JPH0434971B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Technical Field) The present invention relates to an anti-inflammatory analgesic ointment containing indomethacin as an active ingredient. Indomethacin is 1-(p-chlorobenzoyl)-5-methoxy-2-ethylindole-3
- Acetic acid (molecular formula: C ₁₉ H ₁₆ CINO ₄ Molecular weight:
It is an excellent non-steroidal anti-inflammatory analgesic with the chemical name 357.79). (Prior Art) Indomethacin is a so-called non-steroidal anti-inflammatory analgesic that is widely used in the field of orthopedics for anti-inflammatory analgesic purposes, and the clinical effects of each have been confirmed. Most of these drugs are administered orally, and a small portion of them are parenterally administered in the form of suppositories. However, while oral non-steroidal anti-inflammatory analgesics have certain clinical effects, they are said to be destined to frequently cause side effects such as gastrointestinal disorders. For this reason, various attempts have been made to develop non-steroidal anti-inflammatory drugs with fewer side effects, but no drug has yet been developed that satisfies these requirements. Research on suppositories is being conducted with the aim of reducing side effects by devising the dosage form. However, although the side effects of suppositories have been slightly reduced compared to oral preparations, they still cause gastrointestinal disorders (e.g. nausea, vomiting, heartburn, diarrhea, abdominal pain, etc.).
(loss of appetite, headache, dizziness, etc.) have been observed. Therefore, suppositories must be administered with caution to patients with digestive system disorders. Therefore, in order to eliminate the side effects of such oral preparations and suppository forms, research is being carried out on ointments in which indomethacin is applied locally and absorbed into the skin. However, indomethacin has the property of being poorly soluble in water and common media. Therefore, even if indomethacin is added to the base of ointments, creams, etc. that are currently commonly used, it only exists in a suspended state in the base, and there is a problem with its absorption through the skin. There was a problem that a sufficient therapeutic effect could not be achieved. Recently, an anti-inflammatory and analgesic ointment (Japanese Patent Publication No. 10886-1983) has been known that eliminates this drawback and is made by gelling a combination of indomethacin, a medium consisting of glycols, lower alcohols, and water, and a gelling agent. ing. However, this anti-inflammatory analgesic ointment uses glycols (e.g. propylene glycol, polyethylene glycol, etc.) as a solubilizer for indomethacin.
It had the disadvantage of being highly irritating to the skin (prone to causing rashes) due to the use of large amounts. Also, as an absorption aid for indomethacin, C ₄ to C _14
C1 - _C5 alcohol esters of monocarboxylic acids and _C1 - _C3 alcohol diesters of _C4 - _C10 dicarboxylic acids (e.g. diisopropyl adibate, diethyl sebacate, etc.) are used, but the absorption rate is low. could not be said to be sufficient. Therefore, there has been a desire for an ointment containing indomethacin that is less irritating to the skin and has a higher absorption rate. (Problems to be Solved by the Invention) Therefore, in view of the drawbacks of the prior art, the present invention aims to provide an anti-inflammatory analgesic ointment that is less irritating to the skin and has good absorption of indomethacin into the skin. do. (Means for Solving the Problems) Therefore, in view of the actual state of the prior art, the present inventors aimed to reduce the side effects of non-steroidal anti-inflammatory analgesics, have low irritation to the skin, and have low absorption efficiency. As a result of intensive research in order to provide a high quality ointment, we found that using basic amino acids instead of glycols as a solubilizing agent will cause less irritation to the skin, and that using C ₁ of C ₄ to C ₁₄ monocarboxylic acids as an absorption aid ~ _C5
He discovered that absorption efficiency was high when lactic acid ester was used instead of alcohol ester of C4 _{to C10} dicarboxylic acid and alcohol diester of _C1 to _C3 of C4 to C10 dicarboxylic acid. That is, the present invention provides 0.5 to 1.5% by weight of indomethacin.
and a medium consisting of 0.3 to 10% by weight of basic amino acids, 10 to 60% by weight of lower alcohols, and 20 to 70% by weight of water, and an absorbent selected from the group consisting of 0.2 to 5% by weight of gelling agents and lactic acid esters. Auxiliary agent 0.2-10% by weight
This is an anti-inflammatory analgesic ointment containing the following. These smoke pain relief ointments are novel inventions that can overcome the drawbacks of the prior art, and have great practical value. The active ingredient of the present invention, indomethacin, is 0.5
The effect can be fully expected at ~1.5% by weight. In addition, the conditions that should be met for indomethacin as an ointment are that 0.5 to 1.5% by weight of indomethacin should be dissolved, it should have a refreshing feeling, it should have an excellent feeling of use, and it should have sufficient medicinal efficacy. It must be chemically stable. In general, the stability of indomethacin is largely influenced by its liquid properties, and is unstable in both strong acids and strong alkalis, and the desirable pH is considered to be 4.5 to 6.2. However, indomethacin has very low solubility in acidic conditions and has the problem of crystal precipitation, making it extremely difficult to obtain a stable indomethacin ointment. However, the anti-inflammatory analgesic ointment according to the present invention has a pH of 4.5 to 6.2 and is extremely stable. The basic amino acids used as the solubilizing agent of the present invention include lysine, arginine, orthinine,
Histidine and the like are preferred. However, the optical activity is L
It does not matter whether it is a body, D body, or DL body. As the lactic acid ester used as an absorption aid, those having an alcohol component having 12 to 18 carbon atoms, such as lactate lauryl ester, lactate myristyl ester, and lactate stearyl ester, are preferable because they have good absorbability. As the lower alcohol of the present invention, ethyl alcohol, denatured alcohol, propyl alcohol, benzyl alcohol, etc. are used. In the present invention, a gelling agent is used to make the ointment solid. As the gelling agent and/or thickening agent, carboxyvinyl polymers, hydroxyethyl cellulose, and methyl cellulose which have been previously disclosed (Japanese Patent Publication No. 56-10886) can also be used, as well as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, and ethyl cellulose. Semi-synthetic polymers such as carrageenan {product name: Soagina (product name of carrageenan manufactured by Mitsubishi Acetate Co., Ltd.)}, fur-cerelan, locust bean gum {product name: Soar Locust (product name of locust bean gum produced by Mitsubishi Acetate Co., Ltd.) Product name)},
Natural polymers such as xanthan gum are used alone or in combination. As the carboxyvinyl polymer, Hivis Wako 103, 104, 105 (trade name, manufactured by Wako Pure Chemical Industries, Ltd.) and Carbopol (trade name, manufactured by Gutsudoritsuchi Chemical Co., Ltd.) are used. Furthermore, as the methylcellulose and hydroxypropylmethylcellulose, Metrose (trade name, manufactured by Shin-Etsu Chemical Co., Ltd.) is used. In addition, the blending amount of each base is 0.3 to 10% by weight (preferably 0.5 to 4% by weight) of basic amino acids and 0.2% of lactic acid ester in order to fully demonstrate the usability, stability, solubility, and medicinal efficacy. ~10% by weight (preferably
0.5-4% by weight), lower alcohol 10-60% by weight
(preferably 25-40% by weight), purified water 20-70% (preferably 40-65% by weight) and gelling agent and/or thickener 0.2-5% (preferably 1-4% by weight). % by weight). Next, in the manufacturing method of the present invention, it is preferable to mix according to the following order. A gelling agent and/or thickener is added to purified water to swell and stir. Indomethacin and absorption aid are dissolved in the lower alcohol with stirring. Add the solution dissolved in to the solution of and stir under vacuum until hydrated. A basic amino acid dissolved in purified water is added to the hydrated solution and stirred. Add the PH adjuster to the stirred solution and stir. Further, each stirring step is performed for about 20 minutes at 500 to 3,600 rpm, but when stirring at 10,000 rpm or more, it is necessary to perform the stirring for a short time so as not to break the molecules. Note that the ointment according to the present invention can also contain an antioxidant, a surfactant, a preservative, a PH regulator, etc., if necessary. Citric acid, malic acid, tartaric acid, as a PH regulator
Use diisopropanolamine etc. In particular, diisopropanolamine, when used as a neutralizing agent, has the function of increasing the transparency of the product of the present invention. Furthermore, when about 0.25 w% of -menthol is added to the ointment, the absorption of indomethacin is further improved. (Effects of the Invention) The ointment according to the present invention is stable (resistant to syneresis and discoloration) even when stored for a long period of time. Because it uses basic amino acids rather than glycols as a solubilizer for indomethacin, it is less irritating to the skin. It absorbs well into the skin because it uses lactic acid ester as an absorbent. Since the ointment of the present invention has the above-mentioned composition, it has the characteristic of not being sticky, unlike when glycols are used. The present invention will be described in detail below with reference to Examples. (Example 1) A substance consisting of the following blending amounts was prepared by the method shown below.
Mix to obtain an ointment. 1 Soagina (LX-7) 1.6g 2 Metrose (60SH-4000) 0.3g 3 Indomethacin 1.0g 4 Stearyl lactate 0.5g 5 Ethanol 30.0g 6 L-Arginine 0.5g 7 Diisopropanolamine 0.8g 8 Purified water Make a total of 100g Sufficient amount (a) 20g of the above Soagina and Metrose in purified water
to swell. (b) Dissolve indomethacin in stearyl lactate and ethanol. (c) Add the solution dissolved in (b) above to the solution in (a) and stir until hydrated. (d) Dissolve the above L-arginine in 5 g of purified water, and then add to the hydrated solution of (c). (e) Dissolve diisopropanolamine in 5 g of purified water, add it to (d), then add the remaining amount of purified water and stir until the whole is homogeneous. (f) Next, the pH was adjusted to obtain indomethacin ointment with a pH of 5.8. (Example 2) A substance consisting of the following blending amounts was prepared by the method shown below.
Mix to obtain an ointment. 1 Soagina (LX-8) 2.0g 2 Metrose (60SH-4000) 0.3g 3 Indomethacin 1.0g 4 Stearyl lactate 0.5g 5 Ethanol 32.0g 6 L-Arginine 0.4g 7 Diisopropanolamine 0.7g 8 Purified water Make a total of 100g Sufficient amount (a) 20g of the above Soagina and Metrose in purified water
to swell. (b) Dissolve indomethacin in stearyl lactate and ethanol. (c) Add the solution dissolved in (b) above to the solution in (a) and stir until hydrated. (d) Dissolve the above L-arginine in 5 g of purified water, and then add to the hydrated solution of (c). (e) Dissolve diisopropanolamine in 5 g of purified water, add this to (d), then add the remaining amount of purified water and stir until the whole is homogeneous. (F) Next, the pH was adjusted to obtain indomethacin ointment with a pH of 5.7. (Example 3) A substance consisting of the following blending amounts was prepared by the method shown below.
Mix to obtain an ointment. 1 Soagina (LX-9) 2.5g 2 Metrose (60SH-4000) 0.2g 3 Indomethacin 1.0g 4 Stearyl lactate 0.2g 5 Ethanol 29.0g 6 L-Arginine 0.6g 7 Diisopropanolamine 0.5g 8 Purified water Make a total of 100g Sufficient amount (a) 20g of the above Soagina and Metrose in purified water
to swell. (b) Dissolve indomethacin in stearyl lactate and ethanol. (c) Add the solution dissolved in (b) above to the solution in (a) and stir until hydrated. (d) Dissolve the above L-arginine in 5 g of purified water, and then add to the hydrated solution of (c). (e) Dissolve diisopropanolamine in 5 g of purified water, add this to (d), then add the remaining amount of purified water and stir until the whole is homogeneous. (F) Next, the pH was adjusted to obtain indomethacin ointment with a pH of 5.6. (Example 4) A substance consisting of the following blending amounts was prepared by the method shown below.
Mix to obtain an ointment. 1 Soagina (MV-201) 0.3g 2 Metrose (60SH-4000) 2.4g 3 Indomethacin 1.0g 4 Stearyl lactate 1.5g 5 Ethanol 35.0g 6 L-Arginine 1.0g 7 Diisopropanolamine 0.8g 8 Purified water Make a total of 100g Sufficient amount (a) 20g of the above Soagina and Metrose in purified water
to swell. (b) Dissolve indomethacin in stearyl lactate and ethanol. (c) Add the solution dissolved in (b) above to the solution in (a) and stir until hydrated. (d) Dissolve the above L-arginine in 5 g of purified water, and then add to the hydrated solution of (c). (e) Dissolve diisopropanolamine in 5 g of purified water, add this to (d), then add the remaining amount of purified water and stir until the whole is homogeneous. (f) Next, adjust the pH to obtain indomethacin ointment with a pH of 5.8. (Example-5) A substance consisting of the following blending amount was prepared by the method shown below.
Mix to obtain an ointment. 1 Soagina (MV-201) 0.6g 2 Metrose (60SH-4000) 2.8g 3 Indomethacin 1.0g 4 Lauryl lactate 1.5g 5 Ethanol 35.0g 6 Benzyl alcohol 4.0g 6 DL-lysine 1.0g 7 Diisopropanolamine 0.8g 8 Purification Sufficient amount of water to make a total of 100g (a) 20g of purified water with the above Soagina and Metrose
to swell. (b) Dissolve indomethacin in stearyl lactate, ethanol, and benzyl alcohol. (c) Add the solution dissolved in (b) above to the solution in (a) and stir until hydrated. (d) After dissolving the above DL-lysine in 5 g of purified water
Add to the hydrated solution in (c). (e) Dissolve diisopropanolamine in 5 g of purified water, add it to (d), then add the remaining amount of purified water and stir until the whole is homogeneous. (f) Next, adjust the pH to obtain indomethacin ointment with a pH of 5.8. (Example 6) A substance consisting of the following blending amount was prepared by the method shown below.
Mix to obtain an ointment. 1 Soagina (MV-201) 0.3g 2 Metrose (60SH-4000) 2.6g 3 Indomethacin 1.0g 4 Lauryl lactate 1.5g 5 Ethanol 37.0g 6 DL-lysine 1.0g 7 Diisopropanolamine 0.8g 8 Purified water Make a total of 100g Sufficient amount (a) 20g of the above Soagina and Metrose in purified water
to swell. (b) Dissolve indomethacin in lauryl lactate and ethanol. (c) Add the solution dissolved in (b) above to the solution in (a) and stir until hydrated. (d) After dissolving the above DL-lysine in 5 g of purified water
Add to the hydrated solution in (c). (e) Dissolve diisopropanolamine in 5 g of purified water, add this to (d), then add the remaining amount of purified water and stir until the whole is homogeneous. (f) Next, the pH was adjusted to obtain indomethacin ointment with a pH of 5.8. (Comparative Example: Japanese Patent Publication No. 56-10886) Indomethacin ointment is obtained by mixing the following amounts in the method shown below. 1 Hibis Wako 104 1.0g 2 Indomethacin 1.0g 3 Propylene glycol 12.0g 4 Ethanol 30.0g 5 Diisopropyl adipate 2.0g 6 Diisopropanolamine 1.0g 7 Purified water Enough amount to make a total of 100g A Swell the above 1 in 20g of water let B. Dissolve 2 above in 3, 4, and 5. C. Add B above to A and stir until completely hydrated. D Dissolve the above 6 in 10 g of water, add it to the above C, then add the remaining amount of water and stir until the whole becomes uniform. The absorption rates of the anti-inflammatory and analgesic ointments shown in Example-1, Example-5 and Comparative Example of the present invention obtained as described above were compared and studied using the following method. Experimental method The hair on the dorsal skin of guinea pigs was shaved, and the diameter was measured one day later.
After applying 0.1g of the adjusted ointment within a 2.5cm circle,
It was collected after 5 hours, and the absorption rate was calculated from the collected amount. The results were as shown below.

[Table] It should be noted that the other Examples also showed superiority over the Comparative Examples in terms of absorption rate.

Claims (1)

[Scope of Claims] 1. The following components (a), (b), (c) and (d) (a) 0.5 to 1.5% by weight of indomethacin (b) 0.3 to 10% by weight of basic amino acids, 10 to 10% by weight of lower alcohols 60% by weight of medium and 20-70% by weight of water (c) 0.2-5% by weight of gelling agent and/or thickener (d) 0.2-10% by weight of absorption aid selected from the group consisting of lactic acid esters An anti-inflammatory analgesic ointment containing the following. 2. The anti-inflammatory analgesic ointment according to claim 1, wherein the basic amino acid is lysine, arginine, histidine, or orthinine. 3. The gelling agent and/or thickener is a natural polymer such as carrageenan, furcerelan, locust bean gum, xanthan gum, etc., hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, ethyl cellulose, methyl cellulose, etc. The anti-inflammatory and analgesic ointment according to claim 1 or 2, which is a synthetic polymer such as a semi-synthetic polymer and a carboxyvinyl polymer, and uses at least one kind thereof. 4. Claims 1 and 2 in which the alcohol component of the lactic acid ester has 12 to 18 carbon atoms.
The anti-inflammatory and analgesic ointment according to any one of Items 1 and 3.