JPH0816055B2 - Oral patch - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to an oral patch for use in stomatitis, gingivitis, orthodontic treatment and the like.

<Prior Art> In recent years, a topical transdermal preparation utilizing transdermal absorption of a drug has been actively developed as a preparation for treating or preventing various diseases by administering a drug into a living body. Among them, development of a patch for oral mucosa for the treatment of stomatitis, gingivitis, etc., or for the correction of teeth, etc. has been developed, but as a carrier used in the formulation thereof, Conventionally, a laminated film made of plastic, paper, non-woven fabric, woven fabric, metal foil, or a combination thereof has been used.

<Problems to be Solved by the Invention> However, these carriers have some problems. It is desirable that the carrier for the oral patch satisfy the following conditions. First, since it is used in the oral cavity, it is desirable that it be edible so that there is no concern about safety even if it is accidentally swallowed. Further, since it is wet with saliva, strength and abrasion resistance under wet conditions are required. Furthermore, since it is used for mucous membranes, it is required to be flexible and flexible without any irritation or discomfort during use. For this purpose, the carrier itself is required to have a property of absorbing water to some extent. From the viewpoint of these required performances, conventionally used plastics and metal foils are not edible, have no water absorption, are hard, and have a rough feeling when used. Although paper is edible, it has the drawback of being weak against wetting. Although non-woven fabrics and cloths provide a considerable solution to these problems, they are not edible and have poor moisture absorption, which makes them uncomfortable when used.

<Means for Solving Problems> The inventors of the present invention have made various studies on new carriers that solve these problems, and as a result, contain cellulose produced by a certain kind of microorganism as a main component. It was confirmed that a sheet-like film made of a polysaccharide (hereinafter referred to as bacterial cellulose) can be an excellent carrier for an oral patch that solves the conventional problems, and completes the present invention. Came to. First, in the present invention,
Bacterial cellulose can be obtained as follows.

Microorganisms that produce bacterial cellulose belong to the genus Acetobacter, the genus Pseudomonas, the genus Agrobacterium, and the like. As an example, Acetobacter aceti subsp. Xylinum (Acetobacter aceti subsp.
xylinum) ATCC.10821.

In order to produce bacterial cellulose, microorganisms are inoculated into a normal nutrient medium containing carbon sources, nitrogen sources, inorganic salts, and if necessary, organic micronutrients such as amino acids and vitamins, and the mixture is allowed to stand or gently aerated. To do. Carbon sources include glucose, sucrose, maltose,
Hydrolyzed starch, molasses, etc. are used, other ethanol,
Acids, citric acid, etc. may be used alone or in combination with the above-mentioned other carbon sources. As the nitrogen source, ammonium salts such as ammonium sulfate, ammonium chloride and ammonium phosphate, nitrates, urea, organic or inorganic nitrogen sources such as peptone are used. As organic micronutrients, amino acids, vitamins, aliphatics, nucleic acids, and peptone, casamino acid, yeast extract, soybean protein hydrolyzate containing these substances are used.
When using an auxotrophic mutant that requires amino acids or the like for growth, it is necessary to supplement the required nutrients. Phosphates, magnesium salts, calcium salts, iron salts, manganese salts and the like are used as the inorganic salts.

Cultivation may be carried out under ordinary culture conditions. The pH of the culture solution is controlled to 5 to 9 and the temperature is controlled to 20 to 40 ° C for 1 to 7 days until a predetermined thickness is reached, whereby microbial cellulose is added to the surface layer of the culture solution. Is produced.

The obtained bacterial cellulose has a width of 100-500Å and a thickness of
It has a structure in which ribbon-shaped microfibrils of about 10 to 200Å are entangled with each other, and it is in a gel state containing a large amount of water of 95% or more.

To obtain a sheet-like film from this, gel-like bacterial cellulose having a predetermined thickness is thoroughly washed, then dehydrated by pressing with a pressing machine and dried by heating. Depending on the case, it is also possible to disintegrate this gel-like bacterial cellulose and mix it with 50% or less of fibrous substances such as cellulose obtained by that method or other methods to make paper and process it into a sheet-like film. Is. When the ratio of bacterial cellulose is small, the strength is low and the performance as a carrier is low. The thickness of the film used is 1 to 1,000 μm, but the preferred thickness is 5 to 500 μm.

The sheet-like film thus obtained has excellent properties as compared with the conventional carrier. That is, bacterial cellulose is edible because it has been provided to food, and has a structure in which extremely fine microfibrils are tightly entangled with each other, as compared with ordinary cellulose, and therefore strong strength and resistance even in a wet state. Maintains wear resistance. In addition, it has an excellent ability to absorb water, swells when saliva is absorbed, and is highly flexible, so that it does not damage the oral mucosa and gives little discomfort when applied. In order to prepare an oral patch using the carrier obtained by the present invention, a generally-used patch manufacturing method can be adopted. For example, a method of applying a plaster composition containing a percutaneously absorbable drug to the carrier, drying it, and then applying a pressure-sensitive adhesive, or mixing the plaster composition and the pressure-sensitive adhesive in advance. It is also possible to apply and dry the composition described above, or to apply the plaster composition and the adhesive to a release sheet in advance and then dry and then transfer the composition to the carrier.

Examples of the transdermal drug that can be used in the present invention include the following.

Stomatitis, toothache, indomethacin, voltaren,
Cephalexin, tetracycline hydrochloride, oxytetracycline hydrochloride, fradiomycin, α-amylase, etc. for gingivitis such as diphenyldioxopyrrolidine, epidihydrocholesterin, aspirin, xylocaine
Chloramphenicol, etc. for local anesthesia, procaine hydrochloride, tetracaine hydrochloride, dibucaine hydrochloride, mepivacaine hydrochloride, etc., prostaglandin F ₂ for orthodontics
Examples include α and vitamin D derivatives. Furthermore, drugs for heart disease, neuropsychiatric disease, respiratory disease, etc. are also applied.

Although it is possible to apply these agents alone as a plaster layer, generally, a composition prepared by kneading as an agent with an auxiliary agent such as an excipient and a dissolution aid is used as the plaster layer. . Examples of adjuvants include olive oil, isopropyl myristate, liquid paraffin, purified water, solubilizers such as polyethylene glycol, humectants such as glycerin, sorbitol, and pyrrolidone carboxylate, thickeners such as carboxymethylcellulose, zinc. Representative examples include excipients such as flower, gluten, and agar, pH adjusting agents such as sodium carbonate, surfactants such as cholate, saponin, polyhydric alcohol ester, N-acyl amino acid salt, and dodecylpyrrolidone. Examples include transdermal absorption enhancers. The blending ratio of these is determined by the type and effect of the drug.

The pressure-sensitive adhesive is adopted after considering the release of the drug, the adhesive with the mucous membrane in the presence of water, safety, etc.
Generally, polyacrylic acid type substances, polyvinyl acetate,
Vinyl-based polymeric substances such as partial hydrolysates, rubber-based substances, cellulose derivatives such as methylcellulose, polysaccharides such as agar, proteins such as gelatin, and polyamino acids are used.

<Effects of the Invention> The thus obtained oral patch has good adhesion to the mucous membrane, and the carrier absorbs and swells water appropriately by saliva, so that the entire patch becomes soft and It had a cushioning effect between the teeth and the mucous membranes, did not damage the mucous membranes, had excellent adhesiveness during use, and almost no discomfort was observed. Further, even when it was wet, it retained strong strength and abrasion resistance and did not shake at all.

<Examples> Examples of the present invention will be shown below, and will be described more specifically.

Example 1 Preparation example of bacterial cellulose carrier Sucrose 5 g / dl, yeast extract 0.5 g / dl, ammonium sulfate 0.5 g / dl,
Potassium hydrogen phosphate _{(KH 2 PO 4) 0.3g /} dl, magnesium sulfate (MgSO ₄ 7H ₂ O) medium composition consisting of 0.05g / dl (pH5.0)
50 ml was put in a petri dish and steam sterilized at 120 ° C. for 20 minutes to prepare a culture solution.

Then, to this culture solution, yeast extract 0.5 g / dl, peptone
Acetobacter aceti subspice xylinum (ATCC 1) grown in a test tube slant agar (pH 6.0) composed of 0.3 g / dl and mannitol 2.5 g / dl for 3 days at 30 ℃
0821) was inoculated in 1 platinum loop each and cultured at 30 ° C. By culturing for 4 days, a white gel-like bacterial cellulose film having a thickness of about 3 mm was formed on the upper layer of the culture solution. After washing this membrane with a 2% aqueous sodium hydroxide solution, thoroughly washing it with water, and then pressing it (20-30 kg / cm ² ) with a cloth press or a wire mesh of about 200 mesh with a scissor press to dehydrate it. did. Then, by pressing at 150 ° C. for 5 minutes at 5 kg / cm ² , a dry sheet-like film having a thickness of about 30 μm was obtained. The strength of this film was as follows.

Tensile strength 22 kg / mm ² (21 kg / mm ² ) Tensile modulus 1600 kg / mm ² (400 kg / mm ² ) (): Reference product Polyester film Example 2 Preparation example of blended film 200 ml under the culture conditions of Example 1 30 in Erlenmeyer flask
By culturing for a day, gel-like bacterial cellulose with a thickness of 1 cm or more was obtained. This was sterilized by heating at 120 ° C. for 20 minutes and then washed with a 2% sodium hydroxide solution and water for purification. Next, this purified gel was disintegrated with about 4 times the amount of water using a disintegrator at a stirring speed of 3000 rpm for 30 minutes. 40% by weight of cotton linter pulp disintegration liquid was added to this disintegrated material to obtain a carrier having a thickness of about 100 μm using a rectangular paper machine.

Example 3 Patch for stomatitis (paste composition) parts by weight Voltaren 1 indomethacin 1 agar 10 polyvinyl alcohol 10 polyethylene glycol (# 400) 15 glycerin 5 purified water 50 sodium cholate 1 (pressure-sensitive adhesive) parts by weight Sodium polyacrylate (▲ ▼ = 18,000) 40 Polyacrylamide 40 Purified water 40 plaster The composition obtained by kneading each component was used in Example 1
It was spread to a thickness of about 100 μm on the carrier prepared in (1) and naturally dried. Thereafter, the pressure-sensitive adhesive composition obtained by kneading in advance was spread to a thickness of about 5 μm and naturally dried.

The thus obtained patch for stomatitis absorbs water moderately when the drug surface is applied to the affected part, and is rich in flexibility,
He followed the movement of the affected area well and felt no discomfort. Moreover, there was no shake at all.

Example 4 Orthodontic patch (paste composition) parts by weight prostaglandin F ₂ α 0.1 polyvinyl acetate 20 agar 7 polyvinyl alcohol 7 polyvinylpyrrolidone 2 purified water 200 karaya gum 23 CMC sodium 7 gluten 10 polyethylene glycol ( # 400) 13 sorbitol (70% aqueous solution) 7 sodium carbonate 5 The above paste composition obtained by kneading was applied to the carrier prepared in Example 1 to a thickness of about 500 μm, and dried at 40 ° C. . As a result of sticking the drug surface to the gingiva of the obtained oral patch, as compared with the conventional patch, the feeling of close contact with the gingiva is good, the flexibility is good, and the cushioning effect between the oral mucosa is provided,
He did not heal the mucous membranes.

Example 5 Patch for Gingivitis (Plastic Composition) Parts by Weight Cephalexin 16 Cellulose Acetate Phthalate 20 Hydroxypropyl Cellulose 50 Carboxymethyl Cellulose 30 Glycerin 60 Gelatin 40 Purified Water 100 The above plaster composition obtained by kneading was carried out. The carrier prepared in Example 2 and having a thickness of about 100 μm was coated to a thickness of about 500 μm.
After drying at ℃, the intended oral patch was obtained. As a result of sticking the drug surface of this product to the affected area, the carrier absorbs water moderately, is flexible, and has a good feeling in use. or,
Maintained sufficient durability without loosening when attached.

Claims (1)

[Claims] 1. A sheet comprising a carrier and a plaster layer containing a percutaneously absorbable drug, the main component of which is bacterial cellulose in a gel state obtained by a fermentation method as a carrier, which is dehydrated and dried. A patch for oral cavity, characterized by using bacterial cellulose in the form of a film.