JPS6146451B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to topical ointments, and more particularly to improved topical ointments utilizing carboxyvinyl polymers as gelling agents (ointment bases). Conventionally, cellulose, karaya gum, pectin,
Natural polymer compounds such as gelatin and collagen, natural polymer compounds and their derivatives such as hydroxypropylcellulose, CMC-Na, dextrin, dipotassium glycyrrhizinate, and synthetic polymer compounds such as polyvinyl alcohol, carboxyvinyl polymer, and polyvinylpyrrolidone. Various pharmaceuticals used as gelling agents are known as anti-pruritic agents, anti-inflammatory agents, antiseptics, poultices, etc. Among these, carboxyvinyl polymers are particularly commonly used as gelling agents because they are not affected by the alcohol content in the formulation. Therefore, the thickening and gelling of the formulation by the carboxyvinyl polymer may be due to the presence of neutralizing agents, especially triethanolamine, in the formulation.
This is done by blending organic amines such as diisopropanolamine and triethylamine to neutralize the carboxyl groups of the above polymers [Japanese Patent Publications No. 18250/1980, No. 54/18329, 56
-Refer to Publication No. 10886, etc.]. However, in recent years, the organic amines used as neutralizing agents have been converted into N-nitroso compounds in vitro and in vivo under certain conditions, and these N-nitroso compounds have been shown to be effective against many animal species, from fish to monkeys. It has been reported that it is a carcinogenic substance that exhibits strong carcinogenicity [Shokuei Magazine]
vol. 15, No. 6, December 1974, pp. 419-433]. Additionally, the US Food and Drug Administration (FDA) recently announced the results of analyzing 36 commercially available cosmetic samples for nitrosamines. According to the study, nitrosamines were detected in half of the cases, with the most severe case containing 130,000 PPb (0.13%).
The value was obtained. This nitrosamine is primarily N-nitrodiethanolamine,
The FDA analysis reportedly also found small amounts of other nitrosamines. Furthermore, organic amines are listed in Official Gazette No. 16105 and 16106 published in 1980.
According to the issue, it has been shown that it can cause skin allergies. Therefore, organic amines contained in quasi-drugs used directly on the human body must be labeled as cosmetic ingredients, namely diethanolamine, diisopropanolamine, tripropanolamine, and triethanolamine (see Ministry of Health and Welfare Notification No. 167). In addition, monoethanolamine is required to be labeled. The inventors have studied a number of chemicals that can replace organic amines as highly safe neutralizing agents for the carboxyvinyl polymers that have been conventionally used as gelling agents. As a result, when a predetermined amount of at least one selected from the basic main components, ie, diphenhydramine, dibucaine, lidocaine, chlorpheniramine, and ephedrin, is directly blended without using a neutralizing agent, the carboxyvinyl polymer The viscosity increases, and a transparent and extremely good gel in the form of an ointment is obtained, and the basic compound is
We have obtained completely new knowledge that the original medicinal effects are exerted without being inhibited at all. The present invention was completed based on this new knowledge. That is, the present invention contains 0.5 to 3.5% by weight of at least one basic compound selected from the group consisting of diphenhydramine, dibucaine, lidocaine, chlorpheniramine, and ephedrin as an active ingredient together with menthol and/or camphor. It contains 1 to 3% by weight of carboxyvinyl polymer as a gelling agent, and has a viscosity of 50,000 to 250,000 centipoise at 20°C (as measured by a B-type viscometer).
The present invention relates to a topical ointment characterized by having an ointment form in the range of BH type, No. 7 rotor, 4 rpm use). The topical ointment of the present invention comprises a group consisting of diphenhydramine, dibucaine, lidocaine, chlorpheniramine, and ephedrin, along with menthol and/or carfur, which have been conventionally used as active ingredients for anti-inflammatory and pain medicines. 0.5 to 3.5% by weight of at least one basic compound selected from
It is essential to mix. Each of the above-mentioned basic compounds is itself known as an active ingredient of antihistamines, local anesthetics, and adrenergic nerve agents, but in the present invention, they are used not only as the above-mentioned active ingredients but also as gelling agents. Its greatest feature is that it also serves as a neutralizing agent for carboxyvinyl polymers, and based on this, it produces nitrosamines that act as carcinogenic substances, as seen in conventional products using this type of gelling agent. This product is extremely safe by avoiding the use of neutralizing agents that may cause damage, and has also succeeded in fully demonstrating the medicinal efficacy inherent to the above-mentioned basic compound. It is necessary that the amount of the basic compound is within the above-mentioned range; if it is out of the above-mentioned range, it will be difficult to obtain the desired ointment-form product. Further, as the carboxyvinyl polymer used as the gelling agent in the ointment of the present invention, any of various conventionally used gelling agents can be used. A typical example is the American company Gudrich Chemical Company (B, F, Goodrich).
"Carbopol 934, 940 and 941" commercially available from Chemical Co., Ltd., "Jiyunron Pw-110" commercially available from Nippon Pure Chemical Co., Ltd., "Hibis Wako 103, 104" commercially available from Wako Pure Chemical Co., Ltd. and 105''. The blending amount of the carboxyvinyl polymer is selected from the range of 1 to 3% by weight, which is neutralized (crosslinked) with the above-mentioned specific basic compound to increase the product viscosity from 50,000 to 250,000 centipoise (at 20°C). Use a B-type viscometer BH type, No. 7 rotor, 4 rpm (the same applies hereinafter) and form an appropriate ointment. If the amount of the carboxyvinyl polymer is outside the above range, an ointment having a desired viscosity range will not be obtained. The ointment of the present invention is prepared in the same manner as other ointments of this type, except that predetermined amounts of the above-mentioned specific basic compound and carboxyvinyl polymer are added, and other suitable additives are also added. Can be added and blended. Suitable additives include, for example, coating feel improvers or humectants such as glycerin, propylene glycol, polyethylene glycol, hydropropylcellulose, methylpolysiloxane, polyvinylpyrrolidone and polyvinyl alcohol, polyoxyethylene hydrogenated castor oil (POE20, 40, 80 , 100 mole addition), polyoxyethylene polyoxypropylene glycol ether, and surfactants such as Emarex 640. These additives are generally used in a total amount of about 5 to 100 moles in the formulation. It can be blended in a range of 20% by weight. The method for preparing the ointment of the present invention is not particularly limited, but usually, after preparing menthol and/or camphor and other additives in an alcohol aqueous solution,
This is carried out by adding an aqueous solution of carboxyvinyl polymer to this, further adding at least one basic compound selected from the group consisting of diphenhydramine, dibucaine, lidocaine, chlorferamine, and ephedrin, and stirring thoroughly. . The menthol and/or camphor used here may be in any of the d-form, l-form, and dl-form, respectively. Such as menthol and/or
As the alcohol used as a solvent for camphor and other additives, usual ones such as ethyl alcohol are typically used, but other lower alcohols such as methanol, isopropanol, etc. may be used alone or in combination with the above ethyl alcohol. Good too. The amount of such a solvent to be used can be determined as appropriate on the premise that the active ingredient compound can be dissolved, but it is appropriate to use an amount that is usually in the range of about 30 to 70% by weight in the obtained preparation. Thus, according to the present invention, it is possible to obtain an ointment that is very transparent, stable for a long period of time, spreads well, has a good application feeling, and has a desired viscosity. When applying this ointment to the skin surface where treatment is desired, for example, the gel form slowly disintegrates due to the salt present on the skin surface, resulting in a decrease in viscosity, which facilitates the application and also causes gelation. The bond between the agent and the basic compound as an active ingredient is separated, and the basic compound is gradually absorbed through the skin surface under the influence of the penetrating action of the surfactant, and thus its original pain-relieving, anti-inflammatory, and local effects are relieved. Anesthetic effects, antihistamine effects, etc. are sustained over a long period of time. Furthermore, the ointment of the present invention does not contain triethanolamine, diisopropanolamine, etc. as neutralizing agents, unlike conventional preparations using gelling agents of this type, so there is no risk of carcinogenicity due to these agents. Furthermore, there is no danger of skin allergies. Examples of the topical ointment of the present invention will be given below to explain the present invention in more detail. Example 1 Diphenhydramine 0.5g d-Camphor 3.0 L-Menthol 3.5 Propylene glycol 10.0 Polyethylene glycol-1500 2.0 Polyoxyethylene (80) hydrogenated castor oil 5.0 "Carbopol 940" (Gutdrich Chemical Company, USA) 1.5 Ethanol 42.0 Purified water 32.5 100 g Weigh the specified amounts of propylene glycol, polyethylene glycol-1500, polyoxyethylene (80) hydrogenated castor oil, Carbopol 940, ethanol, and purified water, and dissolve while stirring at a temperature below 40°. Next, d-camphor and l-menthol are added and uniformly dissolved. Further, while stirring the solution vigorously, a specified amount of diphenhydramine is gradually added to form a gel. Then stir for a while to make it even. These operations are performed under vacuum. Thus, a colorless and transparent topical ointment having a pH of 5.6, a viscosity of 18.8×10 ⁴ centipoise at 20° C., and a gel hardness of 700 dynes/cm ² (as measured by an Iio Electric Co., Ltd. M301AR card meter) was obtained. Example 2 Diphenhydramine 1.0 g d-camphor 3.0 L-menthol 3.5 Glycerin 2.0 Propylene glycol 2.0 Polyoxyethylene (80) Hydrogenated castor oil 5.0 "Carbopol 940" 1.3 Ethanol 35.0 Purified water 47.2 g Total 100 g Glycerin, propylene Glycol, polyoxyethylene (80) hydrogenated castor oil, Carbopol
940, ethanol, and purified water, then take the prescribed amounts of each component as described above, and operate in the same manner as in Example 1 to obtain a topical ointment of the present invention. Example 3 In Example 2, polyoxyethylene polyoxypropylene glycol ether is used instead of polyoxyethylene (80) hydrogenated castor oil.
A topical ointment of the present invention is obtained using the same procedure. Example 4 A topical ointment of the present invention is obtained by using lidocaine instead of diphenhydramine in Example 1, and using all other ingredients and procedures as in Example 1. Example 5 In Example 3, lidocaine was used instead of diphenhydramine, and all other ingredients and procedures were the same as in Example 3 to obtain a topical ointment of the present invention. Example 6 In Example 3, chlorpheniramine was used instead of diphenhydramine, and all other ingredients and procedures were the same as in Example 3 to obtain a topical ointment of the present invention. Examples 7 to 9 A topical ointment of the present invention was obtained by the same procedure as in Example 1 using the following components. Example 7 (wt%) l-menthol 3.5% d-camphor 3.0 diphenhydramine 1.0 glycerin 2 propylene glycol 2 polyoxyethylene polyoxypropylene glycol ether 5% ethanol 35 purified water 47.2 Carbopol 940 1.3 Example 8 (wt %) l-menthol 3.5% d-camphor 3.0 diphenhydramine 1.0 lidocaine 2.0 polyethylene glycol 1500 8 ethanol 40 purified water 41.1 Carbopol 940 1.0 hydropropyl cellulose 0.4 Example 9 (wt%) l-menthol 3.5% d-camphor 3.0 Diphenhydramine 1.0% Lidocaine 2 Polyethylene Glycol 1500 8 Ethanol 40 Purified Water 41 "Jiyunron PW-110" 1.5 The properties of the topical ointments of the present invention obtained in each of the above Examples were used to determine the active ingredients when preparing each ointment. Table 1 below shows a comparison with that prepared by increasing the amount of purified water without blending only the basic compound (before gelation).

【table】

[Table] Regarding the viscosity of the sample before gelation, use a B-type viscometer BL.
Samples that could not be measured under the conditions of type 3 rotor 6 rpm 5 minutes (20℃) were measured using a B type viscometer BL type 2.
When measured under the condition of No. rotor 6 rpm (20℃), it was 100 cps in Example 1 and 100 cps in Example 2.
120cps, 95cps in Example 4 and 95cps in Example 9.
It was hot at 100cps.

Claims (1)

[Claims] 1 Contains 0.5 to 3.5% by weight of at least one basic compound selected from the group consisting of diphenhydramine, dibucaine, lidocaine, chlorpheniramine, and ephedrine as an active ingredient together with menthol and/or camphor, and Contains 1 to 3% by weight of carboxyvinyl polymer as a gelling agent, and has a viscosity of 50,000 to 250,000 centipoise at 20°C (B-type viscometer BH type, 7
A topical ointment, characterized in that it has an ointment form in the range of 4 rpm).