JPS63130540A - Analgesic component - Google Patents

Abstract

PURPOSE:To obtain the titled composition having low irritation to mucosa and prolonged analgesic action, by blending a specific hydrogel with a methacrylic acid copolymer, a solubilizer in a specific weight ratio to the copolymer and a water-insoluble partial narcotic agent, etc., as active ingredients. CONSTITUTION:An analgesic composition consisting of (A) 0.2-10wt% based on sum of the composition of a hydrogel comprising a water-soluble high polymer substance and a polyhydric alcohol, (B) a methacrylic acid copolymer selected from aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS and a mixture thereof, (C) a solubilizer which dissolves the component B but not has compatibility with the polyhydric alcohol and (C) one or more active components selected from a water-insoluble and a water-soluble local narcotic agent and a methoxyphenol local narcotic agent. In the preparation, the weight ratio of the components B and C is 1:2-1:25.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to analgesic compositions containing local anesthetics and/or local analgesics. More specifically, the present invention relates to an analgesic composition that is less irritating to mucous membranes, has an active ingredient that remains at the administration site for a long period of time, and exhibits a sustained analgesic effect.

Conventional technology and its problems: Non-water-soluble local anesthetics and water-soluble local anesthetics have been used as drugs to alleviate pain caused by gingival inflammation, toothache caused by caries, perianal inflammation, nasal mucositis, etc., or pain in teeth, mucous membranes, etc. Various drugs are known, such as anesthetics and methoxyphenol local analgesics. These drugs are generally used as external preparations in the form of liquids or ointments, and various proposals have already been made (for example, JP-A-54-46819, JP-A-54-140713, Japanese Patent Publication No. 56-1394
No. 15 and Japanese Patent Publication No. 58-219111).

However, such conventional analgesic compositions have various problems in actual use.

In other words, in the case of a liquid product (liquid), it is necessary to dip a small amount into a small cotton ball and apply it to the affected area; in the case of oral administration,
The drug may adhere to other gums or the tongue, causing unpleasant anesthesia. Furthermore, the administered active ingredient quickly flows out of the affected area due to saliva and exudate, resulting in poor sustainability of the effect of the active ingredient. In addition, the anal area, nasal mucosa, etc.
When administered to mucosal sites, it also has poor persistence due to its unique structure.

On the other hand, ointments do not have these disadvantages, but they may be highly irritating to the diseased area, the time it takes for the drug to adhere to the diseased area is short, and furthermore, the release of the active ingredient from the ointment base may be insufficient. There are problems in that it is insufficient or cannot release the active ingredient in a sustained manner.

Means for Solving the Problems In view of the above circumstances, the present inventors have developed a method that is easy to handle and
As a result of intensive research to obtain an analgesic composition that exhibits sufficient adhesion and local retention when applied to wet surfaces and that continuously releases the active ingredient, an ointment has already been filed. When a specific water-insoluble local anesthetic, a water-soluble local anesthetic, a methoxyphenol derivative, a local analgesic, or a pharmaceutically acceptable salt thereof is blended with the base (Japanese Patent Application No. 60-2G3314), The present inventors have discovered that the resulting composition remains at the administration site for a long period of time, exhibits a sustained effect, and has low mucosal irritation, leading to the completion of the present invention.

That is, the present invention provides (a) a hydrogel formed from a water-soluble polymeric substance and a polyhydric alcohol, (b) an aminoalkyl methacrylate copolymer E1
a methacrylic acid-based copolymer selected from the group consisting of an aminoalkyl methacrylate copolymer RS, or a mixture thereof; (c) a solubilizer that dissolves the methacrylic acid-based copolymer but is incompatible with the polyhydric alcohol; and (d) one or more active ingredients selected from the group consisting of a water-insoluble local anesthetic, a water-soluble local anesthetic, a methoxyphenol local analgesic, or a pharmaceutically acceptable salt thereof. The present invention provides an analgesic composition characterized in that the weight ratio of the methacrylic acid copolymer to the solubilizer is 1:2 to 1:25.

The present invention provides for the application of an active ingredient, a local anesthetic, a local analgesic, or a pharmaceutically acceptable salt thereof, to a specific mixture of bases, namely a hydrogel, a methacrylic copolymer, and a solubilizing agent. It is characterized by the fact that it is blended. .

Therefore, the analgesic composition of the present invention has excellent adhesion to the diseased site, and since the active ingredient is sustainedly released by the methacrylic acid copolymer coating, - it exhibits a sustained effect on the diseased site over a long period of time. At the same time, low irritation to mucous membranes is achieved.

Therefore, the composition of the present invention can be directly administered locally in the oral cavity, such as periodontal pockets, teeth, nasal mucosa, and the anal area, and exhibits its effects over a long period of time.

Next, the analgesic composition of the present invention will be explained in more detail.

The water-soluble polymeric substance constituting the hydrogel, which is a component of the composition of the present invention, is preferably one that is soluble in the polyhydric alcohol, which is another component of the hydrogel. Examples of such water-soluble polymer substances include polyvinyl alcohol, polyvinylpyrrolidone, carrageenan, locust bean gum, guar gum, hydroxyethylcellulose, xanthan gum, tragacanth gum, starch, and succinoglucan. These seem to be independent, but 2
More than one species can be used in combination.

Among these, hydroxyethylcellulose is particularly preferred and exhibits excellent sustained release properties for local anesthetics and local analgesics.

In addition, the amount of water-soluble polymer blended is 0.2 based on the total amount of the composition.
It is preferable that the amount is about ˜IO weight %.

Next, polyhydric alcohols that are other components of the hydrogel used in the present invention include glycerin, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, hexylene glycol,
．． Examples include 5-pentanediol and 1.3-butylene glycol. These can be used alone or in combination of two or more. Among these, particularly preferred are glycerin, propylene glycol, and 1,3-butylene glycol, which are less irritating to the oral mucosa.

In addition, the amount of polyhydric alcohol blended is 5% based on the total amount of the composition.
Preferably, it is 0 to 85% by weight.

The blending ratio of the water-soluble polymeric substance and polyhydric alcohol in the hydrogel is preferably 1:9 to 1:400. If the blending ratio of the water-soluble polymer substance is less than this, it is difficult to maintain the stability of the formulation;
If it exceeds this range, the viscosity will increase, making kneading difficult in terms of the manufacturing process.

The amount of the hydrogel to be added to the total composition is 5
Preferably, it is 5 to 90% by weight. If the blending amount is out of this range, it will be difficult to maintain the stability of the formulation.

Next, the methacrylic acid-based copolymers to be used in the composition of the present invention include aminoalkyl methacrylate copolymer E known as Eudragit E, aminoalkyl methacrylate copolymer R9 known as Eudragit R6, and combinations thereof. Something is used.

The amount of the methacrylic acid copolymer blended is preferably 05 to 10% by weight based on the total amount of the composition. If the amount is less than 0.5% by weight, it may be difficult to obtain a sustained release effect of the active ingredient, while if it exceeds 10% by weight,
Due to the high viscosity, kneading is difficult due to the manufacturing process.

Next, the solubilizing agent used in the present invention dissolves the methacrylic acid copolymer, but is incompatible with polyhydric alcohol.

Such a solubilizer makes it possible to uniformly disperse the hydrogel in the form of particles in the composition.

Examples of such solubilizers include esters of lower fatty acids with lower polyhydric alcohols such as lyacedin, tributyrin, and diacetyl ethylene glycol, or diethyl sebacate, diethyl phthalate, dibutyl phthalate, diisopropyl adipate, and dibdel succinate. Examples include esters of lower alcohols and nocarboxylic acids. These may be used alone or in combination of two or more. Among these, triacetin is particularly preferred as it is excellent in safety and usability.

The blending amount of the surface solubilizer based on the total amount of the composition is 5 to 25
% by weight is preferred. If the amount of the solubilizer exceeds this range, it will be difficult to obtain a sustained release effect of the active ingredient.

Further, the weight ratio of the methacrylic acid copolymer di-solubilizer blended into the composition is 1.2 to 1:25. If the blending ratio of solubilizer is less than this, the formulation will be unstable,
The sustained release effect of local anesthetics and local analgesics cannot be obtained. On the other hand, if the blending ratio of the solubilizer is higher than this, the local anesthetic and local analgesic will be rapidly eluted. The desired sustained release property cannot be obtained.

That is, the ratio of the methacrylic acid copolymer and the solubilizer added to the composition was studied as follows. A metal flat plate (50 x 50 mm) was welded to the lower part of the rotating shaft of the test device specified in the dissolution test method of the Japanese Pharmacopoeia, and a cheek pouch desicca extracted from a hamster was spread and fixed on this plate.

Apply an ointment on this mucous membrane [Composition: Nioidragit R9 blending amount; 0°1.0.5.2, 0.50.10.0.20.
Amount of triacetin added to 0% by weight: 2,5.5.
0, ■0.0.25.0.50.0.75.0% by weight,
1 g of hydroxyethylcellulose (12.0% by weight, remainder glycerin) was applied and rotated at 37°C and 100 rpm in artificial saliva, and adhesion to mucous membranes and retention were visually determined. As a result, good retention properties were obtained when the ratio of triacetin dihydrogen 1 to RS was in the range of 1.2 to 1:25.

Note that the composition of the present invention can contain up to several percent of water.

Next, the active ingredients in the composition of the present invention, such as water-insoluble local anesthetics, water-soluble local anesthetics, and methoxyphenol-based local analgesics, may be used in the free form or in pharmaceutically acceptable acid salts. It can be in any form of addition salt.

For example, water-insoluble local anesthetics include ethyl aminomoriguchi octaate, D-piperinolacetamino-Q, ethyl frate, lidocaine, dibucaine, etc. Ethyl aminobenzoate is preferred.

In addition, water-soluble local anesthetics include propyvacaine hydrochloride, dibucaine hydrochloride, lidocaine hydrochloride, tetracaine hydrochloride, p-butylaminobenzoic dinoethylaminoethyl mepivacaine hydrochloride, fupivacaine hydrochloride, protopitocaine hydrochloride, and hexothylene hydrochloride. Examples thereof include butaniricaine hydrochloride, butaniricaine hydrochloride, ocimbupropylene hydrochloride, mepril hydrochloride, piperocaine hydrochloride, etc. Among them, dibucaine hydrochloride, lidocaine hydrochloride, tetracaine hydrochloride, and diethylaminoethyl p-butylaminobenzoate hydrochloride are preferred.

Furthermore, methoxyphenol-based local analgesics include thymol, guaiacol, taleosote, chojiura, eugenol, isoeugenol, and the like, with chojiura and eugenol being preferred.

These active ingredients may be used alone or in combination of two or more.

In addition, from the viewpoint of medicinal efficacy, the amount of these compounds is generally 1-10% by weight in the case of water-insoluble local anesthetics and methoxyphenol-based local analgesics, and in the case of water-insoluble local anesthetics, based on the total amount of the composition. In the case of an agent, the amount is preferably about 0.1-1% by weight.

Therefore, a preferred formulation of the analgesic composition of the present invention is:
It is as follows.

0.1-1% by weight Local analgesic: 1-10% by weight Water-soluble polymer substance 0.2-10.0% by weight Solubilizer 5.0-25.0% by weight Methacrylic acid copolymer 0.5 ~10.0% by weight polyhydric alcohol balance The analgesic composition of the present invention can be prepared by conventionally known formulation techniques.

For example, a predetermined amount of a water-soluble polymer substance is added to polyhydric alcohol, heated appropriately to mix and dissolve thoroughly, and then cooled to obtain a hydrogel. A water-soluble local anesthetic, or a pharmaceutically acceptable salt thereof, is added to this hydrogel to obtain a mixture. On the other hand, a water-insoluble local anesthetic and/or a methoxyphenol local anesthetic is added to a solution prepared by dissolving the methacrylic acid copolymer in a solubilizer, and this is prepared by adding the above-mentioned active ingredient or its pharmaceutical agent. Mix into a mixture containing acceptable salts to obtain the desired composition. The active ingredients may be dissolved or suspended in one or both of polyhydric alcohols and solubilizers, either alone or in combination, and if necessary heated within a range that does not impair the stability of the drug. You may do so.

In preparing the composition of the present invention, the predetermined components may be appropriately blended in other orders, and if desired, an appropriate amount of ethanol, isopropanol, or nonionic surfactant may be added. In addition, in order to improve the usability, d
, Q-menthol, thymol and the like may be added in appropriate amounts.

The composition thus obtained is in the form of a viscous liquid or paste.

EXAMPLES Furthermore, the present invention will be explained in more detail based on Examples and Test Examples.

Example 1 An analgesic composition was produced with the following composition.

Yield Dish ■ Ethyl aminobenzoate 1O10 eugenol 5.0 Hydroxyethyl cellulose 4.0 Glycerin 67.
0 Triacetin 12.0 Eudragit Rs 2.0 Glycerin 135
After heating to ℃, hydroxyethylcellulose was added and dissolved, and the mixture was cooled. On the other hand, Eudragit RS was dissolved in triacetin, and a solution obtained by adding and dissolving ethyl aminobenzoate and eugenol was added to the mixture and mixed uniformly to obtain a desired composition.

Example 2 An analgesic composition was produced with the following composition.

Dietylaminoethyl benzoate 0.5 xanthan gum 0.5 glycerin
83.0 Diethyl sebacate 14
．． After heating 0 Eudragit E 2,0 glycerin to 120°C, xanthan gum was added and dissolved. After dissolving, the mixture was cooled to 40°C, and jedylaminoethyl hydrochloride p-butylaminobenzoate was added and mixed. Meanwhile, Eudragit E was dissolved in diethyl sebacate,
The obtained liquid was added to the mixture and mixed uniformly to obtain a desired composition.

Example 3 An analgesic composition was produced with the following composition.

1'iEi Dish 1 Ethyl aminobenzoate 5.0 Dibucaine hydrochloride 1.0 Eugenol
3.0 hydroquine edil cellulose 2.0
Glycerin 75.0 Triacetin
12,0 Eudrakit R92,0 Hydroxyethyl cellulose was dissolved in glycerin in the same manner as in Example I above. After dissolving, the mixture was cooled, dibucaine hydrochloride was added, and the mixture was mixed uniformly.

On the other hand, Eudragit R8 was dissolved in triacetin, ethyl aminobenzoate and eugenol were added and dissolved in the resulting solution, and this was added to the mixture and mixed uniformly to obtain a desired composition.

Example 4 An analgesic composition was produced with the following composition.

Ball ``-minute % weight ethyl aminobenzoate 8.0 dibucaine hydrochloride 0.3 eugenol
2.0 Hydroxyedyl cellulose 2.
0 Glycerin 71.7 Triacedin 14.0 Eudragit R82.0 A mixture of dibucaine hydrochloride, hydroxyethylcellulose and glycerin was prepared in the same manner as in Example 3. A mixture of triacetin, Eudragit R8, ethyl aminobenzoate, and eugenol was added to this and mixed uniformly to obtain a desired composition.

Example 5 An analgesic composition was produced with the following composition.

Yield: Weight % Ethyl aminobenzoate 2.0 Lidocaine hydrochloride 0.2 Soybean oil
2,0 polyvinylpyrrolidone 2
．． 0 Propylene glycol 65.8 Dibutyl phthalate! 8.0 Eudragit E
4.0 propylene glycol 65
After heating to ℃, polyvinylpyrrolidone was added and dissolved.

After cooling, lidocaine hydrochloride was added and mixed uniformly. on the other hand,
Eudragit E was dissolved in dibutyl phthalate, and ginger oil was added to the resulting liquid, which was added to the mixture and mixed uniformly to obtain a desired composition.

Test Example 1 (Adhesion Test) The adhesion of the analgesic composition obtained in the above example was measured.

A metal flat plate (50 x 50 mm) was welded to the lower part of the rotating shaft of the test device specified in the elution test method of the Japanese Pharmacopoeia, and the cheek pouch mucosa extracted from the hamster was spread and fixed on this plate. Each test sample I obtained in Examples 1 to 5 was placed on this mucous membrane.
g and 1100r at 37°C in artificial saliva.
The sample was rotated at 500 p and the adhesion time to the mucous membrane was measured.

In addition, as a control example, by the same method as the above example,
A composition of the same formulation was prepared and used in the test.

Ethyl aminobenzoate 10.0 Eugenol 5.0 Control Example I Q-Menthol 3.0 Tragacanth gum powder (200 mesh passes) 33.0 White petrolatum; Plasdibase = I; 2 mixture 49.0 p-Butylamide hydrochloride, benzoin Dietylaminoethyl acid 0.5 Control example 2 Tragacanth gum powder (200 mesh passes) 33.0 White petrolatum: Plastibase-1;2 mixture 66.5 Dietyl aminobenzoate 5.0 Dibucaine hydrochloride 1.0 Control example 3 Eugenol 3. 0 Gum tragacanth powder (200 mesh passes) 33.0 White petrolatum, Plastibase-1=2 mixture 58.0 Ethyl aminobenzoate 8.0 Dibucaine hydrochloride 0.3 Control example 4 Eugenol 2.0 Gum tragacanth powder (200 mesh passes) 33.0 White petrolatum: Plastibase-1:2 mixture 56.7 Ethyl aminobenzoate 2.0 Lidocaine hydrochloride 0.2 Control example 5 Clove oil 8.0 Tragacanth gum powder (200 mesh) 33.0 White petrolatum: Plastibase-1:2 mixture 56.8 The results are shown in Table 1 below.

Table 1 Example 1 121 〃 2 129 〃 4 135 〃 5 1O5 Control Example 1 54 〃 2 63 〃 3 58 〃 4 51 〃 5 49 As is clear from Table 1, the composition of the present invention was excellent. It was found that it has a strong adhesive property and sticks to mucous membranes for a long time.

Therefore, compared to conventional compositions, the analgesic composition of the present invention can adhere to the affected area, especially in the oral cavity, for a long time, exhibits its effect continuously, and can be suitably used as an analgesic for toothache. sell.

Test Example 2 (Analgesic effect) 35 mg of the composition obtained in the above example and control example
was applied to the corneas of guinea pigs (5 animals per group x 3 groups), and 90
I removed it every second. Next, the cornea of this guinea pig was stimulated over time using pig hair, and the local anesthetic effect was observed using the eyeblink reaction method.

Furthermore, 24 hours later, the cornea was observed with the naked eye, and the degree of cloudiness was scored according to the following criteria, and the total for each group was calculated to determine mucous membrane irritation.

Condition of mucosal irritation cornea No localization is observed O Slight cloudiness in a part of the cornea 1 Clear cloudiness in a part of the cornea 2 Clear cloudiness in the entire cornea 3 Cloudiness accompanied by corneal epithelial detachment 4 The results are as follows. Shown in Table 2. rta, ■, in the table. is the average value for the three groups of the time when the blink response was suppressed by 75% and 50% in each group.

Table 2 Example 1 24.0 40.0 4
”2 4,7 15.8 3〃3
6.0 24.0 2〃4 8. [l
20.5 2〃5 10.9
30.1 4 Control Example 1 to. 0
22.5 15〃2 1.2 2.
9 6〃3 1.6 3.5
7〃4 2.2 5.0 6th 2nd
As is clear from the table, the analgesic composition of the present invention was found to exhibit good analgesic effect and to have extremely low irritation to mucous membranes.

Effects of the Invention As described above, the analgesic composition of the present invention has excellent adhesion to diseased areas, and the anesthetic and analgesic active ingredients are sustainedly released by the methacrylic acid copolymer coating. Therefore, the drug should be released continuously over a long period of time to the diseased area. Therefore, the composition of the present invention can be administered directly to periodontal lesions, intraoral openings, such as periodontal pockets, postoperative Ig''L areas, nasal mucosa, and anal mucosa, and can be administered for a long period of time. Patent applicant with analgesic effect: Fu Morioka, patent attorney, Zanstar Co., Ltd.

Claims (15)

[Claims] (1) (a) Hydrogel formed from a water-soluble polymeric substance and a polyhydric alcohol, (b) Aminoalkyl methacrylate copolymer E,
a methacrylic acid-based copolymer selected from the group consisting of an aminoalkyl methacrylate copolymer RS, or a mixture thereof; (c) a solubilizer that dissolves the methacrylic acid-based copolymer but is incompatible with the polyhydric alcohol; and (d) one or more active ingredients selected from the group consisting of a water-insoluble local anesthetic, a water-soluble local anesthetic, a methoxyphenol local analgesic, or a pharmaceutically acceptable salt thereof. , an analgesic composition characterized in that the weight ratio of the methacrylic acid copolymer to the solubilizer is 1:2 to 1:25. (2) The amount of the water-soluble polymer substance in the hydrogel is 0.2 to 10% by weight based on the entire composition.
) Analgesic composition. (3) The weight mixing ratio of the water-soluble polymer substance and polyhydric alcohol in the hydrogel is 1:9 to 1:400.
1) Analgesic composition. (4) The water-soluble polymeric substance is one or more selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, carrageenan, locust bean gum, guar gum, hydroxyethylcellulose, xanthan gum, tragacanth gum, starch, and succinoglucan. The analgesic composition according to item (1) above, which is a water-soluble polymeric substance. (5) The analgesic composition according to item (1) above, wherein the water-soluble polymeric substance is hydroxyethyl cellulose. (6) The polyhydric alcohol is glycerin, ethylene glycol, diethylene glycol, propylene glycol,
Dipropylene glycol, hexylene glycol, 1,
The analgesic composition according to item (1) above, which is one or more polyhydric alcohols selected from the group consisting of 5-pentanediol and 1,3-butylene glycol. (7) The analgesic composition according to item (1) above, wherein the polyhydric alcohol is glycerin, propylene glycol, or 1,3-butylene glycol. (8) The analgesic composition according to item (1) above, wherein the amount of the methacrylic acid copolymer is 0.5 to 10% by weight based on the entire composition. (9) The blending amount of the solubilizer is 5 to 2 with respect to the entire composition.
The analgesic composition according to item (1) above, which is 5% by weight. (10) The analgesic composition according to item (1) above, wherein the solubilizer is selected from the group consisting of esters of lower polyhydric alcohols and lower fatty acids, and esters of lower alcohols and dicarboxylic acids. (11) The analgesic agent according to item (10) above, wherein the solubilizing agent is selected from the group consisting of triacetin, tributyrin, diacetyl ethylene glycol, diethyl sebacate, diethyl phthalate, dibutyl phthalate, diisopropyl adipate, and dibutyl succinate. Composition. (12) 1 to 10% by weight of a water-insoluble local anesthetic, 0.1 to 1% by weight of a water-soluble local anesthetic, based on the entire composition;
The analgesic composition according to item (1) above, which contains 1 to 10% by weight of a methoxyphenol local analgesic and an active ingredient selected from the group consisting of pharmaceutically acceptable salts thereof. (13) The analgesic composition according to item (1) above, wherein the water-insoluble local anesthetic is ethyl aminobenzoate or ethyl p-piperidylacetylaminobenzoate. (14) Item (1) above, wherein the water-soluble local anesthetic is dibucaine hydrochloride, lidocaine hydrochloride, tetracaine hydrochloride, or diethylaminoethyl p-butylaminobenzoate hydrochloride.
Composition for pain relief. (15) The analgesic composition according to item (1) above, wherein the methoxyphenol-based local analgesic is clove oil or eugenol.