JPH062667B2 - Patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention relates to a patch having an adhesive layer containing a drug on the surface of a support, and in particular, the drug has a high transdermal absorbability and a long time. The present invention relates to a patch that does not reduce the adhesiveness.

(Prior Art) In order to obtain a medicinal effect on the whole body or a local area, an adhesive patch containing a drug (physiologically active substance) in an adhesive layer is applied to the skin surface, and the drug is absorbed through the skin. It is being appreciated. The transdermal administration method using such a patch has many advantages over conventional oral administration methods. For example, when a drug is orally administered, the drug absorbed in the intestine is circulated to the liver and metabolized, so that a considerable amount of the drug is decomposed before its drug effect is exerted. In contrast, in the transdermal administration method, the absorbed drug does not pass through the liver during the first circulation in the body. Therefore, metabolism in the liver does not significantly reduce drug efficacy. Oral administration of non-steroidal anti-inflammatory drugs is more likely to cause gastrointestinal disorders, but transdermal administration is less likely to cause such gastrointestinal disorders. By controlling the absorbability of a drug, it is possible to reduce the side effects caused by a large amount of the drug being absorbed in a short time. The frequency of drug administration can be reduced if a constant blood concentration can be maintained for a long time.

However, even if a drug is administered using a patch, the drug is unlikely to penetrate the skin and bioavailability is often low. Since the stratum corneum on the skin surface has a barrier function of preventing foreign substances from entering the body, a sufficient amount of drug capable of exerting a pharmacological effect is not absorbed through the skin.

A patch containing an absorption enhancer has been produced in order to weaken the barrier function of the stratum corneum and absorb a sufficient amount of a drug. For example, JP-A-57-9714, JP-B-58-43368, JP-A-58-52216, JP-A-59-27978,
Japanese Patent Publication No. 59-7688, Japanese Patent Publication No. 60-19890, JP 6
Japanese Unexamined Patent Publication No. 0-13720 and Japanese Unexamined Patent Publication No. 60-11431 disclose a patch containing an absorption promoter in an adhesive layer.

Among the above absorption enhancers, for example, salicylic acid, urea, and dimethyl sulfoxide are known to dissolve keratin, but even if these are added, the transdermal absorbability of the drug is not necessarily good. Propylene glycol, glycerin, sodium pyrrolidonecarboxylate, etc. can retain water in the stratum corneum, but almost no drug absorption promoting effect is observed.
Dimethylsulfoxide is irritating to the skin and easily causes erythema and rash. When a dicarboxylic acid ester such as diisopropyl adipate or a fatty acid ester is contained in the pressure-sensitive adhesive layer, the compatibility between the pressure-sensitive adhesive and the drug decreases, and the drug is likely to precipitate from the pressure-sensitive adhesive. The tackiness may decrease. Sulfur-containing compounds such as calcium thioglycolate also cause malodors. In addition to the above compounds, myristic acid ester, adipic acid ester, lauryl sulfate ester, polyoxystyrene alkyl ether and the like are also disclosed. However, even if these absorption enhancers are used, the absorption amount of the drug through the skin is not always sufficient. It cannot be said that there is. Thus, the current situation is that there is no patch available that can effectively absorb the drug.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional drawbacks, and an object thereof is to provide a patch capable of effectively absorbing the contained drug through the skin. is there. Another object of the present invention is to provide a pressure-sensitive adhesive containing an absorption enhancer in the pressure-sensitive adhesive layer, which enhances the transdermal absorbability of a drug and is non-irritating to the skin and safe for the living body. Still another object of the present invention is to provide a patch containing an absorption enhancer, which does not reduce the adhesiveness of the adhesive, does not cause the drug to precipitate, and does not cause denaturation of the contained drug. To provide the agent.

(Means for Solving Problems) The patch of the present invention is a patch in which an adhesive layer containing a drug, a surfactant and a fatty acid ester is provided on the surface of a support, and the surfactant is N -Acyl sarcosine,
The fatty acid forming the acyl group of the N-acyl sarcosine and the fatty acid forming the fatty acid ester each have 6 to 18 carbon atoms, whereby the above object is achieved.

The surfactant used in the present invention acts as a transdermal absorption enhancer for the drug contained therein. Such a surfactant is an N-acyl sarcosine of the formula: Here, R is an aliphatic hydrocarbon group having 5 to 17 carbon atoms.

Such a compound is a sarcosine (N-methylglycine) derivative of a fatty acid, and the fatty acid has 6 to 18 carbon atoms (corresponding R has 5 to 17 carbon atoms). When the carbon number is out of the range of 6 to 18, the absorbability of the drug contained in the adhesive layer is lowered. Examples of the fatty acid include caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, valmitic acid, margaric acid, stearic acid, hexadecenoic acid, oleic acid, and linoleic acid. These may be used as a mixture of two or more kinds. For example, coconut oil fatty acid which is a mixture thereof is preferably used.

The above-mentioned surfactant is contained in the pressure-sensitive adhesive layer containing the pressure-sensitive adhesive, the surfactant and the fatty acid ester described below, in an amount of 0.1 to 20% by weight, preferably 0.1 to 10% by weight. If the amount of the surfactant is too small, the drug absorption promoting effect cannot be obtained. If it is excessive, the surfactant will leach out from the adhesive layer.

Although the initial pressure-sensitive adhesive of the pressure-sensitive adhesive to which the above-mentioned surfactant is added is good, the pressure-sensitive adhesiveness is slightly decreased over time, and the patch tends to peel off from the skin surface. Therefore, a fatty acid ester is added for the purpose of ensuring the temporal stability of the adhesive force. This fatty acid ester consists of an ester of a fatty acid and an alkyl alcohol, and the fatty acid has 6 carbon atoms.
~ 18, and the alkyl alcohol has 1 to 20 carbon atoms,
It is preferably 2 to 14. Examples of such fatty acid ester include isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, myristyl myristate, and hexyl laurate.

When the above fatty acid ester is added, the tackiness of the pressure-sensitive adhesive described below is improved. Furthermore, since the fatty acid ester makes the skin and the adhesive easier to adapt to each other, the decrease in the adhesiveness due to the surfactant is suppressed and the adhesive force lasts for a long time. The presence of the fatty acid ester increases the diffusion rate of the drug and surfactant in the adhesive matrix, which enhances the action of the surfactant, and the adhesiveness of the adhesive layer to the skin is sufficient. Will improve further. Thus, the fatty acid ester has both effects of imparting tackiness and promoting percutaneous absorption of the drug.

The fatty acid ester is contained in the adhesive layer in an amount of 0.5 to 50% by weight, preferably 0.5 to 20% by weight. If the amount is too small, the effect of maintaining tackiness cannot be obtained. When it is excessive, the fatty acid ester is leached from the adhesive layer.

The drug (physiologically active substance) used is not particularly limited as long as it can penetrate the skin by transdermal administration. For example, non-steroidal anti-inflammatory drug, steroidal anti-inflammatory drug, vasodilator, antiarrhythmic drug, antihypertensive drug, antitumor drug,
Local anesthetics, hormones, antihistamines, anticoagulants,
These include diuretics, psychotropic drugs, hypnotics, and antibiotics.

Non-steroidal anti-inflammatory agents include salicylic acid, aspirin, acetaminophen, diclofenac sodium, ibuprofen, sulindac, naproxen, ketoprofen, flufenamic acid, ibhenac, fuenbufen, alclofenac, phenylbutazone, mehenamic acid, bendazac, piroxicam , Such as flurbiprofen.

Steroid anti-inflammatory drugs include hydrocortisone, prednisolone, fluocinolone acetonide, fludoxycortide, methylprednisolone, hydrocortisone acetate, triamcinolone acetonide, dexamethasone, betamethasone acetate, diflucortron valerate, clobetasol propionate, and fluocinonide. There is.

Vasodilators include diltiazem, verapamil, pentaerythritol tetranitrate, dipyridamole, and isosorbide dinitrate.

Antiarrhythmic agents include propanolol, pindolol,
Examples include quinidine, ajmaline, prazimarin, and alprenolol. Antihypertensive agents include clonidine. Anti-tumor agents include 5-fluorouracil, 1-
(2-tetrahydrofuryl) -5-fluorouracil,
Examples include mitomycin C. Local anesthetics include benzocaine, procaine, lidocaine and tetracaine. Hormonal agents include steroid hormones such as estrogen, estradiol, testosterone, and progesterone; peptide hormones such as insulin; prostaglandins. Antihistamines include cycloheptazine hydrochloride, diphenhydramine, phenbenzamine and the like. Anticoagulants include heparin, diuretics include thiazide, and psychotropic drugs include scopolamine and clofluperol. Hypnotics include phenobarbital and amobarbital; antibiotics include tetracycline and chloramphenicol. The blending amount of these drugs varies depending on the type of drug, the purpose of use of the patch, etc., but the drug is usually contained in the adhesive layer in a proportion of 0.1 to 30% by weight.

The base of the patch (adhesive) is not particularly limited as long as it has an adhesive force capable of fixing the patch on the skin surface at room temperature for a long time. For example, an acrylic, rubber-based, silicone resin-based adhesive or the like may be used, and an acrylic-based and rubber-based adhesive is usually used.

In the case of acrylic adhesives, because of their adhesive properties,
(Co) polymer of (meth) acrylic acid alkyl ester obtained from aliphatic alcohol having 4 to 18 carbon atoms and (meth) acrylic acid and / or the above (meth) acrylic acid alkyl ester and other functional monomer The copolymer of 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, 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 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 monomers 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; coumaric acid; crotonic acid. Maleic anhydride also gives the same (co) polymerization components as maleic acid. Examples of the amide group-containing monomer include alkyl (meth) acrylamides such as acrylamide, dimethyl acrylamide, and diethyl acrylamide; alkyl ether methylol (meth) acrylamides such as butoxymethyl acrylamide and ethoxymethyl acrylamide; diacetone acrylamide; and vinylpyrrolidone. As a monomer having an amino group,
For example, dimethylamino acrylate.

Copolymerizable monomers other than the above and vinyl acetate, styrene,
Examples include α-methylstyrene, vinyl chloride, acrylotolyl, ethylene, propylene and butadiene, which may be copolymerized. (Meta) in the adhesive
50% of acrylic acid alkyl ester as (co) polymerization component
It is preferable that the content is at least wt%.

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

If necessary, various additives such as rosin-based resins, polyterpene resins, coumarone-indene resins, petroleum-based resins, terpene-phenol resins, etc. may be included in the above-mentioned adhesives; liquid polybutene, mineral oil, lanolin, liquid poly Plasticizers such as isoprene and liquid polyacrylate; fillers; antioxidants are added.

As a support for the patch, a support usually used for patches is used. Materials for such a 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. , Aluminum, etc. These are, for example, a single layer sheet (film) or a laminate of two or more sheets (laminate).
Used as a body. Materials other than aluminum may be used as woven or non-woven fabrics.

A pressure-sensitive adhesive layer containing a drug and a surfactant is formed on the surface of the support to obtain a patch. To form the pressure-sensitive adhesive layer, various coating methods such as a solvent coating method, a hot melt coating method, and an electron beam curing emulsion coating method can be used. Among them, the solvent coating method is preferably used. To form the pressure-sensitive adhesive layer by the solvent coating method, for example, the pressure-sensitive adhesive is diluted with an appropriate solvent, and a drug, a surfactant, a fatty acid ester and, if necessary, a compounding agent are added and mixed uniformly. , Apply the obtained solution on the surface of the support and dry it. Instead of directly applying the solution to the surface of the support, the solution may be applied onto a release paper coated with a silicone resin or the like, dried and then brought into close contact with the support. Such release paper is used to protect the surface of the adhesive layer of the patch until use. Even in coating methods other than the solvent coating method, it is recommended that a release paper be placed to protect this surface after forming the adhesive layer. The thickness of the pressure-sensitive adhesive layer varies depending on the purpose of use, but is usually 30 to 200 μm. If it is less than 30 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient. When it exceeds 200 μm, the drug contained in the pressure-sensitive adhesive layer near the support does not sufficiently diffuse, and the drug release property decreases.

(Operation) When the patch of the present invention is applied to the surface of the skin, the contained drug is easily absorbed through the skin. Although the detailed mechanism is unknown, it is considered that the surfactant acts on the skin to denature the protein, increase the water content and soften it. Therefore, it is generally considered that the stratum corneum on the skin surface, which is difficult to penetrate the drug, is softened and the contained drug is easily absorbed through the skin. Furthermore, since the fatty acid ester is contained, the adhesive strength is improved, and the adhesive strength is not reduced due to the surfactant. Since the patch can be applied to the skin surface for a long time, the drug is effectively absorbed. The fatty acid ester increases the diffusion rate of the drug and the surfactant in the adhesive and, as a result, improves the initial absorption performance of the drug. Since the sufficiently diffused surfactant acts on the skin, the transdermal absorption rate of the drug also increases. In such a patch, a sufficient amount of the drug to obtain the required drug effect is easily absorbed, so that it is not necessary to include a large amount of the drug in the adhesive layer as in the conventional case. Moreover, it is possible to maintain the effective blood concentration for a long time. That is, the bioavailability of the drug is high. Such a percutaneous absorption promoting effect and a drug effect sustaining effect are much higher than those using conventional absorption promoting agents. Moreover, the surfactants and fatty acid esters used in the present invention are not irritating to the skin and are highly safe. It does not modify the contained drug. Excellent compatibility with adhesives. Since the compatibility between the drug and the adhesive does not change, the drug does not precipitate from the surface of the adhesive layer after preparation.

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

Example 1 (A) Preparation of patch: 2-ethylhexyl acrylate 90
An ethyl acetate solution containing 25% by weight of a copolymer consisting of 10% by weight of vinylpyrrolidone and 25% by weight of vinylpyrrolidone was prepared. To 100 parts by weight (solid content) of this solution, 10 parts by weight of diclofenac sodium as a drug, 2.0 parts by weight of sarcosine myristate as a surfactant and 5.0 parts by weight of isopropyl palmitate as a fatty acid ester were added and stirred sufficiently. Apply this on polyethylene film,
Dry in a gear oven at 70 ° C for 20 minutes to reduce the thickness of the adhesive layer.
A patch of 50 μm was obtained.

(B) Performance evaluation of patch: using the patch obtained in (A)
It was cut to a size of 50 cm ² and attached to the skin surface of the dehaired back of Japanese white rabbits. 0.5 hours later, 1 hour later,
After 2 hours, 4 hours, 6 hours, 10 hours and 24 hours, blood was collected from the auricular vein of rabbits and centrifuged to obtain plasma. This was extracted with benzene and subjected to Ni ⁶³ ECD gas chromatography to measure the drug concentration. The results are shown in Table 1.

Separately, the patch obtained in the item (A) was punched out to a diameter of 36 mm and stuck to the inside of the human upper arm. After 8 hours and 24 hours, the adhesiveness of the patch to the skin and the presence or absence of disorders such as redness and rash on the skin surface were examined. The results are shown in Table 2.
In Table 2, ○ indicates that the patch is in good contact with the skin surface, Δ indicates that the patch is slightly peeled off, and × indicates that the patch easily peels off.

Comparative Example 1 (A) Preparation of patch: The same as in Example 1 (A) except that the surfactant and fatty acid ester were not added.

(B) Performance evaluation of patch: Using the patch obtained in this Comparative Example (A), the same procedure as in Example 1 (B) was performed. The results are shown in Tables 1 and 2.

Comparative Example 2 (A) Preparation of patch: Same as Example 1 (A) except that fatty acid ester was not added.

(B) Performance evaluation of patch: Using the patch obtained in this Comparative Example (A), the same procedure as in Example 1 (B) was performed. The results are shown in Tables 1 and 2.

Comparative Example 3 (A) Preparation of patch: Same as Example 1 (A) except that no surfactant was added.

(B) Performance evaluation of patch: Using the patch obtained in this Comparative Example (A), the same procedure as in Example 1 (B) was performed. The results are shown in Tables 1 and 2.

From Tables 1 and 2, it is understood that the patch of the present invention has good drug absorbability through the skin and its adhesive force does not decrease with time. On the other hand, it is clear that when only the surfactant is added, the drug absorbability is quite good, but the adhesive strength decreases with time. When only the fatty acid ester is added, the adhesive strength is good and the initial absorbability of the drug is good, but it is observed that the drug absorbability decreases with time.

Example 2 (A) Preparation of patch: 2-ethylhexyl acrylate 60
An ethyl acetate solution containing 20% by weight of a copolymer composed of 40 parts by weight of vinyl acetate and 40 parts by weight of vinyl acetate was prepared. This solution 10
0.6 parts by weight of hydrocortisone acetate to 0 parts by weight (solid content),
2.0 parts by weight of lauroyl sarcosine and 5 parts by weight of isopropyl myristate were uniformly mixed. This was applied onto a polyethylene film and dried at 70 ° C. for 20 minutes to obtain a patch having an adhesive layer thickness of 50 μm.

(B) Performance evaluation of patch: Using the patch obtained in the section of this Example (A), a drug permeability test was conducted by an in vitro diffusion cell. The drug permeability (%) after 24 hours is shown in Table 3.
The test method is as follows.

In Vitro Diffusion Cell Method for Drug Permeability: Opening Diameter is 25
cm Franz diffusion cell is prepared. A physiological saline adjusted to pH 7.2 is put into the receptor part of the Franz diffusion cell, and the temperature of the receptor part is kept constant by circulating hot water of 37 ° C on the outer wall part. The test piece (circle having a diameter of 2 cm) of the patch obtained in the item (A) is attached to the epidermis (4 cm x 4 cm) of the flank of the rat, which is subjected to the hair removal treatment, and the epidermis is attached to the cell. Fill the receptor liquid, being careful not to let air bubbles enter between the skin and the surface of the receptor liquid. After 24 hours, the receptor liquid is sampled, the drug concentration is measured by high performance liquid chromatography using a reversed phase column, and the drug permeability is calculated from the following formula.

Example 3 (A) Preparation of patch: Same as Example 2 (A) except that 2 parts by weight of sarcosine caproate and 5 parts by weight of myristyl caprylate were used instead of lauroyl sarcosine and isopropyl myristate. .

(B) Performance evaluation of patch: Using the patch obtained in this Example (A), the same procedure as in Example 2 (B) was carried out. The results are shown in Table 3.

Example 4 (A) Preparation of patch: Same as Example 2 (A) except that 2 parts by weight of sarcosine stearate and 5 parts by weight of hexyl laurate were used instead of lauroyl sarcosine and isopropyl myristate. .

(B) Performance evaluation of patch: Using the patch obtained in this Example (A), the same procedure as in Example 2 (B) was carried out. The results are shown in Table 3.

Comparative Example 4 (A) Preparation of patch: The same as in Example 2 (A) except that the surfactant and fatty acid ester were not added.

(B) Performance evaluation of patch: The patch obtained in this Comparative Example (A) was used and tested in the same manner as in Example 2 (B). The results are shown in Table 3.

Comparative Example 5 (A) Preparation of patch: The same as in Example 2 (A) except that 5 parts by weight of urea was used instead of lauroyl sarcosine and isopropyl myristate.

(B) Performance evaluation of patch: Using the patch obtained in this Comparative Example (A), the same procedure as in Example 2 (B) was carried out. The results are shown in Table 3.

Comparative Example 6 (A) Preparation of patch: The same as in Example 2 (A) except that 5 parts by weight of diisopropyl adipate was used instead of lauroyl sarcosine and isopropyl myristate.

(B) Performance evaluation of patch: Using the patch obtained in this Comparative Example (A), the same procedure as in Example 2 (B) was carried out. The results are shown in Table 3.

Comparative Example 7 (A) Preparation of patch: The same as in Example 2 (A) except that 5 parts by weight of propylene glycol was used instead of lauroyl sarcosine and isopropyl myristate.

(B) Performance evaluation of patch: Using the patch obtained in this Comparative Example (A), the same procedure as in Example 2 (B) was carried out. The results are shown in Table 3.

It can be seen from Table 3 that the patch of the present invention is superior in drug permeability through the skin as compared with the patch using a conventional absorption enhancer.

(Effect of the Invention) According to the present invention, as described above, by incorporating N-acyl sarcosine and fatty acid ester in the pressure-sensitive adhesive layer, the transdermal absorbability of a drug is extremely excellent, and the adhesive property is maintained for a long time. A patch that does not deteriorate is obtained. Since the drug absorbability is excellent, it is not necessary to include a large amount of drug in the adhesive layer as in the conventional case in order to obtain a necessary pharmacological effect.
Adhesiveness does not decrease over time, so effective blood levels of the drug can be maintained for long periods of time. Since the N-acyl sarcosine and fatty acid ester used are not irritating to the skin, rash does not occur even when applied for a long time. It does not alter the drug. Further, the drug does not precipitate due to such a compound. With such a patch, various drugs can be percutaneously absorbed. Therefore, it can be used for various medical purposes depending on the type of drug contained.

Claims (3)

[Claims] 1. A patch comprising an adhesive layer containing a drug, a surfactant and a fatty acid ester on the surface of a support, wherein the surfactant is N-acyl sarcosine, A patch, wherein the fatty acid forming an acyl group and the fatty acid forming the fatty acid ester each have 6 to 18 carbon atoms. 2. The composition according to claim 1, wherein the surfactant is contained in the adhesive layer in a proportion of 0.1 to 20% by weight and the fatty acid ester is contained in a proportion of 0.5 to 50% by weight. Patch. 3. The patch according to claim 1, wherein the pressure-sensitive adhesive of the pressure-sensitive adhesive layer is an acrylic pressure-sensitive adhesive or a rubber-based pressure-sensitive adhesive.