JPH0647536B2 - Liquid containing tocopherols - Google Patents

Description

TECHNICAL FIELD The present invention relates to a liquid agent containing tocopherols, and more specifically, tocopherols even when filled in a container whose surface is formed of polyethylene at least partially. The present invention relates to a liquid preparation containing tocopherols, in which the decrease in the content of the above is favorably prevented and the transparency is maintained for a long period of time.

Problems to be solved by the prior art and invention Tocopherols such as tocopherol acetate are blended as an active ingredient in eye drops and the like, but liquid solutions such as eye drops containing tocopherols such as tocopherol acetate are the same. When it is filled in a polyethylene container and stored, the transparency is lost, white turbidity and precipitation occur, and tocopherols are adsorbed to the container, and the content thereof is lowered.

Usually, as a material for the container that contains eye drops, polyethylene has the problem of allowing the contents to permeate during storage.
When manufacturing a container for such eye drops, the container body is formed using a material such as polyethylene terephthalate or U polymer having low moisture permeability. However, for example, in the case of an eye drop container, in order to instill an appropriate amount during use,
Although it is desirable to use a polyethylene inner stopper having elasticity, the content liquid comes into contact with the inner stopper during overturning during storage or during use. Therefore, when the tocopherols such as tocopherol acetate are contained in the eye drop, the tocopherols are adsorbed by the polyethylene of the inside plug, the content thereof is reduced, and cloudiness and precipitation occur. Therefore, in order to avoid such a problem, when filling an ophthalmic solution containing tocopherols, conventionally, an outer layer that comes into contact with the ophthalmic solution as an inner stopper is formed of a non-adsorptive material such as polybutylene terephthalate, and the inner layer is made of polyethylene. Although the double-layered one formed in 1. was used, the double-layered inner stopper had a problem in terms of cost and cost efficiency.

The present invention has been made in order to improve the above circumstances, even when at least a part of the surface that is in contact with the liquid agent is filled in a container formed of polyethylene, cloudiness, precipitation is prevented, transparency is long-term. It is an object of the present invention to provide a tocopherol-containing liquid agent in which the tocopherols are stably retained and the decrease in the content thereof is prevented while being maintained for a long time.

Means and Actions for Solving Problems The present inventors have conducted diligent studies in order to achieve the above-mentioned object, and as a result, for a liquid preparation such as eye drops containing 0.001 to 0.5% by weight of tocopherols, polyoxyethylene ( Below, PO
Abbreviated as E) hydrogenated castor oil is added, glycyrrhizinate and a quaternary ammonium type cationic surfactant are added, and glycyrrhizinate is added in an amount of 0.1 to 0.5% by weight, and glycyrrhizate is added to the fourth. Specified amount, ie 0.5 to 1 mol, of a quaternary ammonium type cationic surfactant
By blending in a range of 5 moles, the adsorption of tocopherols on polyethylene is favorably prevented, and even if the liquid containing tocopherols comes into contact with polyethylene, the content of tocopherols does not decrease and the transparency of the liquid is long-term. White turbidity maintained over a period of time, no precipitation occurs, for this reason, it was found that polyethylene can be effectively used as a material in the case of producing a container containing a tocopherol-containing liquid agent, which led to the present invention. Is.

In this case, if POE hydrogenated castor oil is not blended, the transparency of the liquid containing tocopherols is maintained, but the content of tocopherols is significantly reduced, and glycyrrhizinate, a quaternary ammonium type cationic surfactant are added. If it is not blended, the solution will become cloudy upon storage and the content of tocopherols will decrease. Furthermore, when the glycyrrhizic acid salt is blended in an amount out of the range of 0.5 to 5 mol per 1 mol of the quaternary ammonium type cationic surfactant, remarkable turbidity and precipitation occur in the liquid agent, and any of the objects of the present invention is achieved. It is not possible to achieve, by blending POE hydrogenated castor oil, glycyrrhizinate, and quaternary ammonium-type cationic surfactant, and further, glycyrrhizate and quaternary ammonium-type cationic surfactant. Only when used in combination with the above-mentioned specific molar ratio range, the transparency of the tocopherol-containing liquid agent is maintained under the contact condition with polyethylene, and the object of the present invention of stably blending the tocopherols is achieved. It is a thing.

Hereinafter, the present invention will be described in more detail.

Examples of the tocopherols used in the present invention include tocopherol, tocopherol acetate, tocopherol succinate, and the like, and one or more of these are used. According to the present invention, when any of these tocopherols is used Also, it can be blended stably because adsorption to polyethylene is prevented.

The amount of tocopherols to be added varies depending on the type of solution, purpose of use, etc., but is generally 0.001 to 0.5% (wt%, the same applies below), especially when used in eye drops.
It is 0.005 to 0.05%.

The tocopherol-containing liquid agent of the present invention contains POE hydrogenated castor oil, glycyrrhizinate, and a quaternary ammonium type cationic surfactant as described above for stabilizing the tocopherols. POE hydrogenated castor oil has a polymerization degree of oxyethylene of about 40 to 1
No. 00 is preferably used. Examples of the glycyrrhizic acid salt include salts of dipotassium, disodium, monoammonium, and one or more of these are used. Further, the quaternary ammonium type cationic surfactant is not particularly limited, but benzethonium chloride, benzalkonium chloride, and cetylpyridinium chloride are preferable, and one or more of these are used.

In this case, the content of POE hydrogenated castor oil is 0.02 to 0.5%, particularly 0.05 to 0.3%, more preferably 0.1 to 0.3% in the case of eye drops. If the amount of POE hardened castor oil is too small, the stabilizing effect of tocopherols is not sufficient, and if it is too large, it may be dispersed in milky white turbidity.

The amount of glycyrrhizinate is 0.1 to 0.5%, and in the case of eye drops, 0.025 to 0.25%, particularly 0.05 to 0.15.
% Is preferable.

In the present invention, a specific molar ratio of glycyrrhizinate and a quaternary ammonium type cationic surfactant, that is, a molar ratio of glycyrrhizinate to a quaternary ammonium type cationic surfactant is 0.5 to 5 mol. If the amount is out of this range, the object of the present invention of stable compounding of tocopherols will not be sufficiently exhibited.

The liquid agent of the present invention, in addition to the components described above, the type of liquid agent,
Appropriate components may be added depending on the purpose of use. For example,
In the case of eye drops, as an active ingredient, sulfa drug, diphenhydramine hydrochloride, potassium aspartate, aminoethyl sulfonic acid, ε-aminocaproic acid, chlorpheniramine maleate, neostigmine methylsulfate and the like can be mixed, Further, a tonicity agent such as sodium chloride and potassium chloride, a polymer additive such as polyhydric alcohol, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose and hydroxypropyl cellulose may be added.

The liquid agent of the present invention is filled in various containers and stored or used.However, in the present invention, even if the tocopherol-containing liquid agent touches polyethylene, cloudiness, precipitation, and a decrease in the content of the tocopherols are prevented. The container containing at least a part of the surface which is in contact with the liquid can be filled with the liquid containing the tocopherols of the present invention.

EFFECTS OF THE INVENTION According to the tocopherol-containing liquid agent of the present invention, POE hydrogenated castor oil, and further a glycyrrhizinate salt and a quaternary ammonium-type cationic surfactant in a specific molar ratio, to stabilize the tocopherols. Even if the liquid agent is contacted with polyethylene, the cloudiness and precipitation of the liquid agent can be well prevented, the transparency can be maintained for a long time, and the decrease in the content of tocopherols can be prevented as much as possible.

Next, the effects of the present invention will be specifically described with reference to experimental examples.

[Experimental example]

A liquid preparation having the formulation shown in Table 1 was prepared, and a polyethylene piece was immersed in the liquid preparation and heated to 40 ° C., and the generation state of cloudiness and precipitation and the residual rate of tocopherol acetate were examined with time. The results are shown in Table 2.

The content of tocopherol acetate was determined by high performance liquid chromatography (column: Partisil-10CCS / C8, mobile phase: acetonitrile: water = 90: 10, measurement wavelength: 284 nm).

As is clear from the results in Table 2, in the state where the polyethylene piece was immersed in the liquid agent, when the POE hydrogenated castor oil was not blended (composition C), the liquid agent had good transparency, When the residual ratio of tocopherol acetate is significantly reduced, and the molar ratio of dipotassium glycyrrhizinate to benzalkonium chloride is too high (composition D), the tocopherol acetate content is not significantly reduced, but the liquid formulation becomes cloudy. , Precipitation occurred. Further, when dipotassium glycyrrhizinate and benzalkonium chloride were not blended (composition E), the appearance of the liquid preparation was deteriorated and the content of tocopherol acetate was also decreased. On the other hand, when POE hydrogenated castor oil is blended and dipotassium glycyrrhizinate and benzalkonium chloride are blended in a predetermined molar ratio range (compositions A and B), the transparency of the liquid formulation is maintained and tocopheryl acetate is retained. It was found that the decrease in the content of sucrose was satisfactorily prevented.

Examples will be shown below, but the present invention is not limited to the following examples.

[Example 1] Eye drops Sodium chloride (0.6 g) and potassium chloride (0.3 g) were added to about 80 ml of distilled purified water and dissolved, and then chlorpheniramine maleate (0.02 g) and methylsulfate neostigmine (0.002 g) were dissolved.
And 0.1 g of dipotassium glycyrrhizinate is added and dissolved. Next, 0.015 g of tocopherol acetate mixed with 0.15 g of POE (40) hydrogenated castor oil at warm time was added to the above liquid, 0.01 g of benzalkonium chloride was added, and distilled purified water was added to make the total amount. Make up to 100 ml and, after passing, store in an eye dropper container having a polyethylene inner stopper.

[Example 2] Eye drops Approximately 80 ml of distilled purified water with sodium chondroitin sulfate
0.1 g, diphenhydramine hydrochloride 0.03 g, dipotassium glycyrrhizinate 0.2 g and boric acid 1.2 g were added and dissolved, and then tocopherol acetate 0.02 g was POE (60) hydrogenated castor oil.
After adding 0.3 g of the mixture mixed at warm time to the above liquid, add 0.03 g of benzethonium chloride and add distilled purified water to make 100 ml, and store it in an eye dropper container with a polyethylene inner stopper. .

Each of the eye drops of Examples 1 and 2 maintained the transparency even when stored for a long period of time, and prevented the decrease of the tocopherol acetate content.

Claims (2)

[Claims] 1. Tocopherol 0.001 to 5% by weight, polyoxyethylene hydrogenated castor oil 0.02 to 0.5% by weight,
0.1 to 0.5% by weight of glycyrrhizinate and quaternary ammonium type cationic surfactant are blended in an amount of 0.5 to 5 mol of glycyrrhizinate per 1 mol of the surfactant. Liquid formulation containing tocopherols. 2. The liquid agent according to claim 1, wherein the quaternary ammonium type cationic surfactant is one or more selected from the group consisting of benzethonium chloride, benzalkonium chloride and cetylpyridinium chloride. .