JP2507158B2 - Transdermal formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention is used for direct application to a biological membrane such as skin or mucous membrane to administer a required drug through the biological membrane to the internal circulatory system. More specifically, it relates to a transdermal absorption preparation comprising a drug, an adhesive base, and a percutaneous absorption obtained by holding on a support an adhesive layer containing an absorption promoter that weakens the barrier function of the skin and promotes absorption of the drug. It relates to improvement of the absorption enhancer in a pharmaceutical preparation.

(Prior Art) Conventionally, oral drugs, injections, suppositories, etc. have been appropriately adopted as the dosage form when administering a drug into the body, but in recent years, the development of transdermal absorption preparations has the following advantages. It is being actively promoted. That is, in a transdermal drug, since the drug absorbed in the body does not pass through the liver in the first circulation, the drug absorbed in the intestine circulates to the liver and is metabolized as in the case of the oral administration method, and its drug effect is exerted. There is no downside.

Compared with injections, the patient's mental burden and physical pain are less.

It is easy to maintain the blood concentration at the required level for a long time, and continuous administration is possible for a long time.

 Administration can be easily discontinued if desired.

By the way, since this kind of transdermal drug delivery system is intended to administer a drug to the internal circulatory system via the stratum corneum of the skin, which originally has a barrier function of preventing foreign substances from entering the body,
It is not always easy to administer a drug in an amount sufficient to exert the desired drug effect, and usually the patch area of the formulation is increased or an absorption enhancer is added to the base to enhance drug release. Such measures are taken.

However, since a transdermal preparation has a side effect of irritating the skin, it is preferable that the application area of the preparation is as small as possible. That is, during the period of applying the preparation to the skin, since the application layer of the preparation is in contact with the skin surface, the skin in that portion is prevented from having normal actions such as secretion, metabolism and stretching. , I will always be stimulated by the adhesive layer itself. As a result, erythema develops on the applied part of the skin, and in severe cases, scab formation and edema formation are involved,
It may even last for several days after removal of the transdermal formulation. Therefore, in order to reduce such side effects, it is desired to reduce the application area of the transdermal preparation.

Conventionally, various absorption promoters have been proposed for the purpose of reducing the application area and improving the transdermal absorbability of drugs. As a conventional example of the technique for improving the release of a drug to the skin by adding a specific absorption enhancer as described above, for example, polyoxyethylene alkyl ether represented by polyoxyethylene uralyl ether is used as the absorption enhancer. Absorption-promoting absorption of one or more of nonionic surfactants, both surfactants, anionic surfactants and fatty acid esters of polyhydric alcohols used (see JP-A-58-79918). What is used as an agent (see JP-A-61-210024), cholic acid derivative, pantranic acid derivative, ethacrynic acid, para-aminobenzoic acid derivative, sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, Uses an absorption promoter selected from anionic surfactants and amphoteric surfactants (special Akira see JP 62-132828), those using ethylene oxide addition type nonionic surfactants represented by polyoxyethylene monooleate (JP 64
Japanese Patent No. 56622) is known.

(Problems to be Solved by the Invention) Since the absorption enhancer acts on the skin during the period when the transdermal absorption preparation is applied to the skin, it should not cause skin irritation.

However, the absorption enhancers used in the above-mentioned conventional percutaneous absorption preparations are compounds that are surely observed to have the effect of promoting percutaneous absorption, but all have the drawback that they have strong skin irritation. . Moreover, in general, the absorption enhancer having a higher transdermal absorption promoting effect tends to have stronger skin irritation, and therefore, an absorption promoting agent having a high transdermal absorption promoting effect and a low skin irritation has not yet been developed. The current situation is that there are none.

In view of the above situation, the object of the present invention is to allow percutaneous permeation of a sufficient amount of a drug to exert a desired drug effect even with a small patch area, and to stimulate the skin with an absorption promoter. It is to provide a percutaneously absorbable preparation which is reduced as much as possible.

(Means for Solving the Problems) As a result of repeated studies to achieve the above-mentioned object,
In a two-layer system consisting of an adhesive base layer containing a drug and an absorption enhancer and a support holding the same, the combined use of two specific compounds as the absorption enhancer improves the transdermal permeability of the drug. In addition, it was completed with the knowledge that there is little or no skin irritation.

That is, the percutaneous absorption preparation according to the present invention is a percutaneous absorption preparation in which an adhesive layer comprising an adhesive base, an absorption promoter and a drug is held on a support, and the absorption promoter is a polyoxyethylene derivative. And polyethylene glycol.

The components, manufacturing method and application method of the percutaneous absorption preparation according to the present invention will be described in detail.

i) In the percutaneous absorption preparation according to the present invention, a polyoxyethylene derivative and polyethylene glycol are used in combination as the absorption enhancer.

Polyoxyethylene derivatives are known to have a transdermal absorption enhancer effect for a wide range of drugs, but in order to expect a high absorption enhancer effect, it is necessary to use this at a high concentration, and as a result, skin The stimulation is at a level that cannot be ignored. However, when polyethylene glycol is used in combination with this, even if a low concentration of polyoxyethylene derivative is used, a high absorption promoting effect is exerted, and skin irritation is reduced as compared with the case of using the polyoxyethylene derivative alone. .

Examples of the polyoxyethylene derivative include polyoxyethylene alkyl ester represented by polyoxyethylene monooleate, polyoxyethylene (1
5) Polyoxyethylene alkyl amines represented by oleylamine, polyoxyethylene alkyl ethers represented by polyoxyethylene (15) lauryl ether, polyoxyethylene alkylamides represented by polyoxyethylene (15) stearic acid amide , Polyoxyethylene (4) polyoxyethylene alkyl ether phosphate represented by sodium lauryl ether phosphate, polyoxyethylene (2) polyoxyethylene polyhydric alcohol alkyl ester represented by sorbitan monolaurate, and the like. To be Examples of the polyoxyethylene alkyl ether phosphate include sodium polyoxyethylene (8) oleyl ether phosphate, potassium dipolyoxyethylene (4) nonylphenyl ether phosphate, and the like in addition to the above. The numerical value in parentheses in the compound name indicates the number of oxyretylene units.
One of these polyoxyethylene derivatives may be used alone or in combination of two or more thereof depending on the drug and the adhesive base.

As polyethylene glycol which is another component of the present absorption enhancer, one having a molecular weight of 10,000 or less is preferable.

The amount of the absorption enhancer to be effectively exerted the effect of promoting percutaneous absorption depends on the type of drug and adhesive base, but is 0.1 to 45% by weight in the patch layer of the percutaneous absorption preparation. Is the range. The reason is that the amount of the absorption promoter is 0.
If it is less than 1% by weight, it is not possible to absorb a sufficient amount of the drug through the skin into the internal circulatory system to develop the desired drug effect. This is because the amount of the adhesive base compound is reduced, and the adhesiveness of the preparation to the skin is deteriorated. A particularly preferable amount of the present absorption enhancer is in the range of 0.5 to 30% by weight in the adhesive layer. The ratio of polyethylene glycol to the entire absorption enhancer varies depending on the type and amount of polyoxyethylene derivative, the type of drug and the adhesive base, but is 5 to 99.
It is in the range of wt%, preferably in the range of 10 to 95 wt%.

ii) The adhesive base used in the percutaneous absorption preparation of the present invention is
There is no particular limitation as long as it has excellent compatibility with the absorption enhancer, does not impair the adhesiveness of the adhesive layer, and can provide good long-term stability of the preparation. Examples of preferable adhesive bases include acrylic adhesive bases, rubber adhesive bases, and silicone adhesive bases.

As the acrylic adhesive base, particularly, a carbon number of 4-18
Homopolymer or copolymer of (meth) acrylic acid alkyl ester obtained from aliphatic alcohol and (meth) acrylic acid and / or copolymerization of the above (meth) acrylic acid alkyl ester with other functional monomer Coalescence is preferably used.

Examples of the (meth) acrylic acid ester include butyl acrylate, isobutyl acrylate, hexyl acrylate, octyl acrylate, 2-ethylhexyl acrylate, isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, acrylic acid. Stearyl, methyl methacrylate, ethyl methacrylate,
Examples thereof include butyl methacrylate, isobutyl methacrylate, -2 ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, isodecyl methacrylate, lauryl methacrylate and stearyl methacrylate.

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. 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: maleic acid monoalkyl esters such as butyl maleate: maleic acid: fumaric acid:
Examples include crotonic acid. Maleic anhydride also gives the same (co) polymerization components as maleic acid. Examples of the monomer having an amide group include acrylamide, dimethyl acrylamide, and diethyl acrylamide (alkyl (meth) acrylamide): butoxymethyl acrylamide,
Examples thereof include alkyl ether methylol (meth) acrylamide such as ethoxymethyl acrylamide, diacetone acrylamide, and the like. Examples of the monomer having an amino group include dimethylaminoethyl acrylate and vinylpyrrolidone.

Copolymerizable monomers other than the above, vinyl acetate,
Vinyl alcohol, styrene α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene and the like can also be used. (Meta) in the adhesive base
50% of acrylic acid alkyl ester as (co) polymerization component
Preferably, it is contained in an amount of at least% by weight.

If necessary, a polyfunctional monomer is added to the acrylic adhesive base, and the acrylic adhesive base is copolymerized with other monomer components. The addition of this polyfunctional monomer causes only slight cross-linking between the resulting polymers, which increases the internal cohesive strength of the adhesive base. Therefore, the so-called adhesive residue phenomenon at the time of peeling off the patch can be almost eliminated irrespective of the property of the applied skin and the amount of perspiration. Moreover, the addition of this polyfunctional monomer does not have any adverse effect on drug release and low skin irritation. Examples of such polyfunctional monomers include di (meth) acrylate and tri (meth) acrylate.
Acrylate, tetra (meth) acrylate and the like are included, but are not limited thereto. More specifically, di (meth) acrylate obtained by combining polymethylene glycols such as hexamethylene glycol and octamethylene glycol with (meth) acrylic acid; polyalkylene glycols such as polyethylene glycol and polypropylene glycol Di (meth) acrylate obtained by combining with (meth) acrylic acid; tri (meth) acrylate such as trimethylolpropane tri (meth) acrylate or glycerin tri (meth) acrylate; and pentaerythritol tetra (meth) acrylate. There is a tetra (meth) acrylate of. You may use these polyfunctional monomers in combination of 2 or more types.
The polyfunctional monomer is used in a proportion of 0.005 to 0.5% by weight based on all the monomers used for producing the adhesive base. When the amount of the polyfunctional monomer used is less than 0.005% by weight, the effect of improving the internal cohesive force by cross-linking is small, and when it exceeds 0.5% by weight, the adhesive base obtained by the polymerization is apt to cause gelation and It also affects the diffusion and release.

As a rubber-based adhesive base, 100 parts by weight of a rubber elastic material such as natural rubber, styrene-isoprene-styrene / block copolymer (SIS), polyisoprene, polybutene, polyisobutylene, ethylene-vinyl acetate copolymer, etc. ,
A resin prepared by adding 20 to 200 parts by weight of a tackifying resin and an appropriate amount of a softening agent, a stabilizer and the like is used.

As the silicone-based adhesive base, those containing polydimethylsiloxane as a main component are used.

In the adhesive base, for example, rosin resin, polyterpene resin, coumarone-indene resin, petroleum resin,
A tackifier such as a terpene-phenol resin; a plasticizer such as liquid polybutene, mineral oil, lanolin, liquid polyisoprene, and liquid polyacrylate; a filler; a compounding agent such as an antioxidant is added as necessary.

Particularly preferred as the adhesive base used in the percutaneous absorption preparation of the present invention is (a) the above (meth) acrylic acid ester monomer 60 to 99: 5% by weight, and (b) the homopolymer is water-soluble. And a copolymer obtained from a blend containing the monomer (a) and 0.5 to 40% by weight of a copolymerizable vinyl monomer. As the vinyl monomer (b),
Examples include vinylpyrrolidone, maleic anhydride, vinyl alcohol, (meth) acrylic acid and the like. By using this copolymer, good compatibility between the adhesive base and the absorption enhancer is exhibited, the adhesiveness of the adhesive layer is not impaired, and the long-term stability of the preparation is improved. To be The monomer (a) plays a role of exerting the adhesiveness of the adhesive layer, and the vinyl monomer (b) plays a role of exhibiting the compatibility between the adhesive base and the absorption promoter. Therefore, if the proportion of the monomer (a) is less than 60% by weight, the adhesiveness of the adhesive layer to the skin will deteriorate. Further, if the proportion of the vinyl monomer (b) is less than 0.5% by weight, the compatibility between the adhesive base and the absorption promoter becomes poor.

III) The drug (physiologically active substance) used in the percutaneous absorption preparation of the present invention is not particularly limited as long as it can permeate a biological membrane transdermally or transmucosally. Examples of the drug include antipyretic and analgesic agents, steroidal anti-inflammatory agents, vasodilators, hypertensive / arrhythmic agents, antihypertensive agents, antitussive and expectorant agents,
Antitumor agent, local anesthetic, hormone agent, asthma / nasal allergy treatment agent, antihistamine, anticoagulant, antispasmodic agent, cerebral circulation / metabolic agent, antidepressant / anxiety agent, vitamin D preparation, hypoglycemic agent, anti Examples include ulcer agents, hypnotics, and antibiotics.

Examples of antipyretic analgesics include indomethacin, salicylic acid, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibufenac, fenbufen, alclofenac, phenylbutazone, mefenamic acid, bendazac. , Piroxicam, flurbiprofen, pentazocine, buprenorphine hydrochloride, butorphanol tartrate and the like.

Examples of steroidal anti-inflammatory agents include hydrocortisone, prednisolone, fluocinolone acetonide, fludroxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate, diflucortron valerate, clobetasol propionate, Examples include fluocinonide.

Examples of vasodilators include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, isosorbide dinitrate, nifedipine, nitroglycerin and the like.

Examples of agents for hypertension / arrhythmia include propanolol, atenolol, pindolol, quinidine sulfate, azmarin,
Examples include alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, and disopyramide.

Examples of antihypertensive agents include clonidine hydrochloride, captopril, prazosin hydrochloride, penbutrol sulfate, guanabenz acetate, guanfacine hydrochloride, bunazosin hydrochloride, ellanapril maleate, arotinolol hydrochloride, bunitrolol hydrochloride and the like.

Examples of the antitussive expectorant include procaterol hydrochloride, terbutaline sulfate, fenoterol hydrobromide, tulobuterol hydrochloride, ambroxol hydrochloride, pirbuterol hydrochloride, mabuterol hydrochloride, clenbuterol hydrochloride, trimetoquinol hydrochloride, formoterol fumarate and the like. .

Anti-tumor agents include 5-fluorouracil, 1- (2
-Tetrahydrofuryl) -5-fluorouracil, mitomycin C and the like are exemplified.

Examples of the local anesthetic include benzocaine, procaine, lidocaine and tetracaine.

Examples of hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, progesterone and prostaglandins, and peptide hormones such as insulin.

Examples of the asthma / nasal allergy therapeutic agent include ketotifen fumarate, azelastine hydrochloride, sodium cromoglycate and the like.

Examples of the antihistamine include cycloheptazine hydrochloride, diphenhydramine hydrochloride, fenbenzamine, mequitazine and the like.

 Examples of anticoagulants include heparin and the like.

Examples of the antispasmodic include scopolamine and clofluperol.

Examples of the cerebral circulation / metabolism improver include vinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, brovincamine fumarate, dihydroergotoxine mesinate, ifenprodil tartrate, isoxuprine hydrochloride and the like.

Examples of antidepressant / anxiety agents include maprotiline hydrochloride,
Examples include etizolam, diazepam, bromazepam, amitriptyline hydrochloride, mianserin hydrochloride and the like.

Examples of vitamin D preparations include alfacalcidol, ergocalciferol and the like.

Examples of hypoglycemic agents include glibenclamide, gliclazide and the like.

Examples of anti-ulcer agents include clevobride malate, famotidine, glycopyrronium bromide and the like.

Examples of the sleeping pill include phenobarbital and amobarbital.

Examples of antibiotics include tetracycline and chloramphenicol.

The compounding amount of these drugs varies depending on the type of drug, the purpose of use of the transdermal preparation, etc., but is usually 0.1
Is in the range of up to 30% by weight.

iv) The support, which is flexible, has the function of imparting self-supporting properties to the transdermal preparation and also preventing volatilization and migration of the drug in the adhesive layer, and is a drug-impermeable sheet or a drug-impermeable sheet. It is composed of a film, a laminate of these, a woven fabric or a non-woven fabric, and the like. Examples of the material of the support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon,
Examples thereof include ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride and aluminum. Of these materials, a material having a conformability to the skin surface is preferably used. In particular, polyethylene terephthalate and ethylene-
A laminated film with a vinyl acetate copolymer is preferable. The thickness of the support is 500 μm or less, preferably 5 to 150
μm.

v) The transdermal patch according to the present invention usually has a release paper on the surface thereof. As the release paper, a polyethylene terephthalate film treated with silicon is often used, but the release paper is not limited to this. The thickness of the release paper is 100 μm or less, preferably 5 to 50 μm
m.

vi) As a method for producing the percutaneous absorption preparation according to the present invention, a usual method for producing an adhesive tape can be applied. A typical example thereof is a solvent coating method, and in addition to this, an emulsion coating method, a hot melt method, a method by electron beam crosslinking and the like are used. To produce the transdermal preparation according to the present invention by a solvent coating method, for example, an adhesive base, a drug and an absorption enhancer,
Further, if necessary, the compounding agent is dissolved or dispersed in a suitable solvent, and the resulting solution or dispersion is directly applied on the surface of the support and dried to form a patch layer having a thickness of 30 to 200 μm.
Further, this solution or dispersion may be coated on a protective release paper, and the adhesive layer obtained after drying may be brought into close contact with the support.

vii) The transdermal preparation thus obtained is usually applied directly to the skin surface for the purpose of administering the drug through the skin to the internal circulatory system. It may also be applied to the mucosa for the same purpose as above. Further, this drug for transdermal absorption may of course be applied to the skin or mucous membrane for the purpose of treating a diseased part of the skin or mucous membrane.

(Function) The percutaneous absorption preparation according to the present invention uses a combination of a polyoxyethylene derivative and polyethylene glycol as an absorption enhancer, and therefore, a sufficient amount of the drug for exhibiting the desired drug effect is passed through the skin. It can be absorbed and the skin irritation caused by the absorption enhancer is reduced.

The detailed mechanism of action of the absorption enhancer comprising a polyoxyethylene derivative and polyethylene glycol on the skin is not certain, but it is considered as follows.

(A) The use of the present absorption enhancer significantly improves the release amount of the drug per unit area and unit time and the migration of the drug into the skin. It is considered that this is because the above substances change the physical properties of the adhesive base and penetrate into the skin to change the physicochemical properties of the stratum corneum to reduce the barrier function of the stratum corneum. As a result, the partition coefficient of the drug between the adhesive base and the skin changes, or the diffusion rate of the drug in the skin is increased, the release amount of the drug is improved, and the required amount of the drug is easily transferred to the skin. Permeate and is absorbed by the circulatory system of the body.

Therefore, a transdermal preparation having a larger effective dose than a conventional product having the same area as that of a conventional transdermal preparation using an absorption enhancer can be obtained. In other words, the same effect as the conventional product can be obtained with the transdermal preparation having an area smaller than that of the conventional product.

(B) Regarding the reduction of skin irritation, since this absorption enhancer is a substance having an excellent effect of promoting percutaneous permeation as described above, the application area required for drug administration is small, and the skin is not required for long-term use. Has less damage.

In addition, since a transdermal absorption preparation with a small area as described above provides sufficient medicinal effects, it is possible to avoid erythema in people who are sensitive to skin irritation, or to reduce the area of erythema as much as possible. Sent. In addition, since the transdermal preparation has such a small area, the sticking operation is easy and there is little discomfort due to sticking. (C) Furthermore, the absorption enhancer has the desired medicinal effect as described above. Since a sufficient amount of the drug to be expressed is easily percutaneously absorbed, it is not necessary to include a large amount of the drug in the patch layer as in the conventional case.

In addition, the use of the absorption enhancer can maintain the effective blood concentration for a long time and enhance the bioavailability of the drug.

In addition, since this absorption enhancer does not modify the drug, it has excellent compatibility with the adhesive base and does not change the compatibility of the drug with the adhesive base. The drug does not precipitate from it.

(Example) Next, the present invention will be specifically described based on Examples.

(A) Production of percutaneous absorption preparation Example 1 i) Preparation of acrylic adhesive base 2-ethylhexyl acrylate 302.0 g, vinylpyrrolidone 98.0 g and hexamethylene glycol dimethacrylate 40.0 mg (0.02 based on all monomers) Was added to 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, a polymerization initiator solution prepared by dissolving 2 g of uroaroyl peroxide in 100 g of cyclohexane and 242.9 g of ethyl acetate were added little by little, and a polymerization reaction was carried out for 12 hours. . Thus, an ethyl acetate solution of acrylic adhesive base having a solid content concentration of 35% by weight was obtained.

ii) Preparation of a liquid containing an adhesive composition for patching The resulting adhesive base solution contains isosorbide dinitrate as a drug, and polyoxyethylene (4) sodium lauryl ether phosphate and polyethylene glycol (molecular weight 400) as absorption promoters. Ethyl acetate solution,
Solid content (weight sum of adhesive base, drug and absorption enhancer)
Concentration of 25% by weight and solid concentration of isosorbide dinitrate, sodium polyoxyethylene (4) lauryl ether phosphate and polyethylene glycol are 15.5%, 1% and 10% by weight, respectively. In addition to the above, the entire liquid was uniformly mixed with a dissolver. Thus, an ethyl acetate solution containing the patch formulation was prepared.

iii) Preparation of percutaneous absorption preparation Step ii) on a release paper made by siliconizing a 38 μm thick polyethylene terephthalate (PET) film.
After applying the preparation solution of, dry it for 30 minutes at 60 ℃,
The adhesive layer of m was formed. Then, a support having a thickness of 34 μm formed by laminating a copolymer of PET and ethylene-vinyl acetate (PET-EVA) was adhered to the adhesive layer. Thus, a percutaneous absorption preparation was prepared.

Examples 2 to 4 In step ii) of Example 1, polyoxyethylene (4) sodium lauryl ether phosphate and polyethylene glycol (molecular weight 400) were used as absorption promoters, and the composition of the solid content concentration shown in Table 1, respectively. And other operations were performed in the same manner as in Example 1 to prepare a percutaneous absorption preparation.

Comparative Examples 1 to 5 In step ii) of Example 1, one of polyoxyethylene (4) sodium lauryl ether phosphate and polyethylene glycol (molecular weight 400) was used as an absorption promoter, and solid content shown in Table 1 was used. A transdermal preparation was prepared by using the compounded composition of medium concentration or by using neither of them, and performing other operations in the same manner as in Example 1.

Example 5 i) Preparation of acrylic adhesive base 30 g of 2-ethylhexyl acrylate, 264 g of 2-ethylhexyl methacrylate, 40 g of dodecyl methacrylate
And 64 g of acrylic acid was charged into a separable flask,
Further, 170 g of ethyl acetate was added to adjust the monomer concentration to 70% by weight. The solution was heated to a temperature of 70 ° C. under a nitrogen atmosphere, a polymerization initiator solution prepared by dissolving 2 g of lauroyl peroxide in 100 g of cyclohexane and 470 g of ethyl acetate were added little by little, and a polymerization reaction was carried out for 12 hours. Thus, an ethyl acetate solution of acrylic adhesive base having a solid content concentration of 35% by weight was obtained.

ii) Preparation of a liquid containing a formulation for application to the obtained adhesive base solution, indomethacin as a drug, and polyoxyethylene sorbitan monolaurate and polyethylene glycol (molecular weight as an absorption promoter)
An ethyl acetate solution containing 600) is added to the solid content (adhesive base,
The concentration of the drug and the absorption enhancer is 25% by weight, and the concentration of indomethacin, polyoxyethylenesorbitan monolaurate and polyethylene glycol in the solid content is 2% by weight, 5% by weight and 20% by weight, respectively.
The whole solution was uniformly mixed with a dissolver in such a manner that it was added in an amount of wt%. Thus, an ethyl acetate solution containing the patch formulation was prepared.

iii) Preparation of percutaneous absorption preparation By the same operation as in step iii) of Example 1, a sticking layer was formed on a release paper made of silicon-treated PET, and PET was formed on this layer.
-A support made of EVA was brought into close contact with the support to prepare a percutaneous absorption preparation.

Comparative Example 6 A transdermal preparation was prepared in the same manner as in Example 5, except that polyethylene glycol was not used in step ii) of Example 5.

Example 6 In step i) of Example 5, acrylic acid was not used, 140 g instead of 170 g of ethyl acetate and 380 g instead of 470 g of ethyl acetate were used, and polyethylene glycol was solidified in step ii) of Example 5. A percutaneous absorption preparation was prepared by using the compounding composition having a concentration of 3% in minutes and performing other operations in the same manner as in Example 5.

Comparative Example 7 A transdermal preparation was prepared in the same manner as in Example 6, except that polyethylene glycol was not used and other operations were performed in the same manner as in Example 6.

Example 7 i) Preparation of rubber-based adhesive base As a rubber elastic body, styrene-isoprene-thretin.
Block copolymer (Califlex TR manufactured by Shell Chemical Co., Ltd.
1107) 140 parts by weight of an alicyclic hydrogenated petroleum resin (Arakawa Chemical Co., Alcorn-P90) as a tackifier, and 100 parts by weight of polybutene as a softening agent (HV-30 manufactured by Nisseki Chemical Co., Ltd.)
0) 25 parts by weight of cyclohexane was dissolved in 483.38 parts by weight to obtain a cyclohexane solution of a rubber-based adhesive base having a solid content concentration of 35.41% by weight.

ii) Preparation of a formulation-containing liquid for application to the obtained adhesive base solution, piroxicam as a drug, and polyoxyethylene myristyl ether and polyethylene glycol (molecular weight 400) as absorption promoters.
Of a tetrahydrofuran solution containing a so that the concentration of solids (adhesive base, drug and absorption enhancer) is 15% by weight and the concentration of piroxicam, polyoxyethylene myristyl ether and polyethylene glycol in solids is 15% by weight. Were added so as to be 2% by weight, 2% by weight and 1% by weight, respectively, and the whole liquid was uniformly mixed with a dissolver. Thus, a cyclohexane / tetrahydrofuran mixed solution containing the patch preparation was prepared.

iii) Preparation of percutaneous absorption preparation By the same operation as in step iii) of Example 1, a sticking layer was formed on a release paper made of silicon-treated PET, and PET was formed on this layer.
-A support made of EVA was brought into close contact with the support to prepare a percutaneous absorption preparation.

Comparative Example 8 In step ii) of Example 7, polyoxyethylene myristyl ether was used in a blending composition having a concentration of 20% by weight in solid content without using polyethylene glycol, and other operations were performed in the same manner as in Example 7. A percutaneous absorption preparation was prepared.

Example 8 In step ii) of Example 1, in an adhesive base solution having a solid content concentration of 35% by weight, crystals of estradiol having an average particle size of 20 μm as a drug, and polyoxyethylene monolaurate and polyethylene as an absorption promoter were used. An ethyl acetate solution containing glycol (molecular weight 1000) was added so that the concentration of solid content (adhesive base, drug and absorption enhancer) was 25% by weight, and estradiol, polyoxyethylene monolaurate and Polyethylene glycol solids concentration of 15% by weight, 2% by weight and 30% respectively
A percutaneous absorption preparation was prepared in the same manner as in Example 1 except that the content was adjusted to 100% by weight.

Comparative Example 9 A transdermal preparation was prepared in the same manner as in Example 8 except that polyethylene glycol was not used in step ii) of Example 8.

Example 9 In step ii) of Example 1, ethyl acetate containing nifedipine as a drug and polyoxyethylene oleylamine and polyethylene glycol (molecular weight 400) as an absorption promoter in an adhesive base solution having a solid content concentration of 35% by weight. The solution should have a solid content (adhesive base, drug and absorption enhancer weight) of 25% by weight, and nifedipine, polyoxyethylene oleylamine and polyethylene glycol concentrations of 15% each. %,
In addition to 15% by weight and 2% by weight, the other operations were performed in the same manner as in Example 1 to prepare a percutaneous absorption preparation.

Comparative Example 10 A transdermal preparation was prepared in the same manner as in Example 9 except that polyethylene glycol was not used in step ii) of Example 9.

(B) Performance evaluation of percutaneous absorption preparation i) Rabbit skin migration test Examples 1, 2, 3, 4, 7 and Comparative Examples 1, 3, 4,
With respect to the transdermally absorbable preparations Nos. 5 and 8, the drug transfer test to rabbit skin was carried out by the method shown in Test 1.

Test 1 A test piece of percutaneous absorption preparation (area on the back and ventral side of a hairless rabbit (New Zealand White))
10 cm ² ) was attached, and after 24 hours, this was peeled off and collected.
The number of repetitions was 4 times for each preparation. When the drug was isosorbide dinitrate, these test pieces were subjected to extraction treatment with methanol, and the residual amount of isosorbide dinitrate in the transdermal preparation was measured by high performance liquid chromatography. The difference between the initial amount of isosorbide dinitrate of the percutaneous absorption preparation and the remaining amount after the test was taken as the amount transferred to the skin for 24 hours. In the case of piroxicam, the percutaneous absorption preparation was subjected to extraction treatment with chloroform, and the residual amount of piroxicam in the percutaneous absorption preparation was measured by high performance liquid chromatography to determine the skin transfer amount as in the case of isosorbide nitrate. .

The transfer amount of the drug in the skin of rabbit for each transdermal preparation is summarized in Table 2.

As is clear from Table 2, when a combination system of a polyoxyethylene derivative and polyethylene glycol is used as an absorption enhancer, drug transfer at a level equal to or higher than that when a high concentration polyoxyethylene derivative that causes skin irritation is used. The amount is admitted.

ii) Rabbit skin irritation test Examples 1, 2, 3, 4, 7 and Comparative Examples 1, 3, 4,
With respect to the percutaneously absorbable preparations Nos. 5 and 8, an irritation test on rabbit skin was carried out by the method shown in Test 2.

Test 2 For rabbit skin treated in the same manner as Test 1,
The erythema state of the skin was visually observed 1 hour and 48 hours after peeling off the percutaneously absorbable preparation. In this test, neither edema nor crust formation was observed.

The degree of erythema was evaluated according to the following 5 criteria of 0-4.

0 ... no erythema 1 ... slightly erythema that can be barely discerned 2 ... clear erythema 3 ... medium erythema 4 ... strong erythema of deep crimson The average value (the sum of the scores at each time divided by 4 for each iteration) The skin irritation index of the transdermal preparation was used. Table 3 shows the obtained evaluation results.

As is clear from Table 3, skin irritation is hardly observed when a combination system of a polyoxyethylene derivative and polyethylene glycol is used as an absorption enhancer.

iii) Skin permeability test Examples 1, 5, 6, 8, 9 and Comparative Examples 2, 6, 7,
With respect to the 9 and 10 transdermal preparations, a drug permeability test was performed on the extracted skin of the hairless mouse by the method shown in Test 3.

Test 3 First, the diffusion cell (1) shown in the attached drawing was prepared. The diffusion cell (1) is composed of a bottomed cylindrical receptor tank (2) with a bottom, and a cylindrical bottomed donor tank (3) arranged on this. An opening (4) is provided in 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. ) Is provided. Then, by overlapping the upper flange (5) and the lower flange (6) so as to face each other, the donor tank (3) and the receptor tank (2) are airtightly and concentrically stacked. A side-projecting sampling port (7) is attached to the side of the receptor tank (2), and a magnetic stirring bar (9) is placed inside the receptor tank (2).

Hairless mice (8-week-old, male) were sacrificed by cervical dislocation and immediately peeled off the skin to remove subcutaneous fat.
A m × 5 cm piece of skin was obtained. The skin piece (8) is sandwiched between the upper flange (5) and the lower flange (6) of the diffusion cell (1), and the opening (4) of the donor tank (3) is cut into the skin piece (8). I tried to close it completely. On the upper surface of the skin piece (8), a test piece (10) obtained by punching out a percutaneously absorbable preparation into a circle having an area of 3.14 cm ² was attached. In the receptor tank (2),
The receptor solution prepared by the following method was filled.

Then, the diffusion cell (1) was placed in a constant temperature bath kept at a temperature of 37 °, and the receptor liquid was stirred by a magnetic stirring device. 24 hours after the start of the test Sampling port (7)
1 ml of the receptor liquid was collected from the sample and the amount of the drug permeating into the receptor liquid was measured by high performance liquid chromatography. Table 4 shows the measured permeation amount of each transdermal preparation.

Preparation method of receptor solution NaH ₂ PO ₄ (5 × 10 ^-4 mol), Na ₂ HPO ₄ (2 × 10 ^-4 mol), NaCl (1.5 × 10 ^-1 mol) and gentamicin 10 m
g in 500 ml of distilled water and adjust the pH of the resulting solution to 0.1 N
After adjusting to 7.2 with aOH aqueous solution, set the volume to 1000 with distilled water.
ml.

As is clear from Table 4, when the polyoxyethylene derivative is used in combination with polyethylene glycol as the absorption enhancer, the skin permeation amount is remarkably increased as compared with the case where polyethylene glycol is not used.

iv) Human skin migration test With respect to the percutaneous absorption preparations of Example 1 and Comparative Example 1, a drug migration test to human skin was carried out by the method shown in Test 4.

Test 4 Each test piece (area: 10 cm ² ) of the percutaneous absorption preparations of Example 1 and Comparative Example 1 was attached to the upper arm of a subject (an elastically healthy person), and after 24 hours, they were peeled and collected. These test pieces were subjected to extraction treatment with methanol, and the residual amount of isosorbide dinitrate in the percutaneous absorption preparation was measured by high performance liquid chromatography. The test was carried out by 8 subjects for each transdermal preparation, and the difference between the initial drug amount of the transdermal preparation and the residual amount after the test was taken as the 24-hour skin transfer amount, and the average thereof was taken. Table 5 shows the transfer amount of the drug in the human skin for each transdermal preparation.

As is clear from Table 5, when the combination of polyoxyethylene derivative and polyethylene glycol is used as the absorption enhancer, the skin irritation is also observed with respect to the drug transference to human skin as well as the drug transference to rabbit skin. A drug transfer amount equal to or higher than that when the high concentration polyoxyethylene derivative that expresses is used is observed.

v) Human Skin Irritation Test The transdermal preparations of Example 1 and Comparative Example 1 were subjected to a human skin irritation test by the method shown in Test 5.

Test 5 In the method of Test 4, the erythema state of the skin was visually observed 1 hour and 48 hours after peeling off the percutaneous absorption preparation.
In this test, neither edema nor crust formation was observed.

 The criteria for erythema are as shown in Test 1.

The average value of the scores of 8 persons was used as the skin irritation index of each transdermal preparation. Table 6 shows the obtained evaluation results.

As is clear from Table 6, when a combination system of a polyoxyethylene derivative and polyethylene glycol is used as an absorption enhancer, almost no irritation to human skin is observed.

(Effect of the invention) The percutaneous absorption preparation according to the present invention uses a combination of a polyoxyethylene derivative and polyethylene glycol as an absorption enhancer, and therefore, a sufficient amount of the drug to exert the desired drug effect on the skin. In addition to being absorbed through the skin, the skin irritation caused by the absorption enhancer can be greatly reduced.

It is considered that such remarkable effects of the present invention are due to the following mechanism of action of the absorption enhancer comprising a polyoxyethylene derivative and polyethylene glycol.

(A) The use of the present absorption enhancer significantly improves the release amount of the drug per unit area and unit time and the migration of the drug into the skin. This is because the above substances change the physical properties of the adhesive base and penetrate into the skin to change the physicochemical properties of the stratum corneum to reduce the barrier function of the stratum corneum. As a result, the partition coefficient of the drug between the adhesive base and the skin changes, or the diffusion rate of the drug in the skin is increased, the release amount of the drug is improved, and the required amount of the drug is easily transferred to the skin. Permeate and is absorbed by the circulatory system of the body.

Therefore, compared with the conventional drug-containing transdermal preparation,
It is possible to obtain a percutaneous absorption preparation having a larger effective dose than conventional products having the same area. In other words, the same effect as the conventional product can be obtained with the transdermal preparation having an area smaller than that of the conventional product.

(B) Regarding the reduction of skin irritation, since this absorption enhancer is a substance having an excellent effect of promoting percutaneous permeation as described above, the application area required for drug administration is small, and the skin is not required for long-term use. Has less damage.

In addition, since a transdermal absorption preparation with a small area as described above provides sufficient medicinal effects, it is possible to avoid erythema in people who are sensitive to skin irritation, or to reduce the area of erythema as much as possible. Sent. And since the transdermal preparation has a small area in this way, in addition to being able to easily perform the sticking operation,
It is possible to reduce the feeling of strangeness caused by sticking.

(C) In addition, as described above, since the absorption enhancer easily transdermally absorbs a sufficient amount of the drug to exert the desired drug effect, a large amount of the drug can be applied as in the past. It need not be included in the layer.

In addition, the use of this absorption enhancer can maintain the effective blood concentration for a long time, and enhance the bioavailability of the drug.

In addition, since this absorption enhancer does not modify the drug, it has excellent compatibility with the adhesive base and does not change the compatibility of the drug with the adhesive base. The drug does not precipitate from it.

(D) Thus, according to the percutaneous absorption preparation of the present invention, since a combined use system of a polyoxyethylene derivative and polyethylene glycol is used as an absorption enhancer, the above-mentioned remarkable effects are exhibited.

[Brief description of drawings]

The drawing is a perspective view showing a diffusion cell used for testing the skin permeability of a drug contained in a transdermal preparation.

Claims (2)

(57) [Claims] 1. A percutaneous absorption preparation comprising a support and an adhesive layer comprising an adhesive base, an absorption enhancer and a drug, wherein the absorption enhancer comprises a polyoxyethylene derivative and polyethylene glycol. A percutaneous absorption preparation characterized by the following. 2. The content of the absorption promoter in the adhesive layer is 0.1 to 45.
The formulation according to claim 1, wherein the formulation is wt%.