KR100325122B1 - Method of manufacturing skin disease treatment and protective transdermal drug system - Google Patents

Abstract

The present invention relates to a method for the preparation of a transdermal permeable drug delivery system for the treatment and protection of skin diseases, the method being selected from the group consisting of polyvinyl alcohol, sodium alginate, methyl celluloid, hydroxypropylmethylcelluloid, pectin and mixtures thereof Adding a first water-soluble polymer to distilled water, followed by mixing, a dissolving aid which is one or a mixture of two compounds having a glycol monoalkyl ester group in the mixed solution, a covalent agent having a HLB value of 10 or less, polyethylene glycol, polyvinyl Adding a drug solution comprising pyrrolidone, a transdermal drug and an alcohol, followed by mixing to form a gel and ethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, carboxymethyl cellulose, polyacrylic acid, Dextran, a second number selected from the group consisting of poloxomers and mixtures thereof It provides a method for producing a transdermal permeable drug delivery system for treating and protecting skin diseases comprising the addition of a soluble polymer. The transdermal permeable drug delivery system for treating and protecting skin diseases produced by this method has a high initial skin penetration.

Description

Method of manufacturing a transdermal permeable drug system for the treatment and protection of skin diseases

[Industrial use]

The present invention relates to a method for preparing a transdermal drug delivery system for treating and protecting skin diseases, and more particularly, to a method for preparing a transdermal permeable drug delivery system for treating and protecting skin diseases with high drug permeability.

[Prior art]

The method of administering a drug to a patient can be divided into oral administration and transdermal penetration method. Of these, percutaneous permeation is an advantage in many respects than oral in order to supply drugs locally, especially to the skin. For example, oral administration is due to metabolism of the liver, which is a significant part of the decomposition, in order to obtain a certain drug, an excessive amount of drug should be administered, and the drug must be repeatedly administered to maintain the drug.

In contrast, the percutaneous penetrating drug delivery system can solve the above-mentioned disadvantages caused by oral administration because the administered drug is delivered to the affected area directly and in a controlled manner without undergoing metabolism of the liver.

In addition, since the pain and psychological burden of the patient caused by the injection method can be reduced and there is no discomfort, research in this field is being actively conducted.

Representative drugs currently used in drug delivery systems delivered to the skin are erythromycin, hydroquinone and ascorbic acid.

Among these, erythromycin is a macrolide family produced by Streptomyces erythreus and is an effective antibiotic for diphtheria, whooping cough, legionellosis and respiratory infections, and also as an acne treatment for the facial area. It has an antimicrobial effect that suppresses propagation of Propionbacterium acnes , which is the cause of Commercially available formulations using erythromycin include Yegrin solution of Dong Pharmaceutical Co., Ltd. and Acnemycin emulsion of Dong-A Pharmaceutical Co., Ltd., and other formulations in addition to gel preparations are under development (US Pat. Nos. 5,707,635, 4,497,794, and 4,692,329). When the erythromycin cream is applied to the skin, the drug permeation is insignificant and ineffective, and the erythromycin solution is inconvenient to rub several times for sufficient drug permeation when applied to the affected area.

Second, since hydroquinone has an effect of inhibiting melanin-producing enzymes or reducing the concentration of melanin when applied to the skin, it is commercially available as a whitening product that changes into white skin and clean skin (Domina cream commercially available from Taeguk Pharmaceuticals). As described above, techniques for obtaining a whitening treatment effect using hydroquinone are described in US Pat. Nos. 4,764,505, 4,536,779, and 5,063,056. However, the whitening effect of hydroquinone could not be satisfactorily obtained yet.

Third, ascorbic acid acts similar to hydroquinone as vitamin C. It has a function to make skin white and elastic by inhibiting melanin production and promoting collagen synthesis. Many pharmaceutical and cosmetic companies are studying the related drugs such as vitamins A and E. Research on ascorbic acid has not yet reached a satisfactory level.

As described above, various techniques for treating transdermal drug delivery systems for the treatment and protection of skin diseases have been studied. In particular, recently, Korean Patent Application Publication No. 97-20096, "External, Controlled Soft Hydrogel-type External Preparation and Its "Method of production" is used for a substrate composed of 10 to 20% by weight of polyvinyl alcohol, 5 to 15% by weight of ethanol, and 1 to 5% by weight of a nonionic surfactant, and a method of using a skin permeation accelerator when the permeation amount is low is described. have. However, this method uses a small amount of ethanol and nonionic surfactants, so it is necessary for a long time to form a film, and the initial permeation rate is low even with the use of a skin permeation accelerator, and 4 µg of drug per ml of the skin drug delivery system used even after 4 hours. (0.5% indomethacin) permeated. In addition, if the amount of ethanol and nonionic surfactant is increased to increase the initial permeation amount, various problems in stability test, i.e., it can be used as a jelly without fluidity when left at 4 ° C. or below for 24 hours after gel preparation can be used. There is a problem that does not form a constant thickness when applied to the skin.

The present invention is to solve the above problems, an object of the present invention is a skin disease that can increase the initial permeation rate by using a covalent agent and a dissolution aid having a hydrophilic-lipophilic balance (HLB) of 10 or less It provides a method for producing a transdermal permeable drug delivery system for treatment and protection.

Another object of the present invention is to prepare a transdermal permeable drug delivery system for treating and protecting skin diseases in which the amount of alcohol can be increased by using a co-agent and a dissolution aid, thereby shortening the film formation time and increasing the initial permeation amount. To provide.

It is another object of the present invention to provide a method for preparing a transdermal permeable drug delivery system for treating and protecting skin diseases that can be applied evenly to the skin even when the amount of alcohol is increased by using a co-agent and a dissolution aid. will be.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic cross-sectional view of a Franz diffusion mechanism used to investigate skin penetration of the transdermal drug delivery system of the present invention and comparative example.

Figure 2 is a graph showing the skin permeation amount of the transdermal penetration drug delivery system prepared by the method of Example 1-3 and Comparative Example 1-2 of the present invention.

Figure 3 is a graph showing the skin permeation amount of the transdermal penetration drug delivery system prepared by the method of Example 4-5 and Comparative Example 3 of the present invention.

[Means for solving the problem]

In order to achieve the above object, the present invention comprises the steps of adding a first water-soluble polymer selected from the group consisting of polyvinyl alcohol, sodium alginate, methyl celluloid, hydroxypropylmethyl celluloid, pectin and mixtures thereof to distilled water and mixing ; b) a dissolution aid which is one or a mixture of two compounds having a glycol monoalkyl ester group in the mixed solution, a covalent agent having a HLB value of 10 or less, polyethylene glycol, polyvinylpyrrolidone, a transdermal drug and an alcohol Adding a drug solution, followed by mixing to form a gel; And c) adding to the gel a second water soluble polymer selected from the group consisting of ethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, carboxymethyl cellulose, polyacrylic acid, dextran, poloxomer and mixtures thereof. It provides a method for producing a transdermal permeable drug delivery system for the treatment and protection of skin diseases.

Hereinafter, the present invention will be described in more detail.

In the percutaneous permeation drug delivery system of the present invention, the drug is rapidly permeated by ethanol and a dissolution aid in the gel state when applied to the skin, and the drug is gradually permeated by the formation of a polymer membrane at the same time, and the dissolution aid and the co-agent It is a new form of transdermal permeable drug delivery system for skin dropping off automatically. As the film is automatically dropped in this way, the use of the transdermal permeable drug delivery system of the present invention does not require a separate removal of the film, thereby simplifying its use.

Hereinafter, the method for preparing the transdermal permeable drug delivery system of the present invention will be described in detail.

The first water-soluble polymer is added to the distilled water and dispersed. The first water-soluble polymer may be any polymer that can be used as a water-soluble biocompatible polymer, but a polymer selected from the group consisting of polyvinyl alcohol, sodium alginate, methyl celluloid, hydroxypropylmethyl celluloid, pectin, and mixtures thereof Preference is given to using. The amount of polymer added is 6-15% by weight, based on the total drug delivery system weight.

The dispersion is mixed with a homogenizer at 85 to 95 ° C. for 60 to 90 minutes to completely dissolve the water soluble polymer in distilled water to prepare a first water soluble polymer liquid. 46-53% by weight of the drug solution of the entire drug delivery system is added to the first water-soluble polymer liquid, and mixed homogeneously with a homogenizer to form a gel.

The drug solution, based on the total drug delivery system weight 5-30% alcohol, 5-25% dissolution aid, 3-8% covalent agent, 3-4% polyethylene glycol, polyvinylpyrrolidone 2 It is prepared by mixing 3% by weight to 1% by weight of drug.

By using solubilizers and co-agents, the transdermal permeable drug delivery system of the present invention can be used for a long time as it does not change to jelly form. The alcohol may use ethanol or isopropyl alcohol. The dissolution aid may use one or a mixture of two groups of glycol monoalkyl ester groups, and representative examples thereof may include diethylene glycol monoethyl ester. In addition, as the co-agent, a compound having an HLB value of 10 or less may be used. Representative examples thereof include polyglyceryl-6-linoleate and polyethylene glycol-6, which are commercially available as polyethylene glycol-6-glyceryl monooleate and LAFRAFILE. Glyceryl linoleate can be used alone or in combination.

The polyethylene glycol is used having a polymerization degree of 200 to 6000, the addition amount is 3 to 4% by weight based on the total drug delivery system weight. The drug may be used any drug that can be transdermal, and typical examples thereof are antibiotics erythromycin, triamcinolone acetone, gentamicin sulfate, neomycin sulfate, antidiabetic ketoconazole, itraconazole, fluconazole, econazol itrate, non- Indomethacin, ketoprofen, ibprofen, pyroximem, steroidal anti-inflammatory drugs, vitamin A, vitamin B, vitamin C, vitamin B ₂ , vitamin B ₆ , melanin pigment inhibitors hydroquinone, ascorbic acid and Tocopherol, hydrosbenzoylperoxide, nicotine and oxybenzone.

In the case of using a melanin inhibitor as the drug, co-surfactants, excipients, preservatives, antioxidants and stabilizers may be further added to the drug solution. As the co-surfactant, a compound having an HLB value of 10 to 17 is used, and the amount of the cosurfactant is 1 to 15% by weight based on the total weight of the drug delivery system. The excipient may be any compound used to prepare the transdermal drug delivery system. The preservative may be used as any compound as long as it can inhibit the physiological activity of the microorganism in the product and inhibit the growth, and typical examples thereof include methyl paraoxybenzoate and propyl paraoxybenzoate. As the antioxidant, any compound can be used as long as it can prevent oxidation of the product, and representative examples thereof include tocopherol acetate and the like. In addition, the stabilizer may be used meta sodium sulfite or sodium acetate.

To the gel is added 0.01-2% by weight of the second water soluble polymer of the total drug delivery system weight such that the viscosity of the prepared gel is maintained at 10000-28000 mPa · s. If the viscosity of the gel is maintained in the above range it can be prevented from flowing when applied to the skin. As the second water-soluble polymer, any biocompatible polymer may be used as any polymer, but polyvinyl alcohol, ethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, carboxymethyl cellulose, polyacrylic acid, dextran, poloxomer, and these Preference is given to using polymers selected from the group consisting of mixtures of

EXAMPLE

Hereinafter, preferred examples and comparative examples of the present invention are described. However, the following examples are only preferred embodiments of the present invention, and the present invention is not limited to the following examples.

(Example 1)

12 g of polyvinyl alcohol was slowly added to 53 g of distilled water and dispersed, and the dispersion was mixed with a homogenizer at 90 ° C. for 70 minutes to completely dissolve polyvinyl alcohol in distilled water.

To 31 g of ethanol, 20 g of diethylene glycol monoethyl ester, 5 g of polyethylene glycol 200, 4 g of polyvinylpyrrolidone, 5.3 g of erythromycin and 7 g of polyethylene glycol-6-glyceryl mono oleate were added to dissolve to prepare an ethanol solution. The ethanol solution was added to the polyvinyl alcohol solution, mixed thoroughly and homogeneously with a homogenizer, and 0.2 g of polyacrylic acid was added thereto to prepare a transdermal permeable drug delivery system.

(Example 2)

Except that 20 g of polyglyceryl-6-linoleate and polyethylene glycol-6-glyceryl linoleate were added with 5 g of LABRAFIL 1944 and 15 g of diethylene glycol monoethyl ester instead of 20 g of diethylene glycol monoethyl ester It carried out similarly to Example 1.

(Example 3)

Except that 20 g of polyglyceryl-6-linoleate and polyethylene glycol-6-glyceryl linoleate were added with 10 g of LABRAFIL 1944 and 10 g of diethylene glycol monoethyl ester instead of 20 g of diethylene glycol monoethyl ester. It carried out similarly to Example 1.

(Example 4)

Same as Example 1, except that 5.2 g of hydroquinone, 0.35 g of tocopherol acetate, 0.1 g of sodium metabisulfite, 0.025 g of sodium acetate, 0.05 g of methyl paraoxybenzoate, and 0.05 g of paraoxybenzoate were added instead of 5.3 g of erythromycin. It was carried out.

(Example 5)

The procedure was carried out in the same manner as in Example 3, except that 0.35 g of tocopherol acetate, 0.1 g of sodium metabisulfite, 0.025 g of sodium acetate, 0.05 g of methyl paraoxybenzoate, and 0.05 g of propyl paraoxybenzoate were added instead of 5.3 g of erythromycin.

A skin permeation comparative experiment was conducted using the transdermal permeable drug delivery system for treating and protecting the skin disease prepared in Example 1-5 and related products commercially available as a comparative example. The product name, manufacturer, type and amount of drug of the related products used as comparative examples are shown in Table 1 below.

TABLE 1

The skin permeation experiment was carried out as follows using a Franz-type diffusion mechanism having a total volume of about 20 ml and a diffusion area of 5 cm 2, shown in FIG. 1.

After 6 weeks of age, hairless mice were euthanized and the skin was peeled off, and subcutaneous fat inside the skin was carefully removed and washed. Subsequently, the washed skin was placed on the skin 3 on the diffusion solution injector 1 of the Franz-type diffusion device and covered with a cap 5. The diffusion solution injector 1 contains a phosphate buffered saline (PBS), pH 7.4, and the diffusion solution injector 1 is placed in a container through which water can be supplied and discharged. It is installed. 36.degree. C. water was put into the water inlet 9 of this container, and water was discharged into the water discharge port 11, and the temperature of this container was maintained at 36.5 ° C. Subsequently, the drugs of Examples 1-5 and Comparative Examples 1-3 were introduced into the sample inlet 7 formed on one side of the diffusion solution injector 1, respectively. After a certain time, the buffer in which the drug is dissolved is diffused to the diffusion solution discharge portion inside the cap 5. The buffer solution was taken from the diffusion solution discharge part, and the concentration of the drug was measured by HPLC. The results are shown in FIGS. 2 and 3, respectively.

As shown in FIG. 2, the erythromycin gel formulation of Examples 1-3 of the present invention had a significantly higher skin permeation rate than the acnemycin emulsion of Comparative Example 2, and had an initial permeation amount than the example green liquid of Comparative Example 1 having good fluidity. Equivalent or more than doubled. In addition, as shown in Figure 3, the hydroquinone drug formulation of Example 4-5 of the present invention also had a better skin permeation amount than Domina cream, a conventional hydroquinone formulation of Comparative Example 3.

As described above, the transdermal penetration drug delivery system of the present invention has a very high initial skin penetration rate, can be stored for a long time, and can shorten the film formation time. It is thought that the skin permeation amount is increased because the skin is expanded by ethanol and the path through which the drug is permeated by the dissolution aid and the co-agent is expanded. In addition, after a certain time elapses after the film is formed, the film is automatically dropped. The automatic falling of the film is a very unique phenomenon.

Claims (4)

a) adding a first water-soluble polymer selected from the group consisting of polyvinyl alcohol, sodium alginate, methyl celluloid, hydroxypropylmethylcelluloid, pectin, and mixtures thereof to distilled water to mix; b) a dissolution aid which is one or a mixture of two compounds having a glycol monoalkyl ester group in the mixed solution, a covalent agent having a HLB value of 10 or less, polyethylene glycol, polyvinylpyrrolidone, a transdermal drug and an alcohol Adding a drug solution to mix, and mixing to form a gel; And c) adding a second water-soluble polymer selected from the group consisting of ethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, carboxymethyl cellulose, polyacrylic acid, dextran, poloxomer and mixtures thereof As a method of manufacturing a transdermal permeable drug delivery system for the treatment and protection of skin diseases comprising: The amount of the first water-soluble polymer added is 6 to 15% by weight based on the weight of the transdermal penetration drug delivery system, The drug solution may comprise 5 to 25% by weight of the dissolution aid, 3 to 8% by weight of the covalent agent, 3 to 4% by weight of the polyethylene glycol, and the polyvinylpyrrolidone based on the weight of the transdermal penetration drug delivery system. 2 to 3% by weight, 1 to 15% by weight of the transdermal drug and 5 to 30% by weight of alcohol, the amount of the drug solution is added 46 to 53 weight based on the weight of the transdermal drug delivery system %ego, The amount of the second water-soluble polymer added is 0.01 to 2% by weight based on the percutaneous permeation drug delivery system. The method of claim 1, Wherein said dissolution aid is diethylene glycol monoethyl ester. The method of claim 1, The covalent agent is selected from the group consisting of polyethylene glycol-6-glyceryl mono oleate, polyglyceryl-6-rioleate and mixtures thereof. The method of claim 1, The polymerization degree of the said polyethyleneglycol is 200-6000 manufacturing methods.