JPH0653659B2 - Mucoadhesive formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a mucoadhesive preparation applied to mucosa, and more specifically, the present invention relates to an adhesive layer holding a drug and a non-adhesive layer not holding a drug. And a mucoadhesive preparation comprising

Prior Art When the affected area is a mucous membrane, it is natural to administer the drug to the mucous membrane, but in addition to this, the medication may be administered to the mucous membrane. The example is as follows.

(1) The mucosal site has relatively high transdermal absorbability.

(2) Oral administration causes the drug to pass through the digestive system, which may cause problems of decomposition and side effects depending on the drug. Mucosal administration of drugs is carried out to avoid such problems.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention As described above, as a new route of drug administration, a formulation aiming at absorption of the drug through the mucous membrane has recently been receiving attention.

Especially for transdermal absorption from the oral mucosa, lozenges,
Buccal agents, sublingual tablets, liquid agents, ointments, etc. are known,
Since lozenges, buccal agents, and sublingual tablets give a foreign body sensation to the oral cavity, patients often chew and swallow them, and liquids, ointments, etc. can easily be swallowed by saliva. However, the amount swallowed may be greater than the amount percutaneously absorbed, and is not necessarily suitable as a formulation.

In recent years, oral mucosa-adherent sustained release preparations composed of water-soluble polymer substances have been proposed. In this type of sustained-release preparation, the adhesive layer constituting it adheres to the mucous membrane by being moistened by the moisture of the mucous membrane in the body cavity such as the oral cavity, nasal cavity, and vagina,
The drug held in the sustained-release preparation is supplied to the affected area or the whole body by the transdermal absorbability of mucous membranes.

Such sustained-release preparations have improved retention properties and the like as compared with conventional products, but their initial adhesiveness is weak and it is difficult to mount them, and therefore mounting failures often occur, or 2-3
It had the drawback of dissolving in saliva over time. The present invention is intended to provide a mucoadhesive preparation which does not have the above-mentioned drawbacks, that is, a mucoadhesive preparation having good adhesion to mucous membrane, capable of adhering for a long time, and capable of continuously releasing a drug.

Means for Solving the Problems As a result of studies to improve the above-mentioned drawbacks, the present inventors have found that (a) a non-adhesive and poorly water-soluble layer, and (b) polyacrylic acid or a salt thereof. 97 to 30% by weight of a high molecular compound, and 1,500 to 4,
Polyethylene glycol in the range of 800,000 3-7
The present invention has been achieved by knowing that the above-mentioned problems can be solved by an adhesive preparation comprising an adhesive layer containing a drug in an adhesive component of 0% by weight.

The components of the present invention will be described in detail below.

(Non-adhesive layer) The non-adhesive component forming the non-adhesive layer is a pharmaceutically acceptable one in which one or more cellulose ethers are hardly soluble with one or two or more organic acids, and Other necessary known pharmaceutically acceptable excipients, binders, coloring agents,
It consists of additives such as flavoring agents, flavoring agents and lubricants.

Cellulose ether Examples of the cellulose ether include methyl cellulose, ethyl cellulose, propyl cellulose, ethyl methyl cellulose, hydroxy cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose and the like. Among the above-mentioned cellulose ethers, the viscosity of a 2% aqueous solution is 15 to 15 from the viewpoint of the solubility and the ease of the operation of making it insoluble by an organic acid.
Methyl cellulose of 8,000 cps is preferred.

Organic acids Examples of organic acids include citric acid, tartaric acid, tannic acid, and the like, and tannic acid is preferable from the viewpoint of easy operation of making the cellulose ether insoluble.

Ratio of Cellulose Ether to Organic Acid The ratio of these cellulose ether to organic acid is 100: 0.2 to 20 in weight ratio, which is 100: 0. The range of 5 to 10 is preferable.

The degree of poor solubility can be freely adjusted by the type of cellulose ether and the type and proportion of the organic acid.

(Adhesive Layer) The adhesive layer is formed from an adhesive component and a drug.

Adhesive component As an adhesive component, 97 to 30% by weight of a polymer compound consisting of polyacrylic acid or a salt thereof, polyethylene glycol (number average molecular weight of 1,500 to 4,800,00)
0) is added in an amount of 3 to 70% by weight. If the blending ratio of polyethylene glycol is less than 3% by weight, the delayed solubility becomes insufficient, and the blending ratio is 70% by weight.
If it exceeds the range, the tackiness becomes insufficient, and therefore, both are not preferable. From the viewpoint of adhesive strength and delayed solubility, polyethylene glycol (number average molecular weight is 10,000 to 400,000) is added to carboxyvinyl polymer in an amount of 5 to 6
It is preferable to add 0% by weight.

The adhesive strength and the degree of delayed solubility can be freely adjusted by the molecular weight and addition amount of polyethylene glycol.

Other Ingredients If desired, known excipients, binders, colorants, corrigents, flavoring agents, lubricants and the like which are pharmaceutically acceptable as other ingredients may be added to the adhesive component.

Drug It is desirable that the drug is uniformly dispersed and contained in the adhesive layer.

Examples of the drug to be used include a local therapeutic / therapeutic drug, a prophylactic drug, and a systemic drug expected to be transdermally absorbed from mucous membranes. Examples include anti-inflammatory steroids, non-steroidal anti-inflammatory analgesics, local anesthetics, vasodilators, vasoconstrictors, beta blockers, calcium blockers,
Sympathomimetics, diuretics, antihistamines, antibiotics,
Examples include oral germicides.

Further, the preferable amount and concentration of the drug in the mucoadhesive preparation vary depending on the size of the mucoadhesive preparation, the type and efficacy of the drug, the release characteristics of the mucoadhesive preparation, the usage time of the mucoadhesive preparation and the like.

(Form of formulation) Although the thickness and shape of the mucoadhesive formulation are not limited, the thickness of the non-adhesive layer is about 0.1 to 2.0 mm and the thickness of the adhesive layer is about 0.1 to 2.0 mm. And the diameter is 3.0 to 2
A flat plate-shaped circle of 0.0 mm is preferable, and particularly in the case of an oral mucosa-adhesive preparation, the thickness of the non-adhesive layer is about 0.15 to 1.0 mm,
The thickness of the adhesive layer is about 0.15 to 1.0 mm, and a flat circular plate having a diameter of 10 mm or less is preferable.

(Formulation Method) The mucoadhesive preparation of the present invention can be prepared by various methods, and the most preferable preparation method is the tableting method. As an example of the conditions of the tableting method, a single-shot tableting machine can be used to tablet at a pressure of 1 to 8 ton / 10 mmφ at room temperature.

The mucoadhesive preparation of the present invention can be formulated not only by the tableting method but also by the coating method or the casting method.

Examples The present invention will be described below with reference to examples.

Reference example Carboxy vinyl polymer [Carbopol 941 ,
-F Goodrich Chemical Company (BF Good
rich Chemical Corporation
n)] 100 parts by weight of polyethylene glycol of each molecular weight
Mixture (abbreviated as PEG) and mixed for adhesive layer base
Get a powder. Press 100 mg of mixed powder with a force of about 1.5 tons.
Shrink to make a monolayer tablet with a diameter of 10 mm and add it to 100 m of water.
Time to sink and dissolve (absorb water to form a completely transparent gel)
Was observed. The results are shown in Table 1.

Example 1 Carboxy vinyl polymer (Carbopo
941 ) 50 parts by weight and polyethylene glycol
Take 50 parts by weight (molecular weight is 20,000)
Adhesive layer by mixing 0.0312 parts by weight of dexamethasone
A powder for use was obtained.

As the non-adhesive layer base, methyl cellulose (15 cp
s) Mix 10 parts by weight of a 10% by weight aqueous solution with 2 parts by weight of a 5% by weight aqueous solution of tannic acid and stir 80
After heat-treatment at 15 ° C. for 15 minutes, the mixture was cooled to room temperature, a solid was precipitated with acetone, and the solid was washed with hexane and dried to obtain a powder for a non-adhesive layer.

80 mg of powder for adhesive layer as the lower layer, 80 mg of powder for non-adhesive layer
Was used as an upper layer and was compression-molded using a multilayer tableting machine with a force of about 1.5 tons to obtain a two-layer tablet preparation having a diameter of 10 mm.

Example 2 A carboxyvinyl polymer (carb
Paul 934 ) 10 parts by weight and polyethylene glycol
1 part by weight (molecular weight 270,000) is taken as a drug
And 0.0343 parts by weight of triamcinolone acetonide
The mixture was mixed to obtain an adhesive layer powder.

As the non-adhesive layer base, methyl cellulose (15 cp
s) 1 part by weight of an aqueous solution of 5% by weight tannic acid is mixed with 10 parts by weight of an aqueous solution of 10% by weight, and while stirring, 8
After heat treatment at 0 ° C. for 30 minutes, the mixture was cooled to room temperature, acetone was added to precipitate a solid, and the solid was washed with hexane and dried to obtain a non-adhesive layer powder. Using these powders, a bilayer tablet formulation was obtained in the same manner as in Example 1.

Evaluation With respect to the mucoadhesive preparations of Examples 1 and 2, using 20 panelists each, a sticking test to the oral mucosa was carried out.

The fingertips were lightly wetted, the non-mucosal layer of the mucoadhesive preparation was attached, and lightly pressed to the oral mucosa local area for administration.

No administration failure was observed in any of them, and all of them dissolved without disappearing for 5 hours or more and disappeared.

EFFECTS OF THE INVENTION As described above, the mucoadhesive preparation provided by the present invention has a non-adhesive layer made of a substance in which a pharmaceutically acceptable cellulose ether is poorly soluble with an organic acid, and is made of polyacrylic acid or a salt thereof. Adhesion to the mucosa is good because part of the adhesive layer has a delayed solubility in the water of the mucous membrane after it is attached to the mucous membrane by adding polyethylene glycol to the molecular substance. It is a mucoadhesive preparation that does not migrate and can be attached for a long time and does not give a foreign body sensation.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Kotaro Tashiro, 5-11-15, Nukiinami-cho, Koganei-shi, Tokyo (56) Reference JP-A-59-196814 (JP, A)

Claims (2)

[Claims] 1. A layer of (a) a pharmaceutically acceptable cellulose ether insolubilized with an organic acid, and (b) a polymer compound consisting of polyacrylic acid or a salt thereof, in an amount of 97 to 30% by weight, and a molecular weight. A mucoadhesive preparation comprising an adhesive layer comprising an adhesive component composed of 3 to 70% by weight of polyethylene glycol in the range of 1,500 to 4,800,000 and a drug. 2. The mucoadhesive preparation according to claim 1, wherein the drug is one or more of a mucosal absorbable drug and a topical drug.