JP4866546B2 - Emulsion ointment containing diclofenac - Google Patents

Description

  The present invention relates to an emulsion ointment having excellent physicochemical stability, chemical stability of diclofenac or a salt thereof, little skin irritation, and good skin absorption.

  Diclofenac or a salt thereof is an excellent non-steroidal anti-inflammatory / analgesic agent and is widely used in the clinical setting as an oral or suppository. However, when administered orally or rectally, gastrointestinal, renal, and liver disorders are known as side effects. Especially, particularly for the gastrointestinal tract, serious side effects are observed, so that they act locally or systemically without going through the gastrointestinal tract. Various preparations for external use containing diclofenac or a salt thereof for the purpose of caking are proposed.

Gel ointments, poultices, and tapes are already known as external preparations containing diclofenac or a salt thereof as an active ingredient. However, there are various problems in formulating diclofenac or a salt thereof into an external preparation. . For example, although diclofenac or its salt has excellent anti-inflammatory / analgesic activity, it has a low fat solubility and poor percutaneous absorption compared to other nonsteroidal anti-inflammatory / analgesic agents such as indomethacin or ketoprofen. There is. Moreover, since the solubility of diclofenac or its salt with respect to the solvent which can be mix | blended with an external preparation is low, even if it can melt | dissolve at the time of manufacture, there exists a problem that a crystal | crystallization precipitates with time and a therapeutic effect falls. Furthermore, diclofenac or a salt thereof causes an ester reaction with the base component, and there is a problem that the content decreases with time.

  In order to solve these problems, studies have been conducted on external preparations containing various diclofenac or salts thereof. For example, gel preparation using diclofenac sodium dissolved in water and lower alcohol (Patent Document 1), preparation stability containing diclofenac or a salt thereof, nonionic polymer, dibasic acid ester and lower alcohol Anti-inflammatory analgesic gel preparation (Patent Document 2), oily ointment (Patent Document 3) using a solubilizing agent such as propylene glycol, stable diclofenac sodium-containing preparation for skin application (Patent Document 4) containing urea and sodium edetate , Diclofenac sodium, liquid fatty acid, stable patch containing crotamiton (Patent Document 5), stable transparent aqueous solution (Patent Document 6) composed of diclofenac sodium, fatty acid dialkyrolamide, and water are known.

  Among these gel preparations, since water and lower alcohol are contained in the formulation, it is easy to ensure the solubility and stability of diclofenac or a salt thereof, and excellent in transdermal absorption. Skin irritation and skin irritation caused by blending a large amount of alcohol are problematic. On the other hand, when it is used as a patch, it is difficult to dissolve diclofenac or a salt thereof in the plaster, and it is necessary to add a special dissolution aid. When the solubilizing agent is used and the solubility of diclofenac or a salt thereof in the paste is increased, the transferability of diclofenac or a salt thereof to the skin is deteriorated, and the anti-inflammatory analgesic effect is reduced. Furthermore, when the patch is applied to a joint or the like, there is a drawback that it is easy to peel off and it is difficult to maintain the effect.

For emulsion ointments, diclofenac sodium, fatty acid, carboxylic acid dialkyl ester as an essential component and an emulsifying external preparation (Patent Document 7), diclofenac sodium, carboxylic acid dialkyl ester, oleyl alcohol and polyhydric alcohol are also included. Although emulsified external preparations (Patent Document 8) with excellent transdermal absorbability and little skin irritation have been proposed, none of them are satisfactory in terms of stability, skin absorbability, and skin irritation, and are still unsatisfactory. In fact, an emulsion ointment containing diclofenac or a salt thereof as an active ingredient is not commercially available.
JP 59-76013 A International Publication No. 92/07561 Pamphlet JP 59-33211 A Japanese Patent Laid-Open No. 6-48939 JP-A-7-89853 JP-A-9-208542 Japanese Examined Patent Publication No.7-116026 Japanese Patent Laid-Open No. 9-12452

  Accordingly, an object of the present invention is to provide an external preparation containing diclofenac or a salt thereof having little skin irritation, excellent feeling in use, good storage stability and skin absorbability.

  In view of such circumstances, the present inventors have intensively studied to develop an external preparation containing diclofenac or a salt thereof which is an emulsion type with less skin irritation and excellent in stability over time. As a result, when diclofenac or a salt thereof is added to an emulsion base combined with carboxylic acid dialkyl ester, N-alkylpyrrolidone, polyhydric alcohol, and dibutylhydroxytoluene, there is less skin irritation, crystal precipitation, discoloration, diclofenac or its The present invention has been completed by finding that an emulsion ointment containing diclofenac or a salt thereof which does not show deterioration in stability such as a decrease in salt content and is excellent in skin absorbability can be obtained.

  That is, the present invention provides an emulsion ointment containing diclofenac or a salt thereof, carboxylic acid dialkyl ester, N-alkylpyrrolidone, polyhydric alcohol and dibutylhydroxytoluene.

  The emulsion ointment of the present invention is excellent in the chemical stability of diclofenac or a salt thereof and not only has improved physicochemical stability such as precipitation of crystals and discoloration of the preparation even when stored for a long period of time. Compared to commercially available gel ointments, cataplasms or tapes, it has good transdermal absorption and has an excellent pharmacological effect.

  Examples of the salt of diclofenac which is an active ingredient of the emulsion ointment of the present invention include various pharmaceutically acceptable inorganic or organic salts. For example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; alkylamine salts such as dimethylamine salt, diethylamine salt, trimethylamine salt and triethylamine salt; monoethanol salt; Examples thereof include alkanolamine salts such as diethanolamine salt, diisopropanolamine salt, triethanolamine salt and triisopropanolamine salt. As diclofenac or a salt thereof, a diclofenac alkali metal salt is preferable, and diclofenac sodium is particularly preferable. The content of diclofenac or a salt thereof in the emulsion ointment is preferably 0.1 to 5% by weight (hereinafter simply referred to as “%”), and particularly preferably 0.5 to 3%. If the content of diclofenac or a salt thereof is too low, the required pharmacological effect cannot be expected.If the content of diclofenac or a salt thereof is too high, diclofenac or a salt thereof can be dissolved in the emulsion ointment base. It may become difficult and formulation may be difficult.

  Examples of the carboxylic acid dialkyl ester that is one of the components blended as the base of the emulsion ointment of the present invention include dialkyl esters of aromatic dicarboxylic acids such as dimethyl phthalate, diethyl phthalate, and dibutyl phthalate; Examples thereof include dialkyl esters of aliphatic dicarboxylic acids such as diisopropyl acid, diisobutyl adipate, diethyl adipate, diisopropyl sebacate, and diethyl sebacate. As the carboxylic acid dialkyl ester, diisopropyl adipate and diethyl sebacate are particularly preferable. The content of the carboxylic acid dialkyl ester in the emulsion ointment is preferably 1 to 40%, particularly preferably 5 to 20%. When the content is small, the solubility of diclofenac or a salt thereof is deteriorated and crystal precipitation occurs. On the other hand, if the content is too large, there may be adverse effects such as difficulty in emulsification or increased skin irritation.

Examples of N-alkylpyrrolidone which is one of the components blended as the base of the emulsion ointment of the present invention include N-methyl-2-pyrrolidone, N-ethylpyrrolidone, N-propylpyrrolidone, N-isopropylpyrrolidone. N-lower alkylpyrrolidone such as N-butylpyrrolidone and N-isobutylpyrrolidone. As N-alkylpyrrolidone, N-methyl-2-pyrrolidone is particularly preferable. The content of N-alkylpyrrolidone in the emulsion ointment is preferably 0.5 to 10%, particularly preferably 1 to 8%. When the content is small, the solubility of diclofenac or a salt thereof is deteriorated and crystal precipitation occurs. On the other hand, when there is too much content, emulsification may become difficult.

  Examples of the polyhydric alcohol which is one of the components blended as the base of the emulsion ointment of the present invention include polyethylene glycol having an average molecular weight of 200 to 20000 such as polyethylene glycol 300 and polyethylene glycol 400, propylene glycol, 1, Examples include dihydric alcohols such as 3-butylene glycol; trihydric or higher alcohols such as glycerin and diglycerin. As the polyhydric alcohol, a dihydric alcohol is preferable, and propylene glycol and 1,3-butylene glycol are particularly preferable. The content of polyhydric alcohol in the emulsion ointment is preferably 1 to 30%, particularly preferably 5 to 20%.

  The content of dibutylhydroxytoluene, which is one of the components blended as the base of the emulsion ointment of the present invention, is preferably 0.001 to 1%, particularly 0.01 to 0.5%. preferable. If the content is too small, there may be a problem with the stabilizing effect of diclofenac or a salt thereof, and if the content is too large, it causes skin irritation or discoloration.

  By adding a chelating agent to the emulsion ointment of the present invention, it is possible to suppress discoloration caused by a trace amount of metal mixed in from manufacturing equipment. Examples of the chelating agent include edetic acid or an alkali metal salt thereof, an alkali metal salt of hydroxyethylethylenediamine triacetic acid, an alkali metal salt of dihydroxyethylethylenediamine diacetate, diethylenetriaminepentaacetic acid, or an alkali metal salt thereof. As the chelating agent, an alkali metal edetate is preferable, and sodium edetate is particularly preferable. The content when a chelating agent is blended in the emulsion ointment is preferably 0.001 to 1%, particularly preferably 0.005 to 0.2%.

The emulsifying type of the emulsion ointment of the present invention may be either W / O type or O / W type, but O / W type is preferred.
Examples of the emulsifier include anionic surfactants and nonionic surfactants, and nonionic surfactants are particularly preferable. Nonionic surfactants include, for example, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene castor oil, polyoxyethylene Examples include ethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene alkyl ether, polyglycerin fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, and propylene glycol fatty acid ester. As the nonionic surfactant, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester and the like are preferable. These nonionic surfactants may be blended singly or in combination of two or more. The content of the emulsifier in the emulsion ointment is preferably 0.2 to 10%, particularly preferably 1 to 5%.

  The emulsion ointment of the present invention can be blended with a gelling agent in order to further improve the stability and the feeling of use. Examples of the gelling agent include carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and the like. As the gelling agent, carboxyvinyl polymer is particularly preferable. The content when the gelling agent is blended in the emulsion ointment is preferably 0.05 to 3%, particularly preferably 0.2 to 1%.

  In the emulsion ointment of the present invention, in order to further improve the emulsion stability, for example, higher alcohols such as cetanol, stearyl alcohol, cetostearyl alcohol, and petrolatum, liquid paraffin, squalane and the like generally used in cosmetics and external preparations. In addition to hydrocarbon oils, oil agents such as isopropyl myristate and medium chain fatty acid triglycerides may be blended. The content of the oil agent in the emulsion ointment is preferably from 1 to 30%, particularly preferably from 3 to 15%. If the amount of the oil agent is small, improvement in stability and feeling of use cannot be expected, and if it is too large, emulsification may be difficult.

  The pH of the emulsion ointment of the present invention is preferably 5.5 to 8.5, particularly preferably in the range of 6 to 7.5. Examples of the weakly basic pH adjuster for pH adjustment include 1 to 3 alkanolamines or alkylamines. Specific examples of the alkanolamine include monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine and the like, and examples of the alkylamine include dimethylamine, diethylamine, trimethylamine and triethylamine. Examples of the acidic pH adjuster include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as citric acid, lactic acid, malic acid, and succinic acid.

  If necessary, the emulsion ointment of the present invention may contain a preservative such as benzoic acid or an alkali metal salt thereof, salicylic acid or an alkali metal salt thereof, and a lower alkyl ester of paraoxybenzoic acid. As the preservative, paraoxybenzoic acid alkyl esters such as paraoxybenzoic acid methyl ester and paraoxybenzoic acid ethyl ester are preferable. The content of the preservative in the emulsion ointment is preferably 0.05 to 0.5%.

  The emulsion ointment of the present invention can be produced by mixing and emulsifying a water phase component and an oil phase component by a conventional method. At this time, it is preferable to produce an emulsion having an average particle size of 3 μm or less, and particularly preferably 1 μm or less. The average particle diameter of the emulsified particles can be measured, for example, by a laser diffraction scattering method.

  The emulsion ointment of the present invention does not require the use of a large amount of lower alcohol, so there is no skin irritation, excellent usability, physicochemical stability, chemical stability of diclofenac or a salt thereof, and skin absorption. Excellent.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1
Production of emulsion ointment Components (2) to (10) and (13) in Table 1 were dissolved at 70 to 80 ° C. to obtain an oil phase. Components (11) to (12) and component (19) are mixed and heated to 70 to 80 ° C., and then components (1), (14), (15) and (16) are dissolved to form an aqueous phase. did. Add the water phase to the oil phase and emulsify, then cool, add the component (17) swollen with a part of the component (19), stir, and finally add the component (18) until uniform The mixture was stirred to obtain an emulsion ointment. The pH was 7.0 (25 ° C.). The emulsion type of the obtained emulsion ointment was an O / W type emulsion system, and the average particle size was 0.45 μm.

Example 2
The emulsion ointments of the present invention products 1-2 and comparative products 1-3 produced in Example 1 were stored in a constant temperature room at 4 ° C., and the precipitation of crystals was visually observed. The results are shown in Table 2.

  It was confirmed that the emulsion ointment of the present invention was excellent in storage stability because no crystal precipitation was observed even when stored in a cold place for a long time. On the other hand, in Comparative products 1 and 3, precipitation of crystals was observed from the time of manufacture. In Comparative Product 2, no precipitation of crystals was observed at the time of manufacture, but precipitation of crystals was observed over time, and the feeling of use was impaired, and percutaneous absorption was hindered by the precipitation of crystals, which also affected the pharmacological effect. there were.

Example 3
After the emulsion ointments of the present invention products 1-2, comparative product 2 and comparative product 4 produced in Example 1 were filled in an aluminum laminate tube and stored in a thermostatic chamber at 50 ° C. and 60 ° C. for 1 month. The residual rate of diclofenac sodium was measured by HPLC. Further, the color change of the emulsion ointment stored under the same conditions was visually observed. These results are shown in Table 3.

  Even if the emulsion ointment of the present invention is stored under severe conditions of 1 month at 50 ° C. and 60 ° C., the chemical stability of diclofenac sodium is good, and discoloration of the emulsion ointment is also observed. It had excellent storage stability. On the other hand, although the discoloration was not recognized in the comparative product 2, the chemical stability of diclofenac sodium was clearly inferior to the products 1 and 2 of the present invention. Further, the emulsion ointment of Comparative product 4 was discolored, and the chemical stability of diclofenac sodium was clearly inferior.

Example 4
The skin transferability of diclofenac sodium from the emulsion ointment of the present invention product 2 was compared with a commercially available gel ointment containing diclofenac sodium. In the test, each preparation was applied to the back-extracted skin of Yucatan micropig, and after 4 hours, the ointment was wiped off. The results are shown in Table 4.

The emulsion ointment of the present invention had higher diclofenac sodium keratin migration compared to a commercially available diclofenac sodium-containing gel ointment.

Claims (10)

0.1 to 5% by weight of diclofenac sodium, 1 to 40% by weight of carboxylic acid dialkyl ester selected from diethyl sebacate and diisopropyl adipate , 0.5 to 10% by weight of N-methyl-2-pyrrolidone , propylene glycol And an emulsion ointment containing 1 to 30% by weight of a polyhydric alcohol selected from 1,3-butylene glycol and 0.001 to 1% by weight of dibutylhydroxytoluene, and having an average particle diameter of 1 μm or less . Furthermore, emulsion ointment agent according to claim 1 Symbol mounting comprises a chelating agent 0.001% by weight. The emulsion ointment according to claim 2 , wherein the chelating agent is sodium edetate. The emulsion ointment according to any one of claims 1 to 3 , further comprising 0.2 to 10% by weight of a nonionic surfactant. The emulsion ointment according to any one of claims 1 to 4 , further comprising 0.05 to 3% by weight of a gelling agent. The emulsion ointment according to claim 5 , wherein the gelling agent is a carboxyvinyl polymer. The emulsion ointment according to any one of claims 1 to 6 , further comprising 0.05 to 0.5% by weight of a preservative. The emulsion ointment according to claim 7 , wherein the preservative is a paraoxybenzoic acid ester. The emulsion ointment according to any one of claims 1 to 8 , which has a pH of 5.5 to 8.5. The emulsion ointment according to any one of claims 1 to 9 , comprising alkanolamine or alkylamine as a pH adjuster.