JPH0459293B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel gel ointment base, and more specifically, it has excellent solubility for poorly soluble drugs such as indomethacin and Bufekimak, does not precipitate the main drug even when stored in a cold place for a long period of time, and does not cause discomfort during use. This invention relates to a gel ointment base that does not cause "kinking". Gel ointments are transparent, jelly-like, external applications in which the active ingredient is substantially completely dissolved in the ointment base, and the skin penetration of the active ingredient is generally lower than that of traditional ointments or creams. Because it has the advantage of having a large surface area and less stickiness on the coated surface, it has been actively researched in recent years, and some of it has even been put into practical use. For example, Japanese Patent Publication No. 56-10886 describes a medium consisting of 3 to 35% by weight of glycols, 10 to 50% by weight of lower alcohols, and 30 to 50% by weight of water, and a gelatinized material such as carboxyvinyl polymer or hydroxyethyl cellulose. A gel ointment base for indomethacin in combination with
Publication No. 18250 states that approximately 15% by weight of ethanol, approximately
A gel ointment base for steroids consisting of 35% by weight propylene glycol, about 2% by weight carboxyvinyl polymer and amine as a gelling agent, and a balance amount of water has been disclosed;
No. 55-40604 proposes the use of a cellulose-based polymer material soluble in water and alcohols, such as hydroxypropyl cellulose, as a gelling agent for a gel ointment base. However, these gel ointment bases that have been proposed so far do not have sufficient solubility for poorly soluble drugs, or the polymeric substances used as gelling agents are expelled in the form of scum during friction application. It has drawbacks such as a phenomenon called "twisting" and is not completely satisfactory. Therefore, the present inventors have conducted intensive studies on ointment bases that do not have such drawbacks, and have found that they contain carboxyvinyl polymer as a gelling agent, propylene carbonate, propylene glycol, polyethylene glycol, and ethyl alcohol as essential components. It has been discovered that when combined with a solvent system, an ointment base can be obtained that has excellent dissolving power for poorly soluble drugs and does not cause the drugs to precipitate even when stored at low temperatures for long periods of time, and also does not cause sagging.The present invention completed. Thus, the present invention provides a gel ointment base containing carboxyvinyl polymer, propylene carbonate, propylene glycol, polyethylene glycol, and ethyl alcohol as essential components and having a pH of 4 to 10. . The gel ointment base of the present invention will be explained in more detail below. The carboxyvinyl polymer used as a gelling agent in the ointment base of the present invention has a carboxyl group in the molecule and has a number average molecular weight of about 1,000,000.
It is a water-soluble vinyl polymer with a molecular weight of about 3,000,000 [For more information on its characteristics and other details, please refer to the Ministry of Health, Labor and Welfare, Central Pharmaceutical Affairs Council, Cosmetic Raw Materials Standards Investigation Committee, "Cosmetic Raw Materials Standards" Supplementary Notes, pp. 56-65, Showa January 46
For example, Hibis Wako 103, 104 from Wako Pure Chemical Industries, Ltd.
and 105 trade names, also BFGoodrich
From Chemical Co. (Cleveland, Ohio, USA)
Those commercially available under the trade names Carbopol 934, 940 and 941 can be used. These carboxyvinyl polymers can be neutralized with basic substances to adjust the performance of the gel, if necessary. Basic substances that can be used to neutralize this carboxyvinyl polymer include, for example, ammonia; monoethylamine, diethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine,
Amines such as triisopropanolamine, tributylamine, and trioctylamine; alkali metal salts such as sodium hydroxide, potassium hydroxide, sodium borate, and potassium carbonate; among these, amines are usually preferred;
Of these, diisopropanolamine is most suitable. The amount of the carboxyvinyl polymer mentioned above is not exact and can vary widely depending on the amount of other ingredients, but generally it is 0.5 to 5% by weight based on the weight of the ointment base. , preferably 0.7 to 3% by weight, more preferably 1 to 2% by weight. Further, the amount of the above-mentioned basic substance used as necessary for neutralizing the carboxyvinyl polymer is generally 150 parts by weight or less, preferably 10 to 100 parts by weight, per 100 parts by weight of the carboxyvinyl polymer.
The amount can be 130 parts by weight, more preferably 10 to 100 parts by weight. On the other hand, the gel ointment base of the present invention is characterized in that a combination of propylene carbonate, propylene glycol, polyethylene glycol, and ethyl alcohol is used as the solvent system. The amount of each of these solvent components to be blended is not strictly limited and can be varied widely as needed, but it is generally advantageous to blend them in the following proportions based on the weight of the ointment base. be.

[Table] As the polyethylene glycol used as a component of the above solvent system, polyethylene glycol with a number average molecular weight generally in the range of about 200 to about 600, preferably in the range of about 200 to about 400, is suitable. The average molecular weight is approx.
300 polyethylene glycol is optimal. Furthermore, the proportions of the above four solvent components can be freely changed within the above range depending on the type and amount of the carboxyvinyl polymer or the type and amount of the active ingredient, etc. Although it is possible to obtain an optimal formulation for the main drug, it has been found that from the viewpoint of the solubility of the main drug, it is suitable to combine the above four types of solvent components in the following relative ratios. That is, propylene glycol is 0.1 to 4 parts by weight per 1 part by weight of propylene carbonate.
Parts by weight, preferably 0.2 to 1.5 parts by weight, polyethylene glycol 0.1 to 4 parts by weight, preferably 0.2 to 1.5 parts by weight
It has been found that particularly advantageous results are achieved when the ethyl alcohol is incorporated in a ratio of 2.0 parts by weight and ethyl alcohol in a ratio of 0.2 to 12 parts by weight, preferably 0.5 to 12 parts by weight. In addition to the above-mentioned components, the gel ointment base of the present invention can further contain water, if necessary, as a component to further stabilize the gel pharmaceutically. When blended, water is 40% by weight or less, preferably 1% by weight based on the weight of the ointment base.
It can be blended in an amount of ~35% by weight, more preferably 3-30% by weight. Furthermore, the gel ointment base of the present invention can further contain diisopropyl adipate, if necessary. This diisopropyl adipate is effective in promoting the penetration of the main drug contained in the base into the skin, and is generally 5% by weight or less, preferably 1 to 5% by weight, based on the weight of the ointment base.
More preferably, it can be blended in an amount of 2 to 4% by weight. Furthermore, the gel ointment base of the present invention may further contain sodium ethylenediaminetetraacetate (EDTA-Na), isopropyl myristate, sucrose fatty acid ester, etc. as optional components. The above EDTA-Na is effective in preventing the gel structure from being destroyed by ultraviolet rays, and is generally blended in an amount of 0.1% by weight or less, preferably 0.005 to 0.05% by weight, based on the weight of the ointment base. I can do it. On the other hand, isopropyl myristate and sucrose fatty acids are useful for suppressing the occurrence of sagging, and each can be incorporated in an amount of 5% by weight or less, preferably 0.5 to 3% by weight, based on the weight of the ointment base. In addition, the above-mentioned sucrose fatty acid esters are listed in the "Food Additives Official Guidebook" (4th edition),
B-537-542 (September 10, 1978, published by Hirokawa Shoten)
Those listed in can be used. The gel ointment base of the present invention can be prepared from the above-mentioned components according to a method known per se, by mixing the above-mentioned components with each other and stirring until uniform. The ointment base of the present invention thus prepared can have a pH of 4 to 10, preferably 4 to 7, more preferably 5 to 7, by adjusting the amount of the basic substance in the dropper. and generally between 100000 and
It is desirable to have a viscosity of 400,000 cps, preferably in the range of 150,000 to 300,000 cps. As mentioned above, the gel ointment base provided by the present invention has excellent solubility of poorly soluble drugs, and the drugs do not precipitate even when stored at low temperatures for long periods of time. It has various advantages, such as not causing any unpleasant "wrinkling" when used, and also has excellent skin permeability of the main drug. It exhibits remarkable effects as an external base for poorly soluble drugs such as hexyl esters, especially non-steroidal anti-inflammatory drugs. The method for preparing an ointment using the ointment base of the present invention is not particularly limited, and any conventional method can be used. For example, the main ingredients are first mixed with propylene carbonate, propylene glycol, polyethylene glycol and ethyl An ointment can be prepared by dissolving it in a mixture of alcohols, then adding carboxyvinyl polymer to swell it, and then gelling it by adding other auxiliary ingredients if necessary. The present invention will be further explained below with reference to Examples. Example 1 Carboxyvinyl polymer (Hivis Wako 104 manufactured by Wako Pure Chemical Industries, Ltd.) 1.5w/w% Diisopropanolamine 0.20 Propylene carbonate 15.00 Propylene glycol 15.00 Polyethylene glycol #300 15.00 Purified water 5.00 Ethyl alcohol
Add the carboxyvinyl polymer to a mixture of appropriate amounts of propylene carbonate, propylene glycol, polyethylene glycol, and ethyl alcohol in an amount sufficient to make the total amount 100.00% ,
Mix well. Add purified water to the resulting mixture,
Mix well and add a solution of diisopropanolamine in a small amount of ethyl alcohol. Add the remaining amount of ethyl alcohol to make up the total volume and stir until homogeneous. The properties of the base thus obtained are summarized in Table 1 below. Example 2 Carboxyvinyl polymer (Hibis Wako)
104) 2.50w/w% Diisopropanolamine 0.30 Propylene carbonate 20.00 Propylene glycol 20.00 Polyethylene glycol #300 10.00 Purified water 5.00 Ethyl alcohol
Add the carboxyvinyl polymer to a mixture of appropriate amounts of propylene carbonate, propylene glycol, polyethylene glycol and ethyl alcohol in an amount sufficient to make the total amount 100.00% and mix well. Add purified water to the resulting mixture, mix well, and add a solution of diisopropanolamine in a small amount of ethyl alcohol. Add the remaining amount of ethyl alcohol to make up the total volume and stir until homogeneous. The properties of the base thus obtained are summarized in Table 1 below. Example 3 Carboxyvinyl polymer (Hibis Wako)
1.50w/w% Diisopropanolamine 0.20 Propylene carbonate 30.00 Propylene glycol 20.00 Polyethylene glycol #300 10.00 Purified water 10.00 Ethyl alcohol
Add the carboxyvinyl polymer to a mixture of appropriate amounts of propylene carbonate, propylene glycol, polyethylene glycol and ethyl alcohol in an amount sufficient to make the total amount 100.00% and mix well. Add purified water to the resulting mixture, mix well, and add a solution of diisopropanolamine in a small amount of ethyl alcohol. Add the remaining amount of ethyl alcohol to make up the total volume and stir until homogeneous. The properties of the base thus obtained are summarized in Table 1 below. Example 4 Carboxyvinyl polymer (Hibis Wako)
104) 2.50w/w% Diisopropanolamine 0.20 Propylene carbonate 10.00 Propylene glycol 15.00 Polyethylene glycol #300 15.00 Diisopropyl adipate 3.00 Purified water 10.00 Ethyl alcohol
Add the carboxyvinyl polymer to a mixture of appropriate amounts of propylene carbonate, propylene glycol, polyethylene glycol, diisopropyl adipate, and ethyl alcohol in an amount sufficient to make the total amount 100% and mix well. Add purified water to the resulting mixture, mix well, and add a solution of diisopropanolamine in a small amount of ethyl alcohol. Add the remaining amount of ethyl alcohol to make up the total volume and stir until homogeneous. The properties of the base thus obtained are summarized in Table 1 below. Regarding the bases obtained in Examples 1 to 4 above,
The pH and viscosity were measured, and the sample was applied by rubbing on the skin to observe "wrinkle". The appearance of all the samples was colorless to pale yellow and transparent gel-like. Next, the samples left at room temperature, low temperature (5°C, 0°C, -5°C) or 40°C for 3 months were visually observed for changes in appearance. The results regarding these points are shown in Table 1 below. The pH and viscosity were as indicated, and no twisting during use was observed in any of the samples, and no change in appearance was observed after 3 months at each temperature.

[Table] Room temperature − − − −

Claims (1)

[Scope of Claims] 1. A gel ointment base containing carboxyvinyl polymer, propylene carbonate, propylene glycol, polyethylene glycol and ethyl alcohol as essential components and having a pH of 4 to 10. 2. The gel ointment base according to claim 1, which contains carboxyvinyl polymer in an amount of 0.5 to 5% by weight, based on the weight of the base. 3 Based on the weight of the base, the patent claims contain 5 to 50% by weight of propylene carbonate, 1 to 40% by weight of propylene glycol, 1 to 40% by weight of polyethylene glycol, and 10 to 60% by weight of ethyl alcohol. The gel ointment base according to scope 1. 4 Claims 1 to 4 containing 0.1 to 4 parts by weight of propylene glycol and 0.1 to 4 parts by weight of polyethylene glycol per 1 part by weight of propylene carbonate.
The gel ointment base according to any one of Item 3. 5 Claims 1 to 1 containing 0.2 to 1.5 parts by weight of propylene glycol and 0.2 to 2.0 parts by weight of polyethylene glycol per 1 part by weight of propylene carbonate.
The gel ointment base according to any one of Item 3. 6. The gel ointment base according to any one of claims 1 to 5, further comprising diisopropyl adipate. 7. The gel ointment base according to claim 6, which contains diisopropyl adipate in an amount of 5% by weight or less based on the weight of the base. 8 Claims 1 to 7 further containing water
The gel ointment base according to any of paragraphs. 9. The gel ointment base according to any one of claims 1 to 8, which contains water in an amount of 15% by weight or less based on the weight of the base. 10. The gel ointment base according to any one of claims 1 to 9, further containing an amine. 11. The gel ointment base according to claim 10, wherein the amine is diisopropanolamine. 12 Add amines to the carboxyvinyl polymer
The gel ointment base according to claim 10, which contains 150 parts by weight or less per 100 parts by weight. 13. The gel ointment base according to any one of claims 1 to 12 for use in poorly soluble drugs. 14. The gel ointment base according to claim 13, wherein the poorly soluble drug is a non-steroidal anti-inflammatory agent.