JPH0364483B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a drug, and more specifically, an aqueous solution of a water-soluble polymer of an aliphatic carboxylic acid or its salt and a slightly soluble aluminum compound are mixed at a pH of 4.0 to 100% in the presence of an organic acid containing a hydroxyl group in the molecule or a salt thereof. This invention relates to a drug formulation containing in its composition a synthetic polymer gel obtained by reacting with 6.0. Conventionally, soluble polymers of aliphatic carboxylic acids or their salts exhibit high viscosity in aqueous solutions mainly due to repulsion due to the negative charge of the carboxyl groups in the molecules, so they have been widely used as thickeners in foods and medicines. It has been used in fields such as cosmetics. However, if a certain amount or more of polyvalent metal ions are mixed into the mucus containing this substance under stirring,
It reacts immediately to form a non-uniform floc-like precipitate,
Its usefulness as a thickener is reduced. As a result of research on polyvalent metal salts of aliphatic carboxylic acid polymers, the present inventors have found that the aluminum salts obtained under certain reaction conditions have excellent suitability as base compositions for drug formulations. He discovered this and completed this invention. That is, in the present invention, the synthetic polymer gel is mainly composed of an aluminum salt of a water-soluble polymer of an aliphatic carboxylic acid or a salt thereof, and the gel is added to an aqueous solution of a water-soluble polymer of an aliphatic carboxylic acid or a salt thereof. A synthetic polymer gel is formed in a base material by reacting an aluminum compound with low solubility in a solution solvent in the presence of an organic acid or its salts containing a hydroxyl group in the molecule in the pH range of 4.0 to 6.0. death,
Alternatively, by incorporating it into the base composition, we have succeeded in obtaining a drug drug with excellent properties such as self-shape retention, water-retentivity, and thermal stability. The above synthetic polymer gel is a transparent and homogeneous elastic gel mainly composed of aluminum salt of a water-soluble polymer of aliphatic carboxylic acid or its salts.
% of water stably, and does not ooze out the contained water even when compressed, and has an extremely excellent self-containing property that does not cause fluidity even when a large amount of water is contained inside. It has shape retention properties.
Furthermore, the above synthetic polymer gel has the property of gradually evaporating the water content from the gel surface over time, and even when it contains a large amount of water, when it comes into contact with water, it swells without melting and absorbs further water. This does not change even when coexisting with other drug ingredients. The injection drug of this invention has the following characteristics. (1) Self-retention: It can contain a large amount of water, has no fluidity even if it contains a large amount of water, has strong elasticity, and does not collapse easily when pressed. (2) Water-retaining property: Even if it is compressed with about 90% water inside, it will not spit out water, and even if you touch its surface, you will only feel a slight dampness and your hands will not get wet. There isn't. (3) Thermal stability: Even after this drug was sealed in an aluminum foil bag and placed in a constant temperature bath at 50°C for two weeks, it retained its original shape, and the so-called so-called No exudation of water as a result of syneresis is observed. (4) Transparency: Highly transparent, homogeneous, and has a clean appearance. (5) Water absorption: Even when it contains a large amount of water, it swells and absorbs even more water when it comes into contact with new water, so it does not cause the so-called sagging phenomenon. (6) Moisture wicking ability: When a water-absorbing syrup is left indoors, the water gradually evaporates from the surface. At this time, the latent heat of vaporization is taken away, so the drug itself is always kept at a temperature lower than room temperature, and has an excellent cooling effect. In this invention, the aliphatic carboxylic acid polymer specifically refers to a synthetic polymer compound containing acrylic acid, methacrylic acid, maleic anhydride, etc. as a constituent unit, and includes polyacrylic acid, polymethacrylic acid, polymethacrylic acid, Examples include carboxyvinyl polymers. Maleic anhydride can be considered an aliphatic carboxylic acid because it is easily hydrolyzed in water to produce a carboxylic acid. These monomers may form a polymer consisting only of themselves or may combine with other monomers to form a copolymer, and the present invention may be applied to either of these. For example, methoxyethylene/maleic anhydride copolymer is an example. Polymers of aliphatic carboxylic acid esters, aliphatic carboxylic acid amides, and aliphatic nitriles are not included in this invention, but if a part of them is hydrolyzed to form free carboxylic acids or their salts, it is considered that they are water-soluble. Included as long as In addition, soluble salts are salts of primary, secondary, and tertiary organic bases such as alkali metal salts, ammonium salts, and mono-, di-, and triethanolamine salts that dissolve in water. say something Furthermore, aluminum compounds include hydroxides such as aluminum hydroxide, normal salts of inorganic or organic acids such as aluminum chloride, aluminum sulfate, aluminum acetate, aluminum stearate, or their basic salts, aluminum alum, etc. double salts such as, as well as aluminate salts such as sodium aluminate, inorganic aluminum complex salts and organic aluminum chelate compounds. Even if these aluminum compounds are water-soluble, they can be made poorly soluble by appropriate treatment, so the solubility of the aluminum compound itself as a starting material is not a concern. In order to obtain a stable gel by reacting a water-soluble polymer of aliphatic carboxylic acid or its salts with an aluminum compound as listed above, the reaction within the system is not local but global. Preferably, it occurs uniformly. In other words, since the carboxylic acid polymer solution has a high viscosity, when the aluminum compound solution is added under stirring, the reaction proceeds at the interface between both solutions before uniform mixing of both solutions is achieved. This results in the formation of a floc-like precipitate that is non-uniform and less useful. Such a floc-like precipitate does not have any of the excellent properties described above for the synthetic polymer gel of the present invention. Crosslinking of aliphatic carboxylic acid polymers with aluminum has been theoretically predicted for some time, but the reason why it has not reached the level of practical use is that it has been extremely difficult to overcome this heterogeneity. . According to the present invention, this problem has been solved by using a poorly soluble aluminum compound with low solubility. Even aluminum compounds with high solubility can be converted into poorly soluble salts by adjusting the pH of the solution after dissolution. The amount of the poorly soluble aluminum compound blended is preferably 0.3 to 5% by weight of the water-soluble polymer of aliphatic carboxylic acid or its salts in terms of aluminum. The reaction rate between the above polymer and the aluminum compound is controlled by the surface area and dissolution area of suspended aluminum compound particles and the pH of the solution. PH
The lower the pH, the faster the reaction, but if it is too low, the gel strength will be weak, and on the other hand, the reaction will be slow around pH 7, so the pH value is preferably in the range of 4.0 to 6.0. Furthermore, the present inventors have found that the reaction speed can be increased by adding an organic acid containing an OH group in the molecule or a salt thereof to the reaction system. These organic acids include those generally called oxyacids such as glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, and salicylic acid. The reason why such organic acids act to promote the above reaction is thought to be due to the chelating ability of the OH group within the molecule, and the OH group and carboxylic acid act cooperatively to form a poorly soluble It is presumed that this is because the aluminum salt is gradually dissolved in the system and aluminum is gradually released. Therefore, the reaction rate can be adjusted by adjusting the amount added. The synthetic polymer gel contained in the drug of the present invention can also be produced by adding a sparingly soluble aluminum compound to a solution containing two or more of the above carboxylic acid polymers. For example, a gel is made by adding an aluminum compound to a sodium polyacrylate solution mixed with carboxyvinyl polymer and crosslinking it.
It has high elasticity and water-retaining properties, making it extremely useful as a base component for syrup medicines. In the present invention, the amount (W/W%) of the water-soluble polymer of aliphatic carboxylic acid or its salts in the aqueous solution is in the range of 0.5 to 30% when preparing a gel that is practically meaningful as a drug composition. is appropriate, and the amount of synthetic polymer compound used is 0.5 to 10
A range of % is appropriate. In recent years, many medicines have been commercialized in the form of paste-like medicinal materials spread on a support cloth, but the medicine of the present invention is also a product in a similar form by adding several kinds of additives. It can be applied to the purpose of making. In bottle medicines that are intended to cool affected areas such as bruises and sprains, water, which is originally included in the ingredients, is an important effective ingredient because it removes heat from the affected area in the form of latent heat of vaporization. It can be said to be one of the ingredients. Therefore, water is the source of usefulness, and the higher its content, the more effective it is. However, with conventional drug bases,
When a large amount of water is added, the consistency of the base decreases, causing problems such as contamination of the affected area, but the present invention's syrup can stably contain more than 90% water, and is an advantage in this respect. Its usefulness is enormous. Example 1 35 g of sodium polyacrylate and 50 g of sodium carboxymethylcellulose were suspended in 200 g of propylene glycol, and 400 ml of water was added to the suspension.
and 150 ml of 1N hydrochloric acid were added and stirred. After obtaining a uniform gel-like liquid, add 5 g of aluminum hydroxide.
suspended in 50 ml of water, 12 g of peppermint oil, 8 g of DL-camphor, 9 g of DL-menthol, 9 g of methyl salicylate, ``Polysorbate''
80'' was mixed to form a homogeneous oily liquid and added to the above gel-like liquid while stirring vigorously, and after the addition was completed, 50ml of 1M lactic acid buffer (PH5.0) and water were added. was added to bring the total amount to 1000 g, and the reaction was carried out. The gel-like liquid thus obtained was spread on a flannel or nonwoven fabric, cut and sealed in an aluminum bag to obtain a syrup. The viscosity of a 0.5% aqueous solution of sodium polyacrylate is 1400 to 1800 cps, and the average degree of polymerization is 30000 to 40000.
It was hot. Example 2 50 g of starch was placed in 500 ml of water, heated to about 90° C., and stirred to dissolve. After it became a translucent gel-like liquid, it was cooled to 60°C, 20g of gelatin was added and stirred to uniformly dissolve it, and after dissolution, it was further cooled to 35°C. Separately, 35 g of sodium polyacrylate was suspended in 200 g of glycerin and added to the above starch solution with stirring. After the sodium polyacrylate crystals are completely dissolved,
20 ml of 3N sulfuric acid, 31 g of tartaric acid, 8 g of l-menthol, 30 g of methyl salicylate prepared separately,
A mixed solution of 2 g of "Polysorbate 80" was added with vigorous stirring. Finally, 5% aluminum alum solution
Add aluminum hydroxide suspension obtained by mixing 20 ml of 5% sodium hydroxide solution to 60 ml 6 under vigorous stirring to adjust the pH to 4.5 to 5.5, and add water to make a total volume of 1000 g.
After that, the mixture was stirred again to mix uniformly. The resulting gel-like liquid was spread on a cloth to a thickness of 2 mm, the surface was covered with polyethylene film, the pieces were cut into pieces of 20 cm x 14 cm, and they were sealed in an aluminum bag and the drug was poured into the bag. Obtained. Example 3 20 g of carboxyvinyl polymer was added and dissolved in 500 ml of water, and 35 g of sodium polyacrylate kneaded with 60 g of propylene glycol, 29 g of delta gluconolactone and
Add 140g of 70% sorbitate solution and stir until it becomes a transparent gel-like liquid.Next, mix the previously prepared mixture of 25g of salicylic acid glycol ester, 5g of methyl salicylate, and 2g of "Polysorbate 80" with 5% aluminum chloride solution. An aluminum hydroxide suspension prepared by adding 20 ml of 5% sodium hydroxide solution to 34 ml was added to adjust the pH to 4.5 to 5.5, and the mixture was vigorously stirred until a homogeneous gel-like liquid was obtained. Finally the whole amount
Water was added to give a total weight of 1000 g, and the mixture was stirred again until it became homogeneous. Using the obtained gelatinous liquid, a syringe having the same specifications as in Example 2 was obtained. In addition, the delta gluconolactone is dissolved in water and hydrolyzed,
It becomes gluconic acid. The cooling effects and thermal stability of the syrups obtained in Examples 1 to 3 above are shown in Table 1 below in comparison with three types of commercially available syrups.

【table】

[Table] The cooling effect was evaluated using a sample with the film attached to the paste surface at 20°C.
Calculate the amount of evaporation per 1 g of the initial weight of the paste based on the value obtained by leaving the support fabric side up in a 60% RH room for 24 hours and measuring the amount of water evaporation from the support fabric surface as a change in weight during that time. and further 20℃
It was obtained by converting it into the latent heat of vaporization. However, the initial weight of the paste can be calculated from the initial weight of the sample by immersing it in water at 90°C and crushing it with a spatula to disperse the paste, then taking the support cloth, washing it with water, drying it, and measuring its weight. The weight of the film is subtracted. For volatile active ingredients such as methyl salicylate, thymol, and terpenoids, weight correction was performed assuming that 10% of the labeled amount evaporated with water in 24 hours. Thermal stability was determined by sealing a sample in an aluminum bag, heating it at 50°C for two weeks, leaving it at room temperature for one day, opening the bag, and observing changes in properties. As is clear from the above results, it is recognized that the syrup according to the present invention is significantly superior to commercially available products in terms of both cooling effect and thermal stability.

Claims (1)

[Claims] 1 An aqueous solution of a water-soluble polymer of an aliphatic carboxylic acid or its salts, and an aqueous solution of a water-soluble polymer of an aliphatic carboxylic acid or its salts in terms of aluminum.
An aliphatic carboxylic acid or its salt obtained by reacting 0.3 to 5% by weight of a poorly soluble aluminum compound in the presence of an organic acid containing a hydroxyl group in the molecule or its salt at pH 4.0 to 6.0. A drug containing a synthetic polymer gel mainly composed of a water-soluble polymer, aluminum salt.