JPH06256168A - Ointment base and composition for treating periodontosis using the same - Google Patents

Abstract

(57) [Summary] [Purpose] A stable, non-irritating ointment base that exerts sufficient adhesiveness and local retention on a moist surface to give a long-lasting effect to the active ingredient and uses it. The composition is provided. [Structure] A water-soluble polymer, a polyhydric alcohol, a lower alcohol, a vinyl acetate resin and water, and an ointment base having a pH of 4 to 10 and a lower alcohol and water content of 50% by weight or less of the total amount A composition for treating periodontal disease, which comprises a non-steroidal anti-inflammatory agent. [Effect] An ointment base suitable for application to the moist surface of mucous membranes and the like, and a non-steroidal anti-inflammatory agent containing the ointment base, which stays at the administration site for a long time and is durable. It is possible to provide a composition for treating periodontal disease, which exhibits the effect of.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an ointment base and a composition for treating periodontal disease using the ointment base. For more details,
A paste or ointment base suitable for application to moist surfaces such as mucous membranes and a base for cosmetics and a non-steroidal anti-inflammatory agent for suppressing alveolar bone absorption and gingivitis together with the base The present invention relates to a composition for treating periodontal disease, which retains at an administration site for a long time and exerts a sustained effect.

[0002]

2. Description of the Related Art Conventionally, various substances are known as bases for pharmaceutical preparations and cosmetics, but those having sufficient adhesiveness and local retention when applied to moist surfaces such as mucous membranes. Is not found yet. For example, as an ointment base to be applied to a wet surface, a mixture of an oily base such as liquid paraffin and petrolatum with a water-absorbent polymer substance such as sodium carboxymethyl cellulose is conventionally used. However, there is a problem that the particle size of the solid component is large and the pain and irritation upon application are high.

In order to solve this problem, an ointment base containing polyacrylic acid or a salt thereof has been proposed (JP-A-52).
-1141616, JP-A-53-86011), lacking in salt resistance, and due to interaction with polyacrylic acid,
There is a problem that the medicinal agents and active ingredients to be blended are destabilized.

In view of such circumstances, the present inventors applied the composition to a wet surface to exhibit sufficient adhesiveness and local retention, give a sustained effect to the drug and the active ingredient to be blended, and form a film. The inventors have conducted extensive studies to obtain an ointment base which has good formability and does not have the above-mentioned drawbacks and problems. As a result, they have found that the objective can be achieved by combining a water-soluble polymer with a polyhydric alcohol, a lower alcohol, a vinyl acetate resin and water. Furthermore, it was newly found that the composition obtained by mixing the above-mentioned base with a non-steroidal anti-inflammatory drug stays at the administration site for a long time and the effect is persistent.

[0005]

The present invention provides an ointment base comprising (a) a water-soluble polymer, (b) a polyhydric alcohol, (c) a lower alcohol, (d) a vinyl acetate resin and (e) water. And a composition for periodontal treatment comprising a non-steroidal anti-inflammatory agent or a pharmaceutically acceptable salt as an active ingredient in the ointment base.

The ointment base of the present invention shows sufficient adhesion and local retention when applied to a wet surface, and is a uniform solid substance,
Since it does not contain solids of large particle size, there is no problem of irritation during application. Hereinafter, the present invention will be described in detail.

Examples of the water-soluble polymer which is the component (a) of the ointment base of the present invention include gum arabic, guar gum, tragacanth gum, locust bean gum, carrageenan, agar, starch, pregelatinized starch, dextrin, alginic acid and alginate. , Natural polymers such as pectin, xanthan gum, succinoglucan, dextran, pullulan, gelatin, chitin, chitosan, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, salts thereof (eg, sodium salt, calcium salt, etc.) ), Propylene glycol alginate, semi-synthetic polymeric substances such as carboxymethyl starch, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyacrylic acid,
Water-soluble acrylic acid copolymers and salts thereof (eg, sodium salts, etc.), polyvinyl methyl ether, methoxyethylene maleic anhydride copolymer, starch-synthetic polymeric substances such as acrylic acid graft copolymer, and mixtures thereof, These may be appropriately neutralized if necessary.
The water-soluble polymer is used in an amount such that an appropriate paste-like or ointment-like viscosity is obtained, and is usually used in the range of 0.1 to 10% by weight based on the total amount of the ointment base obtained.

Examples of the polyhydric alcohol as the component (b) include glycerin, ethylene glycol and propylene glycol. The polyhydric alcohol is used in an amount such that an appropriate paste-like or ointment-like viscosity is obtained, usually 40% by weight or more based on the total amount of the ointment obtained.

Examples of the lower alcohol as the component (c) include ethanol, propanol, and isopropanol. The lower alcohol dissolves the water-soluble polymer substance to give an appropriate paste-like or ointment-like viscosity, usually 5 to 4 based on the total amount of the ointment base obtained.
It is used in an amount of 0% by weight, preferably 10 to 30%.

The vinyl acetate resin as the component (d) has been used as a gum base, which is described in the official compenditure for food additives, and it is particularly preferable to use the one having a polymerization degree of 200 to 500. In the present invention, the (d)
The component contributes to the adhesion to the wet surface of the ointment base and the improvement of local retention, and in terms of its performance, based on the total amount of the ointment base, it is 0.2 to 60% by weight, preferably 2 to 20%. Used in the range. The component (d) dissolves or swells in lower alcohols, but is insoluble in water and polyhydric alcohols.

The water as the component (e) dissolves the water-soluble polymer as the component (a) to obtain an appropriate paste-like or ointment-like viscosity, usually based on the total amount of the ointment base obtained. It is used in the range of 5 to 40% by weight, preferably 2 to 20%. In the present invention, this component (e) water and (c)
The sum of the amount of the lower alcohol as a component and the total amount of the ointment base is 50% by weight or less. This maintains the proper physical properties of the base.

In the ointment base of the present invention, for example, a water-soluble polymer as the component (a) and a lower alcohol as the component (c) are mixed to form a gel. Separately, this is mixed with a vinyl acetate resin swollen with a lower alcohol, and then a polyhydric alcohol as the component (b) and water as the component (e) are added in appropriate amounts, and the pH is adjusted appropriately to a uniform level. It can be produced by mixing with. The pH is adjusted to a range of 4.0 to 10.0 from the viewpoint of stability of the base, irritation and the like. This pH adjustment is sodium citrate, hydrochloric acid, sodium hydroxide,
Normal p such as triethanolamine and triethylamine
It can be carried out using an H modifier.

The ointment base of the present invention can be applied to a wet surface, for example, the oral cavity, the lips, the eyes, the vagina, etc., by formulating a desired medicinal agent and necessary additives at appropriate steps in the production. An ointment-like or paste-like pharmaceutical preparation or cosmetic suitable for application can be prepared.

Thus, the composition for treating periodontal disease of the present invention is an ointment-like or paste-like composition obtained by formulating the ointment base of the present invention with a nonsteroidal anti-inflammatory agent. The non-steroidal anti-inflammatory agent to be used may be a free one or a pharmaceutically acceptable acid addition salt, and for example, indomethacin, indomethacin, sulindac, tolmethine, acemethacin, progourmetacin, etc., and salicylic acid, aspirin , Aspirin aluminum, salicylosalicylic acid, diflunisal, and the like, and phenylacetic acid-based compounds include 4-biphenylylacetic acid, ibufenac, ibuprofen, ketoprofen, fenoprofen, flurbiprofen, and the like. Examples of the basic non-steroidal anti-inflammatory agent include mepyrizole, tiaramide, tinolidine, benzydamine, perisoxal, etc. From the viewpoint of efficacy, generally, it is 0.0 with respect to the total amount of the composition.
The compounding amount is about 5 to 5.0% by weight, preferably about 0.2 to 2.0% by weight. The composition of the present invention can be produced by uniformly mixing a nonsteroidal anti-inflammatory agent with the ointment base by a conventional method, and if desired, further additives such as a surfactant, a stabilizer and a preservative. Can be appropriately mixed.

The composition of the present invention can be used by directly applying it to the affected part of the periodontal disease, if necessary. The amount to be used can be appropriately selected depending on the degree of disease, the condition of the patient, etc.
It is preferably about 0.1 to 100 mg once, and the application can be continued 1 to 5 times a day until the desired effect is observed.

[0016]

EXAMPLES Next, the present invention will be described in more detail with reference to examples and test examples. Example 1 Ingredients wt% Carboxyvinyl Polymer 2.0 Ethanol 30.0 Water 15.0 Vinyl Acetate Resin 5.0 1N Sodium Hydroxide Appropriate Flurbiprofen 0.2 Glycerin The rest Flurbiprofen was dissolved A carboxyvinyl polymer was dissolved in an ethanol solution and gelled. Separately, a vinyl acetate resin swollen with ethanol was mixed with the gel, glycerin and water were added in appropriate amounts, and the pH was adjusted to 5.0 with 1N sodium hydroxide. A composition for treating periodontal disease was obtained.

Example 2 Ingredients% by Weight Carboxyvinyl Polymer 1.0 Ethanol 10.0 Water 10.0 Water Vinyl Acetate Resin 2.0 Flurbiprofen 0.2 1N Sodium Hydroxide Appropriate Glycerin Remaining Flurbiprofen A carboxyvinyl polymer was dissolved in an ethanol solution in which was dissolved to form a gel. Separately, a vinyl acetate resin swollen with ethanol was mixed with the gel, glycerin and water were added in appropriate amounts, and the pH was adjusted to 6.0 with 1N sodium hydroxide. A composition for treating periodontal disease was obtained.

Example 3 Components Weight% Carboxyvinyl Polymer 5.0 Ethanol 30.0 Water 5.0 Vinyl Acetate Resin 20.0 Flurbiprofen 0.2 1N Sodium Hydroxide Appropriate Glycerin Remaining Flurbiprofen A carboxyvinyl polymer was dissolved in an ethanol solution in which was dissolved to form a gel. Separately, a vinyl acetate resin swollen with ethanol is mixed with the gel, glycerin and water are added in appropriate amounts to adjust the pH to 4.0 with 1N sodium hydroxide, and the mixture is uniformly mixed to give a desired paste-like tooth. A composition for treating periodontal disease was obtained.

Example 4 Ingredients% by weight Hydroxypropyromethyl cellulose 2.0 Ethanol 30.0 Water 10.0 Vinyl acetate resin 10.0 Flurbiprofen 0.2 1N sodium hydroxide Appropriate amount Glycerin balance Flurbipro Hydroxypropyl methylcellulose was dissolved in an ethanol solution in which phen was dissolved to form a gel. Separately, a vinyl acetate resin swollen with ethanol is mixed with the gel, glycerin and water are added in appropriate amounts, and the pH is adjusted to 4.0 with 1N sodium hydroxide. A composition for treating periodontal disease was obtained.

Example 5 Ingredients% by Weight Hydroxypropylmethyl Cellulose 2.0 Ethanol 30.0 Water 10.0 Vinyl Acetate Resin 10.0 1N Sodium Hydroxide Appropriate Flurbiprofen 0.2 Propylene Glycol Balance Flurbipro Hydroxypropyl methylcellulose was dissolved in an ethanol solution in which phen was dissolved to form a gel. Separately, a vinyl acetate resin swollen with ethanol was mixed with the gel, propylene glycol and water were further added in appropriate amounts, and the pH was adjusted to 4.0 with 1N sodium hydroxide. A composition for treating periodontal disease was obtained.

Test Example 1 Adhesion Test to Oral Mucosa The adhesion of the compositions obtained in the above Examples to the oral mucosa
The test was performed according to the dissolution test method of the Japanese Pharmacopoeia. A metal flat plate (50 x 50
mm) was welded, and the cheek pouch mucosa extracted from the hamster was spread and fixed. 1 g of a sample of each test composition was applied on the mucous membrane, and the mixture was placed in artificial saliva at 37 ° C for 10
It was rotated at 0 rpm and the adhesion time was measured. Further, as Comparative Examples, the compositions of Controls 1 to 3 shown below were produced, and
The same test was conducted by adjusting the pH to 7.

Control 1 component wt% carboxyvinyl polymer 2.0 ethanol 30.0 water 15.0 flurbiprofen 0.2 1N sodium hydroxide qs glycerin balance

Control 2 components wt% Carboxy vinyl polymer 2.0 Ethanol 30.0 Water 30.0 Vinyl acetate resin 2.0 Flurbiprofen 0.2 1N Sodium hydroxide qs glycerin balance

Control 3 components wt% carboxyvinyl polymer 2.0 ethanol 10.0 water 50.0 vinyl acetate resin 5.0 flurbiprofen 0.2 1N sodium hydroxide proper amount glycerin balance The results are shown in Table 1. ..

[0025]

[Table 1]

As is clear from the results shown in Table 1, the composition using the base of the present invention has adhesiveness to the oral mucosa for a long time. As a result, the composition using the ointment base of the present invention can adhere to the affected area for a long time and exhibit a long-lasting effect, as compared with the conventional composition. Further, it was revealed that the composition for treating periodontal disease containing the non-steroidal anti-inflammatory agent of the present invention has a sustained release effect. The sustained release effect is shown below.

Test Example 2 Release Test of the Active Ingredient from the Composition The test was carried out using the composition obtained according to Example 1 and Control 1. A Franz cell, which is a horizontal membrane type diffusion cell, was used as the test apparatus. PBS on the receptor side
(-) Was put, the composition for treating periodontal disease was placed on the cellulose membrane, and the mixture was stirred at 37 ° C. The receptor solution was collected over time and quantified by HPLC. The HPLC conditions are as follows.

Column: Inertsil ODS-5μ
4.6 × 150 mm Column temperature: 40 ° C. Mobile phase: Acetonitrile / 0.05 M KH ₂ PO ₄ / triethanol amine = 35: 65: 0.02 Detection wavelength: 246 nm

The results are shown in FIG. The release amount after 8 hours was 42% in Example 1 and 96% in Control 1. As is clear from this result, the composition of the present invention slowly releases the contained non-steroidal anti-inflammatory drug.

Test Example 3 Utility of Alveolar Bone Resorption Inhibition and Gingivitis To test the usefulness of the composition of the present invention, J. Peri
optional Research 18, 110-1
17 (1983) followed by a 12 week study period using the hamster model. The 12-week study period was divided into the first 6 weeks in which soft food was given to cause resorption of alveolar bone and the latter 6 weeks in which test samples were given. The model used was 6 hamsters per group for 15 weeks. Each group is as follows.

(1) Control group A normal solid sample was given for 12 weeks. (2) Untreated group Soft food was given for 12 weeks. (3) Test group The compositions of Examples 1 to 5 and Controls 1 to 3 were administered once a day for 5 times.
The application of 0 mg dose to the lower gingiva of the hamster was carried out for the last 6 weeks. The results were evaluated according to the following criteria. Criteria (1) Absorption of alveolar bone The distance from the cementum-enamel boundary (CEJ) in the mandibular bone specimen to the alveolar crest (AM) was used as an index. (2) Gingival inflammation Gingiva was visually observed and evaluated according to the following criteria. ++ ... Severe inflammation with marked redness and hypertrophy + ... Moderate inflammation with redness and mild edema ± ... Mild inflammation with slight changes in gingival color -... No inflammation Table 2 Shown in.

[0032]

[Table 2]

As is clear from the results shown in Table 2, the composition for treating periodontal disease containing the non-steroidal anti-inflammatory agent of the present invention exhibits good therapeutic effects on alveolar bone absorption and gingival inflammation.

[0034]

INDUSTRIAL APPLICABILITY According to the present invention, an ointment base for pharmaceuticals and cosmetics suitable for application to moist surfaces such as mucous membranes and a long-term non-steroidal anti-inflammatory agent containing the same It is possible to provide a composition for treating periodontal disease which stays at the administration site and exerts a long-lasting effect.

[Brief description of drawings]

FIG. 1 is a graph showing the results of a release test of the composition of the present invention.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 45/00 ABE 8415-4C 47/32 F 7433-4C 47/36 F 7433-4C 47/38 F 7433-4C 47/42 F 7433-4C

Claims (12)

[Claims] 1. A method comprising (a) a water-soluble polymer, (b) a polyhydric alcohol, (c) a lower alcohol, (d) a vinyl acetate resin and (e) water, and comprising (c) component and (e) component. The total amount is 50% by weight or less of the total amount, and the pH is 4.0 to 10.0.
The ointment base is characterized in that 2. The component (a) is gum arabic, guar gum, tragacanth gum, locust bean gum, carrageenan, agar, starch, pregelatinized starch, dextrin, alginic acid, alginate, pectin, xanthan gum, succinoglucan, dextran, Pullulan, gelatin, chitin, chitosan, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, salts of these cellulose derivatives, propylene glycol alginate, carboxymethyl starch, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyacrylic acid, water-soluble -Type acrylic acid copolymer and its salt, polyvinyl methyl ether, methoxyethylene maleic anhydride copolymer, starch-acrylic acid group The ointment base according to claim 1, which is selected from the group consisting of raft copolymers and mixtures thereof. 3. The ointment base according to claim 1, containing 0.1 to 10% by weight of the component (a). 4. The ointment base according to claim 1, wherein the component (b) is selected from the group consisting of glycerin, ethylene glycol and propylene glycol. 5. The ointment base according to claim 1, which contains 40 weight% or more of the component (b). 6. The ointment base according to claim 1, wherein the component (c) is selected from the group consisting of ethanol, propanol and isopropanol. 7. The ointment base according to claim 1, wherein the component (d) is a vinyl acetate resin having a degree of polymerization of 200 to 500. 8. The ointment base according to claim 1, which contains the component (d) in an amount of 0.2 to 60% by weight. 9. The ointment base according to claim 1, which contains 5 to 40% by weight of component (e). 10. A composition for treating periodontal disease, which comprises the ointment base according to claim 1 and a non-steroidal anti-inflammatory drug or a pharmaceutically acceptable salt thereof as an active ingredient. 11. The non-steroidal anti-inflammatory agent is selected from the group consisting of indole acetic acid anti-inflammatory agents, salicylic acid anti-inflammatory agents, phenylacetic acid anti-inflammatory agents and basic non-steroidal anti-inflammatory agents. The composition as described. 12. A non-steroidal anti-inflammatory drug is added to 0.05 to 5.
The composition according to claim 10, which contains 5.0% by weight.