JPH02142727A - Anti-inflammatory and analgesic cream pharmaceutical for external use - Google Patents

Abstract

PURPOSE:To obtain the subject safe pharmaceutical without any change with time by blending specific amounts of indomethacin and l-menthol as active ingredients with a nonionic surfactant, fatty acid ester, carboxyvinyl polymer, etc., as base ingredients and the remainder of water. CONSTITUTION:A cream pharmaceutical obtained by containing 0.3-2wt.% indomethacin and 1-5wt.% l-menthol as active ingredients with 2-10wt.% nonionic surfactant, 5-25wt.% fatty acid ester and 0.3-2wt.%, preferably 0.5-1.5wt.% carboxyvinyl polymer, 0.01-0.2wt.% sodium hydrogensulfite, 0.01-0.2wt.% dibutylhydroxytoluene, 0.1-3wt.% organic base and the remainder of water. The above-mentioned pharmaceutical has excellent percutaneous absorbability with improved pharmacological effects.

Description

Detailed Description of the Invention (a) Industrial Application Field The present invention relates to an anti-inflammatory and analgesic topical cream preparation containing indomethacin as an active ingredient. It is marketed in various dosage forms such as ointments, creams, poultices, and liquids. However, since indomethacin is a drug with poor stability, it is extremely difficult to maintain its stability in formulations, and a decrease in its content due to hydrolysis and esterification reactions is unavoidable. In particular, in the case of cream formulations, if a solubilizer is added to dissolve indomethacin, liquid separation tends to occur and color changes occur, so it has been difficult to create a dissolving cream in which indomethacin is dissolved. For this reason, commercially available indomethacin cream preparations are suspension-type preparations in which indomethacin is dispersed in a cream.

However, suspension-type preparations have lower transdermal absorption than molten-type preparations and cannot provide sufficient pharmacological effects, so a soluble-type cream preparation with good stability has been desired.

(c) Problems to be solved by the invention Until now, when creating a cream formulation containing indomethacin, since indomethacin is a poorly soluble drug,
Various compounds such as crotamiton, higher alcohols, and benzyl alcohol have been investigated as solubilizing agents. However, since indomethacin is a drug with poor stability, it reacts with these solubilizers or other cream bases in the formulation, resulting in decomposition products, decreasing the content of indomethacin, and changing the color of the cream. was seen. As a result, pharmacological effects may not be sufficient or skin irritation may occur due to decomposition products. In addition, it was difficult to commercialize the product because it lost its commercial value due to color change. Therefore, the aim of the present invention is to obtain an indomethacin-containing cream formulation that is stable over time.

(d) Means for Solving the Problems The present inventors have conducted various studies on cream formulations stably containing inlmethacin. It has been found that a cream formulation of 100% solves all of the above problems. That is, 0.3 to 2% by weight of indomethacin as the active ingredient.
, 1 to 5% by weight of p-menthol, 2 to 10% by weight of a nonionic surfactant as a base component, 5 to 25% by weight of fatty acid ester, and 0.3 to 0.3% of carpoquinhinyl polymer.
2% by weight, 0.01 to 0.2% by weight of sodium bisulfite, and 0.01 to 0.2% of dibutylhydroxytoluene.
A cream preparation with a composition of 0.1 to 3% by weight of an organic base and the remaining amount of water has excellent stability of indomethacin and thermal stability as a formulation, and has excellent transdermal absorption. I understand. Below, regarding the ingredients of the present invention,
This will be explained in more detail.

Although l-menthol is an active ingredient, it also has the effect of dissolving indomethacin. The appropriate amount of l-menthol to be blended is 1 to 5% by weight; if it is too small, indomethacin will not be sufficiently dissolved, and if it is too large, the odor of l-menthol will be too strong, which is undesirable. Nonionic surfactants include polyoxyethylene alkyl ether, polyoxyethylene phenyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, etc. Those with HL B of 10 to 20 are used, but
In particular, polyoxyethylene sorbitan fatty acid ester is preferable from the viewpoint of feeling in use and cream stability. These surfactants may be present in an amount of 2 to 10% by weight. Examples of fatty acid esters include medium to long chain fatty acid esters such as isopropyl myristate, isopropyl palmitate, diisopropyl sebacate, diethyl sebacate, diisopropyl adipate, glycerin tricaprylate, glycerin tricaprylate, and propylene glycol tricaprylate. Among these fatty acid esters,
The combination of isopropyl myristate and diisopropyl adipate is most preferred from the viewpoint of solubility of indomethacin and feeling of use. These fatty acid esters are blended in an amount of 5 to 25% by weight, preferably 10 to 20% by weight, either singly or in combination of two or more. As the carboxyvinyl polymer, for example, Carhobol 934°940.941 manufactured by Guttrich Chemical Co., Ltd. or Hivis Wako 103, 104, 105 manufactured by Wako Pure Chemical Industries, Ltd. are used. The amount of carboxyvinyl polymer is 0.3
-2% by weight, preferably 0.5-1.5% by weight.

For the purpose of preventing coloration of cream formulations, sodium bisulfite is added in an amount of 0.01 to 0.2% by weight, preferably 0.03 to 0.
．． 1% by weight and 0.0% dibutylhydroxytoluene
1-0.2% by weight, preferably 0.02-0.1% by weight
It is blended. Here, the blending ratio of the two is very important for preventing coloration of the preparation, and 0.05 to 0.2 parts by weight of sodium bisulfite and 0.05 to 0.2 parts of dibutylhydroxytoluene are added to 1.5 parts of indomethacin. is most preferred. As the pH adjuster, organic bases such as triethanolamine, diisopropanolamine, triisopropanolamine, etc. are blended. The blending amount of these organic bases is such that the pH of the preparation is 5 to 7, preferably 5.2.
It is adjusted as appropriate so that it becomes ~6.3.

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

Next, the manufacturing method of the present invention will be described. To produce the cream formulation of the present invention, first, indomethacin is mixed with l-menthol, dibutylhydroxytoluene, a surfactant,
A fatty acid ester is added and dissolved by heating, and a carboxyvinyl polymer swollen in water is added thereto and stirred to emulsify. Next, an organic base and sodium bisulfite dissolved in a small amount of water are added to this, and the mixture is stirred until the whole is homogeneous.

Note that the above manufacturing method is only an example, and the cream formulation of the present invention can be manufactured even if the mixing order is partially changed. EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example 1 0.75 g of indomethacin, 3 g of p-menthol, 5 g of borisorhate (60), 5 g of diisopropyl adipate, and 0.05 g of dibutylhydroxytoluene.

10g of isopropyl myristate was added and dissolved by heating to 75°C. This solution contains 0 carboxyvinyl polymer.
．． A swollen solution of 8 g was added to 64.9 g of water and stirred to emulsify. Next, 0.1 g of sodium hydrogen sulfite and 0.4 g of diisopropanolamine were dissolved in 10 g of water, and this was added to the above emulsion and stirred until homogeneous to obtain an anti-inflammatory analgesic cream preparation. .

Example 2 1 g of indomethacin, 3 g of p-menthol, 5 g of polysorbate (60), 10 diisopropyl sebacate
g, dibutylhydroxytoluene 0.05g.

5 g of isopropyl palmitate was added and heated to 70° C. to melt it. Add 1g of carboxyvinyl polymer to this solution.
The swollen solution was added to 64.6 g of water and stirred to emulsify. Next, 0.05 g of sodium bisulfite and 0.3 g of diisopropanolamine were dissolved in 10 g of water, and this was added to the above emulsion and stirred until homogeneous to obtain an anti-inflammatory analgesic cream preparation. .

Reference Example 1 5 g of crotamiton, 5 g of polysorbate (60), 3 g of squalane, and 15 g of isopropyl myristate were added to 0.75 g of indomethacin and dissolved by heating to 70°C. A solution of carboxyvinyl polymer Ig swollen in 59.75 g of water was added to this and stirred to emulsify. Next, add 10 g of water to 0.5 diisopropanolamine.
A solution containing the above was added, and the mixture was further stirred until it became homogeneous 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, the mixture was stirred and swollen, and then 0.4 g of diisopropanolamine was suspended.
g was added to form a gel. 3 g of medium chain fatty acid triglyceride was added to this and mixed and emulsified to obtain an anti-inflammatory analgesic cream preparation.

Test Example 1 (Stability Test) To test the thermal stability of indomethacin over time,
The cream formulations of Example 1 and Reference Example 1 were filled into aluminum tubes, stored at 40°C, and the content of indomethacin was periodically determined. The results are shown in Table 1.

Table 1 Stability test of cream formulation As seen from Table 1, the cream formulation of Example 1 was superior to the cream formulation of Reference Example 1 in terms of stability of indomethacin over time.

Test Example 2 (Percutaneous Absorption Test) In order to examine the percutaneous absorption of indomethacin, rats were tested for the cream formulation of Example 1, Reference Example 2, and a commercially available cream formulation containing 0.75% indomethacin. A skin absorption test was conducted.

The test results are shown in Table 2.

(Test method) A specimen was applied to the shaved back skin of a rat, and 4 hours later, blood was collected from the femoral artery, centrifuged bone 1iiiI & serum was obtained and used as a sample. Aliquot 0.5 ml of serum into a test tube, add 0.5 ml of distilled water and 0.1 ml of 60% perchloric acid,
Add 6+++1 ether and transfer to another test tube, 0.5N
Washed with 41 portions of hydrochloric acid. The ether layer was dehydrated with anhydrous sodium sulfate, separated into 3 ml portions, and the solvent was distilled off. 1m of residue
After dissolving in 1 methanol and filtering, 20 μl was analyzed by HPLC.
was injected into the body, and the blood concentration was measured.

Table 2 Transdermal absorption test of indomethacin cream formulation (Blood concentration 2 μg/0.5 ml) As seen from Table 2, the cream formulation of Example 1, which is a soluble type, is different from the cream formulation of Reference Example 2, which is a suspension type. It had a significantly higher blood concentration and better transdermal absorption compared to .

(n) Effects of the Invention In the cream formulation containing indomethacin obtained by the present invention, since indomethacin has good thermal stability, no decrease in indomethacin content or color change is observed over time. Therefore, the medicinal efficacy of indomethacin is maintained over a long period of time, and there is no skin irritation caused by decomposition products, which is preferable from the viewpoint of safety. In addition, the cream formulation of the present invention has excellent transdermal absorption, so it has excellent pharmacological effects, and can treat inflammatory diseases such as joint pain, lower back pain, bruises, sprains, muscle pain, and elbow inflammation. It is a medically useful preparation as a medicine.

Engineering 2

Claims (1)

[Claims] 1. As an active ingredient, indomethacin is 0.3 to 2% by weight, l-menthol is 1 to 5% by weight, and as a base component,
2 to 10% by weight of nonionic surfactant, 5 to 25% by weight of fatty acid ester, and 0.0% of carboxyvinyl polymer.
3 to 2% by weight, and 0.01 to 0.0% sodium bisulfite.
2% by weight, 0.01 to 0 dibutylhydroxytoluene
．． An anti-inflammatory and analgesic external cream preparation consisting of 2% by weight, 0.1 to 3% by weight of an organic base, and the remaining amount of water.