JP2557046B2 - Layered formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Field of Application> The present invention relates to a layered preparation for treating various diseases by administering a drug into a living body through the skin.

<Prior art> In recent years, instead of oral administration or injection by injection of a drug having a pharmacological activity to treat various diseases, the purpose is to simplify the operation, maintain the pharmacological effect and reduce the side effects. The transdermal administration has attracted attention, and various drug formulations have been developed.

These transdermal preparations usually have a basic structure of a support and a pressure-sensitive adhesive layer containing a drug, and are devised to improve the transdermal absorbability of the drug and the storage stability. Is elaborate.

One of the important techniques in the development of transdermal preparations to be applied to the skin is a technique for preventing irritation to the applied skin surface. A method in which the stratum corneum present in the skin when a drug is transdermally administered into a living body functions as a barrier layer at the time of absorption, so that the skin surface to be applied is sealed and the amount of water retention in the stratum corneum is increased to make it loose. Although so-called occlusive bandage therapy (ODT therapy) is generally used, it can be expected to improve percutaneous absorption, but it tends to cause skin irritation such as stuffiness and rash on the skin, and people with weak skin such as infants and the elderly. Was unsuitable for.

Therefore, attempts have been made to perforate the support in order to prevent the above-mentioned rash and to adopt a support having moisture permeability, but the drug diffuses and moves in the support during storage, and If a drug that exudes from the skin or contains a volatile or sublimable drug is used, the amount of the drug may obviously decrease, and a therapeutically effective amount of the drug may not be released from the drug product during use. It was a fatal defect.

<Problems to be Solved by the Invention> An object of the present invention is to provide a laminated preparation which prevents the occurrence of irritation on the skin surface and the loss of the contained drug during storage as described above.

Another object of the present invention is to provide a method for applying a laminated preparation on the skin, which prevents the occurrence of irritation on the skin surface and the loss of the contained drug during storage.

<Means for Solving Problems> That is, according to the present invention, a pressure-sensitive adhesive containing a drug is laminated on one surface of a support having moisture permeability, and the other surface of the support is substantially free of the drug. It is intended to provide a laminated preparation in which a transferable sheet is releasably laminated.

As described above, the layered preparation of the present invention provides a preparation having good transdermal absorbability that eliminates the irritation on the skin surface, which is a drawback of the conventional preparations, and prevents the loss of the contained drug. Since a non-drug transfer sheet is laminated on the back surface of the product, there is no loss of drug from the back surface of the support during storage.
It is percutaneously absorbed by ODT therapy, but when applied to people who are prone to skin rash, the drug non-migratory sheet is peeled from the support before or after application to the skin to allow the formulation to express moisture permeability, This is to prevent irritation such as rash.

The support used in the present invention holds the pressure-sensitive adhesive layer described below, is an important member for preventing rash and stuffiness when attached to the skin surface, and a material having moisture permeability is adopted. To be done.

The moisture permeability is not particularly limited as long as it can prevent stuffiness on the skin surface, but the moisture permeability of 100 g / m ² · 24 hours or more (JISZ0208-
1976), and examples of the means for imparting moisture permeability include means that employs a moisture-permeable support as the material itself or that the support is subjected to perforation treatment or porosity treatment. As such a moisture-permeable support,
Ethylene / vinyl acetate copolymer, vinylon, nylon,
A film or sheet formed of polyvinyl chloride, polyamino acid, cellulose diacetate, polyurethane, cellophane or the like can be used, and also a porous film or sheet such as polyethylene or polypropylene, woven fabric,
Nonwoven fabric, paper, etc. can also be used.

Although the thickness of the support is not particularly limited, there is no discomfort when applied to the skin, the thickness is preferably thin in order to follow the movement of the skin without peeling, 10-100 μ
The range of m is good. Further, when an extensible film such as an ethylene / vinyl acetate copolymer is used, good followability is exhibited when the film is attached to a site such as a joint part that undergoes severe flexion movement.

As the pressure-sensitive adhesive containing a drug to be laminated on the support, one that releases the contained drug to the skin surface by diffusion transfer and does not cause deterioration due to decomposition of the drug during storage is used. Also, since it is stuck and fixed on the skin surface by the adhesive force, one that causes less skin irritation during sticking is used. As such a pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive such as natural rubber or synthetic rubber, vinyl ether-based, silicone-based, acrylic pressure-sensitive adhesive can be used.
Copolymer component containing (meth) acrylic acid alkyl ester as a main component for imparting cohesive force, for example, (meth) acrylic acid, vinyl acetate, vinylpyrrolidone, (meth) acrylamide, (meth) acrylic acid hydroxyalkyl ester An acrylic pressure-sensitive adhesive obtained by copolymerizing a monomer such as the above can be favorably used because it satisfies the above characteristics. In preparing these acrylic pressure-sensitive adhesives,
The mixing ratio of the (meth) acrylic acid alkyl ester and the copolymerizable monomer is 50 to 99.5: 50 to 0.5 weight ratio, preferably 70.
It is preferable to copolymerize at a weight ratio of about 99:30 to 1 in terms of adhesive properties.

The drug contained in the pressure-sensitive adhesive is not particularly limited as long as it is a drug that can be absorbed and administered in vivo by transdermal absorption,
For example, anti-inflammatory analgesics, hypnotics, tranquilizers, antihypertensives, antihypertensive diuretics, antibiotics, anesthetics, antibacterial substances, antifungal substances, vitamins, antiepileptics, coronary vasodilators, antihistamines, antitussives. , Sex hormones, antidepressants, cerebral circulation improvers, antiemetics, antiulcers, biomedicals (polypeptides, etc.) and the like can be used. According to the present invention, among these drugs, nandrolone decanoate (a steroidal anti-inflammatory drug), nitroglycerin (a coronary vasodilator), propatil nitrate (a drug that is easily volatilized or sublimated during storage) The same), isosorbide dinitrate (same), salicylic acid (anti-inflammatory analgesic), methyl salicylate (same), 1-menthol (same), etc. can be used to significantly prevent drug loss. The drug content in the pressure-sensitive adhesive varies depending on the type of drug, the type of pressure-sensitive adhesive and the disease to be treated, but is appropriately determined within the range of 0.1 to 30% by weight in the pressure-sensitive adhesive.

Further, a transdermal absorption enhancer such as lower alcohol, glycols, N-methylpyrrolidone, dimethylsulfoxide and dimethylacetamide, and a filler may be added to the above pressure-sensitive adhesive, if necessary.

In the laminated preparation of the present invention, a non-drug transfer sheet on which the drug does not substantially move due to diffusion transfer, volatilization, sublimation or the like is laminated on the other surface of the support. By stacking the sheets, even if the drug contained in the pressure sensitive adhesive diffuses and moves into the support, it does not exude to the back surface and volatilization can be prevented, so that the drug content is prevented from decreasing during storage. In addition, although a skin-adhering thin film is usually used as a support for sticking to the skin, it is very convenient in handling because the rigidity can be imparted by laminating the sheets.

As such a drug non-migratory sheet, for example, a plastic sheet such as polyester, a metal foil, a metal vapor-deposited plastic sheet, a woven fabric, a non-woven fabric, paper or the like in which a metal foil or a drug non-migratory plastic sheet is laminated is used. A sheet having a water vapor permeability of about 10 g / m ² · 24 hours or less is preferably used.

The above-mentioned sheet is laminated on a support in a releasable state, and as a laminating means, there is a method of adhering it with an adhesive force or the like with or without a pressure-sensitive adhesive. What should be done is to make sure that the adhesive strength does not increase or decrease remarkably during storage over time, and the adhesive strength is lower than that of the drug-containing pressure-sensitive adhesive. That is what is being done. That is, after sticking the laminated preparation of the present invention on the skin surface, when the drug non-migratory sheet forming the uppermost layer needs to be peeled off, it must be designed so that the sheet can be peeled off easily. .

The preferred examples of the method of adhering the both are as follows, but modifications or applications of these are also possible.

(A) A method of applying a resin solution for a drug non-migratory sheet to one surface of a predetermined support to form a film.

According to this method, the sheet is adhered to the support in a peelable state by the adhesive force. Further, for the purpose of adjusting the adhesive force, an easily peelable resin such as a silicone resin can be previously coated on the entire surface of the support or on a part thereof.

(B) A method in which a non-bleached kraft paper having a raised rough surface is used as a support, a non-drug transfer sheet is superposed on the paper, and the sheets are heated and pressed at a temperature not higher than the melting temperature of the sheet.

(C) A method of melt laminating a resin for a non-drug transfer sheet on one surface of a support.

(D) The support and the non-drug transfer sheet are formed of a pressure sensitive adhesive,
A method of bonding using a binder having no pressure-sensitive adhesive property.

The laminated preparation of the present invention has the constitution as described above, but in order to prevent the volatilization of the drug or the like from the skin-applied surface side of the drug-containing pressure-sensitive adhesive layer during storage, a silicone-based resin or the like is used. The release liner, such as plastic film or paper, that has been subjected to release treatment with is coated or laminated on the surface, or the release treatment is applied to the back surface (top layer) of the drug non-migratory sheet, and the final product shape is rolled. It shall be wound into a shape.

<Effects of the Invention> As described above, since the laminated preparation of the present invention has a specific constitution, exudation, volatilization and sublimation of the drug during storage of the preparation are prevented, and the decrease in the drug content is reduced. It is a thing. Further, when applied to the skin surface, in a completely sealed ODT therapy, the drug non-migratory sheet that forms the uppermost layer can be peeled off and removed for people who have skin rash etc. The formulation exhibits moisture permeability and also exerts an effect of preventing skin irritation such as rash.

Examples of the present invention will be shown below, but the invention is not limited thereto. In addition, "parts in the text" means parts by weight.

Example 1 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid were charged into a flask under an inert gas atmosphere,
0.3 part of azobisisobutyronitrile was added as a polymerization initiator to initiate polymerization. Adjustment of stirring speed and outer bath temperature,
Then, the inner bath temperature was controlled at 58 to 62 ° C by dropwise addition of ethyl acetate as a diluting solvent, and the polymerization reaction was performed for about 10 hours to obtain an acrylic pressure-sensitive adhesive solution.

20 parts of isosorbide dinitrate was added to 80 parts of the solid content of the obtained acrylic pressure-sensitive adhesive solution, and the coating thickness after drying was 40 μm on a release liner treated with silicone. A drug-containing pressure-sensitive adhesive layer was formed by coating and drying.

Porous polypropylene (water vapor transmission rate 1120g / m ²
・ A pressure-sensitive adhesive layer of the liner is laminated on one surface of JIS Z0208-1976 for 24 hours, and the other surface of the support is subjected to a peeling treatment with a silicone resin, and then a polyethylene terephthalate sheet having a thickness of 10 μm (transparent) is used. Humidity of 5 g / m ² · 24 hours, according to JIS Z0208-1976) was laminated to obtain a laminated preparation of the present invention.

Example 2 Acrylic pressure-sensitive adhesive solution was polymerized by the same procedure as in Example 1 except that the composition of the monomers was 90 parts of 2-ethylhexyl acrylate / 10 parts of N-vinyl-2-pyrrolidone. Got

15 parts of methyl salicylate was added to 85 parts of the solid content of the obtained acrylic pressure-sensitive adhesive solution, and the coating thickness after drying was 40 μm on a release liner treated with silicone.
A pressure-sensitive adhesive layer containing a drug was formed by coating and drying so that

Ethylene / vinyl acetate copolymer as support (vinyl acetate content 28%, moisture vapor transmission rate 480g / m ² · 24 hours, JIS Z0208-1976
) Is melt-laminated on the aluminum side of a polyethylene / aluminum laminated sheet (moisture permeability: substantially 0 g / m ² · 24 hours, according to JIS Z0208-1976) and the ethylene / vinyl acetate copolymer side is pressure-sensitive adhesive containing the above drug. The layers were laminated to obtain the laminated preparation of the present invention.

Comparative Examples 1a and 1b In the laminated preparation of Example 1, the polyethylene terephthalate sheet was excluded from Comparative Example 1a, and the porous polypropylene was excluded from Comparative Example 1b.

Comparative Examples 2a and 2b In the laminated preparation of Example 2, the one excluding the polyethylene / aluminum laminated sheet was designated as Comparative Example 2a, and the one excluding the ethylene / vinyl acetate copolymer support was designated as Comparative Example 2b.

Experimental Example 1 In order to test the storage stability of the preparations obtained in each Example and Comparative Example, the remaining amount of the drug was measured by opening and storing in a thermostat at 25 ° C., and the results are shown in Table 1. . The residual ratio was calculated with the initial drug content before storage of the formulation as 100%.

Experimental Example 2 The preparations obtained in the respective Examples and Comparative Examples had a diameter of 3c.
After cutting to a size of m and sticking it on the inside of the upper arm for 24 hours, peel off the drug non-migratory sheet of the example product, and continue to stick, and visually check the skin surface after 1,8,24 hours have passed. The skin irritation of each preparation was examined, and the results are shown in Table 2.

 ─────────────────────────────────────────────────── ─── Continuation of the Front Page Judge Chief Naohiko Teshima Judge Judge Kazuko Miyamoto Judge Hiroyuki Taniguchi (56) Bibliography 60-43327 (JP, U)

Claims (4)

(57) [Claims] 1. A pressure-sensitive adhesive containing a drug is laminated on one side of a moisture-permeable support, and a substantially drug-non-migrating sheet is releasably laminated on the other side of the support. A layered preparation. 2. The laminated preparation according to claim 1, wherein the water vapor permeability of the support is 100 g / m ² · 24 hours or more. 3. The layered preparation according to claim 1, wherein the drug has volatility or sublimability. 4. The substantially non-drug transfer sheet comprises about 10 g / m ²
-The laminated preparation according to claim 1, which has a water vapor transmission rate of 24 hours or less.