temperature of the receptor part constant. A test piece (circle having a diameter of 2 cm) of the patch obtained in item (A) is attached to the epidermis (4 cm × 4 cm) of the depilated flank of a rabbit (male), and the epidermis is attached to a cell. Fill the receptor liquid with care so that no air bubbles enter between the skin and the receptor liquid surface. After 24 hours, the receptor liquid is sampled, the drug concentration is measured by high performance liquid chromatography using a reversed phase column, and the drug permeability is calculated from the following equation.

Comparative Example 2 (A) Preparation of Patch (Tape Preparation): Same as Example 1 (A) except that no absorption promoter was added.

(B) Performance evaluation of patch: The same procedure as in Example 2 (B) was carried out using the patch obtained in this comparative example (A). Table 2 shows the results.

Comparative Example 3 (A) Preparation of Patch (Tape Preparation): Same as Example 1 (A) except that 1 part by weight of urea was used as an absorption enhancer.

(B) Performance evaluation of patch: Using the patch obtained in this comparative example (A), the same procedure as in Example 2 (B) was performed. Table 2 shows the results.

Comparative Example 4 (A) Preparation of Patch (Tape Preparation): Same as Example 1 (A) except that 1 part by weight of diisopropyl adipate was used as an absorption enhancer.

(B) Performance evaluation of patch: Using the patch obtained in this comparative example (A), the same procedure as in Example 2 (B) was performed. Table 2 shows the results.

Comparative Example 5 (A) Preparation of Patch (Tape Preparation): Same as Example 1 (A) except that 1 part by weight of propylene glycol was used as an absorption prompting agent.

(B) Performance evaluation of patch: Using the patch obtained in this comparative example (A), the same procedure as in Example 2 (B) was performed. Table 2 shows the results.

As shown in Table 2, the preparation of the present invention (tape preparation) using the fatty acid monoalkylolamide ethylene oxide adduct as an absorption enhancer is superior in drug permeability through the skin as compared with a preparation using a conventional absorption enhancer. You can see that it is.

Example 3-1 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that lauric acid monoethanolamide was used as an absorption promoter.

(B) Performance evaluation of patch: Using the patch obtained in section (A) of this example, a drug permeability test using an in vitro diffusion cell was performed according to section 2 (B), and after 20 hours. The drug permeability (%) was calculated. However, the excised skin of a nude mouse was used instead of the rabbit flank epidermis. Table 3 shows the results.

Separately, the patch obtained in section (A) of this example was treated with
Stored for months. One month later, the amount of drug in the preparation was measured,
The drug residual rate (%) was calculated. Table 3 shows the results.

Example 3-2 (A) Preparation of Patch (Tape Preparation): Same as Example 1 (A) except that polyoxyethylene (2) lauric acid monoethanolamide was used as an absorption promoter.

(B) Performance evaluation of patch: Using the patch obtained in section (A) of this example, the drug permeability and drug residual rate were measured and calculated in the same manner as in section 3-1 (B). Table 3 shows the results.

Example 3-3 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that polyoxyethylene (5) lauric acid monoethanolamide was used as an absorption promoter.

(B) Performance evaluation of patch: Using the patch obtained in section (A) of this example, the drug permeability and drug residual rate were measured and calculated in the same manner as in section 3-1 (B). Table 3 shows the results.

Example 3-4 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that polyoxyethylene (20) lauric acid monoethanolamide was used as an absorption promoter.

(B) Performance evaluation of patch: Using the patch obtained in section (A) of this example, the drug permeability and drug residual rate were measured and calculated in the same manner as in section 3-1 (B). Table 3 shows the results.

Example 3-5 (A) Preparation of patch (tape preparation): Same as Example 1 (A) except that oleic acid monoethanolamide was used as an absorption enhancer.

(B) Performance evaluation of patch: Using the patch obtained in section (A) of this example, the drug permeability and drug residual rate were measured and calculated in the same manner as in section 3-1 (B). Table 3 shows the results.

Comparative Example 6 (A) Preparation of Patch (Tape Preparation): Same as Example 1 (A) except that no absorption enhancer was added.

(B) Performance evaluation of patch: Using the patch obtained in section (A) of this comparative example, the drug permeability and drug residual rate were measured and calculated in the same manner as in section 3-1 (B). Table 3 shows the results.

From Table 3, it can be seen that the preparation (patch) of the present invention has excellent heat stability and can be stably stored for a long period of time, and the drug is not degraded by the contained absorption enhancer. When the fatty acid monoalkylolamide ethylene oxide adduct is used as the absorption enhancer, the stability is improved as compared with when the fatty acid monoalkylolamide is used as the absorption enhancer. The smaller the number of moles of ethylene oxide added, the higher the skin permeability of the drug.

(Effect of the Invention) According to the present invention, by adding a fatty acid monoalkylolamide and / or a fatty acid monoalkylolamide alkylene oxide adduct to a preparation as an absorption enhancer, isosorbide dinitrate or hydrocortisone acetate can be obtained. Which is excellent in transdermal or transmucosal absorbability of a drug consisting of Because of its excellent drug absorbability, it is not necessary to incorporate a large amount of drug into the preparation as in the prior art in order to obtain the required pharmacological effect. The absorption enhancer used does not irritate the skin or mucous membranes, and does not cause rash even when applied for a long time. It does not alter the drug. Furthermore, the drug is not precipitated due to the absorption enhancer, and the adhesive property of the tape preparation is not reduced.

 ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-55-139313 (JP, A) JP-A-58-52216 (JP, A) JP-A-61-210024 (JP, A)

Claims (4)

(57) [Claims] A transdermal / transmucosal preparation having a pressure-sensitive adhesive layer containing a drug and an absorption enhancer for the drug on one surface of a support, wherein the drug is isosorbide dinitrate or hydrocortisone acetate. A transdermal / transmucosal preparation, wherein the absorption enhancer is a fatty acid monoalkylolamide and / or an alkylene oxide adduct of a fatty acid monoalkylolamide, wherein the fatty acid has 6 to 18 carbon atoms. 2. The transdermal / transmucosal preparation according to claim 1, wherein the addition mole number of the alkylene oxide is 1 to 40. 3. The transdermal / transmucosal preparation according to claim 1, which contains the absorption enhancer in a ratio of 0.5 to 50% by weight. 4. The transdermal skin according to claim 1, wherein said pressure-sensitive adhesive layer is an acrylic pressure-sensitive adhesive or a rubber-based pressure-sensitive adhesive.
Transmucosal preparation.