JPS62149671A - Liquid agent containing tocopherol compound - Google Patents

Abstract

PURPOSE:To provide the titled liquid agent such as eye drop, etc., containing polyoxyethylene hardened castor oil, glycyrrhizic acid salt and quaternary ammonium-type cationic surfactant as well as tocopherols and free from clouding nor precipitation even in contact with polyethylene. CONSTITUTION:The titled liquid agent such as eye drop, etc., contains (A) 0.005-0.05wt% tocopherols, (B) 0.1-0.3% polyoxyethylene hardened castor oil, (C) 0.05-0.15% glycyrrhizic acid salt and (D) quaternary ammonium-type cationic surfactant. The liquid agent can be used in contact with polyethylene without causing clouding and precipitation and keeping the transparency over a long period and, furthermore, the loss of tocopherol content can be prevented. The component D is preferably benzetonium chloride, cetylpyridinium chloride, etc., and the molar ratio of C:D is adjusted to (0.5-5):1.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a liquid preparation containing tocopherols, and more specifically, even when filled in a container whose surface is at least partially made of polyethylene, The present invention relates to a tocopherol-containing liquid preparation that satisfactorily prevents a decrease in the content of tocopherols and maintains transparency over a long period of time.

Problems to be Solved by the Prior Art and the Invention Tocopherols such as tocopherol acetate are formulated as active ingredients in eye drops, etc.; When it is filled into a polyethylene container and stored, there are problems in that transparency is lost, white turbidity and precipitation occur, and tocopherols are adsorbed to the container, reducing their content.

Normally, J-liethylene is used as a material for containers containing eye drops, etc., but it has the problem of allowing the contents to pass through during storage. It is formed using materials such as Tele7 Tallate and U polymer. However, for example, in the case of an eye drop container, it is desirable to use a resilient polyethylene inner stopper in order to dispense the appropriate amount during use, but the liquid may come into contact with the inner stopper during storage or when used do. For this reason, eye drops contain tocopherols such as tocopherol acetate.

Tocopherols are adsorbed by the polyethylene in the inner stopper, reducing their content and causing cloudiness and precipitation. Therefore, in order to avoid such problems, when filling eye drops containing tocopherols, conventionally the outer layer that touches the eye drops as an inner stopper is formed of a non-adsorbent material such as polypropylene, and the inner layer is made of polyethylene. However, the cost of the two-layer inner stopper was high and there was a problem in terms of economic efficiency.

The present invention has been made to improve the above-mentioned situation, and even when filled in a container in which at least a part of the surface that comes into contact with the liquid is made of polyethylene, cloudiness and precipitation are prevented, and n1 transparency is maintained for a long period of time. It is an object of the present invention to provide a tocopherol-containing liquid preparation that is maintained over a long period of time, stably retains tocopherols, and prevents a decrease in the content thereof.

The present inventors conducted intensive studies to achieve the above object, and found that polyoxyethylene (hereinafter abbreviated as POE)
By blending hydrogenated castor oil and glycyrrhizinate in a specific amount, i.e., in the range of 5 to 5 moles, to 1 mole of quaternary ammonium type cationic surfactant, polyethylene of tocopherols. Adsorption to the tocopherols is well prevented, and even when the tocopherol-containing liquid comes into contact with 41J ethylene, the content of tocopherols does not decrease, and the transparency of the liquid is maintained for a long period of time, and cloudiness and precipitation do not occur. For this reason, the present inventors have discovered that polyethylene can be effectively used as a material for manufacturing containers containing tocopherol-containing liquid preparations, and have arrived at the present invention.

In this case, in the case of POE cured castor oil mixture, the transparency of the tocopherol-containing liquid is maintained, but the content of tocopherols is significantly reduced, and the glycyrrhizinate, quaternary ammonium type cationic interface If an active agent is not added, the solution becomes cloudy during storage and the content of tocopherols decreases. Furthermore, if the amount of glycyrrhizinate is outside the range of 0.5 to 5 mol per mol of the quaternary ammonium type cationic surfactant, significant cloudiness and precipitation will occur in the solution, both of which will defeat the purpose of the present invention. However, it is impossible to achieve this by combining three components: poE cured castor tyrrhizinate and a quaternary ammonium type cationic surfactant.

Moreover, only when glycyrrhizinate and a quaternary ammonium type cationic surfactant are used together in the above-mentioned specific molar ratio range, the transparency of the tocopherol-containing liquid preparation can be maintained under the conditions of contact with polyethylene, and the tocopherol The object of the present invention, which is to stably blend the following compounds, is achieved.

The present invention will be explained in more detail below.

The tocopherols used in the present invention include hatcopherol, tocopherol acetate, tocopherol succinate, etc., and 11 or more of these are used, but according to the present invention, any of these tocopherols may be used. In this case, adsorption to mopholyethylene is prevented and a stable formulation is obtained.

The amount of tocopherols to be blended varies depending on the type of liquid, purpose of use, etc., but is generally between 0.001 and 0.000.
5% (weight %, the same applies hereinafter), and especially when used in eye drops, it is 0.005 to 0.05%.

The tocopherol-containing liquid preparation of the present invention contains POE cured castor whole oil lythyrrhizinate and a quaternary ammonium type cationic surfactant, as described above, in order to stabilize the tocopherols. POE here
The degree of polymerization of oxyethylene in hardened castor oil is approximately 40.
~100 are preferably used. Further, as the glycyrrhizinate, one or more of salts such as potassium, nonodium, and monoammonium are used. Further, the quaternary ammonium type cationic surfactant is not particularly limited, but benzethonium chloride, pendelkonium salt, and cetylpyrizonium chloride are preferred, and one or more of these may be used.

In this case, the amount of POE hydrogenated castor oil is 0.02 to 0.
．． It is preferable to set it to 5, especially in the case of eye drops, the knowledge is 0.
．． 0.05 to 0.3%, more preferably 0.1 to 0.3%. If the amount of POE hydrogenated castor oil is too small, the stabilizing effect of tocopherols will not be sufficient, and if it is too large, the mixture may be dispersed into a milky white turbidity.

Mayu, the amount of glycyrrhizinate is 0.1-0.5%
is preferable, and in the case of eye drops, it is 0.025 to 0.25%.
In particular, it is preferably 0.05 to 0.15%.

In the present invention, the glycyrrhizinate and the quaternary ammonium type cationic surfactant are mixed in a specific molar ratio, that is, the molar ratio of glycyrrhizin A to the quaternary ammonium type cationic surfactant is 0.5 to 5 moles. If it is outside this range, the purpose of the present invention, which is to achieve a stable combination of tocopherols, will not be fully achieved.
do not have.

In addition to the above-mentioned components, the liquid preparation of the present invention includes the type of liquid preparation,
Appropriate components can be blended depending on the purpose of use and the like. for example,
In the case of eye drops, sulfa drugs, sophenhydramine hydrochloride, potassium aspartate, aminoethyl sulfonic acid, ε-amitsukagulonic acid, chlorpheniramine maleate, neostigmine methyl sulfate, etc. can be blended as active ingredients. Also, isotonic agents such as sodium chloride and potassium chloride, polyhydric alcohols, etc. Polymer additives such as ribinyl alcohol, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxyzorobyl cellulose, etc. can also be blended.

The liquid preparation of the present invention is filled into various containers and storage stratification is used, but in the present invention, even if the liquid preparation containing tocopherols comes into contact with polyethylene, clouding, precipitation, and a decrease in the content of tocopherols are prevented. Polyethylene can be effectively used as a container material, and the tocopherol-containing liquid agent of the present invention can be filled into a container in which at least a portion of the surface that the liquid agent touches is made of polyethylene.

Effects of the Invention According to the tocopherol-containing liquid preparation of the present invention, the stabilization of tocopherols is achieved by blending POE hydrogenated castor oil, glycyrrhizinate and a quaternary ammonium type cationic surfactant in a specific molar ratio. Achieved,
Even when the liquid comes into contact with polyethylene, cloudiness and precipitation of the liquid are well prevented, and transparency is maintained for a long period of time.
A decrease in the content of tocopherols is also prevented as much as possible.

Next, experimental examples will be shown to specifically explain the effects of the present invention.

[Experiment example]

A liquid preparation having the formulation shown in Table 1 was prepared, and AK and polyethylene pieces were immersed therein and heated to 50° C. Over time, the residual rate of tocopherol acetate was determined based on the difference in the occurrence of white turbidity and precipitation. The results are shown in Table 2.

In addition, the content of tocopherol acetate is 0? Thorntail (Column: Partisil-10CC8/
C8° mobile phase niacetonitrile:water = 90:10. Measurement wavelength: 284 nm).

As is clear from the results in Table 2, when the polyethylene piece is immersed in the liquid, POE
When the cured castor castor oil was not completely mixed (composition C), the transparency of the liquid was good, but the residual rate of tocopherol acetate was significantly reduced, and the molar ratio of dipotassium glycyrrhizinate to pendelkonium chloride was high. When the composition was too high, the content of tocopherol acetate decreased very little, but clouding and precipitation occurred in the solution. In addition, when dipotassium glycyrrhizinate and pendelkonium chloride were not blended (group gE), the appearance of the liquid preparation deteriorated and the content of tocopherol acetate also decreased. On the other hand, when POE cured castor oil is mixed with socarium glycyrrhizinate and pendelkonium chloride in a predetermined molar ratio range (compositions A and B),
It was found that the transparency of the liquid preparation was maintained and a decrease in the content of tocopherol acetate was well prevented.

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

[Example 1] Eye drops Tocopherol acetate 0.015% Chlorpheniramine maleate 0.02 Methyl neostigmine sulfate 0.002 POE (40
) Hydrogenated castor oil 0.15 Dipotassium glycyrrhizinate 0.1 Pendelkonium chloride
0.01 Sodium chloride 0.6 Potassium chloride 0.3 Sodium chloride 0.6. F
, potassium chloride 0.3! After adding and dissolving chlorpheniramine maleate O,02,F, neostigmine methyl sulfate 0.002F, and dipotassium glycyrrhizinate 0.1g and dissolving. Next, add tocopherol acetate 0.015F to POE (40) hydrogenated castor oil 01
After adding a mixture of 5I and warm water to the previous solution, add 0.0 IJl of pendelkonium chloride, add distilled fR water to make a total volume of 100rnl, filter, and then use a polyethylene inner stopper. Store in an eye dropper.

[Example 2] Eye drops Tocopherol acetate 0.02% Sodium fundroitin sulfate 0.1 Diphenhydramine hydrochloride 0.03 POE (60) Hydrogenated castor oil 0.3 Dipotassium glycyrrhizinate 0.2 Benzethonium chloride 0.
03 Boric acid 1.2 Sodium chondroitin sulfate 0.1, P, diphenhydramine hydrochloride 0.03 in distilled purified water of about 13 Qal
After adding and dissolving 2 g of dipotassium glycyrrhizinate and 1.21 g of boric acid, 0.0 g of tocopherol acetate was added.
Add 02F mixed with 0.3g of POK (60) hydrogenated castor oil while hot to the previous solution, then add 0.03.9% of benzethonium chloride and add distilled purified water to bring the total volume to 1QQ.
After filtering, store in an eye drop container with a polyethylene inner stopper.

All of the eye drops of Example 1.2 maintained transparency even after long-term storage, and a decrease in tocopherol acetate content was prevented.

Claims (1)

[Scope of Claims] 1. Contains tocopherols, polyoxyethylene hydrogenated castor oil, glycyrrhizinate, and a quaternary ammonium type cationic surfactant, and the glycyrrhizinate is a quaternary ammonium type cationic surfactant. A liquid preparation containing tocopherols, characterized in that it is blended in a ratio of 0.5 to 5 moles per mole of a cationic surfactant. 2. The liquid agent according to claim 1, which is filled in a container in which at least a portion of the surface that comes into contact with the liquid agent is made of polyethylene. 3. The quaternary ammonium type cationic surfactant according to claim 1 or 2, wherein the quaternary ammonium type cationic surfactant is one or more selected from the group consisting of benzethonium chloride, benzalkonium chloride, and cetylpyridinium chloride. Liquid agent.