JPH0725674B2 - Anti-inflammatory analgesic external cream preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to an anti-inflammatory analgesic external cream preparation containing indomethacin as an active ingredient. More specifically, it relates to an anti-inflammatory analgesic external cream preparation that stably contains indomethacin, which is widely used as a non-steroidal anti-inflammatory analgesic in the orthopedic field.

(B) Conventional Technology Indomethacin has been marketed as a drug having an anti-inflammatory and analgesic action in various dosage forms such as ointments, creams, poultices and liquids. However, since indomethacin is a drug with poor stability, it is very difficult to maintain stability in the preparation, and a decrease in content due to hydrolysis or esterification reaction cannot be avoided. In particular, in the case of a cream preparation, indomethacin is dissolved, so that when a dissolving agent is added, liquid separation easily occurs, and color change occurs, so that it is difficult to prepare a soluble cream in which indomethacin is dissolved. Therefore, the commercially available indomethacin cream formulation is a suspension type formulation in which indomethacin is dispersed in the cream. However, suspension-type preparations have poorer transdermal absorbability than do dissolution-type preparations and a sufficient pharmacological effect cannot be obtained. Therefore, stable-dissolving cream preparations have been desired.

(C) Problems to be solved by the invention In the past, when making a cream preparation containing indomethacin, indomethacin is a poorly soluble drug,
Various compounds such as crotamiton, higher alcohols, and benzyl alcohol have been investigated as solubilizers. However, since indomethacin is a poorly stable drug, it reacts with these solubilizers or other cream bases in the formulation to form a decomposition product, which reduces the content of indomethacin and changes the color of the cream. Was given. For this reason, the pharmacological effect may not be sufficient, or the decomposition product may cause skin irritation. In addition, it is difficult to commercialize the product because the product value is lost due to the change in color. Therefore, it is an object of the present invention to obtain a cream formulation containing indomethacin that is stable over time.

(D) Means for Solving the Problems The present inventors have conducted various studies on a cream preparation containing indomethacin in a stable manner, and as a result, have found that a cream preparation having a certain specific base ingredient and a certain limited composition. Found to solve all the above problems. That is, 0.3 to 2% by weight of indomethacin as an active ingredient,
1-5% by weight of l-menthol, 2-10% by weight of nonionic surfactant and 5% of fatty acid ester as a base component
-25% by weight, carboxyvinyl polymer 0.3-2% by weight, sodium bisulfite 0.01-0.2% by weight, dibutylhydroxytoluene 0.01-0.2% by weight, organic base
It was found that the cream preparation having a composition of 0.1 to 3% by weight and the balance of water is excellent in indomethacin stability and thermal stability as a preparation, and is also excellent in transdermal absorbability. The components of the present invention will be described in more detail below.

Although 1-menthol is an active ingredient, it also has an effect as a dissolving agent for indomethacin. A suitable blending amount of 1-menthol is 1 to 5% by weight. If it is too small, the dissolution of indomethacin is insufficient, and if it is too large, the odor of 1-menthol is too strong, which is not preferable. Examples of nonionic surfactants include polyoxyethylene alkyl ether, polyoxyethylene phenyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene glycerin fatty acid ester, and polyoxyethylene hydrogenated castor oil. HLB of 10 to 20 is used, but in particular,
Polyoxyethylene sorbitan fatty acid ester is preferable from the viewpoint of feeling of use, stability of cream and the like. These surfactants are blended in an amount of 2 to 10% by weight. Examples of the fatty acid ester include medium to long chain fatty acid esters such as isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, glyceryl tricaprylate, glyceryl tricaprate, and propylene glycol tricaprylate. Among these fatty acid esters, the combination of isopropyl myristate and diisopropyl adipate is most preferable from the viewpoint of the solubility of indomethacin and the feeling of use. The blending amount of these fatty acid esters is 5
The amount is 25% by weight, preferably 10 to 20% by weight, and it is blended in one kind or in a combination of two or more kinds. Carboxyvinyl polymer is, for example, Carbopol 934,940,941 manufactured by Goodrich Chemical Co., or Hibis Wako 10 manufactured by Wako Pure Chemical Industries.
3,104,105 etc. are used. The content of carboxyvinyl polymer is 0.3 to 2% by weight, preferably 0.5 to 1.5% by weight. For the purpose of preventing coloration of the cream preparation, sodium bisulfite is 0.01 to 0.2% by weight, preferably 0.0
3-0.1 wt% and dibutylhydroxytoluene 0.01
˜0.2 wt%, preferably 0.02-0.1 wt%.
Here, the mixing ratio of both is very important for preventing coloration of the preparation, and 0.05 to 0.2% by weight of sodium bisulfite and 0.05 to 0.2 part of dibutylhydroxytoluene are most preferable to 1.5 parts of indomethacin. As the pH adjuster, an organic base such as triethanolamine, diisopropanolamine, triisopropanolamine or the like is mixed. The blending amount of these organic bases is such that the pH of the formulation is 5
To 7, and preferably 5.2 to 6.3.

In addition to the above essential components, methylparaben, if necessary,
Preservatives such as propylparaben and isopropylmethylphenol can be added.

Next, the manufacturing method of the present invention will be described. In order to produce the cream preparation of the present invention, first, indomethacin is added with 1-menthol, dibutylhydroxytoluene, a surfactant,
A fatty acid ester is added and heated to dissolve it, and a carboxyvinyl polymer swollen in water is added thereto and stirred to emulsify. Next, an organic base dissolved in a small amount of water and sodium bisulfite are added to this, and the mixture may be stirred until the whole becomes uniform.

The above-mentioned production method is only an example, and the cream preparation of the present invention can be produced even if the compounding order is partially changed. Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1 0.75 g of indomethacin, 3 g of 1-menthol, 5 g of polysorbate (60), 5 g of isopropyl adipate, 0.05 g of dibutylhydroxytoluene, 10 g of isopropyl myristate
Was added and heated to 75 ° C. to dissolve. A solution obtained by swelling 0.8 g of carboxyvinyl polymer in 64.9 g of water was added to this solution, and the mixture was stirred to emulsify. Next, sodium bisulfite 0.
1 g and 0.4 g of diisopropanolamine were dissolved in 10 g of water, and this was added to the emulsion first, and the mixture was stirred until it became homogeneous to give an anti-inflammatory analgesic cream preparation.

Example 2 1 g of indomethacin, 3 g of 1-menthol, 5 g of polysorbate (60), 10 g of diisopropyl sebacate, 0.05 g of dibutylhydroxytoluene, 5 g of isopropyl palmitate
Was added and heated to 70 ° C. to dissolve. To this solution was added a solution obtained by swelling 1 g of carboxyvinyl polymer in 64.6 g of water,
The mixture was stirred and emulsified. Next, sodium bisulfite 0.05g
Further, 0.3 g of diisopropanolamine was dissolved in 10 g of water, this was added to the above emulsion, and the mixture was stirred until it became homogeneous to obtain an anti-inflammatory analgesic cream preparation.

Reference Example 1 Indomethacin 0.75 g, crotamiton 5 g, polysorbate (60) 5 g, squalane 3 g, isopropyl myristate
15 g was added and heated to 70 ° C. to dissolve. To this was added a solution of 1 g of carboxyvinyl polymer swollen in 59.75 g of water,
The mixture was stirred and emulsified. Next, diisopropanolamine 0.
A solution prepared by adding 10 g of water to 5 was added, and the mixture was stirred until it became uniform to obtain an anti-inflammatory analgesic cream preparation.

Reference Example 2 0.75 g of indomethacin was suspended in 5 g of glycerin, 1 g of carboxyvinyl polymer and 89.85 g of water were added and swelled with stirring, and then 0.4 g of diisopropanolamine was added to cause gelation. 3 g of medium-chain fatty acid triglyceride was added thereto and mixed and emulsified to obtain an anti-inflammatory analgesic cream preparation.

Test Example 1 (Stability Test) In order to test the thermal stability of indomethacin over time,
The cream formulations of Example 1 and Reference Example 1 were filled in an aluminum tube, stored at 40 ° C., and the content of indomethacin was quantified periodically. The results are shown in Table 1.

As can be seen from Table 1, the cream preparation of Example 1 was superior to the cream preparation of Reference Example 1 in stability of indomethacin over time.

Test Example 2 (Transdermal Absorption Test) For the purpose of studying the transdermal absorbability of indomethacin, the cream formulation of Example 1, Reference Example 2 and a cream formulation containing 0.75% of indomethacin commercially available in rats were used for transdermal absorption. The test was conducted. The test results are shown in Table 2.

(Test method) A sample was applied to the shaved rat dorsal skin, 4 hours later, blood was collected from the femoral artery, centrifuged, and serum was obtained to obtain a sample. Dispense 0.5 ml of serum into a test tube and add 0.5 and 60 distilled water.
After adding 0.1 ml of% perchloric acid, 6 ml of ether was added and the mixture was transferred to another test tube and washed with 4 ml of 0.5N hydrochloric acid. The ether layer was dehydrated with anhydrous sodium sulfate, and then 3 ml was collected and the solvent was distilled off. Dissolve the residue in 1 ml of methanol, filter, then
Was injected into HPLC and the blood concentration was measured.

As can be seen from Table 2, the dissolution-type cream preparation of Example 1 had significantly higher blood concentration and excellent transdermal absorbability than the suspension-type cream preparation of Reference Example 2.

(E) Effect of the Invention Since the cream preparation containing indomethacin obtained in the present invention has good thermal stability of indomethacin, the content of indomethacin is not decreased and the color change is not observed with time. Therefore, it is preferable from the viewpoint that the drug effect of indomethacin can be maintained for a long period of time, and that there is no skin irritation due to a decomposed product and safety. Further, since the cream preparation of the present invention has very good transdermal absorbability, it has an excellent pharmacological effect and is used as a therapeutic agent for inflammatory diseases such as joint pain, low back pain, bruise, sprain, myalgia, and tendonitis. It is a medically useful preparation.

Claims (1)

[Claims] 1. Indomethacin as an active ingredient is 0.3-
2% by weight, 1 to 5% by weight of 1-menthol, 2 to 10% by weight of a nonionic surfactant as a base component, 5 to 25% by weight of a fatty acid ester, and a carboxyvinyl polymer of 0.
3 to 2% by weight, sodium bisulfite 0.01 to 0.2% by weight, dibutylhydroxytoluene 0.01 to 0.2% by weight,
An anti-inflammatory analgesic external cream preparation comprising 0.1 to 3% by weight of an organic base and the balance of water.