JP2000319170A - Teprenone-containing eye lotion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a teprenone-containing clear eye lotion. SOLUTION: This clear eye lotion is characterized by comprising teprenone, lecithin, a synthetic surfactant and water, or by adding >=15% and <=50% glycerol or acidic material based on total amount to the eye lotion comprising teprenone, lecithin, the synthetic surfactant and water.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an ophthalmic solution containing teprenone, and more particularly to a clear ophthalmic solution containing teprenone or a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Teprenone is known as a therapeutic and preventive agent for peptic ulcer (Japanese Patent Publication No. 63-44726) and a therapeutic and preventive agent for gastritis (Japanese Patent Publication No. 7-103019).
Widely used as capsules or fine granules. Recently, it has been revealed that the mucin layer on the eye surface increases, and an agent for preventing or treating dry eye (JP-A-8-133)
No. 967). On the other hand, since teprenone is oily at room temperature, special measures are required for preparing solution-type preparations such as injections and eye drops. Various techniques are known for converting an oily or fat-soluble drug into a liquid state. In general, a synthetic surfactant is added to an oily or fat-soluble drug to solubilize or emulsify in water. Fairness 2
No. 13643 discloses a technique of solubilizing with hydrogenated lecithin.

[0003]

In the case of producing eye drops containing teprenone according to the prior art, only a cloudy solution was obtained. Needless to say, since the eye drops are dropped directly into the eyes, it is preferable to use a clear solution. As a result of intensive studies to solve the above problems, the present inventor has found that the object can be achieved by the following means, and has completed the present invention.

[0004]

SUMMARY OF THE INVENTION The present invention relates to the use of teprenone,
It is an eye drop consisting of a phospholipid, a synthetic surfactant and water. Teprenone in the present invention is a general name, and the chemical name is 6,10,14,18-tetramethyl-5,9,
It is 13,17-nonadecatetraen-2-one and is represented by the following structural formula.

[0005]

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[0006] Teprenone has eight types of geometric isomers, but is not particularly limited in the present invention, and may be any one type of isomer or a mixture of two or more types.
Teprenone can be produced according to the method disclosed in JP-B-63-44726. Phospholipid is also called phosphatide, and is a general term for a group of complex lipids having a phosphate ester and a CP bond. In the present invention, egg yolk lecithin, soybean lecithin, phosphatidylserine, phosphatidylglycerol, phosphatidylethanolamine or phosphatidylinositol, phosphatidic acid, and the like can be used as phospholipids. Also, hydrogenated lecithin can be used. In each case, commercially available products can be used.

The synthetic surfactant in the present invention includes a cationic surfactant, an anionic surfactant, an amphoteric surfactant and a nonionic surfactant. Examples of the nonionic surfactant include polysorbate 80. , Polyoxyethylene hydrogenated castor oil 60, Cremophor and the like. Examples of the anionic surfactant include sodium alkylbenzenesulfonate. Glycerin used in the present invention is also called glycerol, and commercially available products such as glycerin in Japanese Pharmacopoeia can be used. The concentration of teprenone in the eye drops of the present invention is 0.01 to 5% by weight, preferably 0.1 to 2% by weight, more preferably 0.5 to 1% by weight.
% By weight.

In the present invention, the mixing ratio of teprenone, phospholipid, synthetic surfactant and water is usually 0.15 to 5 parts by weight of phospholipid and 0.1 to 5 parts by weight of synthetic surfactant per 1 part by weight of teprenone. Parts and 100 to 1000 parts by weight of water.

The present invention is also an eye drop wherein glycerin is further added to an eye drop comprising teprenone, a phospholipid, a synthetic surfactant and water. The amount of glycerin added is 1
5% or more and 50% or less. In the present invention, an acidic substance can be further added in addition to teprenone, a phospholipid, a synthetic surfactant and water. Examples of the acidic substance include dimyristoyl phosphatidic acid.
Addition of dipalmitoyl phosphatidyl glycerol (hereinafter referred to as DPPG) makes it easier to prepare a clear solution. Since teprenone and phospholipids are unstable compounds that are susceptible to oxidation, tocopherols and E
It is preferable to add an antioxidant such as DTA.

[0010] Preservatives can also be added to the eye drops of the present invention. Examples of the preservative include parabens such as methylparaben and propylparaben, alcohol derivatives such as chlorobutanol, phenylethyl alcohol and benzyl alcohol, and organic acids such as sodium dehydroacetate, sorbic acid and sodium sorbate. The pH of the eye drop in the present invention is usually 2 to 10, preferably 5 to 9, and more preferably 6 to 9.
８8.

The eye drops of the present invention can be produced as follows. After dissolving teprenone and phospholipid, for example, egg yolk lecithin and tocopherol acetate in a mixed solvent of chloroform and methanol, the solvent is distilled off using an evaporator to form a lipid thin film. It is dried under reduced pressure and the solvent is completely distilled off. A 5% glucose solution is added to the lipid thin film and shaken to suspend the lipid, and then ultrasonically irradiated, for example, with a bath sonicator at 40 ° C. for about 15 minutes. To this, for example, an aqueous solution of Tween 80 and a 5% glucose solution as a synthetic surfactant are added to obtain a clear teprenone-containing ophthalmic solution.

[0012]

[Effect] Phospholipids or surfactants are generally used to solubilize fat-soluble drugs, but these alone cannot provide clear ophthalmic solution containing teprenone at a relatively high concentration. In the present invention, a clear ophthalmic solution can be obtained by containing a phospholipid and a surfactant. Further, by adding glycerin and / or phosphatidic acid or a derivative thereof, a clearer ophthalmic solution can be obtained.
In eye drops, clarity is a very important requirement, and the effect of the present invention is remarkable.

The effects of the present invention will be described below with reference to experimental examples. Experiment 1 Phospholipid (egg yolk phospholipid)
Table 2 shows the absorbance at 700 nm of eye drops (formulations are shown in Table 1) prepared by adding 50 mg. Table 2
Thus, eye drops manufactured using only synthetic surfactants without phospholipids are highly turbid solutions with high absorbance,
It is evident that the addition of the phospholipid decreases the absorbance according to the amount added, resulting in a solution with increased clarity.

[0014]

[Table 1]

[0015]

[Table 2]

Experiment 2 Effect of pH on Clarity of Eye Drops In the formulations shown in Examples 5 and 6, the pH of eye drops was adjusted to 5 to 9 by slightly changing the amount of sodium hydroxide added. And the absorbance at a wavelength of 400 nm was measured. In Example 5, which did not contain phosphatidic acid, the effect of pH on light transmittance was not observed. However, in Example 6, which contained phosphatidic acid, when the pH was changed to an alkaline side, the absorbance decreased, and the pH decreased. The clarity of the eye drops increased accordingly. Figure 1 shows the results
It was shown to.

Experiment 3 Effect of phosphatidic acid content on the clarity of eye drops In the formulation shown in Example 7, the absorbance at a wavelength of 400 nm was measured when the phosphatidic acid content was changed. As a result, the absorbance decreased as the phosphatidic acid content increased, and the clarity increased depending on the phosphatidic acid content. The results are shown in FIG.

[0018]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

Example 1 Teprenone 100 mg, egg yolk lecithin 100 mg and d-α-tocopherol 10 mg
To a chloroform: methanol mixed solvent (2: 1) 10m
After dissolving in 1, the solvent was distilled off using an evaporator to obtain a lipid thin film. This was dried under reduced pressure for 3 hours, and the solvent was completely distilled off. 5 ml of a 5% glucose solution was added to the lipid thin film and shaken to suspend the lipid, followed by ultrasonic irradiation at 40 ° C. for about 15 minutes using a bath sonicator. 20% for this
Tween 80 aqueous solution 0.25 ml, glycerin 3.5 g
Was added, and a glucose solution was further added to obtain 10 ml of clear teprenone-containing ophthalmic solution.

Embodiment 2 In Embodiment 1, DPPG is further added.
Was added, and teprenone-containing ophthalmic solution was obtained in the same manner. Examples 3 to 7 According to the formulation shown in Table 3, the same procedure as in Example 1 was carried out to obtain teprenone-containing eye drops.

[0021]

[Table 3]

[0022]

[Brief description of the drawings]

FIG. 1 is a diagram showing a change in absorbance of an ophthalmic solution when pH is changed.

FIG. 2 is a diagram showing a change in absorbance of an ophthalmic solution when phosphatidic acid is changed.

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Claims (6)

[Claims] 1. An ophthalmic solution comprising teprenone, a phospholipid, a synthetic surfactant and water. 2. The method according to claim 1, wherein 1 part by weight of teprenone is used in an amount of 0.
An eye drop comprising 15 to 5 parts by weight, 0.1 to 5 parts by weight of a synthetic surfactant and 100 to 1000 parts by weight of water. 3. An ophthalmic solution according to claim 1, further comprising glycerin. 4. An eye drop according to claim 1, further comprising an acidic substance. 5. An ophthalmic solution according to claim 2, further comprising glycerin in an amount of 15 to 50% by weight based on the whole amount. 6. The method according to claim 2, further comprising the step of:
Ophthalmic solution containing 0.3 parts by weight.