Emulsion composition

Abstract

The present invention aims to provide a novel formulation that improves the emulsification stability of an emulsifying composition containing ufenamate. [Solution] When an emulsifying composition containing ufenamate is blended with at least one selected from the group consisting of diphenhydramine, allantoin, and its derivatives, the emulsifying stability of the emulsifying composition is improved.

Description

Technical Field

[0001] The present invention relates to an emulsified composition containing bufexamac and exhibiting excellent emulsion stability.

Background Art

[0002] Bufexamac is widely used as a non-steroidal anti-inflammatory agent for pharmaceuticals in topical preparations. However, since bufexamac is a water-insoluble component, it is not easy to stably formulate it in preparations such as topical pharmaceuticals containing water.

[0003] Generally, techniques for stably formulating water-insoluble components in topical compositions have been variously studied depending on the components. Regarding bufexamac, Patent Document 1 describes a topical pharmaceutical emulsion preparation containing (a) bufexamac, (b) glycerol fatty acid monoester, and (c) polyoxyethylene (2 to 50 mol addition) alkyl ether, and containing the components (b) and (c) in a ratio of 0.1 to 1.3 (mass ratio), which can stably formulate bufexamac. Further, Patent Document 2 describes that by formulating (C) diphenhydramine and / or its salt, and (D) a higher alcohol that is solid at 25°C together with (A) at least one selected from the group consisting of glycyrrhetinic acid, glycyrrhizic acid, derivatives thereof, and salts thereof, and (B) bufexamac, the emulsion stability is improved.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] While formulations to improve the emulsification stability of emulsified compositions containing ufenamate have been studied in the past, there is a need for new formulations that can improve the emulsification stability of emulsified compositions containing ufenamate, even for emulsified compositions that do not have the specific composition required for each formulation technology, or for emulsified compositions with new base compositions.

[0006] Therefore, the object of the present invention is to provide a new formulation that improves the emulsification stability of an emulsified composition containing ufenamate. [Means for solving the problem]

[0007] The inventors of this invention conducted diligent research to solve the aforementioned problems and found that in an emulsifying composition containing ufenamate, the emulsion stability can be improved by combining diphenhydramine and allantoin derivatives. Because the emulsion stability achieved by the formulation discovered in this invention is extremely high, it was also found that even in base compositions with a small amount of oily base, which inherently have poor emulsion stability and are prone to phase separation, the emulsion stability can be effectively improved. This invention was completed by further research based on these findings.

[0008] In other words, the present invention provides inventions in the following embodiments. Item 1. An emulsified composition containing (A) ufenamate, (B) diphenhydramine, and (C) at least one selected from the group consisting of allantoin and its derivatives. Item 2. The emulsified composition according to Item 1, wherein the oily base content is 0.05 to 20% by weight. Item 3. The emulsified composition according to item 1 or 2, wherein the content of component (B) per 1 part by weight of component (A) is 0.05 to 1 part by weight. Item 4. The emulsified composition according to any one of items 1 to 3, wherein the content of component (C) per 1 part by weight of component (A) is 0.01 to 0.5 parts by weight. Item 5. An emulsified composition according to any one of items 1 to 4, wherein the pH is 4 to 6. Item 6. An emulsion composition according to any one of items 1 to 5, which is an oil-in-water emulsion composition. [Effects of the Invention]

[0009] The present invention provides a novel formulation that improves the emulsification stability of an emulsifying composition containing ufenamate. [Modes for carrying out the invention]

[0010] The emulsified composition of the present invention is characterized by containing (A) ufenamate (hereinafter also referred to as "component (A)"), (B) diphenhydramine (hereinafter also referred to as "component (B)"), and (C) at least one selected from the group consisting of allantoin and its derivatives (hereinafter also referred to as "component (C)" or "allantoins"). The emulsified composition of the present invention will be described in detail below.

[0011] (A) Ufenamat The emulsified composition of the present invention contains ufenamate as component (A). Ufenamate, also known as butyl flufenamate, is a lipid-soluble compound and is a well-known nonsteroidal anti-inflammatory drug.

[0012] In the emulsified composition of the present invention, the content of component (A) is appropriately set according to the pharmacological effects to be exhibited, but examples include 1 to 20% by weight, preferably 1 to 8% by weight, more preferably 3 to 6% by weight, and even more preferably 4.5 to 5.5% by weight.

[0013] (B) Diphenhydramine The emulsifying composition of the present invention contains diphenhydramine as component (B). While emulsifying compositions containing component (A) inherently have poor emulsifying stability, the emulsifying composition containing component (A) of the present invention can exhibit excellent emulsifying stability by combining component (B) with component (C).

[0014] Diphenhydramine is a fat-soluble compound and is a known drug known to have an antihistamine effect.

[0015] The content of component (B) in the emulsified composition of the present invention is not particularly limited and may be appropriately set according to the degree of emulsification stability to be imparted. For example, 0.01 to 5% by weight can be mentioned. From the viewpoint of more effectively suppressing emulsification stability, the content of component (B) in the emulsified composition of the present invention is preferably 0.1 to 3% by weight, more preferably 0.5 to 1.5% by weight, and even more preferably 0.8 to 1.2% by weight.

[0016] In the emulsified composition of the present invention, the ratio of component (B) to component (A) is determined according to the respective contents of component (A) and component (B). As the content of component (B) relative to 1 part by weight of component (A), for example, 0.05 to 1 part by weight can be mentioned. From the viewpoint of further enhancing emulsification stability, as the content of component (B) relative to 1 part by weight of component (A), preferably 0.1 to 0.5 part by weight, more preferably 0.18 to 0.35 part by weight can be mentioned.

[0017] (C) Allantoins The emulsified composition of the present invention contains at least one selected from the group consisting of allantoin and its derivatives as component (C). An emulsified composition containing component (A) inherently has poor emulsification stability, but the emulsified composition containing component (A) of the present invention can exhibit excellent emulsification stability by blending component (C) in combination with component (B).

[0018] Allantoin is a water-soluble compound also known as 5-ureidohydantoin and is a known drug known to have anti-inflammatory, cell-activating, hemostatic, bactericidal, anti-ulcer and other effects.

[0019] As derivatives of allantoin, there are no particular restrictions as long as they are pharmaceutically acceptable and water-soluble. Specifically, examples include allantoin chlorhydroxyaluminum, allantoin dihydroxyaluminum, etc. These derivatives of allantoin may be used alone or in combination of two or more.

[0020] In the emulsion composition of the present invention, as the component (C), one kind may be selected from allantoin and its derivatives and used, or two or more kinds may be used in combination. Among these components (C), from the viewpoint of further improving the emulsion stability, allantoin is preferably mentioned.

[0021] In the emulsion composition of the present invention, the content of the component (C) is not particularly limited and may be appropriately set according to the degree of emulsion stability to be imparted. For example, 0.01 to 1% by weight may be mentioned. From the viewpoint of more effectively suppressing the emulsion stability, the content of the component (C) in the emulsion composition of the present invention is preferably 0.05 to 0.5% by weight, more preferably 0.08 to 0.3% by weight, and still more preferably 0.18 to 0.25% by weight.

[0022] In the emulsion composition of the present invention, the ratio of the component (C) to the component (A) is determined according to the respective contents of the component (A) and the component (C). As the content of the component (C) relative to 1 part by weight of the component (A), for example, 0.01 to 0.3 parts by weight may be mentioned. From the viewpoint of further enhancing the emulsion stability, as the content of the component (C) relative to 1 part by weight of the component (A), preferably 0.03 to 0.12 parts by weight, more preferably 0.04 to 0.08 parts by weight may be mentioned.

[0023] In the emulsified composition of the present invention, the ratio of component (C) to component (B) is determined according to the respective contents of component (B) and component (C), but for example, the content of component (C) per 1 part by weight of component (B) is 0.05 to 0.5 parts by weight. From the viewpoint of further improving emulsification stability, the content of component (C) per 1 part by weight of component (B) is preferably 0.08 to 0.4 parts by weight, more preferably 0.18 to 0.3 parts by weight.

[0024] Oily base The emulsified composition of the present invention contains an oil phase base component. The oily base is not particularly limited to the extent that it is pharmaceutically or cosmetically acceptable, but examples include oils (medium-chain triglycerides, olive oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc.), mineral oils (liquid paraffin, paraffin, gelling hydrocarbons, petrolatum, etc.), waxes or waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (cetyl isooctanoate, isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, palmite Examples include isopropyl palmitate, cetyl palmitate, ethyl oleate, etc., fatty acid alkyl esters, higher fatty acids (stearic acid, oleic acid, palmitic acid, behenic acid, linoleic acid, lanolin, etc.), higher fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oils (dimethylpolysiloxane, cyclic silicones, etc.).

[0025] These oils may be used individually or in combination of two or more types.

[0026] Among these oily bases, oils are preferred, and medium-chain fatty acid triglycerides and squalane are more preferred, from the viewpoint of further improving emulsification stability. The average number of carbon atoms in the fatty acid chains constituting the medium-chain fatty acid triglycerides is 6 to 12. The average number of carbon atoms in the above fatty acids in the medium-chain fatty acid triglycerides is the weighted average value obtained by weighting the number of carbon atoms of the constituent fatty acids of the medium-chain fatty acid triglycerides (for example, 8 for caprylic acid, 10 for capric acid) according to the composition ratio of the constituent fatty acids. From the viewpoint of further improving emulsification stability, the average fatty acid chain length of the constituent fatty acids is preferably 8 to 10, more preferably 9.5 or less. The number of carbon atoms in each constituent fatty acid of the medium-chain fatty acid triglycerides used in the present invention is not particularly limited as long as the average number of carbon atoms is within the above range, but for example, 6 to 12 is preferred. The constituent fatty acids may be either saturated or unsaturated, but saturated is preferred. A preferred specific example of the medium-chain fatty acid triglycerides used in the present invention is a saturated fatty acid triglyceride with 8 to 10 carbon atoms.

[0027] The total amount of oily base in the emulsified composition of the present invention can be, for example, 0.05 to 20% by weight. From the viewpoint of further improving emulsification stability, it is preferably 0.1 to 20% by weight, more preferably 0.5 to 20% by weight, even more preferably 1 to 20% by weight, and even more preferably 1.2 to 20% by weight.

[0028] Furthermore, because the emulsification stability of the emulsified composition of the present invention is very high, it can effectively improve emulsification stability even in the case of a base composition with a small amount of oily base, which inherently has poor emulsification stability and is prone to phase separation. From this viewpoint, preferred examples of the oily base content (total amount) in the emulsified composition of the present invention include 0.05 to 10% by weight, more preferably 0.05 to 5% by weight, even more preferably 0.05 to 3% by weight, and even more preferably 0.05 to 2% by weight.

[0029] water The emulsifying composition of the present invention contains water as a base component of the aqueous phase. The water content in the emulsifying composition of the present invention is not particularly limited, but for example, it can be 60 to 95% by weight. From the viewpoint of further improving emulsification stability, the water content in the emulsifying composition of the present invention is preferably 60 to 90% by weight, more preferably 60 to 80% by weight.

[0030] Furthermore, because the emulsification stability of the emulsifying composition of the present invention is very high, it can effectively improve emulsification stability even in the case of a base composition with a large amount of water, which inherently has poor emulsification stability and is prone to phase separation. From this viewpoint, preferred examples of the water content in the emulsifying composition of the present invention include preferably 65 to 95% by weight, and more preferably 69 to 95% by weight.

[0031] surfactants The emulsifying composition of the present invention contains a surfactant for emulsifying an oil phase and an aqueous phase. The surfactant is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, but examples include nonionic surfactants, anionic surfactants, cationic surfactants, amphoteric surfactants, etc. Among these other surfactants, nonionic surfactants are recommended from the viewpoint of improving emulsification stability.

[0032] Nonionic surfactants include, specifically, polyoxyethylene hydrogenated castor oil; sorbitan fatty acid esters (e.g., sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate (sorbitan monostearate), sorbitan sesquioleate, sorbitan trioleate, sorbitan penta-2-ethylhexylate diglycerol, tetra-2-ethylhexylate diglycerol) Sorbitan, etc.); Glycerin fatty acid esters (e.g., monocottonseed oil fatty acid glyceryl, monoerucate glyceryl, sesquioleate glyceryl, monostearate glyceryl (glyceryl stearate), α,α'-oleate pyroglutamate glyceryl, monostearate glycerin malate, etc.); Propylene glycol fatty acid esters (e.g., propylene glycol monostearate, etc.); Glycerin alkyl ether; Steareth-2; Polyoxyethylene sorbitan Tan fatty acid esters (e.g., polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tetraoleate, etc.); polyoxyethylene sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan pentaoleate, polyoxyethylene sorbitan monostearate, etc.); polyoxyethylene glycerin fatty acid esters (e.g., polyoxyethylene glycerin monostearate, polyoxyethylene glycerin monoisostearate, polyoxyethylene glycerin triisostearate, etc.); polyoxyethylene fatty acid esters (e.g., polyoxyethylene monooleate, polyoxyethylene monostearate (polyoxyl stearate), polyoxyethylene distearate, polyoxyethylene monodioleate, ethylene glycol distearate, etc.);Examples include polyoxyethylene alkyl or arachidyl ethers (e.g., polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene behenyl ether, polyoxyethylene 2-octyldodecyl ether, polyoxyethylene arachidyl ether, polyoxyethylene cholestanol ether, etc.) and their phosphoric acid or phosphate salts (e.g., sodium polyoxyethylene cetyl ether phosphate); Pluronic® type (e.g., Pluronic®); polyoxyethylene-polyoxypropylene alkyl ethers (e.g., polyoxyethylene-polyoxypropylene-cetyl ether, polyoxyethylene-polyoxypropylene-2-decyltetradecyl ether, polyoxyethylene-polyoxypropylene monobutyl ether, polyoxyethylene-polyoxypropylene hydrogenated lanolin, polyoxyethylene-polyoxypropylene glycerin ether, etc.); and Steareth-21, etc.

[0033] These surfactants may be used individually or in combination of two or more.

[0034] Among these nonionic surfactants, polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ethers (preferably polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene behenyl ether, and polyoxyethylene 2-octyldodecyl ether) are selected from the viewpoint of further improving emulsification stability.

[0035] Examples of HLB values ​​for surfactants include 8 to 20, preferably 9 to 18, and more preferably 10 to 17. The HLB value (hydrophilic-lipophilic balance) indicates the molecular weight of the hydrophilic group portion of the total molecular weight of the surfactant and is determined by Griffin's formula.

[0036] The surfactant content in the emulsifying composition of the present invention can be appropriately set depending on the type of surfactant used, but for example, 2 to 7% by weight, preferably 3 to 6% by weight, and more preferably 4 to 5.2% by weight is used.

[0037] Other ingredients In addition to the components described above, the emulsifying composition of the present invention may contain other commonly used additives as needed. Examples of such additives include polyhydric alcohols, thickeners, pH adjusters, buffers, solubilizers, chelating agents, preservatives, antioxidants, stabilizers, fragrances, colorants, and the like.

[0038] The polyhydric alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, but examples include dihydric alcohols such as propylene glycol, 1,3-butylene glycol, ethylene glycol, isoprene glycol, diethylene glycol, and dipropylene glycol; and trihydric alcohols such as glycerin. These polyhydric alcohols may be used individually or in combination of two or more. Among these polyhydric alcohols, propylene glycol, 1,3-butylene glycol, dipropylene glycol, and glycerin are preferred. When the emulsified composition of the present invention contains a polyhydric alcohol, the polyhydric alcohol content is not particularly limited, but examples include 5 to 15% by weight, preferably 8 to 12% by weight, and more preferably 9 to 11% by weight.

[0039] Examples of thickening agents include cellulose-based thickening agents (e.g., carmellose sodium, hydroxypropylcellulose, hydroxyethylmethylcellulose, methylcellulose, carboxymethylcellulose, etc.), xanthan gum, and carboxyvinyl polymer. These thickening agents may be used individually or in combination of two or more. Among these thickening agents, cellulose-based thickening agents are preferred, and carmellose sodium is more preferred. When the emulsified composition of the present invention contains a thickening agent, the content of the thickening agent is not particularly limited, but for example, it may be 1 to 7% by weight, preferably 1.25 to 5% by weight, and more preferably 1.5 to 3% by weight.

[0040] Furthermore, in addition to the components described above, the emulsified composition of the present invention may optionally contain pharmacoactive ingredients that can exert pharmaceutical or cosmetic physiological functions. Examples of such pharmacoactive ingredients include steroids, antihistamines, local anesthetics, anti-inflammatory agents, bactericides, antipruritics, moisturizers, blood circulation promoting ingredients, vitamins, mucopolysaccharides, and the like. These pharmacoactive ingredients may be used individually or in combination of two or more. Among these pharmacoactive ingredients, dipotassium glycyrrhizinate (anti-inflammatory agent) and heparinoid (anti-inflammatory agent, moisturizer, blood circulation promoting agent) are preferred. When these pharmacoactive ingredients are included in the emulsified composition of the present invention, their content may be appropriately set according to the type of pharmacoactive ingredient used, the expected effect, etc.

[0041] pH The pH of the emulsified composition of the present invention is not particularly limited. Since the emulsified composition of the present invention can exhibit excellent emulsification stability in a weakly acidic pH range suitable for general topical skin preparations, a preferred pH (25°C) of the emulsified composition of the present invention is, for example, 4 to 6, preferably 4.5 to 5.5.

[0042] Formulation The emulsion state of the emulsified composition of the present invention may be either oil-in-water or water-in-oil. Because the emulsion composition of the present invention has excellent emulsion stability, it can effectively improve emulsion stability even in the oil-in-water type, which inherently contains a lot of water and is prone to phase separation. From this viewpoint, an oil-in-water type is a preferred emulsion state for the emulsion composition of the present invention.

[0043] The formulation form of the emulsified composition of the present invention is not particularly limited, and examples include emulsions, creams, gel creams, lotions, etc., with gel creams being preferred.

[0044] Examples of the emulsified composition of the present invention include pharmaceuticals, quasi-drugs, cosmetics, and the like. Among these formulations, pharmaceuticals and quasi-drugs are preferred.

[0045] The emulsified composition of the present invention preferably includes topical preparations, and more preferably topical skin preparations.

[0046] Manufacturing method The emulsified composition of the present invention can be manufactured according to known methods for manufacturing emulsified compositions. For example, the method described below is used for manufacturing the emulsified composition of the present invention. First, an oil-phase composition is prepared by mixing component (A), component (B), an oily base, and other lipophilic components added as needed. Separately, an aqueous-phase composition is prepared by mixing component (C), water, and other water-soluble components added as needed. The surfactant may be added to either the oil-phase composition or the aqueous-phase composition, or both, and mixed, but it is preferable to add it to the oil-phase composition. Next, the obtained oil-phase composition and aqueous-phase composition are mixed and emulsified using an emulsification method such as a homomixer to produce the emulsified composition of the present invention. [Examples]

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0048] Test example A gel-cream-like oil-in-water emulsion composition was prepared with the compositions shown in Tables 1 and 2. Of the components shown in Table 1, NIKKOL Triester F-810 (tri(caprylic / capric acid) glyceryl) was used as the neutralized fatty acid triglyceride, polyoxyethylene hydrogenated castor oil 20 with an HLB of 10.5 was used, and polyoxyethylene behenyl ether with an HLB of 16.5 was used. Specifically, predetermined amounts of components (A), (B), the oily base, and the surfactant from Tables 1 and 2 were measured, heated to 80°C, and mixed to prepare the oil phase composition. Separately, predetermined amounts of component (C) and the aqueous phase component were measured and prepared the aqueous phase composition. After heating the aqueous phase composition to 60°C, the oil phase composition at 80°C was added in small amounts, and emulsification was carried out while mixing. The mixture was then cooled to 25°C to obtain a gel-cream-like oil-in-water emulsion composition.

[0049] The pH (at 25°C) of the obtained gel-cream-like oil-in-water emulsion composition was measured. Furthermore, the obtained gel-cream-like oil-in-water emulsion composition was stored at 50°C for two weeks, and its emulsion stability was evaluated based on the following criteria. The results are shown in Tables 1 and 2.

[0050] (Evaluation criteria for emulsification stability) ◎: The emulsification state was uniform, and no phase separation was observed. ○: There was a tendency towards creaming, but no phase separation was observed. △: Phase separation was observed, but it returned to its original state after mixing. ×: Significant phase separation was observed.

[0051] [Table 1]

[0052] [Table 2]

[0053] As shown in Comparative Example 1, the emulsion composition containing ufenamate exhibited poor emulsion stability, resulting in significant phase separation. Furthermore, as shown in Comparative Example 2, the emulsion stability remained poor and significant phase separation occurred even with the addition of allantoin. On the other hand, as shown in Comparative Example 3, the emulsion composition combining diphenhydramine and allantoin also exhibited poor emulsion stability and significant phase separation. In contrast, as shown in Examples 1-6, when diphenhydramine and allantoin were further added to the emulsion composition containing ufenamate, phase separation was significantly suppressed, and a remarkable improvement in emulsion stability was observed. This improvement in emulsion stability was particularly pronounced in the compositions of Examples 2-6, and this remarkably pronounced effect was similarly achieved at pH 4-6, as shown in Examples 3-5.

Claims

1. An emulsified composition containing (A) ufenamate, (B) diphenhydramine, and (C) at least one selected from the group consisting of allantoin and its derivatives.

2. The emulsified composition according to claim 1, wherein the content of the oily base is 0.05 to 20% by weight.

3. The emulsified composition according to claim 1 or 2, wherein the content of component (B) is 0.05 to 1 part by weight relative to 1 part by weight of component (A).

4. The emulsified composition according to any one of claims 1 to 3, wherein the content of component (C) relative to 1 part by weight of component (A) is 0.01 to 0.5 parts by weight.

5. An emulsified composition according to any one of claims 1 to 4, wherein the pH is 4 to 6.

6. The emulsifying composition according to any one of claims 1 to 5, which is an oil-in-water emulsion composition.

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