JPH07103016B2 - Patch and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a patch capable of transdermally administering a drug, and more particularly to a patch having enhanced transdermal absorbability of the drug and a method for producing the same.

(Prior Art) In order to obtain a drug effect systemically or locally, a patch (transdermal dosage form) is used to absorb a drug (physiologically active substance) through the skin. This transdermal administration method 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. Particularly in the case of non-steroidal anti-inflammatory drugs, oral administration tends to cause gastrointestinal disorders, but transdermal administration has an advantage that such gastrointestinal disorders are less likely to occur. By controlling the absorbability of a drug, it is possible to reduce side effects caused by a large amount of 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. Therefore, attempts have been made to increase the absolute amount of the drug present in the patch and to percutaneously absorb the required amount of the drug. For example, in Japanese Unexamined Patent Publication No. 60-185713, a drug is contained in a base such as a patch, cartilage or cream preparation in an amount equal to or higher than the saturated solubility, and the drug is dispersed in the form of recrystallized fine particles. Transdermal formulations are disclosed. For example, when the patch is applied to the skin surface and the drug dissolved in the base is percutaneously absorbed, the drug present in the form of fine particles in the base is sequentially dissolved and the drug in the dissolved state is replenished. . Therefore, it is considered possible to administer a larger amount of the drug as compared with the conventional preparation in which the drug amount is equal to or lower than the saturated solubility of the drug. However, in reality, the drug present in the form of particles is difficult to redissolve in the base, and therefore the absorption efficiency of the drug through the skin is not as high as expected.

Many patches are prepared that contain an absorption enhancer in order to enhance the absorbability of the drug. As the absorption promoter, many compounds such as salicylic acid, urea, dimethyl sulfoxide, propylene glycol, glycerin, and dimethyl sulfoxide are generally used. However, in either case, the transdermal absorbability of the drug is not always good. In the case of administering the above-mentioned non-steroidal anti-inflammatory drug as a drug, a method of increasing the retention under the skin of the non-steroidal anti-inflammatory drug by increasing the drug efficacy by containing a phospholipid such as phosphatidylcholine in the adhesive is proposed. ，
It is disclosed in JP-A-58-150508 and JP-A-61-172833. Although the anti-inflammatory effect is slightly increased by adding phospholipids, the effect is not so high as to be satisfactory therapeutically. 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. . Another object of the present invention is to provide a patch containing an absorption aid which enhances the transdermal absorbability of the contained drug and is safe for the living body without irritation to the skin. Still another object of the present invention is to provide a patch, which is capable of sustaining its pharmacological effect locally and systemically in a non-steroidal anti-inflammatory drug, for example. Still another object of the present invention is to provide a patch which reduces the frequency of drug administration per day, is easy to use, and can obtain patient compliance.

(Means for Solving the Problems) The patch of the present invention is a patch in which an adhesive layer is provided on one surface of a support, and the adhesive layer comprises a drug and lecithin and / or sorbitan fatty acid ester. And the drug is uniformly dispersed in the pressure-sensitive adhesive layer, whereby the above object is achieved.

The method for producing the patch of the present invention comprises a drug, lecithin and / or
Or a step of uniformly dissolving the sorbitan fatty acid ester and the adhesive base in a solvent; and a step of coating the obtained solution on one side of a support and drying, or a step of coating the obtained solution on a release paper surface and drying And a step of bringing the support into close contact with the surface of the formed pressure-sensitive adhesive layer, whereby the above object is achieved.

The lecithin used in the patch of the present invention refers to glycerophospholipids widely distributed in nature including phosphatidylcholine (lecithin in a narrow sense). Examples of lecithin include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid. Lecithin-containing substances that contain one or more of these and are easily available include soybean lecithin, egg yolk ecithin, hydrogenated lecithin, and the like.

The sorbitan fatty acid ester is an esterified product of sorbitol with a fatty acid having 10 to 26 carbon atoms, preferably 4 to 22 carbon atoms (which may be either saturated fatty acid or unsaturated fatty acid). It includes sorbitan monolaurate,
Examples include sorbitan monopalmitate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate.

The lecithin and / or sorbitan fatty acid ester has the function of increasing the solubility of the drug in the base and, as a result, increasing the drug utilization rate. These compounds are
Usually, it is contained in the below-mentioned adhesive base within a range not exceeding the respective saturated solubilities. Although the concentration varies depending on the composition of the adhesive base and the like, it is usually in the range of 0.5 to 50 parts by weight, preferably 1 to 20 parts by weight with respect to 100 parts by weight of the adhesive base. If the amount is too small, the solubility of the drug in the adhesive base is not improved, so that a large amount of the drug cannot be contained in a substantially amorphous state as described later. Even if it is excessive, not only the effect of promoting percutaneous absorption of the drug in proportion to the content is not obtained, but also the adhesive strength of the adhesive is lowered. The amount of lecithin and / or sorbitan fatty acid ester is preferably a high concentration close to the saturated concentration with respect to the base, as long as the adhesive strength of the adhesive base and the diffusion rate of the drug in the base are not reduced.

The drug (physiologically active substance) used is not particularly limited as long as it penetrates the skin by transdermal administration and exerts a drug effect locally or systemically. For example, non-steroidal anti-inflammatory drugs, steroids, antihypertensive drugs, anesthetics,
Antifungal agents, antiepileptic agents, coronary vasodilators, hormonal agents and antihistamines.

Nonsteroidal anti-inflammatory drugs include piroxicam, phenylbutazone, acetylsalicylic acid, flufenamic acid,
Mefenamic acid, ibuprofen, ketoprofen, flurbiprofen, sulindac, indomethacin, diclofenac, alclofenac, fenbuene, tinolidine, emorfazone, etc. Steroids include corticosteroids such as prednisolone and clobetasol propionate. Antihypertensive agents include clonidine, nifedipine, propranolol and others. Anesthetics include lidocaine and benzocaine. Antifungal agents include clotrimazole and pentamycin. Antiepileptic agents include nitrazepam and meprobamate. Coronary vasodilators include nitroglycerin and isosorbide dinitrate. Hormonal agents include estradiol. Antihistamines include diphenhydramine hydrochloride and diphenylimidazole.

These drugs are contained in the base in an amount exceeding the saturation solubility of the drug. And, the compounding amount thereof is preferably at least the usual daily dose of the drug or more. The blending amount varies depending on the type of drug, the composition of the adhesive base, the purpose of use of the obtained patch, etc. For example, when a non-steroidal anti-inflammatory drug is blended as the drug, 100 wt. It is compounded in a proportion of 0.5 to 40 parts by weight, preferably 1 to 25 parts by weight per part. If the amount of the drug is too small, it may not be possible to obtain a sufficient drug effect, and the drug effect may not be sustained.
If it is excessive, the drug will precipitate from the adhesive layer and the adhesive strength will decrease.

The adhesive base of the patch of the present invention is not particularly limited as long as it has sufficient adhesive force to fix the patch to the skin at room temperature for a long time. For example, an acrylic-based, rubber-based, silicone resin-based pressure-sensitive adhesive can be used, and an acrylic-based and rubber-based pressure-sensitive adhesive is usually used.

Acrylic adhesives are
Polymers and / or copolymers (including copolymers containing other polar monomers as copolymerization components) containing an alkyl group (meth) acrylic acid alkyl ester having 1 to 18 carbon atoms are preferably used. Examples of the (meth) acrylic acid alkyl ester include methyl (meth) acrylate,
Examples include ethyl (meth) acrylate, butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, and dodecyl (meth) acrylate. Other polar monomers include (meth) acrylic acid, vinylpyrrolidone,
There are monomers having a hydrophilic group such as diacetone acrylamide, (poly) ethylene glycol (meth) acrylate, (poly) propylene glycol (meth) acrylate, and 2-hydroxyethyl (meth) acrylate. When the content of the polar monomer in the copolymer is high, the solubility of the drug in the copolymer is high, and it becomes possible to obtain a patch containing the drug in a high content. Among the acrylic pressure-sensitive adhesives, a copolymer of (meth) acrylic acid alkyl ester and vinylpyrrolidone and / or diacetone acrylamide is particularly preferably used. As the (meth) acrylic acid alkyl ester used for such a copolymer, butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, dodecyl (meth) acrylate and the like are particularly preferable. Vinylpyrrolidone and / or diacetone acrylamide is usually contained in the above copolymer in an amount of 5 to 50% by weight, preferably 10 to 40% by weight. If it exceeds 50% by weight, the copolymer becomes hard and the tackiness is slightly lowered.

Examples of the rubber-based adhesive include styrene-isoprene-styrene block copolymer, styrene-butadiene copolymer,
Examples include polybutene, polyisoprene, butyl rubber, and natural rubber. Silicone rubber such as polyorganosiloxane is used as the silicone resin adhesive.

The patch of the present invention may further contain an absorption promoter and other additives, if necessary. As an absorption promoter, N-
At least one of acyl-N-methylglycine (N-acylsarcosine), fatty acid diethanolamide and polyoxyethylene-added fatty acid diethanolamide (POE-added fatty acid diethanolamide) is preferable. Among the above absorption enhancers, examples of N-acyl-N-methylglycine include lauroyl sarcosine, myristoyl sarcosine, palmitoyl sarcosine, and oleoyl sarcosine. Examples of the fatty acid diethanolamide include lauroyl diethanolamide, caproyl diethanolamide, myristoyl diethanolamide, and coconut oil fatty acid diethanolamide. Examples of POE-added fatty acid diethanolamide include polyoxyethylene lauroyl diethanolamide and polyoxyethylene coconut oil fatty acid diethanolamide.

The absorption promoter is preferably contained in the adhesive base at a concentration close to its saturated solubility. The concentration varies depending on the composition of the adhesive base and the amount of lecithin, etc.
0.2 to 30 parts by weight, preferably 0.5 to 100 parts by weight of base
It is contained in a proportion of up to 15 parts by weight. If it is too small, the effect of promoting percutaneous absorption of the drug cannot be obtained. If the amount is excessive, the adhesive physical properties of the adhesive base are deteriorated, and the patch applied to the skin surface is likely to be peeled off due to perspiration, for example.

Other additives include softeners, fillers, anti-aging agents and the like. Examples of the softening agent include fatty acid esters such as isopropyl myristate and medium-chain fatty acid triglyceride; and higher alcohols such as triacetin, triethyl citrate, and octyldodecanol.

As a support for the patch, a support usually used for patches is used. Examples of such a support include polyethylene, polyester, polyamide, polyethylene-vinyl acetate copolymer, polyvinylidene chloride, polyurethane,
A film made of aluminum or the like; a laminate film thereof; a non-woven fabric or the like.

A patch is obtained by forming a drug-containing (adhesive) layer containing a drug and an absorption aid (lecithin and / or sorbitan fatty acid ester) on the surface of the support. To form the pressure-sensitive adhesive layer, various coating methods such as a solvent coating method and a hot melt coating method are used. Among them, the solvent coating method is preferable. To form the pressure-sensitive adhesive layer by the solvent coating method, for example, the pressure-sensitive adhesive base is diluted with a suitable solvent, and the drug, lecithin and / or sorbitan fatty acid ester, and if necessary, the above-mentioned absorption promoter or addition are added thereto. The agent is added and uniformly mixed and dissolved, and the resulting solution is applied to the surface of the support and dried. 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, and dried and then brought into close contact with the support. As the solvent, those having a low boiling point and capable of dissolving an adhesive base, a drug and the like are preferable. The type of solvent is appropriately selected according to the type of adhesive base or drug. For example, ethyl acetate, cyclohexane, toluene, tetrahydrofuran, methylene chloride, methanol, ethanol and the like are used. As the release paper, polyester film, polyethylene-coated high-quality paper, polyolefin-coated glassine paper, polypropylene film, or other film having a silicone release treatment on one side is used. Such release paper is
Used to protect the pressure-sensitive adhesive layer surface of the patch until use. In the hot melt coating method, the solvent used in the above solvent coating method is not used, but instead, the adhesive base, the drug and the like are uniformly dissolved by heating and the coating is performed on the support or the release paper. The thickness of the pressure-sensitive adhesive layer also varies depending on the purpose of use, but is usually about 30 μm to about 2 mm. If it is less than 30 μm, the required amount of drug cannot be contained and the adhesiveness is insufficient. Above 2 mm, it becomes difficult to remove the solvent, especially in the case of solvent coating. Drug release is also reduced.

(Function) The adhesive layer of the patch obtained by the present invention is transparent in a state where the drug, lecithin and the like are uniformly dissolved immediately after preparation. When this patch is stored at room temperature, the drug gradually precipitates. The drug is uniformly deposited throughout the adhesive base, and the deposit is substantially amorphous. That is,
Instead of recrystallized particles of the drug as described in the prior art, they are in an amorphous state or exist as ultrafine particles that are difficult to observe. This drug state is achieved due to the presence of ethylene and / or sorbitan fatty acid ester in the adhesive base. The substantially amorphous drug readily diffuses into the adhesive base at lower temperatures than the drug present as recrystallized particles and is absorbed through the skin. Therefore, the utilization efficiency of the drug is increased. Due to the presence of lecithin and / or sorbitan fatty acid ester, the solubility of the drug in the base is also increased, and the drug can be contained in the adhesive base at a high concentration. Therefore, a patch that can exert its medicinal effect over a long period of time can be obtained. Since lecithin and sorbitan fatty acid ester do not impair the adhesiveness of the adhesive base, it is not necessary to separately prepare the adhesive layer and the drug-retaining layer, and the usual patch (adhesive layer on the support) It can be easily prepared in the form of a patch provided with. That is, the adhesive layer has both a function as a drug reservoir and a function as an adhesive. For example, when a non-steroidal anti-inflammatory drug is used as the drug, the anti-inflammatory effect can be exerted not only locally but systemically over a long period of time. Since it is not given orally, it does not cause fire extinguisher problems.

When a drug absorption promoter is further contained in the pressure-sensitive adhesive layer, a higher drug transdermal absorbability can be obtained due to the synergistic effect with the lecithin and the like. As described above, when the patch of the present invention is used, the single dose of the drug can be increased and the drug release is sustained.
The number of doses per day can be reduced and patient compliance obtained.

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

Example 1 2-ethylhexyl methacrylate, 2-ethylhexyl acrylate and dodecyl acrylate (molar ratio 8: 1:
1) was polymerized with lauroyl peroxide in ethyl acetate to obtain a copolymer (SDK) solution with a solid content of 50% and a weight average molecular weight of 1.09 million. 100 parts by weight of a copolymer (adhesive base) obtained by drying this solution, 7 parts by weight of piroxicam,
5 parts by weight of soybean lecithin and 15 parts by weight of isopropyl myristate (IPM) were added to 330 parts by weight of methylene chloride and uniformly dissolved. This solution was spread on a polylaminated glassine release paper and dried at 60 ° C to form an adhesive layer having a thickness of 80 µm. A polyethylene terephthalate film was adhered as a support to the pressure-sensitive adhesive layer to obtain a patch having release paper.

(B) Evaluation of patch The following items were tested. The results are shown in the table below. The results of Examples 2 to 9 and Comparative Examples 1 to 3 described later are also shown in the table below.

Appearance of pressure-sensitive adhesive layer: After the patch was stored at room temperature for 7 days, the pressure-sensitive adhesive layer was visually observed and, if necessary, observed using a polarizing microscope.

Evaluation of drug skin permeability: A drug permeability test was carried out by an in vitro diffusion cell by the following method. The drug permeability (%) after 24 hours is shown in the table below. This drug permeability is a measure of the amount of drug percutaneously absorbed when the patch is applied over 24 hours. The drug absorption index is the amount of drug administered ×
It is shown by drug permeability.

Measuring method of drug permeability by in vitro diffusion cell: Opening diameter is 25
Prepare a Franz diffusion cell of cm. A phosphate buffer solution adjusted to pH 7.2 is put in the receptor part of the Franz diffusion cell, and hot water of 37 ° C is circulated on the outer wall part to keep the temperature of the receptor part constant. A test piece of the patch is attached to the epidermis (approximately 3 cm ² ) of the back of the nude mouse, 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, and the drug permeability is calculated from the following formula.

Ball tack value: The ball tack value was measured according to JIS Z 0237 (adhesive tape / adhesive sheet test method).

Comparative Example 1 The same as Example 1 except that soy lecithin was not added.

Example 2 The same as Example 1 except that 5 parts by weight of lauroyl sarcosine was further added to the base solution.

With respect to this patch, the drug absorbability was evaluated by the following method. First, this patch was cut into 2.5 cm x 2.5 cm, and this was applied to the upper arms of 5 panelists for 24 hours. The amount of drug present in the patch was determined by extracting the drug from the patch after application with methanol and measuring its concentration by HPLC. The amount of drug in the patch used in advance was measured, and the drug absorption rate (%) was calculated by the following formula.

As a result, the drug absorption rate was 12.8%. This patch 100c
By applying m ² to the skin surface, it can be seen that a therapeutically effective amount of about 5.4 mg of piroxicam can be percutaneously absorbed per day.

Example 3 The same as Example 1 except that 2 parts by weight of lauroyl sarcosine was further added to the base solution.

Example 4 The same as Example 1 except that 2 parts by weight of lauroyl sarcosine was added to the base solution to make the amount of soybean lecithin 20 parts by weight.

Example 5 The same as Example 1 except that 10 parts by weight of lauroyl sarcosine was further added to the base solution.

Example 6 The copolymer (SDK) solution obtained in Example 1 (solid content 50
%), 8 parts of indomethacin to 100 parts by weight of solid content
By weight, soy lecithin 5 parts by weight and isopropyl myristate (IPM) 15 parts by weight were added and mixed to obtain a uniform solution. This was spread on polyester release paper and dried at 60 ° C. to form a 50 μm thick adhesive layer. A polyethylene film was adhered to this pressure-sensitive adhesive layer as a support to obtain a patch having release paper.

Example 7 The same as Example 6 except that sorbitan trioleate was used instead of soybean lecithin.

Comparative Example 2 The same as Example 1 except that soybean lecithin was not added.

Example 8 2-Ethylhexyl acrylate and vinylpyrrolidone (molar ratio 65:35) were polymerized in ethyl acetate using lauroyl peroxide as a catalyst to obtain a copolymer solution having a solid content of 35% and a weight average molecular weight of 720,000. 100 parts by weight of a copolymer (adhesive base) obtained by drying this solution, 20 parts by weight of piroxicam, 5 parts by weight of soybean lecithin and 5 parts by weight of lauroyl sarcosine were added to 330 parts by weight of methylene chloride and uniformly dissolved. . Using this solution, a patch was prepared according to Example 1.

Comparative Example 3 The same as Example 8 except that soybean lecithin and lauroyl sarcosine were not used.

Example 9 The same as Example 2 except that lauroyl diethanolamide was used instead of lauroyl sarcosine and the amount of IPM was 10 parts by weight.

From the comparison between Example 1 and Comparative Example 1, it can be seen that the patch of the present invention containing lecithin in the base material has excellent transdermal absorbability and good adhesiveness. Furthermore, the patch (Example 2) containing an absorption enhancer has further improved drug permeability. Regarding the patch containing a large amount of lecithin (Example 4), the drug permeability is improved, but the effect proportional to the amount of lecithin cannot be obtained. The tackiness is also slightly reduced.
The patch containing a large amount of the absorption enhancer (Example 5) further improves the drug permeability, but since the adhesiveness of the adhesive decreases, it is easily peeled off due to sweating or the like. For the patch of Comparative Example 2 containing no lecithin and sorbitan fatty acid ester, the drug crystallized and precipitated from the adhesive base, but for the patch of Examples 6 and 7 containing lecithin or sorbitan fatty acid ester, precipitation The drug does not crystallize. Therefore, it has excellent drug permeability,
The adhesive strength does not decrease. In the case of a patch (Example 8) which uses an adhesive base containing vinylpyrrolidone and contains lecithin, it is possible to contain a large amount of drug particularly in the adhesive base.

(Effects of the Invention) According to the present invention, as described above, the lecithin and / or the sorbitan fatty acid ester and the drug in a substantially amorphous state exceeding the saturated solubility are contained in the adhesive base, and A patch having extremely excellent absorbency can be obtained. Since the drug absorbability is excellent, it is possible to increase the single dose of the drug. Since the drug release is sustained, the number of doses per day can be reduced. Since the lecithin and sorbitan fatty acid ester used are not irritating to the skin, they do not cause rashes or side effects even when applied for a long time. Furthermore, these factors do not cause the drug to deteriorate and the drug does not precipitate nor does the adhesive property deteriorate. In such a patch, various drugs can be transdermally absorbed, and the therapeutic effect when using the patch is high. Therefore, it can be used for various medical purposes depending on the type of drug contained.

Claims (6)

[Claims] 1. A patch comprising a support and an adhesive layer provided on one surface thereof, wherein the adhesive layer contains a drug and lecithin and / or sorbitan fatty acid ester, and the drug comprises the adhesive. A patch that is uniformly dispersed in the agent layer. 2. The pressure-sensitive adhesive layer further contains an absorption promoter for the drug, and the absorption promoter is one of N-acyl-N-methylglycine, fatty acid diethanolamide and polyoxyethylene-added fatty acid diethanolamide. The patch according to claim 1, which is at least one of the following. 3. The patch according to claim 1, wherein the adhesive base of the adhesive layer contains a copolymer of (meth) acrylic acid alkyl ester and another polar monomer as a main component. 4. A step of uniformly dissolving a drug, lecithin and / or sorbitan fatty acid ester, and an adhesive base in a solvent, and a step of applying the obtained solution on one side of a support and drying.
Alternatively, a method for producing a patch, comprising a step of applying the obtained solution to the surface of a release paper, drying the solution, and then bringing a support into close contact with the surface of the formed pressure-sensitive adhesive layer. 5. A step of dissolving the drug, a lecithin and / or sorbitan fatty acid ester, and an adhesive base together with an absorption promoter of the drug in the solvent, wherein the absorption promoter is N-acyl-N. -The method according to claim 4, which is at least one of methylglycine, fatty acid diethanolamide and polyoxyethylene-added fatty acid diethanolamide. 6. The method according to claim 4, wherein the pressure-sensitive adhesive base of the pressure-sensitive adhesive layer is mainly composed of a copolymer of (meth) acrylic acid alkyl ester and another polar monomer.