JP6929339B2 - Topical composition - Google Patents

Description

The present invention relates to an external composition containing a terpenoid compound. More specifically, the present invention relates to an external composition having excellent formulation stability in which precipitation of a terpenoid compound is suppressed even under low temperature conditions.

Terpenoid compounds such as menthol cause mild sensory paralysis due to a local cooling sensation stimulus and exert analgesic and antipruritic effects. Therefore, they are blended in external compositions and have been widely used for many years. On the other hand, terpenoid compounds have a drawback that they have poor dissolution stability, and even if they are dissolved once, they are easily precipitated when stored under low temperature conditions. Such precipitation of the terpenoid compound not only deteriorates the appearance and properties of the external composition, but also reduces the desired medicinal effect of the terpenoid compound. Therefore, in the external composition containing the terpenoid compound, the terpenoid compound is used. A formulation design that suppresses precipitation is required.

Conventionally, various preparation techniques for suppressing the precipitation of terpenoid compounds have been studied. For example, Patent Document 1 discloses that the precipitation of l-menthol can be suppressed by using 1% by weight or more of l-menthol and camphor in a specific ratio in combination in a water-containing ointment. However, the technique of Patent Document 1 has a drawback that a large amount of camphor is required, there are many restrictions on the formulation design, and the scent of camphor becomes dominant, so that the fragrance tone is also restricted. Further, Patent Document 2 discloses that the precipitation of l-menthol can be suppressed by using l-menthol and propylene glycol, glycerin and / or sorbitol in a specific ratio in the oral composition. ing. However, Patent Document 2 has a drawback that a sufficient effect of suppressing precipitation of l-menthol cannot be obtained.

Against the background of such conventional techniques, it is desired to develop a new formulation technique for suppressing the precipitation of terpenoid compounds.

Japanese Unexamined Patent Publication No. 2002-154952 Japanese Unexamined Patent Publication No. 2003-81798

An object of the present invention is to provide a pharmaceutical technique capable of suppressing the precipitation of a terpenoid compound even when stored under low temperature conditions in an external composition containing a terpenoid compound.

As a result of diligent studies to solve the above problems, the present inventor has found that the precipitation of terpenoid compounds can be suppressed even under low temperature conditions by using a terpenoid compound and a heparinoid in combination in an external composition. ..

In addition, the present inventor found that an external composition containing a terpenoid compound and a heparinoid can suppress the precipitation of the terpenoid compound, but when stored under low temperature conditions, an insoluble aggregate (like moya) that is considered to be derived from the heparinoid. Faced with the new challenge of being prone to the formation of insoluble compounds that appear to be. Therefore, as a result of further diligent studies, the present inventor conducted the above-mentioned insoluble aggregation while suppressing the precipitation of the terpenoid compound under low temperature conditions by containing diphenhydramine in addition to the terpenoid compound and the heparinoid. It was found that the generation of substances can also be suppressed.

The present invention has been completed by further studies based on these findings. That is, the present invention provides the inventions of the following aspects.
Item 1. An external composition comprising a terpenoid compound and a heparinoid.
Item 2. Item 2. The external composition according to Item 1, further comprising diphenhydramine.
Item 3. Item 2. The external composition according to Item 2, wherein the diphenhydramine is contained in an amount of 0.1 to 10 parts by weight per part by weight of the heparinoid.
Item 4. Item 8. The external composition according to any one of Items 1 to 3, wherein the terpenoid compound is a monoterpene.
Item 5. A method for suppressing the precipitation of a terpenoid compound in an external composition containing a terpenoid compound, which comprises coexisting a terpenoid compound and a heparinoid in the external composition.
Item 6. A method for suppressing the formation of insoluble aggregates in an external composition containing a terpenoid compound and a heparin-like substance, which comprises coexistence of a terpenoid compound, a heparin-like substance, and diphenhydramine in the external composition.

According to the present invention, the terpenoid compound has excellent dissolution stability and can suppress the precipitation of the terpenoid compound even when stored under low temperature conditions. Therefore, even in winter or cold regions, the desired medicinal effect of the terpenoid compound can be obtained. It becomes possible to maintain stability.

Further, according to a preferred embodiment of the present invention, in the external composition containing the terpenoid compound and the heparinoid, the formation of insoluble aggregates considered to be derived from the heparinoid can be suppressed, so that the appearance is good. It is also possible to provide extremely excellent formulation stability.

1. 1. External Composition The external composition of the present invention is characterized by containing a terpenoid compound and a heparinoid. Hereinafter, the external composition of the present invention will be described in detail.

Terpenoid compound The external composition of the present invention contains a terpenoid compound. The terpenoid compound has a property that even if it is once dissolved, it easily precipitates when stored under low temperature conditions. However, in the external composition of the present invention, the terpenoid under low temperature conditions is due to the action of a heparinoid, which will be described later. It is possible to effectively suppress the precipitation of the compound.

The terpenoid compound is also called an isoprenoid or a terpene, and is usually a compound in which a plurality of isoprene units (5 carbon atoms) are bonded. Terpenoid compounds include monoterpenes (2 isoprene units), sesquiterpenes (3 isoprene units), diterpenes (4 isoprene units), and triterpenes (6 isoprene units), depending on the number of isoprene units contained. ) Etc. Any of these terpenoid compounds may be used in the external composition of the present invention.

Specific examples of monoterpenes include alcohol-based monoterpenes such as menthol, timole, geraniol, linalol, borneol, cineole, and terpineol; aldehyde-based monoterpenes such as citral, citroneral, perillaldehyde, and safranal; camphor, menthon, and carbo. Examples thereof include ketone monoterpenes such as Menthone and Yonon. Specific examples of sesquiterpenes include chamazulene, santalol, patchurene, cedrol, cedrol, farnesol, eugenol, α-bisabolol, β-cariophyllene alcohol, sclareol, geranyl linalool, isophitol, nerolidol, globrol, guaiol, etc. Examples include α-Santalol, Chamazulene, Farnesol, Germacron, Sesquiterpene, Zernbon, Vetibone and the like. Specific examples of diterpenes include retinal and the like. These terpenoid compounds may be d-form, l-form, or dl-form when optical isomers are present. Further, these terpenoid compounds may be used alone or in combination of two or more.

Among these terpenoid compounds, preferably monoterpenes, more preferably alcohol-based monoterpenes, ketone-based monoterpenes, particularly preferably menthol, borneol, camphor, most preferably, from the viewpoint of suppressing precipitation more effectively. Mentor is mentioned.

In addition, these terpenoid compounds may be used in the form of essential oils containing monoterpenes. The essential oil containing monoterpene can be appropriately selected from known ones and used. For example, the essential oil containing menthol includes peppermint oil, peppermint oil, sparemint oil and the like.

The content of the terpenoid compound in the external composition of the present invention may be appropriately set according to the medicinal effect to be provided in the external composition, and is, for example, 0.1 to 10% by weight, preferably 0.1 to 5 by weight. By weight%, more preferably 0.5 to 5% by weight. In general, the higher the content of the terpenoid compound in the external composition, the more remarkable the precipitation due to storage under low temperature conditions. However, in the external composition of the present invention, the terpenoid compound is as high as 1% by weight or more. Even if the content is high, precipitation due to storage under low temperature conditions can be effectively suppressed. In view of such effects of the present invention, the content of the terpenoid compound in the external composition of the present invention is more preferably 1 to 5% by weight, particularly preferably 2 to 3% by weight.

Heparinoids The external compositions of the present invention further include heparinoids. Heparinoids play a role in suppressing the precipitation of terpenoid compounds caused by storage under low temperature conditions.

The heparinoid is a polysulfated mucopolysaccharide such as chondroitin polysulfate, and is a known drug known to have a moisturizing effect, an anti-inflammatory effect, a blood circulation promoting effect, and the like.

The origin of the heparinoid used in the present invention is not particularly limited, but for example, those obtained by polysulfating mucopolysaccharides, tissues of edible animals (for example, tracheal cartilage of cattle, pigs, etc.) Examples include those extracted from (lungs containing). In the external composition of the present invention, as the heparinoid, the heparinoid contained in the Japanese Pharmacopoeia non-pharmaceutical standard is preferably used.

The content of the heparinoid in the external composition of the present invention may be appropriately set according to the type and content of the terpenoid compound used, and examples thereof include 0.05 to 3% by weight. The content of the heparinoid in the external composition of the present invention is preferably 0.1 to 1% by weight, more preferably 0.1 to 1% by weight, from the viewpoint of more effectively suppressing the precipitation of the terpenoid compound due to storage under low temperature conditions. Is 0.3 to 1% by weight.

Further, in the external composition of the present invention, the ratio of the terpenoid compound to the heparinoid is determined according to each of the above-mentioned contents, but the precipitation of the terpenoid compound due to storage under low temperature conditions is more effectively suppressed. From the viewpoint of the above, the amount of heparinoid is 0.01 parts by weight or more, preferably 0.05 parts by weight or more, more preferably 0.1 parts by weight or more, and particularly preferably 0.3 parts by weight, per 1 part by weight of the terpenoid compound. The above can be mentioned. The upper limit of the heparinoid per 1 part by weight of the terpenoid compound is not particularly limited, and examples thereof include 20 parts by weight, preferably 10 parts by weight.

Diphenhydramine It is desirable that the external composition of the present invention contains diphenhydramine in addition to the terpenoid compound and the heparinoid. Although the external composition containing the terpenoid compound and the heparinoid can suppress the precipitation of the terpenoid compound by storage under low temperature conditions, there is a problem that insoluble aggregates which are considered to be caused by the heparinoid are likely to be formed. By further containing the above, the above-mentioned problems can be overcome and excellent formulation stability can be provided.

Diphenhydramine is a drug known as an antihistamine. Although diphenhydramine can take the form of a salt such as diphenhydramine hydrochloride, diphenhydramine (a non-salt form) is used in the present invention because the salt of diphenhydramine cannot exert the above-mentioned effect of suppressing the formation of insoluble aggregates. NS.

When diphenhydramine is contained in the external composition of the present invention, the content thereof may be appropriately set according to the content of heparinoids and the like, and examples thereof include 0.01 to 3% by weight. From the viewpoint of more effectively suppressing the formation of the above-mentioned insoluble aggregates, the content of diphenhydramine in the external composition of the present invention is preferably 0.1 to 1% by weight or 0.5 to 1% by weight. Can be mentioned.

The ratio of heparinoid to diphenhydramine is determined according to each of the above-mentioned contents, but from the viewpoint of more effectively suppressing the formation of the above-mentioned insoluble aggregates, diphenhydramine per 1 part by weight of the heparinoid. Is 0.1 parts by weight or more, preferably 0.3 parts by weight or more. The upper limit of diphenhydramine per 1 part by weight of the heparinoid is not particularly limited, and examples thereof include 10 parts by weight, preferably 5 parts by weight, and more preferably 3 parts by weight.

Composition for external use of the water present invention, for the preparation or the like into the desired formulation, if necessary, may contain water. In the external composition containing a terpenoid compound, when water is contained, the precipitation of the terpenoid compound by storage under low temperature conditions tends to be remarkable, but in the external composition of the present invention, water is contained. However, the precipitation of terpenoid compounds due to storage under low temperature conditions can be effectively suppressed.

When water is contained in the external composition of the present invention, the content thereof is not particularly limited, and examples thereof include 0.1% by weight or more. Generally, the higher the water content, the more prominent the precipitation of the terpenoid compound due to storage under low temperature conditions. However, in the external composition of the present invention, even if the water content is high, the terpenoid compound tends to precipitate under low temperature conditions. It is possible to effectively suppress the precipitation of terpenoid compounds due to storage in. In view of the effects of the present invention, the water content in the external composition of the present invention is preferably 0.3% by weight or more, more preferably 1% by weight or more, and particularly preferably 5% by weight or more. The upper limit of the water content in the external composition of the present invention is not particularly limited, and examples thereof include 90% by weight, preferably 80% by weight, and more preferably 70% by weight.

Polyvalent alcohol The external composition of the present invention may contain a polyvalent alcohol, if necessary, for the purpose of further enhancing the effect of suppressing the precipitation of the terpenoid compound by storage under low temperature conditions.

The polyhydric alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and for example, propylene glycol, ethylene glycol, 1,3-butylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, etc. Glycerin and the like can be mentioned. These polyhydric alcohols may be used alone or in combination of two or more. Among these polyhydric alcohols, propylene glycol, 1,3-butylene glycol, dipropylene glycol and glycerin are preferable.

When the external composition of the present invention contains a polyhydric alcohol, the content thereof may be appropriately set according to the type of the polyhydric alcohol used, the formulation form of the external composition, and the like. 1 to 50% by weight, preferably 1 to 30% by weight, more preferably 3 to 20% by weight.

Monohydric lower alcohol The external composition of the present invention may contain a monohydric lower alcohol depending on its formulation form and the like.

The monohydric lower alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and has, for example, the number of carbon atoms of ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol and the like. Examples thereof include monohydric lower alcohols 1 to 4. One of these monohydric lower alcohols may be used alone, or two or more thereof may be used in combination. Among these monohydric lower alcohols, ethanol and isopropanol are preferable.

When the external composition of the present invention contains a monohydric lower alcohol, the content thereof may be appropriately set according to the type of the monohydric lower alcohol used, the formulation form of the external composition, and the like. 0.1 to 50% by weight, preferably 1 to 30% by weight.

Other Ingredients In addition to the above-mentioned ingredients, the external composition of the present invention may contain other additives usually used in the external composition in order to obtain a desired pharmaceutical form. Such additives include, for example, aqueous bases, oily bases, thickeners, pH regulators, surfactants, emulsifiers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, etc. Examples include chelating agents, fragrances, coloring agents and the like.

Further, the external composition of the present invention may contain other pharmacological components in addition to the above-mentioned components, if necessary, as long as the effects of the present invention are not impaired. The pharmacological components that can be blended in the external composition of the present invention are not particularly limited, and are, for example, antihistamines (chlorpheniramine maleate, etc.), local anesthetics (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, etc.). Meprilucine or salts thereof, alkyl benzoate (eg, parabutylaminobenzoate diethylaminoethyl hydrochloride), orthokine, oxesazein, oxypolyentoxydecane, funnel extract, percaminpase, tesitdecitin, etc.), anti-inflammatory agents (glycol salicylate, methyl salicylate, etc.) Indomethacin, fervinac, diclofenac sodium, loxoprofen sodium, etc.), bactericides (decalinium chloride, cetylpyridinium chloride, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfaziazine, phenol, etc.), antipruritic agents (thianthol, etc.), skin protectants (Himashi) Oils, etc.), blood circulation promoting components (nonylate vanillylamide, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.), moisturizers (trimethylglycine, methacryloyloxyethyl phosphorylcholine and their co-weights) Amphoteric surfactants such as coalesces (eg, copolymers with alkyl methacrylate) and the like). These medicinal ingredients may be used alone or in combination of two or more. When these pharmacological components are contained in the external composition of the present invention, the content thereof may be appropriately set according to the type of the pharmacological component used, the expected effect, and the like.

Formulation Form / Usage Mode The external composition of the present invention is used as a transdermally applied preparation (external drug, cosmetics, etc.), and is particularly preferably used as an external drug.

The pharmaceutical form of the external composition of the present invention is not particularly limited as long as it can be applied transdermally, and is, for example, a liquid agent (including a lotion agent, a spray agent, an aerosol agent, and an emulsion agent), a water-soluble ointment. Examples thereof include agents, oily ointments, creams, foams, gels, patches and the like. Among these, liquids, ointments and creams are preferable. Preparation of these formulations can be carried out by formulating them with additives according to the formulations according to the known method described in the 16th revised Japanese Pharmacopoeia General Regulations for Formulations.

Since the external composition of the present invention can exert a refreshing action by a terpenoid compound, an analgesic / antipruritic action by a local cooling sensation stimulus, etc., it is applied to the skin where refreshing, analgesic / antipruritic action is required. Further, since the external composition of the present invention can exert a moisturizing action, an anti-inflammatory action, a blood circulation promoting action and the like by a heparinoid, it can be applied to the skin where these actions are required and used.

2. Method for Inhibiting Precipitation of Terpenoid Compound The present invention is a method for suppressing the precipitation of a terpenoid compound in an external composition containing a terpenoid compound, characterized in that the terpenoid compound and a heparin-like substance coexist in the external composition. Provided is a method for suppressing the precipitation of a terpenoid compound.

Regarding the type and content of the terpenoid compound and heparinoid used in the precipitation suppression method, the type and content of other components to be blended, the formulation form of the external composition, and the like, the above-mentioned "1. External composition". It is the same as the case of.

3. 3. Method for Inhibiting the Formation of Insoluble Aggregates in an External Composition Containing a Terpenoid Compound and a Heparinoid The present invention is a method for suppressing the formation of an insoluble aggregate in an external composition containing a terpenoid compound and a heparinoid. Provided is a method for suppressing the formation of insoluble aggregates, which comprises coexistence of a terpenoid compound, a heparinoid, and diphenhydramine in a substance.

Regarding the type and content of the terpenoid compound, heparinoid, and diphenhydramine used in the production suppression method, the type and content of other components to be blended, the formulation form of the external composition, and the like, the above-mentioned "1. External composition". It is the same as the case of "thing".

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Test Example 1: Evaluation of menthol precipitation inhibitory effect An external composition having the composition shown in Table 1 was produced, and the precipitation inhibitory effect of menthol was evaluated. The specific test method is as follows.

First, a heparinoid was mixed and dissolved in purified water to prepare a first solution. Separately, l-menthol and polyoxyethylene hydrogenated castor oil 40 preheated to 60 ° C. were added to propylene glycol and mixed to prepare a second solution. Then, the first solution and the second solution were mixed and stirred to produce a liquid external composition. All of the obtained external compositions were in a state in which all l-menthol was dissolved.

15 g of the obtained external composition was placed in a vial having a diameter of 2.7 cm and a height of 5.5 cm (excluding the lid), sealed tightly, and allowed to stand for 5 hours under light-shielded conditions at 4 ° C. Then, the appearance of the external composition was observed, and the state of precipitation of l-menthol was evaluated. In the evaluation of the state of precipitation of l-menthol, the amount of the precipitate (needle-shaped crystal) of l-menthol observed in Comparative Example 1 was "1", and the precipitate of l-menthol (needle-shaped crystal) was The case where no evidence was observed was set as "10", and the interval was divided into 10 stages according to the amount of precipitates and scored.

The results obtained are shown in Table 1. In the external composition containing no heparinoid, a large amount of l-menthol precipitates were observed (Comparative Example 1). On the other hand, in the external composition containing a heparinoid, the precipitation of l-menthol could be effectively suppressed (Examples 1 to 9). In particular, when a heparinoid was contained in a ratio of 0.15 to 15 parts by weight with respect to 1 part by weight of l-menthol, the effect of suppressing the precipitation of l-menthol was remarkably observed (Examples 1 to 7). ). Furthermore, it was also confirmed that even if the content of l-menthol is as high as 1% by weight or more, the precipitation of l-menthol can be effectively suppressed by containing a heparinoid (Examples 6 to 9). ..

Test Example 2: Evaluation of menthol precipitation suppressing effect and insoluble agglutination suppressing effect An external composition having the composition shown in Table 2 was produced, and the menthol precipitation suppressing effect and the insoluble agglutination suppressing effect were evaluated. The specific test method is as follows.

First, a heparinoid was mixed and dissolved in purified water to prepare a first solution. When diphenhydramine hydrochloride was contained, diphenhydramine hydrochloride was dissolved in the first solution. Separately, l-menthol, dl-camphor or d-borneol, ethanol (95 vol%) and polyoxyethylene hydrogenated castor oil 60 preheated to 60 ° C. were added and mixed with propylene glycol, and the mixture was mixed. Two solutions were prepared. When diphenhydramine was contained, diphenhydramine was dissolved in the second solution. Then, the first solution and the second solution were mixed and stirred to produce a liquid external composition. The obtained external composition was in a state in which l-menthol, dl-camphor or d-borneol were all dissolved.

15 g of the obtained external composition was placed in a vial having a diameter of 2.7 cm and a height of 5.5 cm (excluding the lid), sealed, and allowed to stand for 6 hours under a light-shielded condition of -20 ° C for 11 hours. The temperature was raised to 5 ° C., and the mixture was allowed to stand at 5 ° C. for 1 hour.

The appearance of each external composition after storage under the above conditions was observed, and the state of precipitation of l-menthol was evaluated. In the evaluation of the state of precipitation of l-menthol, the amount of the precipitate (needle-shaped crystal) of l-menthol observed in Comparative Example 2 was "1", and the precipitate of l-menthol (needle-shaped crystal) was The case where no evidence was observed was set as "10", and the interval was divided into 10 stages according to the amount of precipitates and scored.

Further, the appearance of each external composition after storage under the above conditions is visually observed, the presence or absence of insoluble aggregates (insoluble matter that looks like haze) is observed, and insoluble aggregates are generated according to the following criteria. The degree was evaluated.
◯: No insoluble agglomerates were observed.
Δ: Only a small amount of insoluble agglomerates are observed.
X: Insoluble agglomerates are clearly recognized.

The results obtained are shown in Table 2. In the external composition containing no heparinoid, a large amount of l-menthol precipitate was observed (Comparative Example 2). On the other hand, in the external composition containing a heparinoid, the precipitation of monoterpenes could be effectively suppressed (Examples 10 to 22).

On the other hand, in the external composition containing diphenhydramine-free and l-menthol and heparinoids, the formation of insoluble aggregates was observed (Examples 10 and 11). Since the insoluble agglutinin was not found in the external composition containing no heparinoid (Comparative Example 2), it is considered that the insoluble agglutinoid was derived from the heparinoid. In contrast, topical compositions containing diphenhydramine, along with monoterpenes and heparinoids, were able to suppress insoluble aggregates (Examples 12, 13, 15-19, and 21). In particular, when 1 to 10 parts by weight of diphenhydramine was contained with respect to 1 part by weight of a heparinoid, the formation of insoluble aggregates could be remarkably suppressed (Examples 12, 13, 15 to 17, 19 and 21). ). It was also confirmed that the inclusion of diphenhydramine also improved the effect of suppressing the precipitation of l-menthol (Examples 10 and 12).

Formulation Examples Ointments having the compositions shown in Table 3 (Prescription Examples 1 to 10), creams having the composition shown in Table 4 (Prescription Examples 11 to 19), gel preparations having the composition shown in Table 5 (Prescription Examples 20 to 25), And the emulsion having the composition shown in Table 6 (Formulation Examples 21 to 31) was prepared according to a conventional method. All of the obtained pharmaceuticals were excellent in the effect of suppressing the precipitation of monoterpenes and the formation of insoluble aggregates under low temperature conditions, as compared with the case where heparinoids and diphenhydramine were not contained.

Claims (1)

Topical composition (however, when used as an anti-whitening and improving agent, when containing lidocaine and amino alcohol, when containing vitamin A or vitamin A carboxylate, when containing a lipophilic sorbitan-based surfactant, and when urea is used. A method for suppressing precipitation of monoterpene in an external composition containing monoterpene, which comprises coexistence of monoterpene and a heparin-like substance.