JP2879695B2 - Oral mucosa-adhesive film preparation - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a mucoadhesive film preparation, and more particularly, to a film having a mucoadhesive layer comprising a base prepared by mixing a gum substance with a water-soluble cellulose derivative. Formulation.

The film preparation of the present invention is suitable as a preparation which is stuck to the oral mucosa and transdermally absorbs the drug.

[Conventional technology]

Ointments have been frequently used as mucosal preparations. In recent years, various oral mucosal preparations have been proposed as oral mucosal preparations. For example, a formulation in which a mixture of a base of a mucoadhesive substance and a drug is integrally molded,
These are disclosed in JP-B-58-7605, JP-A-59-067218, JP-A-59-186913, and the like. Further, a film preparation having a two-layer structure of a drug-containing mucoadhesive layer based on sodium carboxymethylcellulose and a non-mucoadhesive poorly water-soluble layer is disclosed in Japanese Patent Application Laid-Open No. 58-079916. I have.

[Problems to be solved by the invention]

When a commonly used ointment type mucosal preparation is applied to the oral cavity, the drug is easily swallowed by the movement of the oral mucosa and the tongue, and it is not possible to expect long-lasting efficacy.

In a formulation in which a mixture of a mucoadhesive substance and a drug is integrally molded, the front and back surfaces of the formulation have mucoadhesive properties, so that the formulation may adhere to the finger when applied to an affected area in a narrow space such as the oral cavity. In addition, the preparation may transfer to the mucous membrane other than the affected area even after the adhesion.

Further, in a preparation having a two-layer structure of a mucoadhesive layer and a non-adhesive layer, the disadvantage of the single-layer preparation is improved,
When the base of the mucoadhesive layer is sodium carboxymethylcellulose, the adhesive force to the oral mucosa is insufficient, and it is impossible to prevent the preparation from falling off, exfoliating, or shifting from the affected area.

An object of the present invention is to provide a film preparation having excellent adhesion to the oral mucosa.

[Means for solving the problem]

The present inventors have conducted intensive studies to achieve the above object, and as a result, by using a mixture of a water-soluble cellulose derivative and a gum substance as a base of the mucoadhesive layer, the mucoadhesiveness of the preparation was significantly improved. That is, the present invention has been completed.

The present invention relates to a mucoadhesive layer containing a drug based on a mixture of a water-soluble cellulose derivative and a gum substance, and a non-mucoadhesive layer containing a water-soluble polymer as a base and containing a poorly water-soluble agent. An oral mucosa-adhesive film preparation having a laminated two-layer structure.

The oral mucosa-adhesive film preparation of the present invention has a total thickness in which one side of the film is oral mucosa-adhesive, and is drug-releasing, and the other side is non-adhesive to each site in the oral cavity. Is a film preparation having a two-layer structure of 1 mm or less.

In the present invention, the water-soluble cellulose derivative used as a base for both the mucoadhesive layer and the non-mucoadhesive layer is a water-soluble cellulose derivative having a film-forming property that is harmless to humans and animals. These water-soluble cellulose derivatives include, for example, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose, carboxymethylcellulose, and salts thereof registered with the Japanese Pharmacopoeia.
These are used singly or as a mixture of two or more, and in particular, a mixed system of HPC and HPMC is preferably used since it is excellent in forming a flexible film.

The gum substance used in combination with the water-soluble cellulose derivative as a base for the mucoadhesive layer is a component for improving the mucoadhesive property on the surface of the drug-containing layer, and is, for example, a water-soluble gum such as karaya gum, pectin, tragacanth gum, and guar gum. Natural polysaccharides are used. Among them, karaya gum is preferably used in a mixed system of a water-soluble cellulose derivative and HPC and HPMC.

The amount of the gum substance as the base of the mucoadhesive layer is 5 to 50 parts by weight, preferably 10 to 35 parts by weight, per 100 parts by weight of the water-soluble cellulose derivative (mucoadhesive layer).

Drugs to be incorporated in the mucoadhesive layer can be dissolved or dispersed in a water-soluble cellulose derivative used as a base, and are suitable for curing systemic or local diseases by mucosal absorption, preventive drugs, animal drugs In particular, a drug that is expected to increase the healing effect by sustained release is preferable.

These drugs include, for example, prednisone, prednisolone, prednisolone acetate, hydrocortisone,
Anti-inflammatory steroids such as triamcinolone, dexamethasone and betamethasone; Inflammatory enzymes such as α-chymotrypsin, histamine drugs such as diphenhydramine hydrochloride and chlorpheniramine maleate, oral bactericides such as chlorhexidine hydrochloride, cetylpyridinium chloride, hexylresorcin, nitrofurazone, penicillin and its derivatives, cephalosporin derivatives, erythromycin , Tetracycline hydrochloride, fradiomycin,
Antibiotics such as leucomycin, chemotherapeutics such as sulfamethizole and nalidisic acid, cardiotonic drugs such as digitalis and digoxin, vasodilators such as nitroglycerin and hapaverine hydrochloride, local anesthetics such as lidocaine and procaine hydrochloride,
Antitussive and antitussive agents such as codeine phosphate and bisorbon, drugs for digestive organs such as azulene, phenovaline, pepsin, and vitamin U; enzymes such as lysozyme chloride and trypsin; hypoglycemic agents such as insulin; and other hypotensive and sedative drugs , Hemostatics, sex hormones, antineoplastic drugs and the like.

The poorly water-solubilizing agent blended in the mucosal non-adhesive layer is a component for making the water-soluble cellulose derivative used for the base non-adherent to the mucous membrane, and is water-insoluble having a compatibility with the water-soluble cellulose derivative. Is a substance. As a poorly water-soluble agent,
Examples thereof include higher fatty acids such as shellac, stearic acid, and palmitic acid, and poorly water-soluble cellulose derivatives such as ethyl cellulose and cellulose acetate butyrate, which are registered in the Japanese Pharmacopoeia. In particular, ethyl cellulose excellent in compatibility with the water-soluble cellulose derivative is preferably used.

The compounding amount of the poor water-solubilizing agent is 5 to 40 parts by weight, preferably 10 to 25 parts by weight based on 100 parts by weight of the water-soluble cellulose derivative (non-mucoadhesive layer).

In addition to the above-mentioned components, a plasticizer, a bulking agent, a flavoring agent, a coloring agent, and the like can be added to both the mucoadhesive layer and the non-mucoadhesive layer of the film preparation of the present invention.

The plasticizer is blended for the purpose of adjusting the flexibility of the film. Examples of the plasticizer include active hydrogen containing polyethylene glycol (macrogol), (poly) propylene glycol, glycerin, ethylene oxide-propylene oxide copolymer, spun fatty acid, lauric acid, sucrose, sorbitol, glycerin, pentaerythritol and the like. A compound obtained by adding ethylene oxide or propylene oxide to a compound is used. When the water-soluble cellulose derivative is a mixed system of the HPC and HPMC, the use of macrogol is preferred.

As the bulking agent, excipients generally used for tablets such as avicel, mannitol, lactose, sorbitol, textulin, starch, anhydrous calcium phosphate, amylose and the like are used.

As the flavoring, citric acid, tartaric acid, fumaric acid and other organic acids that impart sourness, sweeteners such as saccharin and glycyrrhizic acid, and menthol are used.

A natural or synthetic flavor is used as a flavoring agent, and a coloring agent such as an edible lake pigment that is commonly used in tablets is used as a coloring agent.

The method for producing the mucoadhesive film preparation of the present invention is not particularly limited, as long as it is a method capable of forming a two-layer structure by laminating a mucoadhesive layer and a non-mucoadhesive layer. The following wet method is preferably adopted as a method for producing a preparation having a rich and uniform thickness.

First, for forming a mucoadhesive layer, a uniform solution or dispersion of a water-soluble cellulose derivative, a gum substance, a drug, and optional additives is prepared.

In addition, a uniform solution or dispersion of a water-soluble cellulose derivative, a poor water-solubilizing agent, and additives to be added as desired is prepared for forming a mucosal non-adhesive layer.

In preparing these solutions or dispersions, one kind of water, methanol, ethanol, isopropanol, acetone, methylene chloride, cellosolve, etc., a mixed solvent of two or more kinds or an aqueous solution thereof can be used, and the solvent is volatilized and removed. It is preferable to use water, ethanol, or a mixed solution of water and ethanol in consideration of the properties and the toxicity of the remaining solvent.

Then, either one of the prepared liquid for forming a mucoadhesive layer or the liquid for forming a mucosal non-adhesive layer is cast in a film-forming mold, and the solvent is dried and removed to form a film. One of the liquids is cast and laminated on the formed film, and the solvent is removed by drying.

As the mold for forming a film, one appropriately designed in consideration of the size, thickness and the like of the film agent formed in one operation is used. In addition, a Teflon-coated plate is preferably used as a mold material in view of the releasability of the cast film.

It is preferable to gradually remove the solvent by drying.
Use the air drying method. The rapid forced drying off of the solvent
It is not preferable because defects easily occur in the film.

Further, the formed film having a two-layer structure is peeled from the mold, and punched into a desired shape and size to obtain a preparation.

The total thickness of the film preparation of the present invention is preferably a thickness that does not give a foreign body feeling when the preparation is applied to the oral cavity, and is usually 1 mm or less. The thickness of the mucosal non-adhesive layer of the film preparation is preferably smaller as long as the non-adhesion to the mucosa on one side of the preparation can be maintained.
~ 0.2mm is adopted.

Alternatively, a method of forming a film by spraying the liquids for forming both layers sequentially on a release plate may be adopted.

[Action]

The oral mucoadhesive film preparation of the present invention has a mucoadhesive on one side of the preparation and a non-mucoadhesive on the other side, and is prepared by mixing a gum substance with a water-soluble cellulose derivative as a base of the mucoadhesive layer. It is characterized by the following.

Cellulose derivatives are bases having excellent sustained release properties, which absorb water, swell and gel, and release the drug incorporated therein over a long period of time. However, although the film of the water-soluble cellulose derivative containing no gum substance also exhibits adhesiveness to mucous membranes, as described above, the adhesiveness to the mucous membrane is insufficient, and in the present invention, the water-soluble cellulose derivative is water-soluble. By forming a film of a base material obtained by mixing a gum substance with a cellulose derivative, its adhesion to mucous membranes is improved. As a result, the sustained release of the cellulose derivative can be effectively used. As the water-soluble cellulose derivative, a mixed system of HPC and HPMC having excellent drug release properties is preferably used, and karaya gum having a large mucoadhesive effect is preferably mixed with this mixed system.

On the other hand, the poor-solubilizing agent incorporated in the non-mucoadhesive layer makes the water-soluble cellulose derivative poorly water-soluble and reduces its mucoadhesiveness.

The oral mucosa-adhesive film preparation of the present invention, as described above, has one side adhered to the mucous membrane and the other side is non-mucoadhesive, so when applied to the mucous membrane in the oral cavity, it was applied. Transfer from the position to another site is prevented, and since the adhesive force to the mucous membrane is strengthened, displacement and peeling are also prevented.

〔Example〕

The present invention will be described in more detail with reference to Examples and Comparative Examples.

However, the scope of the present invention is not limited by the following examples.

In the following examples, "parts" and "%"
Unless otherwise noted, weight is based.

(1) Preparation of a liquid for forming a formulation (a) Liquid for forming a mucoadhesive layer 900 parts of a mixed solution of 85 parts of ethanol and 15 parts of water, 8.8 parts of Macrogol 400 (plasticizer), 2.7 parts of titanium oxide (colorant)
And 4.0 parts of benzidamine hydrochloride (drug) are homogeneously dissolved and dispersed. Further, under stirring, karaya gum (gum substance), a 2% aqueous solution at 20 ° C., having a viscosity of 100 cst, hydroxypropylmethylcellulose (HPMC) (trade name: K-
100LV, manufactured by Dow Chemical Co.), the viscosity of a 2% aqueous solution at 20 ° C. is 4,000 cst, hydroxypropyl methylcellulose (HPMC) (trade name: K-4M, manufactured by Dow Chemical Company) and the viscosity of a 2% aqueous solution at 20 ° C. 400 cp hydroxypropylcellulose (HPC-M) (trade name, HPC-
M, manufactured by Nippon Soda Co., Ltd.) (the above water-soluble cellulose derivative) was gradually added and dissolved to prepare a uniform mucoadhesive layer forming solution: Samples A-1 to A-8.

For comparison, liquids in which the blending of karaya gum was omitted: comparative samples C-1 to C-2 were prepared.

 The composition of each sample is shown in Table 1.

(B) Mucosal non-adhesive layer forming solution Macrogol 4000 (plasticizer) in 800 parts of ethanol 18.
Dissolve 2 parts, 0.012 parts of Blue No. 1 (colorant), and add 20 ° C
Of 2% aqueous solution having a viscosity of 3,000 cp in hydroxypropylcellulose (HPC-H) (trade name: HPC-H, manufactured by Nippon Soda Co., Ltd.), calcium carboxymethyl cellulose (CMC-Ca) (trade name: ECG-505, Nichirin Chemical Industry Co., Ltd.) (the above water-soluble cellulose derivative) and ethylcellulose (EC) (trade name: N-100NF, manufactured by Hercules) (slightly water-solubilizing agent) are gradually added to uniformly dissolve and disperse: sample B-1 to B-5 were prepared.

Further, for comparison, dispersion liquids in which the blending of ethyl cellulose was omitted: Comparative Samples H-1 to H-2 were prepared.

 The composition of each sample is shown in Table 1.

(2) Forming a film preparation A Teflon-coated plate-shaped square film-forming mold having a side of 30 cm is set horizontally, and the above-mentioned (1) is placed in the mold.
Casting the mucoadhesive layer forming solution prepared in (a),
After spreading using a stainless steel blade bar, it was kept at room temperature overnight and air-dried.

Then, the liquid for forming a non-mucoadhesive layer prepared in the above (1) (b) was further cast thereon, spread using a stainless steel blade bar, and kept at room temperature overnight. The film was peeled off from the mold.

This film was cured under vacuum at a temperature of 60 ° C. for 3 hours to obtain a film having a two-layer structure of a mucoadhesive layer and a non-mucoadhesive layer having a total thickness of 250 μm.

This film was punched out using a 10 mmφ punch to prepare oral mucosa-adhesive film preparations: Samples P-1 to P-6 and Comparative Samples X-1 and X-2.

(3) Oral mucosal adhesion test Each oral mucosal adhesive film preparation prepared in the above section (2) was applied to the buccal mucosa of 15 to 20 persons, and the adhesion time was measured.

The average of the respective adhesion times is shown in Table 2, and the adhesion time distributions of the samples of Examples Nos. 1 and 2 and Comparative Example 1 are shown in FIG.

As shown in Table 1 and the attached FIG. 1, the oral mucoadhesive film preparation of the present invention was compared with a preparation containing no gum substance in the mucoadhesive layer (Comparative Example: Sample X-1,2). And the time to adhere to the oral mucosa is greatly extended.

In the case of the preparation containing no sparingly water-soluble agent in the non-mucoadhesive layer (Comparative Example: Samples X-1, 2), the transfer of the preparation to the teeth and gums is observed.

〔The invention's effect〕

The oral mucosa-adhesive film preparation of the present invention, as shown in the above examples, when applied to the oral mucosa, does not shift, peel off, transfer to other parts, and has an adhesive property to the oral mucosa. Very good.

In addition, since the mucoadhesive layer is hardly water-soluble, the drug incorporated in the mucoadhesive layer hardly elutes to the mucoadhesive layer side, and is locally passed through the mucous membrane of the application site in the oral cavity. It is used effectively for the cure and prevention of targeted and / or systemic diseases.

Furthermore, since the drug is gradually absorbed throughout the mucosal attachment time of the preparation, the burden of temporarily administering the drug is reduced.

The present invention provides an oral mucosa-adhesive film preparation having excellent adhesion to the oral mucosa and excellent in mucosal absorption and sustained release of the drug, and its significance in the medical and pharmaceutical fields. Is extremely large.

[Brief description of the drawings]

Fig. 1 Sample P obtained in oral mucosal adhesion test of Example
-1, P-2 and comparative sample X-1 adhesion time distribution diagram

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Mitsuo Yoshimura 3-30-21 Noguchicho, Higashimurayama-shi, Tokyo (72) Inventor Yoshiharu Ishikawa 841-4 Oaza Arahata, Tokorozawa-shi, Saitama (56) References JP-A-63 -265981 (JP, A) JP-A-62-56420 (JP, A) JP-A-59-186913 (JP, A) JP-A-58-79916 (JP, A) (58) . ^6, DB name) A61K 9/70

Claims (2)

(57) [Claims] 1. A mucoadhesive layer containing a drug based on a mixture of a water-soluble cellulose derivative and a gum substance, and a non-mucoadhesive layer containing a water-soluble cellulose derivative as a base and containing a poorly water-soluble agent. A mucoadhesive film preparation in the oral cavity characterized by having a two-layer structure in which is laminated 2. The mucoadhesive film preparation according to claim 1, wherein the water-soluble cellulose derivative of the mucoadhesive layer is a mixture of hydroxypropylcellulose and hydroxypropylmethylcellulose.