JP2000273061A - Terpenoid emulsion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an oil-in-water type terpenoid emulsion which does not lowering the content of the terpenoid, even when stored in a plastic container, by mixing the terpenoid with an oil and a surfactant. SOLUTION: This oil-in-water type terpenoid emulsion comprises (A) a terpenoid (for example, menthol, borneol or camphor), (B) an oil (preferably an animal or vegetable oil containing fatty acid glycerides as main components, especially preferably castor oil), and (C) a surfactant (preferably a nonionic surfactant, especially preferably a polyoxyethylene sorbitan fatty acid ester). The emulsion preferably comprises the component A in an amount of preferably 0.0005-1 W/V %, more preferably 0.001-0.1 W/V %, the component B in an amount of preferably 0.01-20 W/V %, more preferably 0.1-10 W/V %, and the component C in an amount of preferably 0.05-20 W/V %, more preferably 0.5-10 W/V %. The emulsion is preferably charged in a plastic container.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a terpenoid emulsion, particularly to a terpenoid emulsion for filling a plastic container, a terpenoid filled in a plastic container, and a method for suppressing the reduction of the filled terpenoid.

[0002]

2. Description of the Related Art In general, terpenoids such as menthol are often used as a refreshing agent in ophthalmic solutions, nasal drops, oral preparations and the like in order to give a refreshing feeling. Further, those drugs are usually commercialized by being filled in plastic containers.

However, it has been found that when these drugs containing terpenoids are filled in a plastic container, the amount of terpenoids decreases during storage, so that the desired content of terpenoids cannot be maintained for a long period of time.

[0004] Particularly, in ophthalmic preparations where irritation is a problem,
Since the amount of terpenoids that may be contained is smaller than that of skin preparations and the like, the rate of content reduction is large.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a terpenoid-containing substance containing a terpenoid, for example, even when stored in a plastic container, in which a decrease in the terpenoid content during storage is suppressed, An object of the present invention is to provide a terpenoid-containing material for filling plastic containers. Another object of the present invention is to provide a method for suppressing a decrease in the content of terpenoids stored in a plastic container.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted studies to solve the above problems, and found that terpenoids are mixed with an oil and a surfactant to form an oil-in-water emulsion, thereby obtaining a terpenoid. Was found to be able to suppress a decrease in the content of terpenoids even when filled in a plastic container, and further studied to complete the present invention.

That is, the present invention is as follows. (1) An oil-in-water emulsion containing a terpenoid, an oil and a surfactant. (2) The emulsion according to (1), wherein the oil solution of the terpenoid is dispersed in water in the presence of a surfactant. (3) The emulsion according to (1) or (2), wherein the terpenoid is menthol. (4) The emulsion according to (1) or (2), wherein the oil is an animal or vegetable oil. (5) The emulsion according to (4), wherein the animal or vegetable oil is castor oil. (6) The emulsion according to (1) or (2), wherein the surfactant is a nonionic surfactant. (7) The emulsion according to (6), wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester. (8) The emulsion according to any one of (1) to (7), which is used for filling a plastic container. (9) The emulsion according to (8), wherein the material of the plastic container is polyolefin, saturated polyester or polycarbonate. (10) The emulsion according to (9), wherein the polyolefin of the material of the plastic container is polypropylene. (11) The emulsion according to (9), wherein the saturated polyester as the material of the plastic container is polyethylene terephthalate. (12) An oil-in-water emulsion containing a terpenoid, an oil, and a surfactant filled in a plastic container. (13) A method for suppressing reduction of terpenoids filled in a plastic container, wherein the terpenoid is an oil-in-water emulsion containing an oil and a surfactant.

[0008]

DETAILED DESCRIPTION OF THE INVENTION The oil-in-water emulsion of the present invention contains a terpenoid, an oil and a surfactant, and is preferably used for filling plastic containers. The emulsion is an embodiment in which a terpenoid oil solution is dispersed in water in the presence of a surfactant.

As the terpenoid, menthol, borneol, camphor, geraniol, cineol, anethole, limonene, eugenol, etc., monoterpenes, farnesol, nerolidol, etc., sesquiterpenes, phytol, sebrene, etc., diterpenes, etc. are preferably used. , Borneol, camphor and the like.

The amount of terpenoid in the oil-in-water emulsion of the present invention may vary depending on the intended preparation and the like, but is usually 0.0005 to 1 (W / V)%, preferably 0.001 to 0.1 (W / V)%. (W / V)%.

The oil is not particularly limited as long as it can dissolve terpenoids, but when used as a medicine, it must be pharmaceutically acceptable. In particular, animal and vegetable fats and oils containing fatty acid glyceride as a main component are preferred. Animal and vegetable oils and fats include castor oil, soybean oil, peanut oil, cottonseed oil, olive oil, sesame oil, palmitic acid, stearic acid, oleic acid, ricinoleic acid, linoleic acid, linolenic acid, behenic acid, lignoceric acid, arachidic acid, myristic acid, Preferred are middle-chain fatty acid glycerides composed of fatty acids having 14 to 24 carbon atoms such as arachiic acid and palmitooleic acid. When the oil-in-water emulsion of the present invention is in the form of ophthalmic preparations such as eye drops including eye drops and eye wash, castor oil is more preferred from the viewpoint of safety.

The amount of the oil in the oil-in-water emulsion of the present invention can vary depending on the amount of the terpenoid, etc., but is usually 0.01 to 20 (W / V)%, preferably 0.1 to 10 (W / V). V)%.

The surfactant used in the present invention includes:
Any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric surfactant may be used, and a nonionic surfactant is particularly preferable because of good emulsifying action.

Examples of the nonionic surfactant include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether, and polyglycerin fatty acid ester. Glycerin fatty acid ester, sorbitan fatty acid ester and the like.
Particularly preferred are polyoxyethylene sorbitan fatty acid esters.

As the polyoxyethylene sorbitan fatty acid ester, polysorbate 20, 40, 60, 65, 85 and the like in addition to polysorbate 80 are exemplified as preferable ones.

Examples of the anionic surfactant include sodium lauroyl sarcosine, triethanolamine lauroyl-L-glutamate, myristyl sarcosine sodium, sodium lauryl sulfate and the like.

Examples of the cationic surfactant include benzethonium chloride, benzalkonium chloride, cetylpyridium chloride and the like.

Examples of the amphoteric surfactant include betaine lauryldimethylaminoacetate, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine, and alkyldiaminoglycine hydrochloride.

The amount of the surfactant in the oil-in-water emulsion of the present invention can vary depending on the amount of the terpenoid, the amount of the surfactant, and the like.
V)%, preferably 0.5 to 10 (W / V)%.

In the present invention, the emulsion container is not particularly limited as long as it can be used as a container for a solution containing water, but a plastic container is preferred. As the material of the plastic container, polyolefin, saturated polyester and polycarbonate are preferable. Preferred examples of the polyolefin include polyethylene and polypropylene. A preferred example of the saturated polyester is polyethylene terephthalate.

As the water which is the continuous phase of the oil-in-water emulsion, distilled water, sterilized purified water, physiological saline and the like are used.

The oil-in-water emulsion of the present invention can be used for ophthalmic preparations such as eye drops including eye drops and eyewash, nasal preparations such as nasal drops, skin preparations, oral preparations, ear drops, etc. It can be used in the form of

The present invention provides a method for suppressing the reduction of terpenoids filled in a plastic container by using a terpenoid as an oil-in-water emulsion containing an oil and a surfactant. When an ophthalmic agent having a relatively low terpenoid concentration is targeted, the usefulness of the terpenoid reduction suppression method of the present invention becomes most significant.

The oil-in-water emulsion of the present invention is adjusted to have a pH of 3 to 10, preferably 4 to 9.

The pH is adjusted by using a pH adjuster. Examples of the pH adjuster include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, boric acid or a salt thereof (borax), hydrochloric acid, citric acid or a salt thereof (sodium citrate, sodium dihydrogen citrate, etc.). ), Phosphoric acid or a salt thereof (such as disodium hydrogen phosphate and potassium dihydrogen phosphate), acetic acid or a salt thereof (such as sodium acetate and ammonium acetate), and tartaric acid or a salt thereof (such as sodium tartrate).

The oil-in-water emulsion may contain components having a medicinal effect, such as vitamins (eg, retinol palmitate, pyridoxine hydrochloride, tocopherol acetate, etc.), vasoconstrictors (eg, naphazoline hydrochloride), so long as the object of the present invention is not adversely affected. , Tetrahydrozoline hydrochloride, etc.), anti-inflammatory agents (eg, dipotassium glycyrrhizinate, sodium azulene sulfonate, etc.), antihistamines (eg, chlorpheniramine maleate) and the like may be appropriately compounded.

Further, various additives such as a solubilizing agent, a buffering agent, a tonicity agent, a preservative, a stabilizer, a thickener, a chelating agent, and a pH adjuster are appropriately added to the oil-in-water emulsion. It can be blended and manufactured according to a known method.

Examples of solubilizers include polyvinylpyrrolidone, polyethylene glycol, propylene glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl stearate 40 and the like.

The buffer is used so that the pH of the oil-in-water emulsion of the present invention is in the range of 3 to 10, preferably 4 to 9. For example, boric acid or a salt thereof (borax or the like), citric acid or a salt thereof (sodium citrate or the like),
Tartaric acid or a salt thereof (such as sodium tartrate), gluconic acid or a salt thereof (such as sodium gluconate), acetic acid or a salt thereof (such as sodium acetate), phosphoric acid or a salt thereof (sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.) ), Various amino acids and the like, or combinations thereof.

Examples of the tonicity agent include sorbitol, glucose, mannitol, glycerin, propylene glycol, sodium chloride, potassium chloride and the like.

Examples of the preservative include paraoxybenzoic acid esters, benzalkonium chloride, benzethonium chloride, chlorobutanol, benzyl alcohol, sorbic acid or a salt thereof, chlorhexidine gluconate, sodium dehydroacetate, cetylpyridinium chloride, and alkyl chloride And diaminoethylglycine.

Examples of the stabilizer include ascorbic acid, sodium edetate, cyclodextrin, condensed phosphoric acid or a salt thereof, sulfite, citric acid or a salt thereof, and the like.

Examples of the thickener include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium chondroitin sulfate, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol and the like.

Examples of the chelating agent include sodium edetate, sodium citrate, condensed phosphoric acid and salts thereof (condensed sodium phosphate and the like).

The oil-in-water emulsion of the present invention can be produced by a conventionally known method. The method is not particularly limited, but the following method is exemplified as a preferable method. The surfactant is added to water in a weight ratio of 4 to 2000 times, preferably 10 to 200 times, and dissolved at 10 to 40 ° C, preferably 20 to 30 ° C to form an aqueous phase. Separately, terpenoids are added to the oil at 50-80 ° C, preferably 60-80 ° C.
Melt at ~ 70 ° C to oil phase. Aqueous phase at 50-90 ° C,
Preferably, the mixture is heated to 60 to 80 ° C. and 5000 to 8000 rpm, preferably 6,000 to 7, using a homomixer.
While stirring at 000 rpm, the oil phase is added, and while maintaining the temperature, the mixture is further stirred at 6,000 to 12,000 rpm, preferably 8,000 to 10,000 rpm, for 10 to 60 minutes, preferably for 20 to 60 minutes. After stirring, the mixture is cooled to room temperature, the pH is adjusted to 3 to 10, preferably 5 to 8, and the remaining water is added.

When the oil-in-water emulsion of the present invention is used as a pharmaceutical, for example, as an ophthalmic solution for an adult, the terpenoid is 0.0005 to 0.1 (W / V).
%, Preferably 0.001 to 0.05 (W / V)%, it is preferable to administer 2-3 drops per dose. Thus, a favorable refreshing feeling is obtained.

[0037]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, and the effects of the present invention will be clarified by Test Examples, but the present invention is not limited thereto.

Example 1 An eye drop is prepared according to the following formulation according to a conventional method.

Example 2 A nasal drop was prepared according to the following formulation according to a conventional method.

Example 3 A mouthwash is prepared according to the following formulation by a conventional method.

Test Example 1 Test liquid 1 and test liquid 2 were prepared according to the following formulation. Test solution 1: 1-menthol 0.002 g Sodium hydroxide qs sterile purified water qs 100 ml l-menthol 0.002 g was added and dissolved in sterile purified water 80 ml, adjusted to pH 5.5 with sodium hydroxide, and sterilized. After adding purified water to make 100 ml, 0.45
The solution was filtered through a μm filter. (room temperature)

Test solution 2: l-menthol 0.002 g polysorbate 80 1.0 g castor oil 1.0 g sodium hydroxide qs sterile purified water qs 100 ml 1.0 g of polysorbate 80 was added to sterile purified water 80 ml and dissolved. Phase. Separately to 1.0 g of castor oil
-0.002 g of menthol was added and heated to 70 ° C to dissolve to form an oil phase. The aqueous phase is heated to about 70 ° C., and the oil phase is added thereto with stirring at 8000 rpm using a homomixer (TK ROBO MICS Tokushu Kika Kogyo Co., Ltd.), and the mixture is heated at 70 ° C. and 8000 rpm for 15 minutes. Stirred. After stirring, the mixture was cooled to room temperature, the pH was adjusted to 5.5 with sodium hydroxide, and 100 ml of sterilized purified water was added.
Then, the mixture was filtered through a 0.45 μm filter to prepare an emulsion.

Test Method 5 ml of each of Test Solution 1 and Test Solution 2 was placed in each container made of polypropylene and polyethylene terephthalate, sealed, allowed to stand at 50 ° C., and stored. After a week,
The residual amount of l-menthol in each test solution was measured by gas chromatography. Table 1 shows the measurement results. In the table,
Assuming that the amount of 1-menthol before storage was 100.0%, the remaining amount was expressed in%.

[0044]

[Table 1]

According to the measurement results, the test solution 2, ie, the oil-in-water emulsion containing l-menthol, castor oil and polysorbate 80, was stored in a plastic container at 50 ° C. for 1 week compared to the test solution 1. It was found that the decrease in the residual ratio of l-menthol in the case of the above was suppressed.

[0046]

According to the oil-in-water emulsion of the present invention, even when the emulsion is filled in a plastic container, the decrease in terpenoids is extremely small, and the decrease in terpenoid content can be suppressed.

Continued on the front page (72) Inventor Yama ▲ saki ▼ Noriko 1 KCC House 204, 4-366, Minamibeppu, Nishi-ku, Kobe-shi, Hyogo (72) Inventor Hisayuki Nakayama 9-37, Hirota-cho, Nishinomiya-shi, Hyogo Hill House No. 107 F-term (reference) 4C076 AA17 BB24 BB25 CC03 CC10 DD09 DD19 DD26 DD30 DD37 DD38 EE03 EE24 EE53 EE54 FF36 4H006 AA03 AA05 AB20 BB31 FC22 FE12

Claims (13)

[Claims] 1. An oil-in-water emulsion containing a terpenoid, an oil and a surfactant. 2. The emulsion according to claim 1, wherein the terpenoid oil solution is dispersed in water in the presence of a surfactant. 3. The emulsion according to claim 1, wherein the terpenoid is menthol. 4. The emulsion according to claim 1, wherein the oil is an animal or vegetable oil. 5. The emulsion according to claim 4, wherein the animal or vegetable oil is castor oil. 6. The emulsion according to claim 1, wherein the surfactant is a nonionic surfactant. 7. The emulsion according to claim 6, wherein the nonionic surfactant is a polyoxyethylene sorbitan fatty acid ester. 8. The method for filling a plastic container according to claim 1.
8. The emulsion according to any one of items 1 to 7, 9. The emulsion according to claim 8, wherein the material of the plastic container is polyolefin, saturated polyester or polycarbonate. 10. The emulsion according to claim 9, wherein the polyolefin as a material of the plastic container is polypropylene. 11. The emulsion according to claim 9, wherein the saturated polyester as the material of the plastic container is polyethylene terephthalate. 12. An oil-in-water emulsion containing a terpenoid, an oil and a surfactant filled in a plastic container. 13. A method for suppressing reduction of terpenoids filled in a plastic container, wherein the terpenoid is an oil-in-water emulsion containing an oil and a surfactant.