JPH04103528A - Percutaneous absorbable pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain the subject pharmaceutical by containing a polyoxyethylene derivative and polyethylene glycol in combination as an absorbefacient and capable of absorbing an amount of a medicine sufficient to produce expected medicinal effects through the skin and simultaneously relieving skin irritation by the absorbefacient. CONSTITUTION:A percutaneous absorbable pharmaceutical is obtained by using a polyoxyethylene derivative such as a polyoxyethylene alkyl ester, a polyoxyethylene alkylamine or a polyoxyethylene alkyl ether and polyethylene glycol (having preferably <=10000 molecular weight) as an absorbefacient in combination and holding an application layer composed of a tacky base, the absorbefacient and a medicine on a support. The amount of the absorbefacient blended in the application layer is within the range of 0.1-45wt.%, preferably 0.5-30wt.%. Furthermore, the ratio of the polyethylene glycol to the whole absorbefacient is preferably within the range of 10-95wt.%.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention is used to directly apply a drug to a biological membrane such as the skin or mucous membrane and administer a desired drug to the body's circulatory system through the biological membrane. Regarding transdermal absorption preparations, more specifically, transdermal absorption preparations in which a patch layer containing a drug, an adhesive base, and an absorption enhancer that weakens the skin's barrier function and promotes absorption of the drug are held on a support. The present invention relates to improvements in the absorption enhancer in formulations.

(Prior art) In the past, when administering drugs into the body, oral preparations, injection preparations, halved preparations, etc. were adopted as appropriate, but in recent years,
The development of transdermal absorption preparations is being actively pursued due to the following advantages. In other words, in transdermal absorption preparations, ■Drugs absorbed into the body do not pass through the liver during the first circulation; therefore, as in the case of oral administration, drugs absorbed in the intestines circulate to the liver and are metabolized, increasing their efficacy. There is no disadvantage that the amount of energy decreases.

■Less mental burden and physical pain on patients compared to injections.

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

■Administration can be easily interrupted if necessary.

By the way, this type of transdermal absorption preparation administers the drug to the body's circulatory system via the stratum corneum of the skin, which has a barrier function to prevent foreign substances from entering the body, so it does not achieve the desired drug efficacy. It is not always easy to administer a sufficient amount of drug to induce this effect, and it is usually difficult to administer the drug in a sufficient amount to achieve this effect, and it is usually difficult to administer the drug in a sufficient amount to achieve this effect. Measures are being taken.

However, since transdermal absorption preparations have the side effect of irritating the skin, it is preferable that the application area of the preparation be as small as possible. That is, while the preparation is applied to the skin, the skin surface is in contact with the adhesive layer of the preparation, so the skin in that area is not able to perform normal functions such as secretion, metabolism, etc.
In addition to being prevented from expanding and contracting, the adhesive layer itself is constantly irritated. As a result, erythema develops on the skin at the application site, and in severe cases, crusting and edema formation may occur, which may persist for several days even after the transdermal preparation is removed. Therefore, in order to reduce such side effects, it is desired to reduce the application area of transdermal absorption preparations.

Conventionally, various absorption enhancers have been proposed for the purpose of reducing the application area and improving transdermal absorption of drugs. Conventional techniques for improving the release of drugs into the skin by adding a specific absorption enhancer include, for example, using polyoxyethylene alkyl ether, typified by polyoxyethylene lauryl ether, as an absorption enhancer. (Refer to JP-A-58-79918), nonionic surfactants, amphoteric surfactants, anionic surfactants, and one or more of polyhydric alcohol fatty acid esters as absorption enhancers. (Japanese Unexamined Patent Publication No. 61-2
10024), cholic acid derivatives, pantolic acid derivatives, ethacrylic acid, paraaminobenzoic acid derivatives,
Those using an absorption enhancer selected from among sucrose fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene alkyl ether, anionic surfactant, and amphoteric surfactant (JP-A-62-13282
(See Japanese Patent Application Laid-Open No. 64-56622) using an ethylene oxide-added nonionic surfactant represented by polyoxyethylene monooleate.

(Invention or problem to be solved) Since the absorption enhancer acts on the skin during the period when the transdermal absorption preparation is applied to the skin, it must not cause skin irritation.

However, although the absorption enhancers used in the above-mentioned conventional transdermal absorption preparations are compounds that are certainly effective in promoting transdermal absorption, they all have the drawback of being strong skin irritations. Moreover, in general, absorption enhancers with higher transdermal absorption promotion effects tend to cause more skin irritation, so an absorption enhancer with high cinnamon absorption promotion effects and less skin irritation has not yet been developed. is the current situation.

In view of the above-mentioned circumstances, an object of the present invention is to allow a sufficient amount of drug to be permeated through the skin to exert the desired drug effect even if the application area is small, and to prevent skin irritation caused by absorption enhancers. The object of the present invention is to provide a transdermal absorption preparation with reduced absorption as much as possible.

(Means for Solving the Problems) As a result of repeated studies to achieve the above object, the present invention has developed a two-layered adhesive base layer containing a drug and an absorption enhancer, and a support holding the same layer. This study was completed based on the finding that when two specific compounds are used together as absorption enhancers in a system, transdermal permeability of drugs is improved and there is little to no skin irritation.

That is, the transdermal absorption preparation according to the present invention is a transdermal absorption preparation in which a patch layer consisting of an adhesive base, an absorption enhancer, and a drug is held on a support, and the absorption enhancer is polyoxyethylene. It is characterized by consisting of a derivative and polyethylene glycol.

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

i) In the transdermal 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 transdermal absorption enhancer effects for a wide range of drugs, and to expect a high absorption-enhancing effect, they must be used at high concentrations, resulting in skin irritation. It becomes a level that cannot be ignored. However, when polyethylene glycol is used in combination with this, a high absorption promoting effect is exhibited even when using a low concentration of polyoxyethylene derivative, and skin irritation is also reduced compared to when polyoxyethylene derivative is used alone. .

Examples of polyoxyethylene derivatives include polyoxyethylene alkyl esters represented by polyoxyethylene monooleate, polyoxyethylene (15
) polyoxyethylene alkyl amine represented by oleylamine, polyoxyethylene alkyl ether represented by polyoxyethylene (15) lauryl ether, polyoxyethylene alkyl amide represented by polyoxyethylene (15) stearic acid amide, Examples include polyoxyethylene alkyl ether phosphates represented by oxyethylene (4) sodium lauryl ether phosphate, and polyoxyethylene polyhydric alcohol alkyl esters represented by polyoxyethylene (2) sorbitan monolaurate. Examples of polyquine ethylene alkyl ether phosphates include, in addition to those mentioned above, polyoxyethylene (8) sodium oleyl ether phosphate, dipolyoxyethylene (4) nonylphenyl ether potassium phosphate, and the like. In addition, the number in parentheses in the compound name indicates the number of oxine ethylene units.

These polyoxyethylene derivatives may be used alone or in combination of two or more, as appropriate, depending on the drug and adhesive base.

The polyethylene glycol, which is another component of the present absorption enhancer, preferably has a molecular weight of 10,000 or less.

The amount of this absorption enhancer to be incorporated in the patch layer of the transdermal absorption preparation varies depending on the type of drug and adhesive base in order to effectively exhibit the effect of promoting transdermal absorption. It is within the range of 2%.

The reason for this is that if the amount of absorption enhancer is less than 0.1% by weight, a sufficient amount of the drug cannot be absorbed into the body's circulatory system through the skin to produce the desired drug effect, and vice versa. This is because if the amount of the adhesive base exceeds 45% by weight, the amount of the adhesive base will be relatively reduced and the adhesion of the preparation to the skin will deteriorate. A particularly preferred amount of the absorption enhancer is in the range of 0.5 to 30% by weight in the adhesive layer. In addition, the proportion of polyethylene glycol to the total absorption enhancer is
Although it varies depending on the type and amount of polyoxyethylene derivative, drug and adhesive base, 5 to 99% by weight
It is preferably in the range of 10 to 95% by weight.

ii) The adhesive base used in the transdermal absorption preparation of the present invention has excellent compatibility with the absorption enhancer, does not impair the adhesion of the patch layer, and provides good long-term stability of the preparation. There is no particular limitation as long as it is. Preferred adhesive bases include acrylic adhesive bases, rubber adhesive bases, silicone adhesive bases, and the like.

In particular, the acrylic adhesive base has 4 to 18 carbon atoms.
A homopolymer or copolymer of a (meth)acrylic acid alkyl ester obtained from an aliphatic alcohol and (meth)acrylic acid, and/or a copolymer of the above (meth)acrylic acid alkyl ester and other functional monomers. Combination is preferably used.

The above (meth)acrylic esters include butyl acrylate, isobutyl acrylate, hexyl acrylate,
Octyl acrylate, 2-ethylhexyl acrylate,
isooctyl acrylate, decyl acrylate, isodecyl acrylate, lauryl acrylate, stearyl acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, 2-ethylhexyl methacrylate, isooctyl methacrylate, decyl methacrylate, Examples include isodecyl methacrylate, lauryl methacrylate, and stearyl methacrylate.

Examples of the above-mentioned functional monomers include monomers having a heptad-carboxyl group having a hydroxyl group, monomers having an amide group, monomers 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. Monomers with carboxyl groups include α-β such as acrylic acid and methacrylic acid.
Examples include unsaturated carboxylic acids, maleic acid monoalkyl esters such as butyl maleate, maleic acid, fumaric acid, crotonic acid, and the like. Maleic anhydride also provides the same (co)polymerization component as maleic acid. Examples of monomers having an amide group include acrylamide, alkyl (meth)acrylamides such as dimethylacrylamide and diethylacrylamide; alkyl ether methylol (meth)acrylamides such as butoxymethylacrylamide and ethoxymethylacrylamide; and diacetone acrylamide. Examples of monomers having an amino group include dimethylaminoethyl acrylate and vinylpyrrolidone.

As copolymerizable monomers other than those mentioned above, vinyl acetate, vinyl alcohol, styrene, α-methylstyrene, vinyl chloride, acrylonitrile, ethylene, propylene, butadiene, etc. can also be used. In the adhesive base (meta)
Acrylic acid alkyl ester as a (co)polymerization component 5
It is preferable that the content is 0% by weight or more.

If necessary, a polyfunctional monomer is further added to the acrylic adhesive base and copolymerized with other monomer components.

The addition of this polyfunctional monomer causes very slight crosslinking between the resulting polymers, thereby increasing the internal cohesive strength of the adhesive base. Therefore, the so-called adhesive residue phenomenon when peeling off the applied side is almost eliminated, almost regardless of the properties of the skin to which it is applied or the amount of perspiration. Moreover, the addition of this polyfunctional monomer does not have any adverse effect on drug release properties or low skin irritation. Examples of such polyfunctional monomers include di(meth)acrylate, tri(meth)acrylate, and tetra(meth)acrylate.
It is not limited to this. More specifically, di(meth)acrylate obtained by combining polymethylene glycols such as hexamethylene glycol and octamethylene glycol with (meth)acrylic acid; and polyalkylene glycols such as polyethylene glycol and polypropylene glycol. Di(meth)acrylate obtained by combining with (meth)acrylic acid; trimethylolpropane tri(meth)acrylate and glycerintri(meth)acrylate
tri(meth)acrylates such as acrylate; and tetra(meth)acrylates such as pentaerythritol tetra(meth)acrylate. Two or more of these polyfunctional monomers may be used in combination. The polyfunctional monomer is present in a proportion of 0.005 to 0.00% in all monomers used in the production of the adhesive base. It is used in a proportion of 5% by weight.

If the amount of the polyfunctional monomer used is less than 0.005% by weight, the effect of improving internal cohesive force due to crosslinking will be small, and if it exceeds 0.5% by weight, the adhesive base obtained by polymerization will gel. drug diffusion and release.

As the rubber adhesive base, natural rubber, styrene-isoprene-styrene block copolymer (SIS) is used.
It is made by adding 20 to 200 parts by weight of a tackifying resin and appropriate amounts of softeners, stabilizers, etc. to 100 parts by weight of a rubber elastic body such as polyisoprene, polybutene, polyisobutylene, or ethylene-vinyl acetate copolymer. used.

As the silicone adhesive base, one whose main component is polydimethylsiloxane or the like is used.

The above adhesive base includes tackifiers such as rosin resin, polyterpene resin, coumaron-indene resin, petroleum resin, terpene-phenol resin, liquid polybutene, mineral oil, lanolin, liquid polyisoprene, liquid polypropylene, etc. Plasticizers such as acrylates, fillers, and compounding agents such as anti-aging agents are added as necessary.

Particularly preferable adhesive bases for use in the transdermal absorption preparation of the present invention include (a) 60 to 99.5% by weight of the above (meth)acrylic acid ester monomer and Cb') a water-soluble homopolymer. It is a copolymer obtained from a blend containing the monomer (a) and 0.5 to 40% by weight of a copolymerizable vinyl monomer. and nil monomer (b)
Examples include vinylpyrrolidone, maleic anhydride, vinyl alcohol, and (meth)acrylic acid. By using this copolymer, good compatibility between the adhesive base and the absorption enhancer is exhibited, and the adhesiveness of the adhesive layer is not impaired, and the long-term stability of the formulation is improved. It will be done.

The monomer (a) serves to exhibit the adhesive properties of the adhesive layer, and the vinyl monomer (b) serves to exhibit the compatibility between the adhesive base and the absorption promoter. Therefore, if the proportion of monomer (a) is less than 60% by weight, the adhesion of the adhesive layer to the skin will be poor. Furthermore, 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 will be poor.

i) The drug (physiologically active substance) used in the transdermal absorption preparation of the present invention is not particularly limited as long as it can permeate biological membranes transdermally or transmucosally. Examples of drugs include antipyretic and antiinflammatory analgesics, steroid anti-inflammatory agents, vasodilators, antihypertensive and arrhythmic agents, antihypertensive agents, antitussive expectorants,
Antitumor agents, local anesthetics, hormones, asthma/nasal allergy treatments, antihistamines, anticoagulants, antispasmodics, cerebral circulation/metabolism improvers, antidepressants/anxiolytics, vitamin D preparations, hypoglycemic agents, Examples include ulcer medicine, sleeping pills, and antibiotics.

Examples of antipyretic and antiinflammatory analgesics include indomethacin, salicylic acid, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibufenac, fenbufen, alclofenac, phenylbutacin, mefenamic acid, pendazac, Examples include piroxicam, flurbiprofen, pentazocine, buprenorphine hydrochloride, and butorphanol tartrate.

Examples of steroidal anti-inflammatory agents include hydrocortisone, prednisolone, fluocinolone acetonide, fluorousiltide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethacin, betamethasone acetate, diflucortolon valerate, clobetasol propionate, and fluocinonide. Examples include.

Examples of vasodilators include diltiazem, verapamil,
Examples include pentaerythritol tetranitrate, diviridamol, isosorbide nitrate, nifedipine, and nitroglycerin.

Examples of antihypertensive/arrhythmia agents include propanolol, atenolol, pindolol, quinidine sulfate, ajmaline, alprenolol hydrochloride, metoprolol tartrate, nadolol, timolol maleate, shisoviramide, and the like.

Examples of antihypertensive agents include clonidine hydrochloride, captopril, prazosin hydrochloride, penbutolol sulfate, guanabenz acetate, guanfacine hydrochloride, bunazosin hydrochloride, elanapril maleate, atenolol hydrochloride, bunitrol hydrochloride, and the like.

Examples of antitussive expectorants include procaterol hydrochloride, terbutaline sulfate, phenotyrol hydrobromide, tubuterol hydrochloride, amproxol hydrochloride, vilbutyrol hydrochloride,
Examples include mabuterol hydrochloride, clenbuterol hydrochloride, trimethoquinol hydrochloride, and formotyol fumarate.

Antitumor agents include 5-fluorouracil, 1-(2-
Examples include (tetrahydrofuryl)-5-fluorouracil, mitomycin C, and the like.

Examples of local anesthetics include pensicaine, procaine, lidocaine, and tetracaine.

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

Examples of therapeutic agents for asthma and nasal allergies include ketotifen fumarate, azelastine hydrochloride, and sodium cromoglycate.

Examples of antihistamines include cyclohebutadine hydrochloride, diphenhydramine hydrochloride, phenebenzamine, and mequitazine.

Examples of anticoagulants include heparin.

Examples of antispasmodics include scopolamine and clofluverol.

Examples of cerebral circulation/metabolism improving agents include vinpocetine, flunarizine hydrochloride, nicardipine hydrochloride, provincamine fumarate, dihydroergotoxine mesylate, ifenbrozil tartrate, isoxsuprine hydrochloride, and the like.

Examples of antidepressants and anxiolytics include maprotiline hydrochloride, ethidium, diazenocum, bromazenocum, amitributyline hydrochloride, mianserin hydrochloride, and the like.

Examples of vitamin D preparations include Alpha Rundall,
Examples include ergocalciferol.

Examples of hypoglycemic agents include glyhenclamide, glicracit, and the like.

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

Examples of sleeping pills include phenobarbital, amobarbital, and the like.

Examples of antibiotics include tetracycline and chloramphenicol.

The amount of these drugs to be blended varies depending on the type of drug and the purpose of use of the transdermal absorption preparation, and is usually 0.1% in the patch layer.
-30% by weight.

iv) The support is flexible but serves to provide self-support to the transdermal absorption preparation and to prevent volatilization and migration of the drug in the adhesive layer, and is a drug-impermeable sheet or a support. It is composed of films, laminates of these materials, and woven or non-woven fabrics. Examples of materials for the support include cellulose acetate, ethyl cellulose, polyethylene terephthalate, vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyethylene, polyvinylidene chloride, Examples include aluminum. Among these materials, materials that have conformability to the skin surface are preferably used.

In particular, a laminate film of polyethylene terephthalate and ethylene-vinyl acetate copolymer is preferred.

The thickness of the support is 500 μm or less, preferably 5 to 150 μm.
It is μm.

(2) The transdermal patch according to the present invention usually has a release paper on its application surface. A release paper made of a polyethylene terephthalate film treated with silicone 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 5
It is 0 μm.

vi) As a method for manufacturing the transdermal absorption preparation according to the present invention, a conventional method for manufacturing adhesive tapes can be applied. A typical example thereof is a solvent coating method, and other methods such as an emulsion coating method, a hot melt method, and a method using electron beam crosslinking are also used. In order to produce the transdermal absorption preparation according to the present invention by a solvent coating method, for example, the adhesive base, the drug, the absorption enhancer, and, if necessary, the compounding agents are dissolved or dispersed in an appropriate solvent. The solution or dispersion is directly applied to the surface of the support and dried to form an adhesive layer with a thickness of 30 to 200 μm. Alternatively, this solution or dispersion may be applied onto a protective release paper, and after drying, the resulting adhesive layer may be brought into close contact with the support.

vii) The thus obtained transdermal absorption preparation is usually applied directly to the skin surface for the purpose of administering the drug to the body's circulatory system through the skin. It may also be applied to mucous membranes for the same purpose as above. Furthermore, this transdermal absorption preparation may of course be applied to the skin or mucous membranes for the purpose of treating diseased areas of the skin or mucous membranes.

(Function) Since the transdermal absorption preparation according to the present invention uses a combination of a polyoxyethylene derivative and polyethylene glycol as an absorption enhancer, a sufficient amount of the drug to exert the desired drug effect can be applied to the skin. In addition, skin irritation caused by the absorption enhancer is reduced.

The detailed mechanism of action of an absorption enhancer consisting of a polyoxyethylene derivative and polyethylene glycol on the skin is as follows:
Although it is not certain, it can be considered as follows.

(a) By using the present absorption enhancer, the amount of drug released per unit area and unit time and the ability of the drug to migrate into the skin are significantly improved.

This changes the physical properties of the above substance or adhesive base, and
This is thought to be because it penetrates into the skin, changes the physicochemical properties of the stratum corneum, and reduces the barrier function of the stratum corneum. As a result, the distribution coefficient of the drug between the adhesive base and the skin changes, or the diffusion rate of the drug in the skin is increased, which improves the amount of drug released and allows the required amount of drug to be easily delivered to the skin. It passes through the body and is absorbed into the body's circulatory system.

Therefore, compared to a conventional transdermal absorption preparation using an absorption enhancer, a transdermal absorption preparation with a larger effective dose than a conventional product with the same area can be obtained.

In other words, the same effect as the conventional product can be obtained with a transdermal absorption preparation having a smaller area than the conventional product.

(b) Regarding the reduction of skin irritation, this absorption enhancer is a substance that exhibits an excellent transdermal permeation promoting effect as mentioned above, so the patch area required for drug administration is small, and the skin irritation is reduced during long-term use. less damage.

In addition, as sufficient medicinal efficacy can be obtained with a transdermal absorption preparation with a small area as mentioned above, erythema can be avoided even in people who are sensitive to skin irritation, or the area of erythema can be reduced as much as possible. be given Since the transdermal absorption preparation has such a small area, it is easy to apply and there is little discomfort when applied.

(c) Furthermore, as mentioned above, the drug is easily absorbed transdermally in a sufficient amount to produce the desired drug effect, so it is not necessary to apply a large amount of drug as in the past. There is no need to include it in the layer.

Furthermore, by using the present absorption enhancer, the effective blood concentration can be maintained for a long period of time, and the bioavailability of the drug is increased.

In addition, this absorption enhancer does not denature the drug,
It also has excellent compatibility with the adhesive base and does not change the compatibility between the drug and the adhesive base, so the drug does not precipitate from the surface of the transdermal absorption preparation.

(Example) Next, the present invention will be specifically explained based on examples.

(a) Production Example 1 of transdermal absorption preparation 1) Preparation of acrylic adhesive base 2-ethylhexyl acrylate 302.0g 1 vinylpyrrolidone 98. Og and hexamethylene glycol dimethacrylate 40. Omg (0 for the supreme tsuma)
．． 02% by weight) into a separable flask, and further added 400.0g of ethyl acetate to bring the monomer concentration to 50%.
Adjusted to % by weight. This solution was heated to 60°C under a nitrogen atmosphere.
C., a polymerization initiator solution prepared by dissolving 2 g of lauroyl 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. In this way, an ethyl acetate solution of an acrylic adhesive base having a solid content concentration of 35% by weight was obtained.

it) Preparation of a liquid containing a patch formulation: To the obtained adhesive base solution, isosorbide nitrate as a drug and polyoxyethylene (4) as an absorption enhancer are added.
An ethyl acetate solution containing sodium lauryl ether phosphate and polyethylene glycol (molecular weight 400) was mixed with isosorbide nitrate so that the solid content (sum of weights of adhesive base, drug, and absorption enhancer) was 25% by weight. ,
Polyoxyethylene (4) Sodium lauryl ether phosphate and polyethylene glycol were added so that the solid concentration was 15.5% by weight, 1% by weight, and 10% by weight, respectively, and the entire liquid was uniformly mixed with a day silver. Mixed. An ethyl acetate solution containing the patch formulation was thus prepared.

111) Preparation of transdermal absorption preparation 38 μm thick polyethylene terephthalate (PET)
Step i
After applying the preparation solution f), dry at 60°C for 30 minutes,
A sticking layer having a thickness of 80 μm was formed. Next, a 34 μm thick support made of a laminate of PET and ethylene-vinyl acetate copolymer (PET-EVA) was brought into close contact with the adhesive layer. Thus, a transdermal absorption preparation was prepared.

Examples 2 to 4 In step if) of Example 1, polyoxyethylene (4) sodium lauryl ether phosphate and polyethylene glycol (molecular weight 400) were mixed as absorption enhancers at the solid content concentrations shown in Table 1, respectively. A transdermal absorption preparation was prepared by using the same method as in Example 1 and performing other operations in the same manner as in Example 1.

Comparative Examples 1 to 5 In step 11) of Example 1, either polyoxyethylene (4) sodium lauryl ether phosphate or polyethylene glycol (molecular weight 400) was used as an absorption enhancer at the solid content shown in Table 1. A transdermal absorption preparation was prepared by using a medium-concentration formulation or by using neither of the two, and performing other operations in the same manner as in Example 1.

Table 1 (Absorption enhancer) Example 5 ■) 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 were placed in a separable flask. Furthermore, 170 g of ethyl acetate was added to adjust the monomer concentration to 70% by weight. This solution was heated to a temperature of 70° C. under a nitrogen atmosphere, and 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. In this way, an ethyl acetate solution of an acrylic adhesive base having a solid content concentration of 35% by weight was obtained.

if) Preparation of liquid containing formulation for patch Indomethacin as a drug and polyoxyethylene sorbitan monolaurate and polyethylene glycol (molecular weight 6
00) containing ethyl acetate solution containing solid content (adhesive base,
The concentration of indomethacin, polyoxyethylene sorbitan monolaurate, and polyethylene glycol in the solid content was 2% by weight, 5% by weight, and 20% by weight, respectively, so that the concentration (sum of the weight of the drug and absorption enhancer) was 25% by weight. %, and the entire liquid was mixed uniformly using a day silver. An ethyl acetate solution containing the patch formulation was thus prepared.

1ii) Preparation of transdermal absorption preparation By the same operation as in step 11i) of Example 1, an adhesive layer was formed on a release paper made of silicone-treated PET, and a support made of PET-EVA was brought into close contact with this layer. A skin absorption preparation was prepared.

Comparative Example 6 In step iD of Example 5, a transdermal absorption preparation was prepared by performing the other operations in the same manner as in Example 5 without using polyethylene glycol.

Example 6 In step i) of Example 5, no acrylic acid was used,
140g5 ethyl acetate4 instead of 170g ethyl acetate
A transdermal absorption preparation was prepared by using 380 g instead of 70 g, and using polyethylene glycol at a solid concentration of 3% in step ij) of Example 5, and performing the other operations in the same manner as in Example 5. Prepared.

Comparative Example 7 A transdermal absorption preparation was prepared in the same manner as in Example 6 except that polyethylene glycol was not used.

Example 7 1) Preparation of rubber-based adhesive base Styrene-isoprene-thretin block copolymer (manufactured by Shell Chemical Co., Ltd., Cauliflex TR) as a rubber elastic body
1107) 100 parts by weight, alicyclic hydrogenated petroleum resin (manufactured by Arayo Kagaku Co., Ltd., Alcon-P2) as a tackifier.
O) 140 parts by weight, 25 parts by weight of polybutene (manufactured by Nisseki Chemical Co., Ltd., HV-300) as a softener, and 48 parts by weight of cyclohexane.
A cyclohexane solution of a rubber adhesive base having a solid content concentration of 35.41% by weight was obtained by dissolving 3.38 parts by weight.

ii) Preparation of a liquid containing a patch formulation Adding piroxicam and piroxicam as drugs to the obtained adhesive base solution
A tetrahydrofuran solution containing polyoxyethylene myristyl ether and polyethylene glycol (molecular weight 400) as absorption enhancers was added to the solid content (adhesive base,
The concentration in the solid content of piroxicam, polyoxyethylene myristyl ether, and polyethylene glycol was 2% by weight, 2% by weight, and 1% by weight, respectively.
The entire solution was mixed uniformly using a day silver. A mixed solution of cyclohexane and tetrahydrofuran containing a patch formulation was then prepared.

1ff) Preparation of transdermal absorption preparation By the same operation as in step 111) of Example 1, an adhesive layer was formed on a release paper made of silicone-treated PET, a support made of PET-EVA was brought into close contact with this layer, and the A skin absorption preparation was prepared.

Comparative Example 8 In step 11) of Example 7, polyoxyethylene myristyl ether was used at a solid concentration of 20% by weight without using polyethylene glycol, and other operations were performed in the same manner as in Example 7. A transdermal absorption preparation was prepared.

Example 8 In step if) of Example 1, the solid content concentration was 35% by weight.
An ethyl acetate solution containing estradiol crystals with an average particle size of 20 μm as a drug, and polyoxyethylene monolaurate and polyethylene glycol (molecular weight 1000) as absorption enhancers was added to a sticky base solution containing solid content (sticky group). The solid content of estradiol, polyoxyethylene monolaurate, and polyethylene glycol was 15% by weight, 2% by weight, and A transdermal absorption preparation was prepared by adding 30% by weight and performing other operations in the same manner as in Example 1.

Comparative Example 9 In step 11) of Example 8, a transdermal absorption preparation was prepared by performing the other operations in the same manner as in Example 8 without using polyethylene glycol.

Example 9 In step jt) of Example 1, the solid content concentration was 35% by weight.
An ethyl acetate solution containing nifedipine as a drug and polyoxyethylene oleylamine and polyethylene glycol (molecular weight 400) as absorption enhancers was added to a sticky base solution containing the solid content (weight of sticky base, drug and absorption enhancer). sum) so that the concentration is 25% by weight, and the solid concentration of nifedipine, polyoxyethylene oleylamine, and polyethylene glycol is each 15% by weight.
% by weight, 15% by weight and 2% by weight,
Other operations were performed in the same manner as in Example 1 to prepare a transdermal absorption preparation.

Comparative Example 10 In step it) of Example 9, a transdermal absorption preparation was prepared by performing the other operations in the same manner as in Example 9 without using polyethylene glycol.

(b) Performance evaluation of transdermal absorption preparations i) Rabbit skin migration test Example 1.2.3.4.7 and Comparative Example 1.3.4.5
．． Regarding the transdermal absorption preparation No. 8, a drug migration test on rabbit skin was conducted using the method shown in Test 1.

Test 1 A test piece of transdermal preparation (area 10
em2) was applied, and 24 hours later, it was peeled off and collected. The number of repetitions was 4 for each formulation. When the drug was isosorbide nitrate, these test pieces were extracted with methanol, and the remaining amount of isosorbide nitrate in the transdermal absorption preparation was measured by high performance liquid chromatography. The difference between the initial amount of isosorbide nitrate in the transdermal absorption preparation and the remaining amount after the test was defined as the amount transferred to the skin over 24 hours. In the case of piroxicam, the transdermal absorption preparation was extracted with chloroform, the residual amount of piroxicam in the transdermal absorption preparation was measured by high performance liquid chromatography, and the amount transferred to the skin was determined in the same manner as in the case of isosorbide nitrate. .

Table 2 summarizes the amount of drug transferred to the rabbit skin for each transdermal absorption preparation.

When a combination system of polyoxyethylene derivatives and polyethylene glycol is used, the amount of drug transferred is at the same level or higher than when using high-concentration polyoxyethylene derivatives that cause skin irritation.

it) Rabbit skin irritation test Example 1.2.3.4.7 and Comparative example 1.3.4.5
．． The percutaneous absorption preparation No. 8 was subjected to an irritation test on rabbit skin using the method shown in Test 2.

Test 2 The skin of rabbits treated in the same manner as in Test 1 was visually observed for erythema 1 hour and 48 hours after the transdermal absorption preparation was removed.

In this test, no edema or formation of epithelium was observed.

The degree of erythema was evaluated using the following 5-grade criteria from 0 to 4.

0... No erythema 1... Mild erythema that can be barely discerned 2... Obvious erythema 3... Moderate erythema 4... Strong crimson erythema Average value (repeat the sum of the scores for each round) The value divided by 4) was taken as the skin irritation index of each transdermal absorption preparation.

The obtained evaluation results are shown in Table 3.

Table 3 (Rabbit Skin Irritation Index) As is clear from Table 3, when a combination system of a polyoxyethylene derivative and polyethylene glycol is used as an absorption enhancer, almost no skin irritation is observed.

Example 1.5.6.8.9 and Comparative Example 2.6.7.9
．． For each of the 10 transdermal absorption preparations, a drug permeability test was conducted on the excised skin of hairless mice using the method shown in Test 3.

Test 3 First, a diffusion cell (1) shown in the attached drawing was prepared. The diffusion cell (1) has a bottomed cylindrical receptor tank <2)
and a bottomed cylindrical donor tank (3) placed above it.
It consists of There is an opening (4) 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 at the upper end of the receptor tank (2), respectively. By stacking the upper flange (5) and the lower flange (6) facing each other, the donor tank (3) and the receptor tank (2) are stacked airtightly and concentrically. A laterally protruding sampling port (7) is attached to the side of the receptor tank (2), and a magnetic stirrer (9) is placed inside the receptor tank (2).

After sacrificing hairless mice (8 weeks old, male) by cervical dislocation, the skin was immediately peeled off, subcutaneous fat was removed, and approximately 5C
A piece of skin measuring m×5 cm was obtained.

This piece of skin (8) is attached to the upper flange (5) of the diffusion cell (1).
) and the lower flange (6), and the donor tank (3
) was completely closed with a piece of skin (8). Apply the transdermal absorption preparation to the upper surface of the skin piece (8) in an area of 3.
A test piece (10) obtained by punching out a 14 cm2 circle was attached. The receptor tank (2) was filled with a receptor liquid prepared by the following method.

Next, the diffusion cell (1) was placed in a constant temperature bath kept at a temperature of 37'', and the receptor liquid was stirred using a magnetic stirrer.24 hours after the start of the test,
), and the amount of drug permeated into this receptor fluid was measured by high-performance liquid chromatography.
It was fixed at 1. Table 4 summarizes the permeation amount measurements for each transdermal absorption preparation.

Preparation of receptor fluid NaH2PO, (5X10-'mol) Na2HP
O4 (2X10-'mol) NaC1 (1°5X1
0-1 mol) and 10 mg of gentamicin in distilled water.
After adjusting the pH of the resulting solution to 7.2 with a 0.1 N NaOH aqueous solution, the volume was capped at 1000 m/ml with distilled water.

(Margins below) Table 4 (Skin permeability in hairless mice) As is clear from Table 4, when polyoxyethylene derivatives and polyethylene glycol are used together as an absorption enhancer, skin permeability is higher than when polyethylene glycol is not used. It is observed that the amount is significantly higher.

jv) Human skin migration test The percutaneous absorption preparations of Example 1 and Comparative Example 1 were tested for drug migration into human skin using the method shown in Test 4.

Test 4 Each test piece (area: 10CI112) of the transdermal absorption preparations of Example 1 and Comparative Example 1 was applied to the upper arm of a test subject (healthy male subject), and 24 hours later, they were peeled off and collected. These test pieces were extracted with methanol, and the residual amount of isosorbide nitrate in the transdermal absorption preparation was measured by high performance liquid chromatography. The test was conducted on 8 subjects for each transdermal absorption preparation, and the difference between the initial drug amount of the transdermal absorption preparation and the residual amount after the test was taken as the amount transferred to the skin over 24 hours, and the average was taken. Table 5 shows the amount of drug transferred to human skin for each transdermal absorption preparation.

As is clear from Table 5, when a combination system of polyoxyethylene derivatives and polyethylene glycol is used as an absorption enhancer, skin irritation occurs with respect to drug migration into human skin as well as into rabbit skin. The amount of drug transferred was observed to be at the same level or higher than when using a polyoxyethylene derivative at a high concentration.

(2) Human skin irritation test The transdermal absorption preparations of Example 1 and Comparative Example 1 were tested for irritation to human skin by the method shown in Test 5.

Test 5 In the method of Test 4, the state of erythema on the skin was visually observed 1 hour and 48 hours after peeling off the transdermal absorption preparation.

In addition, no edema or formation of epidermis was observed in this test either.

The criteria for determining erythema are as shown in Test 1.

The average value of the scores of the eight people was used as the skin irritation index for each transdermal absorption preparation. The obtained evaluation results are shown in Table 6.

Table 6 (Human skin irritation index) 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) Since the transdermal absorption preparation according to the present invention uses a combination of a polyoxyethylene derivative and polyethylene glycol as an absorption enhancer, a sufficient amount of drug is delivered to the skin to exert the desired drug effect. In addition, skin irritation caused by absorption enhancers can be greatly reduced.

Such remarkable effects of the present invention are thought to be due to the mechanism of action of the absorption enhancer consisting of a polyoxyethylene derivative and polyethylene glycol.

(a) By using the present absorption enhancer, the amount of drug released per unit area and unit time and the ability of the drug to migrate into the skin can be significantly improved.

This is because the above substances change the physical properties of the adhesive base, and
This is because it penetrates into the skin, changes the physicochemical properties of the stratum corneum, and reduces the barrier function of the stratum corneum. the result,
The distribution coefficient of the drug between the adhesive base and the skin is changed, or the diffusion rate of the drug in the skin is increased, the amount of drug released is improved, and the required amount of drug can easily penetrate the skin. absorbed into the body's circulatory system.

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

(b) Regarding the reduction of skin irritation, this absorption enhancer is a substance that exhibits an excellent transdermal permeation promoting effect as mentioned above, so the patch area required for drug administration is small, and the skin irritation is reduced during long-term use. damage or less.

In addition, as sufficient medicinal efficacy can be obtained with a transdermal absorption preparation with a small area as mentioned above, erythema can be avoided even in people who are sensitive to skin irritation, or the area of erythema can be reduced as much as possible. be given Since the area of the transdermal absorption preparation is small, it is easy to apply the preparation and the discomfort caused by application can be reduced.

(c) Furthermore, as mentioned above, the drug is easily absorbed transdermally in a sufficient amount to produce the desired drug effect, so it is not necessary to apply a large amount of drug as in the past. There is no need to include it in the layer.

Furthermore, by using the present absorption enhancer, the effective blood concentration can be maintained for a long period of time, and the bioavailability of the drug can be increased.

In addition, this absorption enhancer does not denature the drug,
Since it has excellent compatibility with the adhesive base and does not change the compatibility between the drug and the adhesive base, the drug does not precipitate from the surface of the transdermal absorption preparation.

(d) Thus, according to the transdermal absorption preparation of the present invention,
Since a combination system of a polyoxyethylene derivative and polyethylene glycol is used as an absorption enhancer, the above-mentioned unique and remarkable effects can be exhibited.

[Brief explanation of the drawing]

The drawing is a perspective view of a diffusion cell used to test the skin permeability of drugs contained in transdermal formulations. Patent applicant: Kaoru Hirota, Representative of Sekisui Chemical Co., Ltd.

Claims (2)

[Claims] (1) In a transdermal absorption preparation in which a patch layer consisting of an adhesive base, an absorption enhancer, and a drug is held on a support, the absorption enhancer is composed of a polyoxyethylene derivative and polyethylene glycol. Characteristic transdermal absorption preparation. (2) The formulation according to claim 1, wherein the amount of the absorption enhancer in the adhesive layer is 0.1 to 45% by weight.