JPS6222713A - Mucosa adherent preparation - Google Patents

Abstract

PURPOSE:The titled preparation having improved adhesivity to the mucosa, consisting of a slightly water-soluble nonadherent layer and an adherent layer obtained by adding a drug to an adherent component containing a high polymer compound of a polyacrylic acid and a specific polyethylene glycol in a specific ratio. CONSTITUTION:A mucosa adherent preparation having improved adhesivity to the mucosa, capable of adhering for a long period, of releasing successively a drug, consisting of (a) a nonadherent, slightly water-soluble layer obtained by making a cellulose ether with an organic acid into slightly soluble and (b) an adherent layer obtained by adding one or more drugs selected from drugs absorbable in the mucosa and external preparations to an adherent composition comprising 97-30wt% high polymer compound of a polyacrylic acid or its salt and 3-70wt% polyethylene glycol having 1,500-4,800,000 number-average molecular weight.

Description

Detailed Description of the Invention: Industrial Application Field The present invention relates to a mucoadhesive preparation applied to mucous membranes. The present invention relates to a mucoadhesive preparation comprising:

Prior Art When the affected area is a mucous membrane, it is natural to administer a drug to the mucous membrane, but there are other cases in which the drug is administered to the mucous membrane. An example of this is as follows.

(1) Mucosal sites have relatively high percutaneous absorption.

(2) When administered orally, drugs pass through the gastrointestinal tract, so depending on the drug, problems such as decomposition and side effects may occur.

To avoid such problems, mucosal administration of drugs is performed.

Problems to be Solved by the Invention As mentioned above, preparations that aim to absorb drugs through mucous membranes have been attracting attention in recent years as a new administration route for drugs.

Especially for transdermal absorption from the oral mucosa, lozenges,
Buccal preparations, sublingual tablets, liquid preparations, ointments, etc. are known, but
Lozenges, buccal tablets, and sublingual tablets give the sensation of a foreign body in the oral cavity, so patients often chew them up and swallow them, and liquids and ointments can easily wash away with saliva. However, the amount that is swallowed may be greater than the amount that is absorbed through the skin, so it is not necessarily suitable as a drug product.

In recent years, oral mucosa-adhesive sustained-release preparations made of water-soluble polymeric substances have been proposed. In this type of sustained-release preparation, the adhesive layer that constitutes it adheres to the mucous membranes by being moistened by the moisture in the mucous membranes in body cavities such as the oral cavity, nasal cavity, and vagina.
The drug held in the sustained-release preparation is delivered to the affected area or the whole body by transdermal absorption through the mucous membrane.

Although these sustained-release preparations have improved retention properties compared to conventional products, they have weak initial adhesion and are difficult to apply, resulting in frequent failures in application, and
It has the disadvantage that it dissolves in saliva over time. The present invention aims to provide a mucoadhesive preparation that does not have the above-mentioned drawbacks, that is, a mucoadhesive preparation that has good adhesion to mucous membranes, remains attached for a long period of time, and is capable of releasing drugs in a sustained manner.

Means for Solving the Problems As a result of research to improve the above-mentioned drawbacks, the present inventors 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 polymer compound consisting of 1°500 to 4,
Polyethylene glycol in the range 800,000 3-7
The inventors have found that the above-mentioned problems can be solved by a mucoadhesive preparation consisting of an adhesive layer containing a drug in an adhesive component of 0% by weight, and have thus arrived at the present invention.

Components of the present invention will be explained in detail below.

(Non-adhesive layer) The non-adhesive component forming the non-adhesive layer is a pharmaceutically acceptable material obtained by making one or more cellulose ethers poorly soluble with one or more organic acids, and Other necessary pharmaceutically acceptable excipients, binders, coloring agents,
Consists of additives such as flavoring agents, deodorants, and lubricants.

Cellulose ether Cellulose ethers include methylcellulose, ethylcellulose, propylcellulose, ethylmethylcellulose, hydroxycellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and the like. Among the above-mentioned cellulose ethers, the viscosity of a 2% aqueous solution is 15 to 8, from the viewpoint of solubility and ease of operation to make it poorly soluble with organic acids.
．． 000 cps methylcellulose is preferred.

Organic acids Examples of organic acids include citric acid, tartaric acid, and tannic acid, but tannic acid is preferred from the viewpoint of ease of operation for rendering cellulose ether dissolvable.

The ratio of cellulose ether to organic acid is 100:1 by weight.
0.2~2o.

From the practical level of low solubility, 100:0.5~1O
A range of is preferred.

The degree of poor solubility can be freely adjusted by changing 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 The adhesive component consists of 97 to 30% by weight of a polymer compound consisting of polyacrylic acid or its salt, and polyethylene glycol (number average molecular weight: 1,500 to 4.800.00).
0) 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 will be insufficient, and if the blending ratio is less than 7% by weight, the delayed solubility will be insufficient.
If it exceeds 0% by weight, the tackiness will be insufficient, so both are not preferred. From the viewpoint of adhesive strength and delayed solubility, polyethylene glycol (number average molecular weight is 10.000 to 400.000) is used in carboxyvinyl polymer.
It is preferable to add 5 to 60% by weight of.

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

Other components The adhesive component may contain other known pharmaceutically acceptable excipients, binders, coloring agents, flavoring agents, deodorants, lubricants, etc. as other components.

It is desirable that the drug be contained in the adhesive layer in a uniformly dispersed manner.

The drugs used include local therapeutic or prophylactic drugs, or systemic drugs that are expected to be absorbed transdermally through mucous membranes. Examples include anti-inflammatory steroids, non-steroidal anti-inflammatory drugs, local anesthetics, vasodilators, vasoconstrictors, beta-blockers, calcium channel blockers,
Sympathomimetic agents, diuretics, antihistamines, antibiotics,
Examples include oral disinfectants.

Additionally, the preference and concentration of the drug in the mucoadhesive formulation will vary depending on the size of the mucoadhesive formulation, the type and potency of the drug, the release characteristics of the mucoadhesive formulation, the duration of use of the mucoadhesive formulation, and the like.

(Form of Formulation) There are no restrictions on the thickness and shape of the mucoadhesive preparation, but the thickness of the non-adhesive layer is approximately 0.1 to 2.0 mm, and the thickness of the adhesive layer is approximately 0.1 to 2.0 mm. and the diameter is 3.0~2
A flat circular shape of 0.0 mm is preferable, and especially in the case of oral mucoadhesive preparations, the thickness of the non-adhesive layer is about 0.15 to 1.0 m.
m, the thickness of the adhesive layer is about 0.15-1.0 mm, and the diameter is 1
A flat circular shape with a diameter of 0 mm or less is preferable.

(Formulation Method) The mucoadhesive preparation of the present invention can be prepared by various methods, but the most desirable preparation method is a tableting method. To give an example of the conditions for the tableting method, tableting can be performed using a single-shot tableting machine at room temperature and at a pressure of 1 to 8 tons/10 mmφ.

The mucoadhesive preparation of the present invention can be formulated by a coating method or a casting method in addition to the tableting method.

Example The present invention will be explained below with reference to Examples.

Reference example carboxyvinyl polymer [Carpopol 94■...l, H.F. Gutdrich Chemikaf 1 Company (B, F
, Goodrich Chemical Corporation
100 parts by weight of polyethylene glycol (abbreviated as PEG) of various molecular weights are mixed with 100 parts by weight of Polyethylene Glycol (abbreviated as PEG) manufactured by A.

Compress 100 mg of the mixed powder with a force of about 1.5 tons to make a single-layer tablet with a diameter of 10 mm. Submerge it in 100 m of water and observe the dissolution time (absorbs water and becomes a completely transparent gel). did. The results are shown in Table 1.

Table 1 (Part 1) Example 1 50 parts by weight of carboxyvinyl polymer (Carpoball 941■) and polyethylene glycol (
50 parts by weight (molecular weight: 20.000) were taken and mixed with 0.0312 parts by weight of dexamethacin as a drug to obtain a powder for an adhesive layer.

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

80 mg of adhesive layer powder is used as the lower layer, and 80 mg of powder for non-adhesive layer is used as the lower layer.
1.5 mg in one layer using a multilayer tablet press.
A two-layer tablet formulation with a diameter of 10 mm was obtained by compression molding with a force of tons.

Example 2 10 parts by weight of carboxyvinyl polymer (Carpopol 934■) and 1 part by weight of polyethylene glycol (molecular weight: 270,000) were used as adhesive layer base, and 0.0343 parts by weight of triamcinolone acetonide was mixed as a drug. An adhesive layer powder was obtained.

As the non-adhesive layer base, methyl cellulose (15 cps
) 5 parts tannic acid per 10 parts by weight of a 10% aqueous solution
1 part by weight of an aqueous solution is mixed with 80 parts while stirring.
After heat treatment at °C for 30 minutes and cooling to room temperature, acetone was added to precipitate a solid, which was washed with hexane and dried to obtain a non-adhesive layer powder. A two-layer tablet formulation was obtained in the same manner as in Example 1 using these powders.

Evaluation Example 1 and 2 of the mucoadhesive formulations were tested for application to the oral mucosa using 20 panelists each.

Lightly wet the fingertip, attach the non-mucosal layer of the mucoadhesive preparation, and administer the drug to the oral mucosa by applying light pressure.

No administration failure was observed in either case, and all dissolved and disappeared without peeling off over a period of 5 hours or more.

Effects of the Invention As described above, the mucoadhesive preparation provided by the present invention has a non-adhesive layer made of a pharmaceutically acceptable cellulose ether made poorly soluble with an organic acid, polyacrylic acid, lylic acid, or
By adding polyethylene glycol to a polymeric substance made of the salt, after adhering to the mucous membrane, a part of the adhesive layer has a delayed solubility in the moisture of the mucous membrane, so it has good adhesion to the mucous membrane and It is a mucoadhesive preparation that does not migrate to the opposite mucosa, can be adhered for a long time, and does not give a foreign body sensation.

Claims (3)

[Claims] (1) A polymer compound 97 consisting of (a) a non-adhesive and poorly water-soluble layer and (b) polyacrylic acid or a salt thereof
-30% by weight, and an adhesive layer comprising a drug contained in an adhesive component consisting of 3 to 70% by weight of polyethylene glycol having a molecular weight of 1,500 to 4,800,000. (2) The mucoadhesive preparation according to claim 1, wherein the non-adhesive layer (a) is a pharmaceutically acceptable cellulose ether made poorly soluble with an organic acid. (3) The drug is one or two of mucosally absorbable drugs and external drugs.
The mucoadhesive preparation according to claim 1 or 2, which is more than one species.