KR100190450B1 - Matrix type transdermal preparation using chitosan - Google Patents

Abstract

The present invention relates to a skin compatible chitosan matrix which directly attaches a chitosan matrix to the skin by mixing an adhesive auxiliary component with chitosan and imparting adhesive force to the chitosan itself, and has a water-soluble dissolving aid and a water dissipation property. The polyurethane film was used as the back layer to stabilize the unstable drug dissolution rate of the chitosan against the water moisture, and it was developed as a systemic transdermal absorption agent by improving the permeation rate of the drug by adding an absorption accelerator in an appropriate ratio.

The skin-compatible chitosan matrix transdermal absorbent prepared in the present invention is a water-soluble natural polymer matrix transdermal absorbent which significantly reduces the skin irritation caused by the adhesive of the conventional systemic transdermal absorbent by directly applying to the skin. By improving the rate instability, chitosan has been introduced into systemic transdermal absorptions such as steroidal drugs, NSAIDs, circulatory drugs, and respiratory drugs.

Description

Matrix Transdermal Absorption Agent Using Chitosan

The present invention relates to a matrix transdermal absorption preparation using chitosan as a polymer matrix and a method for producing the same. More specifically, by preparing a matrix transdermal absorption drug delivery system using chitosan, which has high biocompatibility and biodegradability, and attaches it to the skin, it can reduce skin irritation caused by prolonged use and reduce the skin irritation caused by prolonged use. It relates to a transdermal absorption preparation and a method for producing the same.

This preparation is a transdermal drug that continuously releases drugs of steroidal skeletal structure including estradiol, progestin, testosterone, corticosteroids and derivatives thereof, and high pharmacologically active drugs such as nitroglycerin, nicotine, fentanyl, and clonidine for 1-3 days. As an absorbent type, it aimed at systemic action through the maintenance of systemic drug blood concentration.

Until recently, formulations for delivering drugs into the body have been widely used in clinic mainly as oral preparations and injections. However, the administration of the drug by injection is accompanied by the difficulty of commercial drug administration such as the cumbersome injection and the patient's syringe blood. In addition, when oral administration of these drugs, bioavailability (abbreviated as BA) is very low due to decomposition and hepatic metabolism in the digestive tract, depending on the drug, requiring a large amount of drug administration to maintain the required drug blood concentration. This can lead to serious drug side effects from individual differences. In addition, drugs that cause side effects during the course of administration such as gastrointestinal disorders when administered by oral preparations are not possible for long-term use, and thus, the change of the route of administration is required. In addition, the drug itself has a high pharmacological activity and a narrow safety margin, so it is impossible to orally administer a drug that is difficult to maintain the drug blood concentration through oral.

Systemic administration through the skin can be considered to reduce side effects for these drugs, to increase the BA as much as possible with the minimum dosage required, and to maintain the blood concentration of the drug stably. However, since the skin itself has a function of protecting the body from the external environment, in order to be able to administer the drug through the skin, the drug having high drug efficacy and having hydrophobicity and hydrophilicity is the most ideal transdermal drug. Can be selected. Based on these conditions, the administration of drugs through transdermal absorption has been tried to drugs that require high maintenance of drug efficacy and narrow safety drugs that require constant drug blood concentration or that cannot be formulated orally due to intestinal loss or hepatic metabolism. . These drugs include steroidal drugs such as estradiol, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen and angina drugs such as nitroglycerin, and circulatory drugs such as high blood pressure drugs such as colonidine, There are respiratory drugs such as clenbutrrol (clenbutrrol) and drugs with high pharmacological activity, such as nicotine, fentanyl, fluoruracil (fluoruracil). As a commercially available drug, a motion sickness drug that slowly releases a drug called scopolamin by using a semipermeable membrane has been developed. Diol has been developed as a storage tank and is currently marketed as a transdermal absorbent.

Percutaneous absorption preparations containing these drugs often require a long period of several months to several years, thereby increasing the requirements of patients. In particular, transdermal absorbents that transport steroid-containing drugs, including estradiol, nonsteroidal anti-inflammatory drugs, circulatory drugs, respiratory drugs, and antipsychotic drugs are all used for intractable diseases, requiring a very long period of treatment. As a result, skin irritation such as discomfort, sensation and itching due to long-term use of the topical agent becomes the biggest problem.

In order to alleviate the discomfort and skin irritation that are the drawbacks of the prior art, a method of increasing the flexibility of the patch and reducing the size or reducing the remaining solvent inside the adhesive has been attempted. However, if the flexibility of the thickener is increased as much as possible in order to improve discomfort and skin irritation, it is very difficult to handle the patch because of its practicality. And to reduce the size of the mucus, more absorption accelerators must be used, which in turn can cause skin irritation. In addition, in order to improve the skin side effects, it has been examined to reduce the residual monomers and residual solvents in the conventionally used adhesives or to increase the air permeability of the oxygen and CO ₂ of the tackifier, but due to problems such as a decrease in the dissolution rate of the drug. Difficulties follow. The fundamental solution is to use natural polymers with excellent skin compatibility and to produce a homogeneous polymer solution with polarity over water and ethanol, without using an organic solvent as a solvent to dissolve the polymer.

In order to solve these problems, the present inventors have developed a matrix drug delivery system by selecting chitosan, a natural polymer having excellent biocompatibility, biodegradability, hydrophilicity and adequate breathability, as a base for transdermal absorption.

Chitosan is produced by deacetylating chitin present in crustaceans such as crabs and shrimps, arthropods and mollusks, and is a substance belonging to polysaccharides widely present in nature. Chitosan can be swollen in water and the crystallinity of chitin can be broken down so that it can be dissolved in a solvent. Chitosan and its derivatives can be dissolved in organic or mixed solvents using strong acid, weak acid, or dimethylacetamide-LiCl, etc., and they are applied to various fields such as fiber, paper, medicine, food, cosmetics or waste water treatment by combining functional groups. . In particular, natural polymers, chitin and chitosan, have good biocompatibility and biodegradability. They have no antigenicity against biological tissues, and are known to have wound healing, bactericidal, and anticancer effects. It is applied.

By applying such chitosan to the skin in particular, it is possible to prepare a highly stable hydrophilic polymer solution which significantly reduces the skin action such as erythema and itching, which may appear as a base side effect, and has no antigenicity to the living body, which is known from the literature. .

Examples of this use include published patent numbers GB 2095995, JP 6435609, EP 368253, and the like.

GB 2095995 produced a formulation in which liquid or powdery chitosan was applied to a bleeding skin wound or implanted into a bleeding tissue as part of a foreign body or a patch form using chitosan having high biocompatibility as a hemostatic tool. In addition, JP 6345609 was developed using the antimicrobial activity of chitosan to prepare a water-soluble chitosan and mix it with an antimicrobial material to develop a suppression of Zoia japonica strain in liquid or patch form. In EP 368253, chitosonium polysaccharides and chitosan derivatives were prepared to prepare a drug delivery system applied to the skin and the mucosal membrane. EP 368253 aims at a Lawson type drug delivery system in which a drug-containing polymer solution prepared using such aminopolysaccharides is applied to the skin to form a film on the skin and protect the skin by its moisturizing effect.

Thus, chitosan can be applied as a drug or a therapeutic means itself, and can be used as a base of a drug delivery system with excellent biocompatibility. However, the various formulations of chitosan applied to the skin mentioned above have been used topically on the basis of the pharmacological effects of chitosan and its derivatives themselves, or for systemic purposes as a tool for drug delivery systems. In other words, the existing chitosan skin application formulations have high efficacy and narrow safety margins, and therefore, they cannot be used for drugs that require systemic therapeutic effect through transdermal absorption. It is used as a local drug delivery mechanism for the treatment of inflammation, burns, purulent diseases, skin moisturization, and hemostasis of bleeding areas, or it is applied locally for the pharmacological action of chitosan itself.

In addition, in the existing technology, chitosan itself has a weak skin adhesion force, and in order to apply it to the skin, the chitosan matrix layer needs to be coated with another adhesive layer. The results showed that the merits were halved, and thus, chitosan was used as a liquid and powdered ointment rather than a matrix patch. And water-soluble polymers such as chitosan, when applied to the skin as a transdermal absorption agent may cause a change in drug release rate due to excessive swelling of the skin moisture or irregular swelling due to external moisture penetration, which can be a major problem as a transdermal absorption agent.

In this existing technology, the chitosan matrix has a limitation in being used as a transdermal absorption agent aimed at maintaining systemic drug blood concentration. The problem of chitosan's adhesion and instability against moisture is that although chitosan is a natural polymer material with excellent skin compatibility, the skin application type of chitosan is limited to topical formulations such as rooshon, ointment, and powder. It has become a factor that makes it difficult to develop systemic transdermal absorption preparations for the purpose of transporting phosphorus drugs. Such problems have not been overcome in the above-mentioned Publication Nos. GB 2095995, JP 6345609, EP 368253, and the like, and in particular, chitosan derivatives used as drug delivery mechanisms in EP 368253 do not solve this problem and are used as a quantitative drug transporter. It is mainly applied to topically applied lotion agents, which cannot guarantee the quantitative transport of drugs, not absorbents.

In the present invention, the chitosan was introduced into the percutaneous absorption preparation for the purpose of systemic action, which was not used by the existing technology to compensate for the disadvantage of the chitosan. In the present invention, in order to make up for the shortcomings of chitosan, it was possible to mix with chitosan and use an adhesive support ingredient with excellent adhesive force, and through this, the chitosan matrix was directly attached to the skin to prepare a skin compatible transdermal absorbent which maximizes the advantages of chitosan. . In addition, in order to improve the instability of water in chitosan, a chitosan matrix was prepared to maintain moisture equilibrium at a relative humidity RH of 40-50% by mixing a dissolving aid with a moisturizing property. By preventing the invasion of external moisture and discharging excess skin moisture using the layer), it was possible to improve the instability of the chitosan matrix by water and to keep the drug dissolution rate constant.

Through this process, the present invention introduces chitosan with excellent skin compatibility into the transdermal absorbent preparation for systemic action, thereby significantly reducing the skin side effects of the topical agent by prolonged use of the transdermal absorbent preparation and suitable for long-term systemic transport of the drug. It was aimed at the preparation of suitable chitosan matrix transdermal absorbents. That is, in the present invention, it was intended to optimize the skin compatible systemic transdermal absorbents by improving low adhesion, which is a problem as the transdermal absorbents which chitosan itself has, and instability to skin moisture.

Before describing the present invention in detail, briefly summarize the contents used in the present invention.

1) Poly

-Chitosan: α-chitosan and β-chitosan having a molecular weight of 20,000-500,000 that are soluble in weakly acidic solutions of acetic acid, lactic acid, citric acid and the like, and acidic solutions such as hydrochloric acid and nitric acid.

2) solvent

-Water, ethanol: Water and ethanol as the main solvents to dissolve chitosan and drugs.

3) drugs

-Steroidal drugs such as estradiol, progestin.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketoprofen, pyroxycam and ketorolac.

-Circulatory system drugs such as nitroglycerin, colonidine, and prozosin.

Respiratory system drugs such as clebuterol and salbutamol.

Drugs for the treatment of varicose diseases, such as methadone and fentanyl.

Others: nicotine as a smoking cessation drug, fluorouracil as an anticancer drug, papaverine as an erectile dysfunction drug, and chlorpheniramine as an antihistamine drug.

4) Adhesive auxiliary ingredient

Polyvinylpyrrolidone: Water-soluble polymer with a molecular weight of 30,000-3,000,000.

-Poly (vinylpyrrolidone-vinylacetate) copolymer: A water-soluble polymer as a 60/40 copolymer of polyvinylpyrrolidone and polyvinylacetate.

5) Melting aid

Propylene glycol: molecular weight 76.09, b.p. 188 ℃

Isopropyl alcohol: molecular weight 60.10, b.p. 82.4 ℃

-PEG: Polyethylene glycol series having a molecular weight of 400-6000.

6) Absorption accelerator

-Alkali metal salts of stearic acid, palmitic acid, oleic acid, linoleic acid: bovine metal salts of saturated or unsaturated higher fatty acids of 16-18 carbon atoms.

Low molecular organic acids of lactic acid, fumaric acid and citric acid.

-Surfactant class of Span 20-80, Tween 20-80.

7) back layer film

Polymer film molded from polyurethane: Average molecular weight 100,000

When explaining the functions and features of the adhesive auxiliary component, the dissolution aid, the absorption accelerator, and the back layer film, which are components used in the preparation of the chitosan matrix, which are listed above, are as follows.

First, in order to improve the adhesive performance of chitosan, polyvinylpyrrolidone and poly (vinylpyrrolidone-vinylacetate) copolymer were used as an adhesive auxiliary component. In the present invention, in order to use the skin compatibility of chitosan in the matrix type transdermal absorbent preparation, the purpose of the formulation is to attach chitosan directly to the skin. For this purpose, chitosan and polyvinylpyrrolidone as an adhesive aid component capable of dissolving and excellent adhesion The poly (vinylpyrrolidone-vinylacetate) copolymer was selected and added at 0.5-20 wt% into the chitosan polymer solution and prepared as a clear polymer solution using a chitosan polymer solution and a homogenizer. In particular, since they are dissolved by weak acids such as organic acids, the adhesive components dissolved in weak alkalis using adhesive components dissolved in organic solvents such as vinyl acetate having typical adhesiveness or acrylic acid such as carhopol as a monomer are mixed with chitosan solution. It is difficult to dissolve and for this reason adhesive layer has to be manufactured separately. It was. In contrast, the polyvinylpyrrolidone and poly (vinyrrolidone-vinylacetate) copolymers are easily dissolved and dissolved with the chitosan polymer liquid in weak acidity, thereby imparting proper adhesion to the chitocin matrix. Through this, the chitosan matrix layer dried at an appropriate drying rate has its own adhesive force, and by attaching it directly to the skin, it is possible to maximize the skin compatibility of chitosan, thereby developing a skin-compatible chitosan matrix transdermal absorbent with minimal skin irritation. It is possible.

Next, the solubility aid having a hydroxyl group was used to increase the solubility of the fat-soluble drug in the water-soluble chitosan polymer solution and to improve the stability of the chitosan matrix after drying. As a dissolution aid, a chitosan solution, a PEG series (molecular weight 400-6000) capable of dissolving and dispersing, propylene glycol and isopropyl alcohol were used. 5-40wt% of these hydroxyl auxiliaries were homogeneously mixed with the water-soluble chitosan solution to uniformly dissolve the fat-soluble drug and without crystal precipitation in the chitosan matrix dried at a constant drying rate (11-15%). Could be contained in a dissolved state. In this case, in order not to reduce the adhesive force of the chitosan matrix improved by the adhesive component, it was preferable to use PEG series (molecular weight 400-6000) at 15 wt% or less and propylene glycol, isopropyl alcohol, etc. at 25 wt% or less. In addition, PEG series, propylene glycol and isopropyl alcohol have the ability to retain moisture, and this function is part of RH 40-50 (room temperature) for chitosan matrix dried at a constant drying rate (12-14%). Equilibrium was maintained, and the moisture content was maintained at about 110% at RH 70-90 (room temperature). These dissolution aids, which have a buffering effect on skin moisture, act as a systemic transdermal absorption agent by maintaining the release rate of the chitosan matrix with the solvent-dispersible backing layer to increase the stability of the skin moisture of the chitosan matrix. It is possible to develop.

Absorption accelerators were used to control the release rate of the drug, and hydrophilic absorption accelerators, which are easily dispersed and dissolved in aqueous chitosan polymer solution, were used within the range of not causing skin irritation below 5wt% of the matrix dry mass. In addition, stability of the skin permeation rate of the drug of the transdermal absorption preparation of the present invention and the effect of the absorption promoting agent were observed using a high fat-soluble drug such as estradiol as a comparative drug. Estradiol requires approximately 50 μg of total daily drug dose, and at least 5 μg / cm ² of drug per day is required per day to make it an appropriate sized transdermal absorbent. In the present invention, first, by using an alkali metal salt of saturated, unsaturated higher fatty acids having 16 to 18 carbon atoms, such as stearic acid, palmitic acid, oleic acid, linoleic acid, etc., as an absorption accelerator, estradiol regulates the daily release rate to 8-12 μg / cm ² . Next, estradiol daily release rate was adjusted to 8-9μg / cm ² using low molecular weight organic acid series such as lactic acid, fumaric acid and citric acid, and widely used in cosmetics such as TRUC 20-80 and Span 20-80. The daily release rate of estradiol could be reduced to 8-10 μg / cm ² by using a selected surfactant. These hydrophilic absorption accelerators satisfy all the drug penetration rates of at least 5 μg / cm ² per day, which are required to prepare an appropriate size of estradiol transdermal absorption agent. In half, it showed good results with a drug penetration rate of 8-12 μg / cm ^{2 as} a whole, and the dissolution rate per hour remained stable (see Table 1).

As the back layer film, a moisture-permeable film made of polyurethane (polyurethan) having an average molecular weight of about 100,000 was used. The degree of water swelling of the chitosan matrix changes the porosity between the polymers and this changes the elution of the drug, so that the skin moisture content is an important variable in the drug dissolution rate when applied to transdermal absorbents. In other words, excess moisture in the skin leads to swelling of the chitosan matrix, which increases the porosity of the polymer, thereby increasing the release rate of the drug. It also slows down. In the present invention, in order to control the unstable drug release rate due to moisture of chitosan, which is considered to be a problem when applying chitosan as a systemic transdermal absorption agent in the existing technology, a water-dispersible polyurethane film is used as the back layer of the transdermal absorption agent. The aim was to dissipate excess skin moisture while preventing the invasion of moisture from the outside. As the polyurethane film used herein, a film capable of releasing moisture of 15-30 μg / cm ² per area according to the relative humidity (RH 42-100) inside was used. Polyurethane film having water dissipation acts to prevent the drug dissolution rate from changing by maintaining a constant swelling degree of chitosan by releasing it when the skin moisture is excessive when the transdermal absorbent is applied. In addition, when the moisture is excessively dissipated in conjunction with the above-described moisture-soluble dissolving aid, it prevents the reduction of drug release due to the drying of the chitosan matrix and at the same time, if excess skin moisture is generated, By releasing a constant amount of water around the chitosan matrix, the drug dissolution rate of the chitosan matrix is kept constant. In the present invention, the moisture content of the dissolution aid and the moisture dissipation of the polyurethane film are used to maintain a constant water content in the transdermal absorbent, thereby maintaining the water swelling degree of the chitosan matrix having a relative humidity of RH 40-100% between 95 and 110%. The rate of release of the drug was also maintained at a mean ± 10%. In other words, given that the relative humidity of the skin is between RH 40-90%, it means the maintenance of a stable chitosan matrix in the skin moisture, through which the development of a systemic chitosan matrix transdermal absorption agent is possible.

Hereinafter, the skin-compatible chitosan transdermal absorption drug delivery system of the present invention will be described as follows.

In the present invention, after dissolving chitosan in 0.5-3wt% acetic acid aqueous solution at 1-10wt% and giving adhesiveness to chitosan itself using an adhesive aid component, 0.01-2.0wt drug with a dissolution aid corresponding to 5-40wt%. After dissolving and dissolving the drug well by mixing ethanol contained in%, the absorption accelerator was added to 5% or less of the dry mass and mixed with a homogeneous mixer. The matrix prepared by drying it on a release paper and drying at a constant drying rate (12-14%) for 4-5 hours in a 40 ° C. oven at 20% RH to maintain moisture equilibrium at 40-50% RH. Thereafter, the prepared chitosan matrix was bonded to the polyurethane back layer to prepare a chitosan matrix transdermal absorbent.

The chitosan matrix thus prepared forms a water-soluble natural polymer matrix as described above, which significantly reduces skin irritation and gives its own adhesive ability to directly attach the chitosan matrix itself to the skin. This can solve the skin irritation caused by long-term use, which was a problem of the conventional transdermal absorbents, and can maximize the benefits of chitosan by omitting the necessary adhesion when the chitosan matrix is used for transdermal absorption. In addition, the chitosan matrix type transdermal absorbent according to the present invention can maintain the matrix swelling degree by the internal moisture and keep the drug dissolution rate stable by using a solvent-dispersing polyurethane backing layer with a dissolving aid with moisture. Systemic chitosan matrix transdermal absorbents. In addition, when compared to the conventional product in the chitosan matrix transdermal absorption preparation prepared as compared to the conventional product, the drug content is rather lower than the conventional product, while the skin penetration rate of estradiol for 3 days in each case 8- It remained stable between 14 μg / cm ² , indicating high bioavailability.

And chitosan transdermal absorption type drug shear system prepared by the above method is to apply the following drugs. As a steroidal drug, derivatives thereof including estradiol, progestins and derivatives thereof, testosterone and derivatives thereof, corticosteroids and derivatives thereof, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen, pyroxicam, Auranofin, ketorolac and the like can be used. As circulatory drugs, organic nitrate drugs for treating angina and high blood pressure drugs such as clonidine, reserpine, and prazosin can be used. Other anti-smoking drugs, nicotine, narcotic drugs, fentanyl, anticancer drugs, fluoruracil, anti-immune drugs, physostigmine, antihistamine drugs, chlorpheniramine, drug addiction drugs, methadone, erection Drugs such as papaverine, a drug for treating insufficiency, can be applied as a systemic chitosan matrix transdermal absorption agent.

Although the following examples and comparative examples to the estradiol as a comparative drug look more specifically at the method and effect of the present invention, the scope of the present invention is not limited to the following examples.

(Example 1)

2 wt% of chitosan was added to 0.5 wt% acetic acid, dissolved in a homogeneous mixer for at least 4 hours, and left for one day to be filtered through a glass filter. 20 g of propylene glycol was added to the chitosan polymer as a dissolution aid and mixed, and 50 ml of ethanol containing 0.1 wt% of 17-beta-estradiol was mixed and dispersed by a homogeneous mixer for 30 minutes or more. Since the ultrasonic cleaner (ultrasonic cleaner) was used to completely remove the gas and flexible on the plate attached to the release paper. This was dried for 4 hours and 30 minutes in a 40 ° C. oven having a relative humidity of 20% to prepare a matrix having a drying rate of about 12-14%, which was bonded to the polyurethane back layer. This matrix was mounted in a Franz cell with an effective membrane area of 3.3 cm ² , maintained at 37 ° C., and filled with saline containing 0.001 wt% gentamicin and 20 wt% PEG 400 at the bottom of the mouse skin. After the skin was attached, a skin penetration test was performed. The amount of estradiol eluted from the matrix was quantified at 280 nm using HPLC.

The results are shown in Table 1.

(Example 2)

2 wt% of chitosan was added to 0.5 wt% acetic acid, dissolved in a homogeneous mixer for at least 4 hours, and left for one day to be filtered through a glass filter. To 100 g of chitosan polymer solution, 10 g of PEG 600 was added as a dissolution aid and mixed. 50 ml of ethanol containing 0.1 wt% of 17-beta-estradiol was mixed and dispersed with a homogeneous mixer for 30 minutes or more. After the gas was completely removed by using an ultrasonic cleaner, it was cast on a flat plate on which release paper was attached. This was dried for 4 hours and 30 minutes in a 40 ° C. oven having a relative humidity of 20% to prepare a matrix having a drying rate of about 12-14%, which was bonded to the polyurethane backing layer. This matrix was mounted on a Franz cell with an effective membrane area of 3.3 cm ² , maintained at 37 ° C., filled with physiological saline containing 0.001 wt% gentamycin 20 wt% PEG 400 at the bottom, and the skin of the mouse was attached. . The amount of estradiol eluted from the matrix was quantified at 280 nm using HPLC. The results are shown in Table 1.

(Example 3)

2 wt% of chitosan was added to 0.5 wt% acetic acid, dissolved in a homogeneous mixer for at least 4 hours, and left for one day to be filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of poly (vinylpyrrolidone-vinylacetate) copolymer was added for dissolution. 20 g of propylene glycol was added thereto as a dissolution aid and mixed, and 50 ml of ethanol containing 0.15 wt% of 17-beta-estradiol was mixed and dispersed by a homogeneous mixer for 30 minutes or more. After the gas was completely removed by using an ultrasonic cleaner, it was cast on a flat plate on which release paper was attached. This was dried for 4 hours and 30 minutes in a 40 ° C. oven having a relative humidity of 20% to prepare a matrix having a drying rate of about 12-14%, which was bonded to the polyurethane back layer. The dissolution test was carried out as in Example 1, and the results are shown in Table 1.

(Example 4)

2 wt% of chitosan was added to 0.5 wt% acetic acid, dissolved in a homogeneous mixer for at least 4 hours, and left for one day to be filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of polyvinylpyrrolidone was added for dissolution. 20 g of propylene glycol was added thereto as a dissolution aid and mixed, and 50 ml of ethanol containing 0.15 wt% of 17-beta-estradiol was mixed and dispersed by a homogeneous mixer for 30 minutes or more. After the gas was completely removed by using an ultrasonic cleaner, it was cast on a flat plate on which release paper was attached. This was dried for 4 hours and 30 minutes in a 40 ° C. oven having a relative humidity of 20% to prepare a matrix having a drying rate of about 12-14%, which was bonded to the polyurethane back layer. The dissolution test was conducted as in Example 1, and the results are shown in Table 1.

(Example 5)

2 wt% equivalent of 0.5 wt% acetic acid was dissolved in a homogeneous mixer for at least 4 hours, and then left for one day and filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of poly (vinylpyrrolidone-vinylacetate) copolymer was added for dissolution. Lactic acid, fumaric acid, and citric acid were added as 5 wt% of dry solids as absorption accelerators. 20 g of propylene glycol was added as a dissolution aid and mixed, and 50 ml of ethanol containing 0.15 wt% of 17-beta-estradiol was mixed and dispersed with a homogeneous mixer for at least 30 minutes. After the gas was completely removed by using an ultrasonic cleaner, it was flexible on a flat plate on which release paper was attached. This was dried for 4 hours and 30 minutes in a 40 ° C. oven having a relative humidity of 20% to prepare a matrix having a drying rate of about 12-14%, which was bonded to the polyurethane back layer. The dissolution test was conducted as in Example 1, and the results are shown in Table 1.

(Example 6)

2 wt% equivalent of 0.5 wt% acetic acid was dissolved in a homogeneous mixer for at least 4 hours, and then left for one day and filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of polyvinylpyrrolidone was added for dissolution. To this, lactic acid, fumaric acid, and citric acid were added as 5 wt% of dry solids as absorption accelerators, respectively, and a percutaneous absorption preparation was prepared in the same manner as in Example 5. The dissolution test was conducted as in Example 1, and the results are shown in Table 1.

(Example 7)

2 wt% equivalent of 0.5 wt% acetic acid was dissolved in a homogeneous mixer for at least 4 hours, and then left for one day and filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of poly (vinylpyrrolidone-vinylacetate) copolymer was added for dissolution. Herein, an alkali metal salt of oleic acid and linoleic acid was added as 5 wt% of a dry solid as an absorption accelerator, and a percutaneous absorption preparation was prepared in the same manner as in Example 5. The dissolution test was conducted as in Example 1, and the results are shown in Table 1.

(Example 8)

2 wt% equivalent of 0.5 wt% acetic acid was dissolved in a homogeneous mixer for at least 4 hours, and then left for one day and filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of polyvinylpyrrolidone was added for dissolution. Herein, an alkali metal salt of oleic acid and linoleic acid was added as 5 wt% of a dry solid as an absorption accelerator, and a percutaneous absorption preparation was prepared in the same manner as in Example 5. The dissolution test was conducted as in Example 1, and the results are shown in Table 1.

(Example 9)

2 wt% equivalent of 0.5 wt% acetic acid was dissolved in a homogeneous mixer for at least 4 hours, and then left for one day and filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of poly (vinylpyrrolidone-vinylacetate) copolymer was added for dissolution. After the addition of Span 20, Tween 20, and Tween 60 as 5 wt% of the dry form, respectively, as a water absorption accelerator, a transdermal absorbent was prepared in the same manner as in Example 5. The dissolution test was conducted as in Example 1, and the results are shown in Table 1.

(Example 10)

2 wt% equivalent of 0.5 wt% acetic acid was dissolved in a homogeneous mixer for at least 4 hours, and then left for one day and filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of polyvinylpyrrolidone was added for dissolution. After the addition of Span 20, Tween 20, and Tween 60 as 5 wt% of the dry form, respectively, as a water absorption accelerator, a transdermal absorbent was prepared in the same manner as in Example 5. The dissolution test was conducted as in Example 1, and the results are shown in Table 1.

(Comparative Example 11)

Estraderm TTS 25 was mounted in a Franz cell in the same manner as in Example 1, and the amount of estradiol permeation was determined and shown in Table 1.

(Example 11)

5 wt% equivalent of chitosan in 1.5 wt% acetic acid was dissolved in a homogeneous mixer for at least 4 hours, and left for one day and filtered through a glass filter. To 100 g of chitosan polymer liquid, 2 g of PVP was added and dissolved to increase the adhesion. Ketoprofen was added thereto to 0.1 wt% and dispersed in a homogeneous mixer. Next, the gas was completely removed using an ultrasonic cleaner, and then flexible on a flat plate on which release paper was attached. This was dried for 4 hours and 30 minutes in a 40 ° C. oven having a relative humidity of 20% to prepare a matrix having a drying rate of 12 to 15% and bonding it to a polyurethane layer to prepare a transdermal absorbent.

(Examples 12-25)

The matrix was prepared by the method of Example 11, wherein pyroximal, ketorolac, nitroglycerin, clonidine, prazosin, clenbuterol, salbutamol, mesadon, fentanyl, nicotine, pulluloururacil, papaverine, pizo A transdermal absorbent was prepared by adding 0.1 wt% of the drug selected from stigmine and chlorpheniramine maleate, respectively, and dispersing it in a homogeneous mixer, followed by the following procedure of Example 11.

(Comparative Example 1)

Estraderm TTS 25 was mounted in a Franz cell in the same manner as in Example 1, and the amount of estradiol permeation was determined and shown in Table 1.

Claims (4)

Chitosan matrix was prepared by mixing chitosan with adhesive adjuvant, and as a solvent, dissolution aid and transdermal absorption drug, steroid hormones, ketoprofen, pyricampam, ketorolac, nitroglycerin, prazosin, clenbuterol , After addition of a drug selected from salbutamol, methadone, fentanyl, nicotine, fluorouracil, pizostigmine, papaverine and chlorphenylamine maleate, alkali metal salts of saturated or unsaturated fatty acids having 16 to 18 carbon atoms, lactic acid and fumaric acid A systemically functional skin-adhesive chitosan matrix transdermal absorbent prepared by adding and mixing citric acid, spanning 20-80, and twin 20-80, and adsorbing and mixing the release paper on a flexible paper and then drying the water-dispersible backing layer thereon. The transdermal absorption preparation according to claim 1, wherein the water dispersible back layer is a polyurethane film. The transdermal absorption preparation according to claim 1, wherein the pressure sensitive adhesive component is selected from polyvinylpyrrolidone and poly (vinylpyrrolidone-vinylacetate) copolymer. The transdermal absorption preparation according to claim 1, wherein the dissolution aid is selected from propylene glycol, isopropyl alcohol and polyethylene glycol.