JP4438908B2 - Terpenoid emulsion - Google Patents

Description

【００３９】
実施例２
常法により、次の処方で点鼻剤を調製する。

【００４０】
実施例３
常法により、次の処方で口中剤を調製する。

【００４１】
試験例１
以下の配合処方で試験液１および試験液２を製造した。

滅菌精製水８０ｍｌにｌ−メントール０．００２ｇを加えて溶かし、水酸化ナトリウムでｐＨを５．５に調整し、滅菌精製水を加えて１００ｍｌとした後、０．４５μｍフィルターでろ過した。（室温）
【００４２】

滅菌精製水８０ｍｌに１．０ｇのポリソルベート８０を加えて溶かし、水相とした。別にヒマシ油１．０ｇにｌ−メントール０．００２ｇを加えて７０℃に加熱して溶かし、油相とした。水相を約７０℃に加熱し、ホモミキサー（Ｔ．Ｋ．ＲＯＢＯ ＭＩＣＳ 特殊機化工業株式会社）を用いて、８０００ｒｐｍで攪拌しながら油相を加え、７０℃、８０００ｒｐｍ、１５分間の条件で攪拌した。攪拌後、室温まで冷却し、水酸化ナトリウムを加えてｐＨを５．５に調整し、滅菌精製水を加えて１００ｍｌとした後、０．４５μｍフィルターでろ過してエマルションを製造した。
【００４３】
試験方法
ポリプロピレン製およびポリエチレンテレフタレート製の各容器にそれぞれ試験液１および試験液２を５ｍｌづつ入れて密封し、５０℃で静置、保存した。一週間後、各試験液中のｌ−メントールの残存量をガスクロマトグラフ法により測定した。測定結果を表１に示す。表中、保存前のｌ−メントールの量を１００．０％として、残存量を％で表した。
【００４４】
【表１】

【００４５】
測定結果より、試験液１に比べて、試験液２すなわち、ｌ−メントール、ヒマシ油およびポリソルベート８０を含有する水中油型エマルションでは、プラスチック容器に充填されて５０℃、１週間保存された場合のｌ−メントールの残存率の低下が抑制されることが分かった。
【００４６】
【発明の効果】
本発明の水中油型エマルションは、当該エマルションをプラスチック容器に充填しても、テルペノイドの減少が極めてすくなく、テルペノイドの含有量の低下を抑制することができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a terpenoid emulsion, particularly a terpenoid emulsion for filling a plastic container, a terpenoid filled in a plastic container, and a method for suppressing a decrease in the filled terpenoid.
[0002]
[Prior art]
In general, ophthalmic solutions, nasal drops, mouth preparations and the like are often blended with terpenoids such as menthol as a cooling agent in order to give a refreshing feeling. Furthermore, these drugs are usually filled in plastic containers and commercialized.
[0003]
However, it has been found that when these drugs containing terpenoids are filled in plastic containers, the amount of terpenoids decreases during storage, so that the desired content of terpenoids cannot be maintained for a long period of time.
[0004]
In particular, ophthalmic preparations with irritation are a problem, since the amount of terpenoids that may be contained is small compared to dermatological preparations, etc., and the rate of content reduction is large.
[0005]
[Problems to be solved by the invention]
Accordingly, an object of the present invention is to provide a terpenoid-containing material that contains a terpenoid, for example, a terpenoid-containing material in which a decrease in the content of terpenoid during storage is suppressed even when stored in a plastic container, particularly a terpenoid-containing material for filling plastic containers. Is to provide.
Another object of the present invention is to provide a method for suppressing a decrease in the content of terpenoid stored in a plastic container.
[0006]
[Means for Solving the Problems]
The inventors of the present invention have repeated researches to solve the above problems, and by blending oil and a surfactant with a terpenoid to form an oil-in-water emulsion, the terpenoid is filled in a plastic container. The present inventors have found that it is possible to suppress a decrease in the terpenoid content, and further researched to complete the present invention.
[0007]
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 terpenoid oil solution 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 and 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 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 plastic container is polypropylene.
(11) The emulsion according to (9), wherein the saturated polyester 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 a decrease in terpenoid filled in a plastic container, characterized in that 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 for filling a plastic container. The emulsion is usually an embodiment in which an oil solution of terpenoid is dispersed in water in the presence of a surfactant.
[0009]
As the terpenoid, menthol, borneol, camphor, geraniol, cineol, monoterpene such as anethole, limonene, eugenol, sesquiterpenes such as farnesol and nerolidol, diterpenes such as phytol and semblene, etc. are used, preferably menthol, borneol, Such as camphor.
[0010]
The blending amount of the 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). V)%.
[0011]
The oil is not particularly limited as long as it can dissolve the terpenoid, but when used as a medicine, it should be pharmaceutically acceptable. In particular, animal and vegetable fats and oils mainly composed of fatty acid glycerides are preferred. As animal and vegetable oils and fats, 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, Preferable examples include medium chain fatty acid glycerides composed of fatty acids having 14 to 24 carbon atoms such as arachidic acid and palmitooleic acid. When the oil-in-water emulsion of the present invention is in the form of an ophthalmic preparation such as an eye drop or an eye drop containing an eye wash, castor oil is more preferable from the viewpoint of safety.
[0012]
The blending amount of oil in the oil-in-water emulsion of the present invention may vary depending on the blending amount of terpenoid, etc., but is usually 0.01-20 (W / V)%, preferably 0.1-10 (W / V)%. It is.
[0013]
As the surfactant used in the present invention, any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric surfactant may be used. An activator is preferred.
[0014]
Nonionic surfactants include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyethylene glycol fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkylphenyl ether, polyglycerin fatty acid ester, glycerin fatty acid Examples include esters and sorbitan fatty acid esters. Particularly preferred are polyoxyethylene sorbitan fatty acid esters.
[0015]
Examples of suitable polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 20, 40, 60, 65, 85, and the like.
[0016]
Examples of the anionic surfactant include lauroyl sarcosine sodium, lauroyl-L-glutamate triethanolamine, myristyl sarcosine sodium, sodium lauryl sulfate and the like.
[0017]
Examples of the cationic surfactant include benzethonium chloride, benzalkonium chloride, cetylpyridium chloride and the like.
[0018]
Examples of amphoteric surfactants include lauryldimethylaminoacetic acid betaine, 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolium betaine, and alkyldiaminoglycine hydrochloride.
[0019]
The blending amount of the surfactant in the oil-in-water emulsion of the present invention may vary depending on the blending amount of the terpenoid, the surfactant, etc., but is usually 0.05 to 20 (W / V)%, preferably 0.5 to 10 (W / V)%.
[0020]
In the present invention, the container for the emulsion is not particularly limited as long as it can be used as a container for a solution containing water, but a plastic container is preferable. As the material of the plastic container, polyolefin, saturated polyester and polycarbonate are preferable. Preferable examples of polyolefin include polyethylene and polypropylene. Moreover, a polyethylene terephthalate is illustrated as a preferable example of saturated polyester.
[0021]
As water that becomes the continuous phase of the oil-in-water emulsion, distilled water, sterilized purified water, physiological saline, or the like is used.
[0022]
The oil-in-water emulsion of the present invention is in the form of eye drops, ophthalmic preparations such as eye drops containing eye wash, nasal preparations such as nasal drops, skin preparations, oral preparations, ear drops and the like. Can be used.
[0023]
The present invention provides a method for suppressing a decrease in terpenoid filled in a plastic container by making the terpenoid into an oil-in-water emulsion containing an oil and a surfactant. When the ophthalmic preparation is relatively low, the usefulness of the terpenoid reduction suppression method of the present invention is most remarkable.
[0024]
The oil-in-water emulsion of the present invention is adjusted to have a pH of 3 to 10, preferably 4 to 9.
[0025]
The pH is adjusted by using a pH adjuster. Examples of the pH adjuster include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, boric acid or a salt thereof (borax), hydrochloric acid, citric acid or a salt thereof (sodium citrate, sodium dihydrogen citrate, etc. ), Phosphoric acid or salts thereof (disodium hydrogen phosphate, potassium dihydrogen phosphate, etc.), acetic acid or salts thereof (sodium acetate, ammonium acetate, etc.), tartaric acid or salts thereof (sodium tartrate, etc.), and the like.
[0026]
In the oil-in-water emulsion, unless it is contrary to the object of the present invention, medicinal components such as vitamins (for example, retinol palmitate, pyridoxine hydrochloride, tocopherol acetate, etc.), vasoconstrictors (for example, naphazoline hydrochloride, tetrahydrozoline hydrochloride) Etc.), anti-inflammatory agents (for example, dipotassium glycyrrhizinate, sodium azulene sulfonate, etc.), antihistamines (chlorpheniramine maleate, etc.) and the like may be appropriately blended.
[0027]
Furthermore, the oil-in-water emulsion is appropriately blended with various additives such as a solubilizer, buffer, isotonic agent, preservative, stabilizer, thickener, chelating agent, pH adjuster, It can be produced according to a known method.
[0028]
Examples of the solubilizer include polyvinyl pyrrolidone, polyethylene glycol, propylene glycol, polyoxyethylene hydrogenated castor oil 60, and polyoxyl 40 stearate.
[0029]
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 etc.), citric acid or a salt thereof (sodium citrate etc.), tartaric acid or a salt thereof (sodium tartrate etc.), gluconic acid or a salt thereof (sodium gluconate etc.), acetic acid or its Examples thereof include salts (such as sodium acetate), phosphoric acid or salts thereof (such as sodium monohydrogen phosphate and sodium dihydrogen phosphate), various amino acids, and combinations thereof.
[0030]
Examples of the isotonic agent include sorbitol, glucose, mannitol, glycerin, propylene glycol, sodium chloride, potassium chloride and the like.
[0031]
Preservatives include, for example, paraoxybenzoates, benzalkonium chloride, benzethonium chloride, chlorobutanol, benzyl alcohol, sorbic acid or salts thereof, chlorhexidine gluconate, sodium dehydroacetate, cetylpyridinium chloride, alkyldiaminoethylglycine hydrochloride Etc.
[0032]
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.
[0033]
Examples of the thickener include methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium chondroitin sulfate, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol and the like.
[0034]
Examples of the chelating agent include sodium edetate, sodium citrate, condensed phosphoric acid or a salt thereof (such as condensed sodium phosphate).
[0035]
The oil-in-water emulsion of the present invention can be produced by a conventionally known method. The method is not particularly limited, but preferred methods include the following methods. The surfactant is added to water in an amount of 4 to 2000 times, preferably 10 to 200 times by weight, and dissolved at 10 to 40 ° C., preferably 20 to 30 ° C., to obtain an aqueous phase. Separately, a terpenoid is added to the oil and dissolved at 50 to 80 ° C., preferably 60 to 70 ° C., to obtain an oil phase. The aqueous phase is heated to 50 to 90 ° C., preferably 60 to 80 ° C., and is stirred at 5000 to 8000 rpm, preferably 6000 to 7000 rpm using a homomixer. Stir at 12000 rpm, preferably 8000-10000 rpm for 10-60 minutes, preferably 20-60 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.
[0036]
When the oil-in-water emulsion of the present invention is used as a pharmaceutical, for example, when used as an eye drop for an adult, the terpenoid is 0.0005 to 0.1 (W / V)%, preferably 0.001 to 0.05 (W As an ophthalmic solution containing / V)%, it is preferable to administer 2-3 drops at a time. Thus, a preferable refreshing feeling can be obtained.
[0037]
【Example】
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. However, the present invention is not limited to these examples.
[0038]
Example 1
Eye drops are prepared according to the following prescription according to a conventional method.

[0039]
Example 2
A nasal drop is prepared according to the following prescription by a conventional method.

[0040]
Example 3
In the usual way, prepare a mouth preparation with the following prescription.

[0041]
Test example 1
Test solution 1 and test solution 2 were produced with the following formulation.

To 80 ml of sterilized purified water, 0.002 g of l-menthol was added and dissolved, the pH was adjusted to 5.5 with sodium hydroxide, and sterilized purified water was added to make 100 ml, followed by filtration with a 0.45 μm filter. (room temperature)
[0042]

1.0 g of polysorbate 80 was added to 80 ml of sterilized purified water and dissolved to obtain an aqueous phase. Separately, 0.002 g of l-menthol was added to 1.0 g of castor oil, and the mixture was heated to 70 ° C. and dissolved to obtain an oil phase. The water phase is heated to about 70 ° C., and the oil phase is added while stirring at 8000 rpm using a homomixer (TK ROBO MICS Special Machine Industries Co., Ltd.), under the conditions of 70 ° C. and 8000 rpm for 15 minutes. Stir. After stirring, it was cooled to room temperature, sodium hydroxide was added to adjust the pH to 5.5, and sterilized purified water was added to make 100 ml, followed by filtration with a 0.45 μm filter to produce an emulsion.
[0043]
Test Method 5 ml each of Test Solution 1 and Test Solution 2 were sealed in polypropylene and polyethylene terephthalate containers, respectively, and were allowed to stand at 50 ° C. and stored. One week later, the residual amount of l-menthol in each test solution was measured by gas chromatography. The measurement results are shown in Table 1. In the table, the amount of l-menthol before storage was 100.0%, and the remaining amount was expressed in%.
[0044]
[Table 1]

[0045]
From the measurement results, compared to test liquid 1, test liquid 2, that is, an oil-in-water emulsion containing 1-menthol, castor oil and polysorbate 80, was filled in a plastic container and stored at 50 ° C. for 1 week. It was found that the decrease in the residual rate of l-menthol was suppressed.
[0046]
【The invention's effect】
In the oil-in-water emulsion of the present invention, even if the emulsion is filled in a plastic container, the decrease in terpenoid content can be suppressed with very little decrease in terpenoid.

Claims (8)

A oil-in-water emulsion formed by filling the plastic container,
(A) 0.001 to 0.05 (W / V)% terpenoid,
(B) at least one oil selected from the group consisting of castor oil, soybean oil and olive oil;
(C) at least one surfactant selected from the group consisting of polyoxyethylene hydrogenated castor oil, polysorbate 80 and polyoxyl 40 stearate
An oil-in-water emulsion containing   The emulsion according to claim 1, wherein the terpenoid is at least one selected from the group consisting of monoterpenes, sesquiterpenes and diterpenes.   The emulsion according to claim 1, wherein the terpenoid is at least one selected from the group consisting of menthol, borneol and camphor. The emulsion of any one of Claims 1-3 whose density | concentration of oil is 0.1-10 (W / V)%.   The emulsion according to claim 1, wherein the plastic container is made of polyolefin, saturated polyester or polycarbonate. A port Li olefin polypropylene, emulsion according to claim 5. Saturated polyester is polyethylene terephthalate, emulsion according to claim 5. The (a) 0.001~0.05 (W / V )% of terpenoids,
(B) at least one oil selected from the group consisting of castor oil, soybean oil and olive oil ;
(C) at least one surfactant selected from the group consisting of polyoxyethylene hydrogenated castor oil, polysorbate 80 and polyoxyl 40 stearate
And a method for suppressing a decrease in the terpenoid filled in a plastic container.