KR19980027318A - Percutaneous absorption preparations containing nonsteroidal anti-inflammatory drugs and preparation method thereof - Google Patents

Abstract

The present invention is a transdermal absorbent comprising an impermeable backing layer, an adhesive matrix layer, and a release layer, wherein the adhesive matrix layer is made of polyisobutylene, natural rubber, or resin. , Bioactive drug and pyrrolidone derivatives, propylene glycol, isopropyl myristic acid, crotamiton, polysorbate 80, peppermint oil, alpha limonene, oleic acid, laurin The present invention relates to a transdermal absorption preparation and a method for producing the same, wherein the one or more skin absorption promoters selected from the group consisting of acids, glycerin and lanolin are dispersed and formed.

According to the present invention, it is excellent in adhesion, easy to peel off, almost no skin irritation, can be peeled off and reattached, the skin permeability of the drug is high, and the method of preparation also provides a transdermal absorbent of a nonsteroidal anti-inflammatory analgesic. Can be.

Description

Percutaneous absorption preparations containing nonsteroidal anti-inflammatory drugs and preparation method thereof

The present invention relates to a percutaneous absorption preparation that enhances the percutaneous absorption of nonsteroidal anti-inflammatory drugs, and a method of manufacturing the same.

Nonsteroidal anti-inflammatory analgesics suppress cyclooxygenase and thus strongly inhibit the production of prostaglandins that cause fever, pain, and inflammation. It has been used in a way.

However, oral administration of these drugs results in a rapid rise in initial blood levels and is limited because of side effects such as irritation, ulceration, and hematopoietic disorders in the gut mucosa (Physicians desk reference 50ed .: 1996). Therefore, various studies have been conducted to prevent such side effects caused by oral administration of nonsteroidal anti-inflammatory drugs and to develop a convenient formulation, and in recent years, the transdermal route of administration is particularly promising.

When the drug is administered through the skin, various problems such as inactivation of the drug by the liver during the oral administration, gastrointestinal disorders and the effects of a meal can be avoided, and pain and discomfort during the injection can be eliminated. Very advantageous. In addition, the drug dosage can be easily adjusted, and simply attached to the skin, so that the patient can administer the drug on their own, and when the side effect occurs, the drug can be stopped immediately, and the drug can be continuously absorbed for a long time. It also has the advantage of reducing the number of times.

Generally, transdermal absorbents include a reservoir type in which a drug is encapsulated in a polymer membrane (US Pat. Nos. 3,598,122, 4,058,122, and 4,077,407); Monolithic types in which drugs are mixed and dispersed in a matrix; US Pat. Nos. 4,314,577, 4,291,014, 4,321,252, and 4,438,139; Controlling membranes that control the rate of drug release between the drug-reservoir layer that contains the drug, the adhesive layer that adheres to the skin, the backing layer, and the skin and the drug reservoir layer Laminated types (US Pat. Nos. 4,379,454 and 4,460,372).

However, in the case of storage transdermal absorbents, it is difficult to manufacture an ideal control membrane to control the rate of penetration of the drug and the application area of the skin may be limited due to the nature of the formulation. In addition, the laminated transdermal absorbent has a disadvantage in that the drug-containing layer of several stages having different drug concentrations has to be coated several times, and thus it is difficult to apply to actual production. Because of these problems, most of the products that have been commercialized so far have been simple substrate-based transdermal absorbents.

In simple matrix formulations, the skin permeability of the drug is determined by the absorption accelerator selected in consideration of the intrinsic permeability of each drug, and the choice of the polymeric material used for the substrate is also important. For example, as the polymer material, polyvinyl alcohol, polyvinyl pyrrolidone, or the like is used as an adhesive polymer, and propylene glycol (US Pat. Nos. 4,438,139, 2,547,502, 4,321,252, French Patent 2,547,502, etc.) is used as a softening agent. ), Silicone elastomer (US Patent No. 4,559,222, European Patent No. 430,491, International Patent Publication No. 87 / 07,138, etc.), Acrylic Adhesive (European Patent Application No. 328,806, Japanese Patent Application Laid-Open No. 03 / 44,326) , 02,223,617). Absorption accelerators for promoting the absorption of drugs include fatty acid esters and fatty alcohol ethers of alkanediols (US Pat. No. 4,906,463), oleic acid, propylene glycol (European patent application 430,491), oleic acid, linear alcohol lactates and propylene Glycol or metapyrrole (European Patent Application No. 371,496), saturated acids such as acrylic acid, methacrylic acid, maleic acid and its anhydrides (European Patent Application No. 409,383), polyethylene esters or polysorbates 80 (European Patent Application) 328,806), quenoic acid and salts thereof (Japanese Patent Laid-Open No. 03 / 44,326), higher fatty acid esters derived from lactic acid and alcohols having 1 to 20 carbon atoms and higher fatty acids having 10 to 18 carbon atoms (Japanese Patent Laid-Open No. 02 / 196,714). Also used).

However, these existing simple matrix formulations may cause several problems depending on the nature of the drug to be transdermally administered. That is, the adhesiveness is too strong or too weak to have a problem when attached to or peeled off the skin, may cause skin irritation or not release the drug well.

Therefore, in order to actually produce simple substrate-type transdermal absorbents, skin absorption accelerators for absorbing low skin permeability drugs, duration of drug efficacy, adhesion of preparations to skin, ease of use and removal, and minimization of skin irritation Several points need to be taken into consideration, and efforts have been made to solve these problems by introducing various techniques to simple substrate types.

Korean Patent Publication No. 95-13448 discloses a transdermal patch for a transdermal administration composed of a support, a pressure-sensitive adhesive consisting of 2 to 5 layers, and a release film, but a structure such as manufacturing a structure of the pressure-sensitive adhesive layer in multiple layers. Is complicated, and manufacturing economics are inferior.

The present invention has been made to solve the problems of the simple substrate type warning agent according to the prior art, the adhesive strength is strong, can be easily removed from the skin without irritating the skin, can be used after re-attach, The permeability of the drug is greatly improved as compared to the prior art, the manufacturing method is also to provide a simple transdermal absorbent preparation and its preparation method.

1 is a graph comparing indomethacin permeability in hairless mouse skin.

In order to achieve the above object, according to the present invention, in the transdermal absorption agent consisting of an impermeable backing layer, an adhesive matrix layer and a release layer, the adhesive substrate layer, Biologically active drug, pyrrolidone derivatives, propylene glycol, isopropylmyritic acid, crotamitone, polysorbate 80, peppermint oil, in an adhesive polymer composed of isobutyrene, natural rubber, resin, cellulose-based adhesive, and polyol prepolymer. The present invention provides a transdermal absorbent and a method for preparing the same, wherein the at least one skin absorption enhancer selected from the group consisting of alphalimonene, oleic acid, lauric acid, glycerin and lanolin is dispersed and formed.

A feature of the present invention lies in the composition of a polymer matrix layer having no skin stimulus without being released by sweat and moisture while maintaining a proper adhesion to the skin while simultaneously releasing active ingredients. Is composed of polyisobutyrene, natural rubber, resin, cellulose-based pressure-sensitive adhesives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and preol prepolymer, and may further include sodium polyacrylate. At this time, the amount of the adhesive polymer is preferably 60 to 80 parts by weight based on 100 parts by weight of the adhesive substrate layer.

Biologically active agents that can be used in the transdermal absorption preparations of the present invention, that is, the active ingredient, such as indomethacin, pyricampam, ketoprofen, flubiprofen, naproxen, ibuprofen, phenopropene, diclofenac and the like Steroidal anti-inflammatory drugs. Although the active ingredient varies depending on the effective amount exhibiting pharmacological activity, it is used in less than about 10 parts by weight based on 100 parts by weight of the adhesive substrate layer.

Examples of the absorption accelerator in the transdermal absorbent preparation of the present invention include pyrrolidone derivatives, propylene glycol, isopropylmyristin acid, crotamiton, polysorbate 80, peppermint oil, alpharimonene, oleic acid, lauric acid, glycerin, and lanolin. These can be mentioned, A mixture thereof can also be used.

The skin absorption accelerator used in the present invention has an excellent absorption promoting ability compared to other absorption accelerators, thereby significantly increasing the skin permeability of nonsteroidal anti-inflammatory analgesics, and can be used safely without skin irritation.

In addition, each skin absorption accelerator is used in an amount of 0.1 to 20 parts by weight based on 100 parts by weight of the entire adhesive substrate layer, and the content of the total absorption accelerator is 40 parts by weight or less. If it is less than 0.1 part by weight, the skin transmittance is low, and if it exceeds 40 parts by weight, the pressure-sensitive adhesive is gelled or cured.

The adhesive substrate layer according to the present invention is a biologically active drug and at least one absorption accelerator in a solution obtained by dissolving the adhesive polymer polyisobutylene, natural rubber, resin, cellulose-based adhesive, and polyol prepolymer in an organic solvent such as hexane or toluene. Is added and stirred. The solution can be poured onto an impermeable protective layer to coat an adhesive substrate layer and then dried, and a desorption layer can be laminated thereon to prepare the transdermal absorption formulation.

As the impermeable protective layer, a polyurethane film, an elastic synthetic fiber cotton cloth, a poplin cotton cloth, an aluminum laminate or a polyethylene film may be used, and the detachable layer may be a siliconized polyester film, paper, or a polypropylene film. .

Summarizing the features of the transdermal absorbent preparation according to the present invention is as follows.

First, the manufacturing process is simple and the manufacturing cost is reduced.

Second, the skin permeability of the drug is improved, and by adjusting the drug content or the size of the formulation can be appropriately used according to the age, weight, and degree of symptoms of the person.

Third, it is stable to sweat and moisture so that the agent can be attached and exercise or shower can be freed.

Fourth, there is almost no skin irritation, and detachment is easy.

The following examples are intended to embody the invention and are not intended to limit the scope thereof. Thus, it is included within the scope of the present invention as long as the main components are not changed.

Example 1

96 mg of indomethacin and 100 mg of methylpyrrolidone (N-Methyl-2-Pyrrolidone), 50 mg of crotamitone and 10 mg of polysorbate 80 were mixed. To this mixture, a solution of 350 mg of polyisobutylene, 80 mg of natural rubber, 200 mg of resin, 100 mg of hydroxypropyl cellulose, and 14 mg of polyol prepolymer was added to a small amount of toluene. Then, toluene was added and mixed to make a total of 2.5 g. The drug was dissolved in the adhesive solution and stirred to mix evenly. This solution was poured onto a polyethylene impermeable protective layer to coat an adhesive substrate layer and then dried. After drying, a polypropylene desorption layer was laminated thereon.

Example 2

Prepared in the same manner as in Example 1, 100 mg of methylpyrrolidone, 50 mg of peppermint oil, 10 mg of polysorbate 80 was prepared as a skin absorption promoter.

Example 3

It was prepared in the same manner as in Example 1, but 100 mg of methylpyrrolidone, 50 mg of crotamiton, and 10 mg of peppermint oil were prepared as skin absorption promoters.

Example 4

Preparation was carried out in the same manner as in Example 1, but 100 mg of methylpyrrolidone, 25 mg of oleic acid, 25 mg of propylene glycol, and 10 mg of peppermint oil were prepared as skin absorption promoters.

Example 5

It was prepared in the same manner as in Example 1, but was prepared by adding 100 mg of crotamiton, 50 mg of alphalimonene, and 10 mg of polysorbate 80 as skin absorption promoters.

Comparative Example 1

96 mg of indomethacin and 100 mg of peppermint oil, 200 mg of crotamiton and 1300 mg of glycerin were used as a skin absorption promoter, and 3000 mg of kaolin, 2000 mg of polyvinyl alcohol, 1600 mg of gelatin, and 1704 mg of purified water were prepared as a poultice type.

For the transdermal absorption preparations prepared in Examples and Comparative Examples, the skin transmittance of the drug was measured by the following method. The abdominal skin of a hairless mouse (male, 5-6 weeks old) was extracted and fixed in a Franz diffusion cell, and then a percutaneous absorption agent was attached to the stratum corneum. The inside of the cell was filled with a certain amount of physiological saline solution and stirred. Samples were taken at regular time intervals, and the amount of indomethacin diffused by high performance liquid chromatography was measured. The results are shown in FIG. 1, Example 1, Example 2, Example 2, Example 3, Example 3, Example 4, Example 5, Example 5, Example 2 2, Example 3 3 and Example 4 4, Example 5 is 5, Comparative Example 1 is the skin transmittance of 6. As can be seen in Figure 1, when the warning agent according to the present invention, the drug permeability is significantly higher than in the case of Comparative Example 1, excellent drug expression can be expected.

According to the present invention, it is excellent in adhesion, easy to peel off, almost no skin irritation, can be peeled off and reattached, the skin permeability of the drug is high, and the method of preparation also provides a transdermal absorbent of a nonsteroidal anti-inflammatory analgesic. Can be.

Claims (3)

In the transdermal absorbent agent consisting of an impermeable backing layer, an adhesive matrix layer and a realease layer, the adhesive matrix layer is polyisobutylene, natural rubber, resin, or cellulose type. Biologically active drug and pyrrolidone derivatives, propylene glycol, isopropylmyristin acid, crotamiton, polysorbate 80, peppermint oil, alpharimonene, oleic acid, lauric acid, glycerin And at least one skin absorption enhancer selected from the group consisting of lanolin. The non-steroidal anti-inflammatory drug according to claim 1, wherein the biologically active drug is indomethacin, pyricampam, ketoprofen, flubiprofen, naproxen, ibuprofen, phenopropene, diclofenac Percutaneous absorption agent, characterized in that the analgesic. The percutaneous absorption of claim 1, wherein the adhesive polymer layer contains 60 to 80 parts by weight of the adhesive polymer, 0.1 to 40 parts by weight of the skin absorption accelerator, and 0.001 to 10 parts by weight of the biologically active drug. Formulation.