KR100363476B1 - Transdermal plaster comprising diclofenac or its salt - Google Patents

Abstract

The present invention is a monolayer or multilayer matrix anti-inflammatory analgesic transdermal drug containing diclofenac or salts thereof, and more particularly, comprises a single layer or multilayer matrix layer containing an effective drug, a layer which helps skin penetration of drugs, and a release paper layer. The monolayer or multilayer matrix layer containing diclofenac or salts thereof is a thermoplastic hot-melt adhesive in addition to the active drug, and may be combined with a styrene-butylene copolymer or a styrene-isobutylene-styrene copolymer. Dermal containing adhesive components of ethylene-vinyl copolymer and containing fatty acid amines, fatty acid glycols, higher alcoholols, etc. as transdermal permeation accelerators, and having excellent skin adhesion and minimizing side effects of drugs and side effects of skin. It is to prepare a permeant.

Description

Transdermal plaster comprising diclofenac or its salt}

The present invention relates to a transdermal warning agent, and more particularly, to a warning agent excellent in drug permeability and a method of manufacturing the same.

Diclofenac, one of its nonsteroidal analgesic drugs, or its derivatives is known to have analgesic anti-inflammatory effects by inhibiting the biochemical reaction pathways necessary for the biosynthesis of pain-causing prostaglandins. It is widely used for strong rheumatoid arthritis, osteoarthritis, acute gout, and post-operative traumatic gout, but it is a common side effect of analgesic anti-inflammatory drugs in long-term oral administration. It causes ulcers, anemia and gastrointestinal disorders. As a method for minimizing such side effects, researches formulated into transdermal agents are actively conducted, and representative ones are divided into topical gel preparations, ointment preparations, spray preparations, and patching patches.

Among them, US Pat. Nos. 4,537,776, 5,350,79, and the like are described as technologies related to coating agents such as gel preparations, ointment preparations, and external preparations, and Korean Patent No. 98-08394 is published. Disadvantages of such formulations are in the form of direct application to the skin, which makes it difficult to administer the drug continuously, has a problem to be applied several times for continuous administration, and the application amount is not constant in one application. And there is a drawback to lose the efficacy by buried in the user's clothes or clothes.

In case of foreign patents, US patent 4,738,848 was used to convert diclofenac sodium salt into diclofenac free acid form using citric acid in order to improve transdermal permeability. Patent Publication No. 99-026792 is disclosed. However, in this case, it is limited to diethylammonium of diclofenac, and a method of drying the organic solvent after coating to a predetermined thickness using an organic solvent is used to separate the volatile and nonvolatile components by volatilization of the volatile components. The manufacturing method using the method of spraying a volatile component in one layer as a manufacturing method is disclosed.

However, in such a solvent method, esters such as ethyl acetate, linear or cyclic hydrocarbons such as hexane, heptane or cyclohexane, and aromatic hydrocarbons such as toluene are used as the solvent. However, these solvent methods have the following problems.

(1) The solvent may remain.

(2) There is a fear of adverse effects on the skin such as skin redness due to residual solvent.

(3) Adsorption treatment in the process of evaporating the solvent in the manufacturing process, may cause respiratory diseases of the producer.

(4) There is a fear of work pollution such as blood cell reduction caused by solvent, and especially when aromatic hydrocarbon is used as a solvent, there is a risk of developing leukemia.

(5) A long tunnel is needed to dry the solvent. In other words,

Primary tunnel: 80 ℃, 6m,

2nd tunnel: 100 ℃, 7m,

Tertiary tunnel: long tunnel, such as 70 ℃, 6m is required, it may vary depending on the boiling point of the solvent used.

The present invention solves the above-mentioned problems and is a simple method of adding a volatile component together with an effective drug as a method of using a thermoplastic adhesive that does not use an organic solvent. It is an object of the present invention to provide a warning agent with excellent transdermal permeability of dichrophenac or salts thereof (dichrophenac diemmonium, dichrophenac sodium, dichrophenac beta dimethylamino ethanol).

Another object of the present invention is to provide a transdermal permeation warning agent that simplifies the manufacturing method and has excellent initial drug absorption, and another object is a transdermal which can maintain adhesiveness continuously without repeated side effects of the skin. It is to provide a permeation warning agent.

Still another object of the present invention is to provide a transdermal warning agent that is easy to attach and detach when treated. And to provide a warning for transdermal penetration easy to use in various conditions such as curved joint site.

The present invention has developed a method for minimizing these side effects and simply administering directly to the pain area. The design of this development relates to transdermal administration of monolayer or multilayered matrix analgesic anti-inflammatory agents containing diclofenac or salts thereof (diclofenac diethyl ammonium, diclofenac sodium, diclofenac beta dimethylamino ethanol) In more detail, the drug backing layer, the layer which aids skin penetration of the drug, the monolayer or multilayer matrix layer containing diclofenac or its salts, and the release liner layer removed before adhesion to the skin Stacked in order, the monolayer or multilayer matrix layer is a styrene-butadiene copolymer resin, styrene-isoprene-styrene copolymer resin, ethylene-vinylacetate copolymer as adhesive components, in addition to dichlorophenac or salts thereof. Resin and rosin as adhesive components, and as percutaneous permeation accelerator, higher fatty acid series, fatty acid amine series, fatty acid flax It contains active ingredients such as L-menthol and methyl salicylate, and contains polyol-pete acid ester series, higher alcohol, polyethylene-polypropylene copolymer surfactant, and dissolution aid. We have developed a monolayer or multilayer matrix analgesic anti-inflammatory transdermal drug with excellent permeability and body adhesion.

1A: 1.Backing layer

2. Drug Containing Layer I

3. Drug-containing layer II

4. Release liner

1B: 1. Backing Layer

2. Layer to help skin penetration

3. Drug containing layer

4. Release liner

2: Comparative graph of skin permeation of dicrofenac and salts thereof.

3: Comparative graph of skin penetration of Example 1 group

4: Comparative graph of skin penetration of Example 2 group

5: Comparison of skin penetration rate of Example 3 group

6: Comparative graph of skin penetration of Example 4 group

The present invention consists of two representative methods. Drug backing layer (1), layer for promoting skin penetration of drug (2), layer containing active drug (3) and release liner layer (4) or drug protective layer removed prior to skin adhesion (backing layer; 1), the layer containing the active drug in the layer promoting the skin penetration of the drug (2), the layer containing the active drug (3) and the release liner layer (4) removed before the skin adhesion In the laminated monolayer or multilayer matrix transdermal administration agent, the present invention will be described in detail.

First, in the former case, a nonwoven fabric, an acrylic cloth, a polyester film, a soft polyvinyl chloride, and a polyurethane may be used for the backing layer (1), and the layer (2) for promoting skin penetration of the drug may be polyiso. The ratio of butylene low molecular weight (40,000 to 50,000) to polyisobutylene polymer (800,000 to 1,200,000) is used at a ratio of 1.25 to 1: 1.25: 1, and the layer 3 containing the drug is diclofenac or its salt ( 1 to 25 parts by weight of dichrophenac diemmonium, dichrophenac sodium, dichrophenac beta dimethylamino ethanol (hereinafter referred to as parts); 45 to 95 parts of styrene-butadiene copolymer resin, styrene-isoprene-styrene copolymer resin, ethylene-vinylacetate copolymer resin and rosin as adhesive components; 1-30 parts of higher fatty acid type, fatty acid amine type, fatty acid amide type, polyol-fethiate ester type, higher alcohol, polyethylene-polypropylene copolymerized surfactant, dissolution aid, l-menthol, methyl salicylate as transdermal penetration accelerator. In the matrix form, and in the latter case, a nonwoven fabric, an acrylic cloth, a polyester film, a soft polyvinyl chloride, and a polyurethane drug are contained in the backing layer (1), and the active drug is contained in a layer that promotes skin penetration. The layer 2 may have a ratio of styrene-isoprene-styrene: polyisobutylene polymer (8,000,000 to 10,000,000) in a ratio of 1 to 1.25: 1.25 to 1, and includes an active drug (3 ) Is 1 to 25 parts of diclofenac or salts thereof (dichlorophenac diethyl ammonium, diclofenac sodium, dicrofenac beta dimethylamino ethanol); 45 to 95 parts of styrene-butadiene copolymer resin, styrene-isoprene-styrene copolymer resin, ethylene-vinylacetate copolymer resin and rosin as adhesive components; 1-30 parts of higher fatty acid series, fatty acid amine series, fatty acid amide series, polyol-fethiate ester series, higher alcohol, polyethylene-polypropylene copolymerization surfactant, dissolution aid, l-menthol, methyl salicylate It is provided in the form of a single layer or multilayer matrix contained.

The process of the present invention is prepared using the hot melt method. In more detail, a plasticizer is added and it manufactures using a hot-melt method.

Hot melt method by the addition of the plasticizer of the present invention has the following advantages over the conventional solvent method.

(1) There is no fear of residual solvent.

(2) There is no fear of adverse effects on the skin such as skin redness which is strange to residual solvent.

(3) When the solvent is evaporated in the manufacturing process, it can reduce the respiratory disease of the adsorption treatment and the producer, and the production cost can be drastically reduced because the manufacturing process is simple.

(4) There is no fear of developing leukemia due to blood cell reduction by solvent or solvent used.

(5) The drying process takes a short time and there is no need for a tunnel to dry the organic solvent, so it can be produced in a narrow space.

(6) In the hot-melt method, the upper part is completed by passing the adhesive ingredient containing the effective chemical between the heated roll and the lower cooling roll.

In the present invention, as a plasticizer, mineral oil or plant oil is used as the plasticizer.

As a kind of such a plasticizer, it is preferable to use mineral oil or vegetable oil, such as corn oil, peanut oil, cottonseed oil, castor oil, rapeseed oil, rice bran oil, and soybean oil. 1-10 weight part of such plasticizers are added.

When the plasticizer is added and the hot melt method is performed, the following advantages are obtained.

(1) When the plasticizer is not used, the raw material drugs are melted to facilitate operation when the temperature is 120 ° to 140 ° C. However, when the plasticizer of the present invention is used, the melting temperature is about 70 to 100 ° C. This makes it very easy to work with and, at lower temperatures, depending on the inherent melting point of the material.

(2) It is possible to prevent the deterioration of raw materials due to high temperature melting used in ordinary hot melt method.

(3) The viscosity of easy workability can be arbitrarily adjusted by use of a plasticizer.

More detailed description of the present invention.

The present invention provides an adhesive matrix-derived transdermal agent having excellent skin permeability for diclofenac or its salts (dichlorophenac diethyl ammonium, dicrofenac sodium, dicrofenac beta dimethylamino ethanol) and L- Polyethylene-polypropylene copolymer interface, which may contain volatiles such as menthol, and the like, or a combination of two or three of higher fatty acids, fatty acid amines, fatty acid amides, polyol-fethiate esters, and higher alcohols It is aimed at the production of excellent transdermal agents containing active agents and dissolution aids.

Diclofenac or a salt thereof (dichlorophenac diethyl ammonium, dichlorophenac sodium, dicrofenac beta dimethylamino ethanol) which is an effective drug in the present invention is suitably contained within 1 to 25 parts of the composition, At the following doses, skin permeation is hardly achieved, and at the above doses, adhesion is reduced, and solubility of the drug may be a problem, causing the drug to precipitate on the surface.

As the adhesive component used in the present invention, a thermoplastic adhesive component capable of shortening the production time without using an organic solvent was used. When the solubilizing temperature is too high in the thermoplastic resin, it is excluded that the adhesive component with high economic loss or the viscosity is too high (5000 cps) is excluded. The suitable temperature is most suitable at 80 to 100 ° C, and the viscosity is less than 4000 cps. Most suitable. Of course, the adhesiveness of the skin is excellent, it is possible to use the skin for a long time, the thermoplastic resin provided that there is no side effect was used. In the case of such a thermoplastic adhesive, 45-90 parts is contained. If the adhesive component is 45 parts or less, the active drug, transdermal penetration accelerator, L-menthol, and dissolution aid are used to destroy the inherent physical properties of the adhesive to remove the adhesive force or to destroy the internal cohesion of the adhesive, leaving a residual amount on the skin. May occur. And if it is more than 95 parts does not contain the content of the effective drug and skin permeation accelerator. In the case of the adhesive component, the content of isoprene and butadiene in the styrene-isoprene-styrene copolymer and styrene-butadiene copolymer isoprene and butadiene when comparing solubilization temperature, viscosity, and adhesive force. The content of yen is 40 to 50 parts is most suitable, if it is 40 parts or less, there is almost no adhesiveness, and if it is 50 parts or more, the price is too expensive. In the case of ethylene-vinylacetate copolymerization, the content of vinyl acetate is 40 to 45 parts It was suitable, and if it is 40 parts or less, it is difficult to heat the thermoplastic, difficult to act as a thermoplastic pressure-sensitive adhesive, and even when used, the flexibility of the matrix transdermal administration agent cannot be imparted. The selected styrene-isoprene-styrene copolymer and the ethylene-vinylacetate copolymer were combined in the ratio of 1 to 1.2: 1.2: 1, and the styrene-butadiene copolymer and ethylene were selected. Adhesion was imparted using the ratio of vinyl acetate from 1 to 1.2: 1.2 to 1. And a more detailed description of these methods of use will be described as examples.

In the case of the skin permeation accelerator, it basically contains 5 to 20 parts of a polyethylene-polypropylene copolymerized surfactant, l-menthol, methyl salicylate and a dissolution aid, and includes higher fatty acid series, fatty acid amine series, fatty acid amide series, and polyol- The combination of petty acid ester series and higher alcohols in a ratio of 1: 1 was promoted to promote greater skin permeation, and the content of 5 to 20 parts of the total content was most appropriate. If it is less than 5 parts, the skin permeation of the drug is not good, if more than 20 parts can reduce the adhesive strength of the pressure-sensitive adhesive, up to 5 to 20 parts the skin penetration rate of the drug increases in a proportional proportion, but if more than 20 parts There is a problem that only increases the irritation of the skin without having a constant proportional relationship. Combinations of skin permeation promoters will be described in more detail in the description of the examples.

Polyethylene-polypropylene copolymerized surfactants include Pluronic F-127, F-68, F-88, and the like, and dissolution aids include propylene glycol and glycol. In the case of higher fatty acids, there are one selected from isopropyl myristate, oleic acid myristate, lauryl acid, palmitic acid, and the like. Fatty acid amines include lauryl amine, and the like, and fatty acid amides include diethyl-meth-toluamide. Polyol-pete acid esters include ethylene glycol-mono caprylate, ethylene glycol-mono 2-ethylhexanoate, propylene glycol-mono caprylate, propylene glycol-dicaprylate, glyceryl-mono caprylate, There is one selected from trade names Breeze 30, 52, 72, 92, transcutol and the like. And higher fatty acid alcohol is one selected from lauryl alcohol, cetyl alcohol, oleyl alcohol, 1,3-butanediol.

The composition containing the pressure-sensitive adhesive component, skin permeant, and effective drug selected above was applied at a constant thickness using a release paper. The thickness of the application is also a factor for determining the skin permeation of the drug, the thickness of 30 ~ 500 ㎛ is suitable, and exactly 40 ~ 100 ㎛ was most suitable. When it is 30 μm or less, it is difficult to contain the drug, when it is 500 μm or more, application is difficult, and movement of the effective drug toward the skin was not easy.

This invention is described in more detail based on the following examples, which are not intended to be limiting of the invention.

General Example

Mineral oil or vegetable oil was added to a 400 ml stainless bottle and heated to 80 ° C. Here, the ratio of the styrene-isoprene-styrene copolymer and the ethylene-vinylacetate copolymer as an adhesive component is 1: 1.2 or 1.2: 1, or the styrene-butadiene copolymer, the ethylene-vinylacetate The ratio of 1: 1.2 or 1.2: 1 was administered. Then, while stirring the mechanical stirrer at 200 rpm, dichlorophenac or its salts and polyethylene-polypropylene copolymerized surfactant were administered together and mixed uniformly. The transdermal penetration accelerator and the dissolution aid combined therewith were stirred until clear after administration. Then, the temperature was lowered by adjusting the temperature to 50 ° C. The volatile components, L-menthol or methylsalicylate, which were thus prepared, were finally administered.

It was applied to a certain thickness while putting a release paper between the roll and the cooling roll warmed to 50 ℃ while putting the composition therebetween. This was completely similar to the ambient temperature and then transferred to the drug protective layer was transferred to a 50 ℃ compression roll.

Thus prepared multi-layer or multi-layered matrix was cut to a constant size and the content of the drug was measured, and the measuring method was HPLC. In order to evaluate the performance of a sample cut to a constant size, the skin of a 4-6 week-old hairless rat was removed, subcutaneous fat was removed, and a Franz type diffusion cell was installed. It was then analyzed using HPLC. The results are shown in Figures 3-6.

HPLC analysis conditions

Column: μ-bondapak C18 (10 μm, 3.9 × 300 mm)

Mobile phase: 0.75 M sodium acetate buffer, pH 5.0 / acetonitrile (55: 45, vol / vol)

Flow rate: 1 mL / min

Detector: 282 nm

Example 1 group

※ Dichrophenac Free Acid (hereinafter referred to as DA)

Example 1-1

Preparation of layer 2 to promote skin penetration of drug

Polyisobutylene low molecular weight (40,000 to 50,000): polyisobutylene polymer (800,000 to 1,200,000): mineral oil or vegetable oil = 1.25: 1: 1 is completely solubilized by heating at 80 DEG C, to a thickness of 30 to 40 µm Direct application on acrylic cloth.

Single layer matrix layer containing effective drug (3)

The above composition was applied to the release paper layer at 40-50 μm, and then the drug was transferred to an acrylic cloth having a layer that promotes skin penetration.

Example 1-2

A layer (2) for promoting skin penetration of the drug was used in the method of Example 1-1.

Single layer matrix layer containing effective drug (3)

Prepared as in Example 1-1.

Example 1-3

A layer (2) for promoting skin penetration of the drug was used in the method of Example 1-1.

Single layer matrix layer containing effective drug (3)

Prepared as in Example 1-1.

Example 1-4

A layer (2) for promoting skin penetration of the drug was used in the method of Example 1-1.

Single layer matrix layer containing effective drug (3)

Prepared as in Example 1-1.

Example 1-5

Preparation of the layer (2) which promotes skin penetration of the drug

The above components were applied to a release paper layer at 30 to 35 µm and then transferred to an acrylic cloth.

Preparation of Effective Drug-Containing Layer (2006.01)

The above composition was applied to the release paper layer at 20 to 35 μm, and then the drug was transferred to an acrylic cloth having a layer to promote skin permeation.

Example 1-6

Preparation of the layer (2) which promotes skin penetration of the drug

Preparation of Effective Drug-Containing Layer (2006.01)

The above composition was applied to the release paper layer at 20 to 35 μm, and then the drug was transferred to an acrylic cloth having a layer to promote skin permeation.

Example 1-7

Preparation of the layer (2) which promotes skin penetration of the drug

Preparation of Effective Drug-Containing Layer (2006.01)

The above composition was applied to the release paper layer at 20 to 35 μm, and then the drug was transferred to an acrylic cloth having a layer to promote skin permeation.

Example 1-8

Preparation of the layer (2) which promotes skin penetration of the drug

Preparation of Effective Drug-Containing Layer (2006.01)

The above composition was applied to the release paper layer at 20 to 35 μm, and then the drug was transferred to an acrylic cloth having a layer to promote skin permeation.

Example 2 group

※ Diclofenac diethyl ammonium (hereinafter referred to as DD) is used in place of DA in Example 1.

Example 2-1

DD was used instead of DA in the method of Example 1-1.

Example 2-2

DD was used instead of DA in the method of Examples 1-2.

Example 2-3

DD was used instead of DA in the method of Examples 1-3.

Example 2-4

DD was used instead of DA in the method of Example 1-4.

Example 2-5

DD was used instead of DA in the method of Example 1-5.

Example 2-6

DD was used instead of DA in the method of Example 1-6.

Example 2-7

DD was used instead of DA in the method of Examples 1-7.

Example 2-8

DD was used instead of DA in the method of Examples 1-8.

Example 3 group

Example 1 Example was carried out using diclofenac sodium instead of DA in the Examples of the group.

Example 4 group

Example 1 Examples were performed using diclofenac beta-dimethylaminoethanol instead of DA in the Examples of the group.

As described above, the percutaneous permeation warning agent using the dichrophenac or salts thereof of the present invention not only prevents volatilization of volatile components without using an organic solvent, and also has excellent drug release effect, and has a low side effect. Can be used. In addition, the present invention provides an advantage of effectively and safely treating arthritis by applying to curved joint parts as desired.

Claims (4)

A drug-containing pressure-sensitive adhesive layer containing diclofenac or salts thereof as an active ingredient and a pressure-sensitive adhesive and a skin permeation accelerator; A skin transition layer that helps to transfer dicrofenac or its salts to the skin; And a percutaneous permeation warning agent prepared by a hot melt method using a substrate supporting the pressure-sensitive adhesive layer and the skin transition layer. A drug-containing pressure-sensitive adhesive layer containing diclofenac or salts thereof as an active ingredient and a pressure-sensitive adhesive and a skin permeation accelerator and a plasticizer; A skin transition layer that helps to transfer dicrofenac or its salts to the skin; And a percutaneous permeation warning agent prepared by a hot melt method using a substrate supporting the pressure-sensitive adhesive layer and the skin transition layer. According to claim 1 or 2, wherein the percutaneous permeation warning agent contains 1 to 20 parts by weight of diclofenac or salt thereof of the weight of the drug-containing pressure-sensitive adhesive layer and the skin transition layer, wherein the pressure-sensitive adhesive layer and the skin transition layer A percutaneous permeation warning agent containing 40 to 95 parts by weight, containing 1 to 25 parts by weight of a skin permeation accelerator, and 0 to 10 parts by weight of a plasticizer. The method according to claim 1 or 2, At least one thermoplastic adhesive selected from the group consisting of ethylene-vinylacetate copolymer, styrene-isoprene-styrene, styrene-butadiene copolymer or rosin ester; A polyisobutylene polymer having a molecular weight of 8,000,000 to 10,000,000: a skin transition layer comprising 1 to 1.25: 1.25 to 1 part by weight of 40,000 to 50,000 polyisobutylene low molecular weight or styrene-isoprene-styrene; 0 to 10 parts by weight of a plasticizer selected from vegetable oils such as mineral oil, corn oil, peanut oil, cottonseed oil, sesame oil, rapeseed oil, rice bran oil and soybean oil; Polyethylene-polypropylene copolymerized surfactants selected from Pluronic F-127, F-68, F-88, isopropyl myristate, oleic acid myristate, lauryl acid, palmitic acid, higher fatty acids selected from laurylamine Fatty acid amines such as, fatty acid amides such as diethyl-meth-toluamide, ethylene glycol-mono caprylate, ethylene glycol-mono 2-ethylhexanoate, propylene glycol-mono caprylate, propylene glycol-dicapryl One or more skin permeation promoters selected from latex, polyol-fetiacid esters such as glyceryl-mono caprylate, lauryl alcohol, sacchiol alcohol, oleyl alcohol, higher fatty acid alcohols such as 1,3-butanediol; And A warning agent for transdermal penetration, characterized in that it contains a dissolution aid selected from propylene glycol, glycol.