JP2006335754A - Thin film carrying percutaneous absorption preparation and its manufacturing process - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a biocompatible thin film carrying a percutaneous absorption preparation which very efficiently transfers the percutaneous absorption preparation to the inside of the skin, manifests the dosage effect in a relatively short period of time and greatly reduces the pain experienced in dosage as compared to the conventional methods of dosage such as injections and infusions. <P>SOLUTION: The biocompatible thin film carrying a percutaneous absorption preparation is intended to administer percutaneous absorption preparation 1 in the skin 3 by a means of micro-needles 4 by making it carried on biocompatible thin film 2a and applying the thin film on the skin 3. The manufacturing process comprises a step to form a gel thin film 2b by applying a gel polymer consisting of a biocompatible polymer on hydrophobic release film 6 by adding percutaneous absorption preparation 1 to and making it carried on gel thin film 2b, a step to dry the gel thin film 2b and a step to release film 6. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to a transdermal drug-carrying thin film represented by pharmaceuticals and cosmetics and a method for producing the same.

The skin has the structure of the epidermis, dermis, and subcutaneous tissue from the outermost side.Especially, the epidermis is covered with a membrane made of protein keratin and dead cells called the stratum corneum, which becomes the barrier and the drug is inside It is difficult to penetrate.

In order to break this barrier, usually the surface barrier is chemically destroyed by a drug applied to the adhesive base material, such as a poultice or salve, and the drug applied to the adhesive surface is infiltrated into the skin. . With respect to such a transdermal therapeutic system (TTS), various methods for efficiently absorbing a drug have been proposed.

Patent Document 1 eliminates the occurrence of rash caused by irritation and the like on the skin surface for a long period of time, and modifies the molecular structure of the binder substance added to maintain the skin adhesive strength during application. It is proposed to keep hypoallergenicity and skin adhesion.

Moreover, in patent document 2, the adhesive material is gelatinized and made low irritation | stimulation by making an acrylic adhesive material layer contain an oily liquid component with high compatibility.

As another example of TTS, in Patent Document 3, in order to promote absorption, it can be used for a percutaneous absorption promotion system (electrophoresis) using electrophoresis or a percutaneous absorption system (sonophoresis) using ultrasound. Shows the drug coating technology.
JP-A-3-223212 JP-A-8-81369 Japanese Patent Laid-Open No. 9-77658

However, since the percutaneous absorption agents such as Patent Documents 1, 2, and 3 are used by being attached to the skin surface, there is a risk of inflammation. In addition, it takes a long time to penetrate into the skin, and there is a problem that the addition of a binder substance causes pain when peeling from the skin.

It is necessary to maintain the balance between skin adhesiveness (adhesion) and skin irritation, and to improve the translocation and transdermal absorbability of the contained drug, and satisfy all these points. Developing the formulation is also the ultimate challenge in the future, but this task has not yet been achieved in the current TTS.

In addition, the method of physically transporting drugs using electrophoresis or ultrasound described in Patent Document 3 requires a device other than the product drug in order to emit electricity or ultrasound for administration.

Therefore, in order to solve the above-mentioned problems, the present inventors do not adopt a method of applying a conventional patch to the skin and destroying the stratum corneum in the entire applied surface to absorb the transdermal administration agent. A transdermal drug-carrying thin film for directly administering a transdermal drug into the skin and a method for producing the same are provided.

In the present invention, a transdermal administration agent is carried on a biocompatible thin film, the thin film is attached to the skin, and the transdermal administration agent carried on the thin film is administered into the skin by a transfer means such as a needle-like projection. It is an object of the present invention to provide a transdermal drug-carrying thin film intended for this purpose.

The material of the thin film is polysaccharides such as chitosan, hyaluronic acid, chondroitin sulfate, alginic acid, proteins / peptides such as fibroin, collagen, albumin, casein, gluten, gelatin, polyethylene glycol. It consists of 1 type selected from high molecular groups, such as a polyethylene oxide, polylactic acid, and polybutyric acid, or a mixture of 2 or more types.

The form of the transdermal administration agent is a crystal particle or amorphous solid particle of 10 nm to 500 μm or a composite particle of the transdermal administration agent and an excipient.

The transdermal administration agent is encapsulated in microcapsules of 1 mm or less.

The method for producing a transdermal drug-carrying thin film includes a step of adding a gel polymer comprising a biocompatible polymer on a hydrophobic release film to form a gel thin film, and transdermally administering the gel thin film. A step of adding and supporting an agent, a step of drying the gel-like polymer thin film, and a step of peeling the release film.

The method for producing a transdermal drug-carrying thin film includes a step of adding a gel-like polymer comprising a biocompatible polymer on a hydrophobic release film to form a gel-like thin film, and drying the gel-like polymer thin film. A step of depositing a solution obtained by adding a transdermal agent to a diluted gel polymer on the dried polymer thin film, a step of drying the polymer thin film, and a step of peeling the release film Including.

Moreover, the transdermal administration agent used in the production method is preferably nanoparticles.

Moreover, the method of encapsulating the said transdermal administration agent in a microcapsule and carrying it on a thin film can be taken.

According to the biocompatible transdermal drug-carrying thin film according to the present invention, the transdermal drug can be transferred into the skin very efficiently, and the administration effect can be obtained in a relatively short time. Furthermore, pain at the time of administration is drastically reduced compared to conventional methods such as injection and infusion, allergy concerns such as other patch materials are reduced, and it can be manufactured and used by a very simple method. it can.

This is also epoch-making as a method of using instruments such as microneedles. Conventional microneedles, etc. must be used for blood collection in diagnosis and when used for transdermal administration, microneedles with special measures such as hollowing out must be used. .

By using the method proposed by the present invention, it is possible to administer any transdermal agent into a living body without changing the manufacturing method of an existing microneedle having no cavity or the like. This is a more innovative method.

Based on FIGS. 1 to 9 and Table 1, the transdermal drug-carrying thin film and the method for producing the same according to the present invention will be described.

As shown in FIG. 1 and FIG. 2, the transdermal drug-carrying thin film is made by carrying the transdermal drug 1 on a biocompatible thin film 2a and attaching the thin film 2a to the skin 3 of an animal including a human. It is intended to administer the transdermal administration agent carried on the skin 3 or under the skin 3 by a transfer means such as a microneedle 4.

The material of the thin film 2a is polysaccharides such as chitosan, hyaluronic acid, chondroitin sulfate, alginic acid, proteins and peptides such as fibroin, collagen, albumin, casein, gluten, gelatin, polyethylene glycol, polyethylene oxide, polylactic acid, polybutyric acid It consists of 1 type selected from polymer groups, such as these, or a mixture of 2 or more types.

The form of the transdermal administration agent 1 is a crystalline particle or amorphous solid particle of 10 nm to 500 μm, a composite particle of a transdermal administration agent and an excipient, or a microcapsule of 1 mm or less containing the transdermal administration agent.

3 to 5 show the method for producing the transdermal drug-carrying thin film.

As shown in FIG. 3, a release film 6 is laid on the inner bottom surface of the container 5, and a gel-like polymer made of a biocompatible polymer is added to the upper surface of the release film 6 to form a gel-like thin film 2b. The poorly water-soluble transdermal preparation 1 is uniformly added to the upper surface of the gel-like thin film 2b.

As shown in FIG. 4, the transdermal administration agent 1 settles in the gel-like thin film 2 b with time and settles on the release film 6. A part of the transdermal administration agent 1 exists in the layer of the gel-like thin film 2b, and the other part is exposed from the lower surface of the gel-like thin film 2b and contacts the release film 6.

As shown in FIG. 5, the gel-like polymer thin film 2b is dried and solidified, and after the drying and solidification, the release film 6 is peeled to produce a transdermal agent-supporting thin film.

Since the polymer thin film 2a is hygroscopic and easily bends when contacted with water, it is inappropriate to apply glue to the polymer thin film 2a. Therefore, separate addition methods are used for the slightly water-soluble transdermal agent and the water-soluble transdermal agent.

In the case of adding a water-soluble transdermal agent, a gel-like polymer 2b is formed on the hydrophobic release film 6 to form a gel-like thin film 2b, and the gel-like polymer thin film 2b is added. Dry. On the other hand, a solution obtained by adding a water-soluble transdermal agent to a diluted gel polymer is deposited on the dried polymer thin film 2a, the polymer thin film is dried again, and the release film 6 is peeled off. The transdermal drug-carrying thin film is manufactured by the method.

As a preferred example, a nanoparticle transdermal administration agent 1 is prepared on the gel-like polymer thin film 2a having biocompatibility by a pulse laser deposition method, a sputtering method, or the like and added thereto. At this time, it does not matter whether the transdermal preparation is water-soluble.

As another example, a microcapsule in which the transdermal administration agent 1 is encapsulated by the coacervation method or the like in the polymer having the same or similar properties as the biocompatible thin film 2a is prepared and added.

A method for transdermal administration of the transdermal drug-carrying thin film will be described with reference to FIGS.

As shown in FIG. 1, a transdermal drug-carrying thin film carrying a transdermal drug 1 on a biocompatible polymer thin film 2a is applied to the surface of the skin 3 so that the transdermal drug 1 directly contacts the skin. As shown in FIG. 2, the transdermal administration agent 1 is absorbed into the living body by being pushed into the skin 3 or under the skin 3 by the transfer means represented by the microneedle 4 as shown in FIG. 2.

The transdermal administration agent 1 is carried in an embedded state in the base material layer of the thin film 2a. In this case, one surface or the other surface of the thin film is attached to the surface of the skin 3.

Alternatively, a part of the transdermal administration agent 1 is carried in an embedded state in the base material layer of the thin film 2a and the other part is carried in an exposed state from the surface of the thin film 2a by the manufacturing method. Further, the transdermal administration agent 1 is layered on the surface of the thin film 2a and carried. In this case, the transdermal administration agent 1 exposed on one surface of the thin film is attached so as to contact the surface of the skin 3.

The distance from the outer surface of the human epidermis to the active dermis is about 200 μm, while the radius of curvature of the protrusion tip represented by the microneedle 4 used for administration is 10 μm or less, more preferably 2 to 3 μm, the diameter of the main body Is 10 to 500 μm, more preferably 50 to 300 μm, and the length is 50 μm to 2 mm, more preferably 200 μm to 1 mm. The microneedle 4 pierces the thin film and pierces the skin 3 or below the skin 3, whereby the transdermal administration agent 1 carried on the thin film 2a moves into the skin 3 or under the skin 3 and is absorbed into the body. The A plurality of the microneedles 4 are used at a time to efficiently transfer the transdermal administration agent 1.

When the transdermal administration agent 1 is in a liquid state, the microcapsules enclosing the transdermal administration agent 1 are broken and released by the transfer means such as the microneedle 4 and are applied to the tip of the projection as in the case of the solid drug. The attached drug penetrates into the skin and is absorbed by the body.

This method of administration does not use chemical substances (such as adhesives) that stimulate the epidermal cells when attaching the thin film to the skin. For this reason, it has low irritation to the skin, and has appropriate adhesion to the skin surface due to the properties of the biocompatible thin film 2b. Furthermore, the transdermal administration agent 1 is directly transported into the skin by the transfer means, which is very efficient. Furthermore, the conventional patch can be obtained by changing the length of the microneedle 4 and the concentration of the transdermal administration agent 1. In addition, the release property and transdermal property of the transdermal administration agent can be easily and widely controlled.

A release film 6 made of hydrophobic polyethylene, laminated paper, silicone, or the like is laid on the inner bottom surface of the container 5, and a 0.5% by weight aqueous solution of chitosan as a film raw material and 1.25% by weight of polyethylene glycol are formed on the release film 6. A 1: 1 mixture of aqueous solutions in volume ratio was supplied to prepare a gel polymer thin film. On the gel-like polymer thin film 2b as a base material, 6.2 mg of poorly water-soluble transdermal drug 1 is sprayed per 1 cm ² (FIG. 4), and the poorly water-soluble transdermal drug 1 is precipitated on the inner surface of the thin film ( 5), followed by drying at 50 ° C. for 24 hours to obtain a slightly water-soluble transdermal drug-carrying thin film (FIG. 6). FIG. 6 shows an electron micrograph showing that the slightly water-soluble transdermal administration agent 1 is deposited on the chitosan / polyethylene glycol composite thin film 2a which is a thin film substrate. FIG. 7 shows an electron micrograph of the cross section of the slightly water-soluble transdermal drug-carrying thin film 6.

A release film 6 made of hydrophobic polyethylene, laminated paper, silicone, or the like is laid on the inner bottom surface of the container 5, and a 0.5% by weight aqueous solution of chitosan as a film raw material and 1.25% by weight of polyethylene glycol are formed on the release film 6. A 1: 1 mixture by volume of the aqueous solution was supplied to prepare a gel polymer thin film 2b. The gel-like polymer thin film 2b was dried for 24 hours in 50 ° C. dry air in a dryer and solidified. After solidification, an aqueous solution obtained by dissolving a water-soluble transdermal drug ascorbic acid powder in a chitosan-polyethylene glycol aqueous solution obtained by diluting the gel polymer raw material twice with water was deposited on the surface of the dry polymer thin film. This was dried again at 50 ° C. for 24 hours to obtain an ascorbic acid-carrying thin film. An electron micrograph of the state in which the water-soluble transdermal administration agent 1 is supported on the chitosan / polyethylene glycol base 2a is shown in FIG. A cross section of the ascorbic acid-carrying thin film is shown in FIG. After solidification, the release film 6 was peeled off.

The prepared transdermal drug-carrying thin film was tapped several times from the back, and the amount of adhesion per unit area was measured from the difference between the mass of the transdermal drug dropped and the mass of the transdermal drug mixed (50 mg). Table 1 shows the measurement results.
In both poorly water-soluble and water-soluble, the transdermal drug did not fall off when tapping. As is also observed in FIGS. 6 and 8, the additive transdermal administration agent 1 is firmly fixed to the polymer thin film 2a. Therefore, the amount of adhesion is equal to the amount initially added, and the amount of the transdermal agent can be easily finely adjusted.

It is sectional drawing which showed a mode that the thin film by which the transdermal administration agent 1 was carry | supported in the polymer thin film 2a was attached on the skin surface 3. FIG. The thin film is pierced from the top of the transdermal drug-carrying thin film of FIG. 1 with the microneedles 4 into the skin 3 or below the skin 3, whereby the transdermal drug 1 carried on the thin film 2 a is within the skin 3 or 3 is a cross-sectional view showing a state of moving downward. It is sectional drawing of the moment which added the slightly water-soluble transdermal administration agent 1 in the gel-like polymer thin film 2b. FIG. 5 is a cross-sectional view of the state in which FIG. 4 is left standing for a while and the poorly water-soluble transdermal administration agent 1 is precipitated on the inner surface of the thin film. It is sectional drawing of the poorly water-soluble transdermal agent carrying | support thin film obtained by drying and solidifying FIG. It is a 500,000 times electron micrograph of the surface of the thin film 7 carrying a hardly water-soluble transdermal agent. The length of the scale bar is 50 μm. It is an electron micrograph of 50,000 times the cross section of the thin film 7 carrying a hardly water-soluble transdermal drug delivery agent. The length of the scale bar is 500 μm. Arrows indicate cross sections. It is a 1.7 million times electron micrograph of the ascorbic acid carrying thin film 8 surface. The length of the scale bar is 20 μm. It is an electron micrograph of 140,000 times the cross section of the ascorbic acid carrying thin film 8. The length of the scale bar is 200 μm. Arrows indicate cross sections.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Transdermal administration agent 2a ... Polymer thin film 2b which has biocompatibility ... Gel-like polymer thin film 3 which has biocompatibility ... Skin 4 ... Microneedle 5 ... Container 6 ... Release film 7 ... Slightly water-soluble transdermal administration Agent-carrying thin film 8 ... ascorbic acid-carrying thin film

Claims (8)

  A transdermal administration agent for carrying a transdermal administration agent on a biocompatible thin film, attaching the thin film to the skin, and administering the transdermal administration agent carried on the thin film into the skin by a transfer means Supporting thin film.   The material of the thin film is polysaccharides such as chitosan, hyaluronic acid, chondroitin sulfate, alginic acid, proteins / peptides such as fibroin, collagen, albumin, casein, gluten, gelatin, polyethylene glycol, polyethylene oxide, polylactic acid, polybutyric acid, etc. The transdermal drug-carrying thin film according to claim 1, comprising one or a mixture of two or more selected from the group of polymers.   The transdermal administration agent-supported thin film according to claim 1, wherein the transdermal administration agent is a crystal particle or amorphous solid particle of 10 nm to 500 µm, or a composite particle of a transdermal administration agent and an excipient.   The transdermal drug-carrying thin film according to claim 1 or 3, wherein the transdermal drug is encapsulated in a microcapsule of 1 mm or less.   Adding a gel-like polymer composed of a biocompatible polymer on a hydrophobic release film to form a gel-like thin film; adding a transdermal administration agent to the gel-like thin film; The method for producing a transdermal drug-carrying thin film according to claim 1, comprising a step of drying the polymer thin film and a step of peeling the release film.   A step of adding a gel-like polymer composed of a biocompatible polymer on a hydrophobic release film to form a gel-like thin film, a step of drying the gel-like polymer thin film, and a step of passing through the diluted gel-like polymer. The transdermal administration agent according to claim 1, comprising a step of depositing a solution added with a skin administration agent on the dried polymer thin film, a step of drying the polymer thin film, and a step of peeling the release film. A method for producing a supported thin film.   The method for producing a transdermal drug-carrying thin film according to claim 5 or 6, wherein the transdermal drug is nanoparticles.   The method for producing a transdermal agent-supporting thin film according to claim 5 or 6, wherein the transdermal agent is a transdermal agent encapsulated in microcapsules.

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