JPH06211650A - Ointment adhesive to oral cavity - Google Patents

Abstract

PURPOSE:To provide an ointment adhesive to the oral cavity, having improved taste (bitter taste) of principal drug and excellent aging stability, holding firm bonding force and ensuring high medicinal effect. CONSTITUTION:This ointment adhesive to the oral cavity contains a finely pulverized sticking polymer in a steroid-type anti-inflammatory agent and/or antibacterial agent stabilized by the micro-encapsulation with a film-forming polymer and the addition of citric acid. This invention also relates to the process for the preparation of the ointment.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an oral adhesive ointment. More specifically, the present invention relates to an intraoral adhesive ointment containing a steroidal anti-inflammatory drug and an antibacterial agent, which is excellent in stability over time and adhesiveness in which bitterness of a drug is alleviated.

[0002]

2. Description of the Related Art Attempts have been made for a long time to treat mucosal diseases such as stomatitis and alveolar pyorrhea by attaching an ointment containing a drug to the mucous membrane of the oral cavity. However, research focusing on improving taste (bitterness of drugs) from the viewpoint that the oral cavity is a special part of recognizing taste sensation, although it is the most important factor when it controls the commercial value, It has not been done yet. Further, in order to have a strong mucoadhesive property, the addition of sodium polyacrylate or the like as an adhesive polymer is disclosed in JP-B-54-381.
No. 68, Japanese Examined Patent Publication No. 56-27491, JP-A-3-666.
No. 12, the adhesion time in the test is
It is up to 4 hours and it is hard to say that it has sufficient adhesion.

Further, Japanese Patent Application Laid-Open No. 58-20654 discloses that
An example in which finely pulverized pectin is added as an adhesive polymer is disclosed, but the adhesion time in the test is 1.5 hours, it is difficult to withstand ordinary use, and the effect of pulverization is not sufficient. On the other hand, most of the polymers added for imparting adhesiveness are compounded in the form of sodium salt having a stronger water-absorbing adhesive force. However, these sodium salts are liable to interact with a trace amount of water in the preparation and the compounded drug, which contradicts an increase in adhesiveness, and the stability of the main drug over time could not be ensured.

[0004]

SUMMARY OF THE INVENTION In view of the above-mentioned drawbacks of the conventional oral adhesive ointment, the present invention improves the taste (bitterness) of the main ingredient, and is excellent in stability over time, and further, the adhesion retention The object is to provide an ointment having good oral properties and adhesiveness.

[0005]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that as a method for simultaneously solving the taste (bitterness) and stability over time of the main drug without impairing the release properties of the main drug, the main drug It was found that it is best to microencapsulate the above with a film-forming polymer to stabilize it, and completed the present invention.

The film-forming polymer used for the microencapsulation of the present invention is not particularly limited, but preferably hydroxypropyl cellulose and / or polyvinylpyrrolidone. The film-forming high molecular weight is appropriately selected within the range of 3 to 7 times the weight of the main drug, but is preferably 4 to 6 times. Further, citric acid may be used for stabilization, and the addition amount thereof is appropriately selected within the range of 0.01 to 1.0% by weight, preferably 0.05 to 0.3% by weight. When the content is 1.5% by weight or more, not only does the acidity become so strong that the feeling of use deteriorates, but also the irritation is strong and the product cannot be used.

The adhesive polymer used in the present invention is sodium polyacrylate and / or sodium carboxymethyl cellulose, and the one having an average particle size of 100 μm or less by fine pulverization is used. If the average particle size is larger than 100 μm, it causes blurring, not only making the feeling of use worse, but also the adhesion is poor. The amount of the finely pulverized adhesive polymer is 10 to 4
It is appropriately selected in the range of 0% by weight, but preferably 25 to 3
It is 5% by weight, and if it is 10% by weight or less, the adhesiveness is extremely lowered, and if it is 40% by weight or more, the mixing property with the base is poor, and it is difficult to prepare a homogeneous ointment.

As the ointment base used in the present invention, any mild oily base can be used, but white petrolatum is preferred, and one having a high degree of purification and a uniform molecular weight is preferable. The blending amount is appropriately selected within the range of 60 to 80% by weight, and preferably 65 to 75% by weight.

The steroidal anti-inflammatory drug used in the present invention is prednisolone, dexamethasone, hydrocortisone, triamcinolone, beclomethasone or its esters, and its compounding amount is 0.05 to 1.0% by weight.
It is preferably 0.1 to 0.5% by weight.

The antibacterial agent used in the present invention is cetylpyridinium chloride, decalinium chloride, tetracycline hydrochloride, minocycline or fradiomycin sulfate, and the compounding amount thereof is 0.05 to 5.0% by weight, preferably 0.05% by weight.
It is 1 to 3.0% by weight.

In the method for producing microcapsules according to the present invention, the drug and the film-forming polymer are dispersed or dissolved in a predetermined solvent and then produced using a so-called spray dryer such as a spray dryer.

The oral adhesive ointment of the present invention is prepared, for example, by the following production method. A predetermined amount of steroidal anti-inflammatory drug and antibacterial agent is previously dispersed or dissolved in hydroxypropylcellulose or polyvinylpyrrolidone aqueous solution, and microencapsulated using a spray dryer or the like (1). Separately, citric acid and sodium polyacrylate or sodium carboxymethyl cellulose are finely pulverized to obtain fine powder having an average particle size of 100 μm or less (2). These (1) and (2) and white petrolatum are stirred until they are homogeneous to obtain an intraoral adhesive ointment.

As a flavoring agent, sweeteners such as sucrose, xylitol, sorbitol, mannitol, sodium saccharin, and eucalyptus oil, peppermint oil, cinnamon oil,
Clove oil and the like can be added as a flavoring agent.

The present invention will be described in more detail below with reference to examples.

EXAMPLES Each oral adhesive ointment having the composition shown in Examples 1 to 3 and Comparative Examples 1 and 2 was prepared by the following method. A predetermined amount of steroidal anti-inflammatory drug and antibacterial agent are dispersed or dissolved in hydroxypropylcellulose or polyvinylpyrrolidone aqueous solution in advance, and microcapsules are prepared using a spray dryer (Yamato Scientific Co., Ltd., model name Parbis mini spray). Turn into. Separately, citric acid and sodium polyacrylate or sodium carboxymethyl cellulose are finely pulverized to obtain fine powder having an average particle size of 100 microns or less. Stir the above and white petrolatum until homogeneous to obtain an oral adhesive ointment.

Example 1 Prednisolone 0.2 parts by weight Cetylpyridinium chloride 0.1 parts by weight Copper chlorophyllin sodium 0.02 parts by weight Polyvinylpyrrolidone 1.6 parts by weight Sodium polyacrylate 30.0 parts by weight D-sorbitol 3.0 parts by weight Parts Saccharin sodium 0.5 parts by weight Citric acid 0.1 parts by weight Mint oil 1.0 parts by weight White petrolatum fuel gauge 100 parts by weight

Example 2 Triamcinolone acetonide 0.1 parts by weight Minocycline 2.0 parts by weight Polyvinylpyrrolidone 10.5 parts by weight Sodium polyacrylate 40.0 parts by weight Citric acid 0.05 parts by weight White petrolatum residual amount meter 100 parts by weight

Example 3 Hydrocortisone acetate 0.5 parts by weight Fradiomycin sulfate 0.1 parts by weight Hydroxypropyl cellulose 3.0 parts by weight Sodium carboxymethyl cellulose 35.0 parts by weight Saccharin sodium 0.3 parts by weight Citric acid 0.2 parts by weight Eucalyptus oil 1.0 parts by weight White petrolatum fuel gauge 100 parts by weight

Comparative Example 1 Prednisolone 0.2 parts by weight Cetylpyridinium chloride 0.1 parts by weight Copper chlorophyllin sodium 0.02 parts by weight Sodium polyacrylate (unmilled) 30.0 parts by weight D-sorbitol 3.0 parts by weight Saccharin sodium 0.5 parts by weight Citric acid 0.1 parts by weight Mint oil 1.0 parts by weight White petrolatum fuel gauge 100 parts by weight

Comparative Example 2 Prednisolone 0.2 parts by weight Cetylpyridinium chloride 0.1 parts by weight Copper chlorophyllin sodium 0.02 parts by weight Sodium polyacrylate 30.0 parts by weight D-sorbitol 3.0 parts by weight Saccharin sodium 0.5 parts by weight Part peppermint oil 1.0 part by weight White petrolatum fuel gauge 100 parts by weight

Comparative Example 3 Commercially available sodium polyacrylate-containing medical stomatitis ointment

Comparative Example 4 Commercially available sodium polyacrylate containing general-purpose stomatitis ointment

Test Example 1 With respect to the ointments of Test Example 1 and Comparative Example 1, 20 volunteers were used to evaluate the feeling of use, and the taste (bitterness) and voluminousness were observed. A sensory test was conducted on four items: flirting, adhesion, and overall judgment. In the test, 0.1 g of each ointment was applied to the outside of the gums, and the taste during application did not bother bitterness (+2), less bitterness (+1), normal (0), and slightly bitterness. It was judged as (-1), bitterness (-2), and about the fluffiness, it does not flutter (+2), does not flutter (+1), normal (0), slightly flutter (-). 1), it was judged to be blistering (-2), and the adhesiveness and the overall judgment were preferable (+2), slightly preferable (+1), normal (0), less preferable (-1) and not preferable (-). It was determined as 2) and scored for each average point.

The results are shown in FIG. As is clear from FIG. 1, Example 1 exceeded the feeling of use of Comparative Example 1 in all items, and it was found that the masking effect against the bitterness of the drug was simultaneously obtained by the microencapsulation for stabilization. . In Example 1, the ointment was adhered to all 20 people 3 hours after the start of the test, 13 people after 6 hours, and 6 people after 9 hours, giving very strong adhesion. It was confirmed. On the other hand, in the ointment of Comparative Example 1, the ointment adherence of 16 people was observed 3 hours after the start of the test, and the ointment adhesion of 3 people was observed 6 hours after the start of the test.
It was inferior to Example 1.

(Test Example 2) Stability with time The ointments of Example 1 and Comparative Example 2 were stored under the temperature conditions of 60 ° C and 40 ° C, and the stability of prednisolone and cetylpyridinium chloride with time was examined. As a result, Example 1
And the residual rates of prednisolone after storage at 60 ° C. for 3 weeks in Comparative Example 2 were 95.8% and 65.0%, respectively, and the residual rates of cetylpyridinium chloride were 9 respectively.
It was 5.2% and 80.0%, and the residual ratio of the drug in Example 1 was significantly higher than that in Comparative Example 2.

The residual ratios of prednisolone and cetylpyridinium chloride after storage at 40 ° C. for 6 months in Example 1 and Comparative Example 2 were 95.8% in Example 1 and 90.6% in Comparative Example 2, respectively. And 97.9% in Example 1 and 8 in Comparative Example 2.
It was 0.0%, and the residual ratio of the drug in Example 1 was significantly higher than that in Comparative Example 2.

Test Example 3 With respect to the ointments of Adhesive Example 1 and Comparative Examples 3 and 4, 0.5 g of each ointment was uniformly applied on a semipermeable membrane to evaluate the adhesivity, and the ointment was placed at 37 ° C. Stirring was performed using a stirrer in the artificial saliva kept (Teijin artificial saliva "Saribate (registered trademark)"). The state of each ointment was observed over time to examine the adhesive strength. As a result, in Example 1, strong adhesion was observed on the semipermeable membrane 3 hours after the start of the test, whereas in Comparative Example 3, adhesion was observed after 30 minutes, but not after 1 hour. It was Furthermore, in Comparative Example 4, after 30 minutes, no adhesion was already observed, and it was confirmed that the adhesion in Example 1 was remarkably strong.

(Experimental Example 4) Experience of use The ointment of Example 1 was applied 3 to 4 times a day to the affected areas of 3 volunteers (1 male and 2 female ) who had aphthous stomatitis, and the progress was observed. did. As a result, 3 ~
After 4 days, disappearance of aphtha was observed and healed.

[0028]

EFFECTS OF THE INVENTION As described above, the oral adhesive ointment of the present invention improves the taste (bitterness) of the main ingredient, has excellent stability over time, maintains strong adhesiveness, and has a good medicinal effect. Can be secured.

[Brief description of drawings]

FIG. 1 shows the taste (bitterness), grittyness, adhesiveness, and overall adhesiveness of the ointments of Example 1 and Comparative Example 1 when they were applied to the oral cavity using 20 volunteers to evaluate the feeling of use. The results of the sensory test of the four items of judgment are illustrated. Judgment taste: bitterness is not a concern (+2), bitterness is not a concern (+1), normal (0), bitterness is a little annoying (-
1), I'm worried about bitterness (-2) Hotness: Not hot (+2), Not hot (+1), Normal (0), Hot (-1), Hot (-) 2) Adhesiveness and overall judgment: favorable (+2), slightly favorable (+1), normal (0), less favorable (-)
1), not preferred (-2)

Claims (1)

[Claims] 1. An oral cavity containing a finely pulverized adhesive polymer in a steroidal anti-inflammatory drug and / or antibacterial agent stabilized by microencapsulation using a film-forming polymer and addition of citric acid. Internal adhesive ointment.