JP2015187085A - Emulsified pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an emulsified pharmaceutical composition which has excellent stability with time in emulsified state and provide an emulsified pharmaceutical composition in which an unstable viscosity with time (viscosity increase) is inhibited.SOLUTION: An emulsified pharmaceutical composition comprises the following components: at least one selected from the group consisting of (a) salicylate and (b) terpene; (c) antihistamine in salt form; (d) polyethylene glycol fatty acid ester; (e) sorbitan fatty acid ester; (f) surfactant with an HLB of 10-13; and (g) viscosity improver.

Description

  The present invention relates to an emulsified pharmaceutical composition having excellent stability over time in an emulsified state. More preferably, the present invention relates to an emulsified pharmaceutical composition excellent in viscosity stability in addition to emulsion stability.

  Conventionally, emulsification techniques have been widely used to stably mix water and oil (fats) that normally do not mix with each other, and emulsifiers that reduce the interfacial tension between water and oil are used to obtain stable emulsion compositions. Has been. For example, an oil-in-water emulsion composition in which oil components are dispersed in water is a mixture of water and oil components stably by the action of the emulsifier, and is widely used in pharmaceuticals, cosmetics, etc. as high-value-added preparations. ing.

  For example, an external preparation applied to the skin to suppress pain and inflammation such as stiff shoulders and muscle fatigue is an emulsion preparation having an emulsion form rather than an ointment or gel having a relatively high viscosity. There is an advantage that it is easy to apply to the skin, and it is easy to apply to the skin.

  However, since terpenes such as salicylic acid ester (analgesic component) and l-menthol, which are widely used as components for external anti-inflammatory analgesics, are highly polar components, the emulsion form of the emulsified formulation is destroyed when it is added to the emulsified formulation. There is a problem that the emulsified state becomes unstable over time. Similarly, antihistamines in the form of salts such as chlorpheniramine maleate used as a component for external anti-inflammatory analgesics are also strong in destroying the cross-linking structure of the thickener, so the same as salicylic acid esters and terpenes described above. There is a problem of making the emulsification unstable. For this reason, it is difficult to stably maintain an emulsified state for a long period of time for an emulsified preparation containing a salicylic acid ester, a terpene, and an antihistamine in a salt form, and a technique for overcoming this is desired.

  Patent Document 1 relates to a microemulsion preparation containing a sparingly soluble drug such as salicylic acid ester, in addition to the sparingly soluble drug, an oil component with an IOB of 0.22 to 0.85 (polar oil) and an oil component with an IOB of 0 to 0.20 (nonpolar) It is described that a microemulsion preparation containing a hydrophilic oil), a hydrophilic surfactant and water is excellent in stability and transdermal absorbability. However, in the ratio of the polar oil and the nonpolar oil described in the document 1, when a salt form medicinal component and a thickener are further blended as the other components, the desired emulsion stability cannot be obtained ( (See Examples below).

  Patent Document 2 discloses that an emulsion composition having good thermal stability and usability can be prepared by blending water, an oily component, a hydrophilic surfactant, and a terpene at a specific ratio, and the emulsion composition. Describes that a medicinal component having a salicylic acid ester or a salt form can be further blended. However, the components described in Reference 2 have poor low-temperature stability, and have a problem that the viscosity significantly increases during low-temperature storage. (See examples below)

JP 63-10717 A JP 2012-77027 A

  The object of the present invention is to solve the above-mentioned problems in a pharmaceutical composition (emulsified preparation) in an emulsified form containing at least one of salicylic acid ester and terpene and a salt form of an antihistamine, that is, over time in an emulsified state. An object of the present invention is to provide an emulsified pharmaceutical composition having excellent stability. Another object of the present invention is to provide an emulsified pharmaceutical composition having good viscosity stability by suppressing an increase in viscosity over time of the emulsified composition.

  The inventors of the present invention have intensively studied to solve the above problems, and in preparing an emulsified preparation containing at least one of salicylic acid ester and terpene, and an antihistamine in a salt form, It has been found that the emulsified state can be stably maintained by combining a polyethylene glycol fatty acid ester, a sorbitan fatty acid ester, and a surfactant of HLB 10 to 13 despite the blending of the above components. In the course of the above studies, the present inventors formulated at least one of salicylic acid ester and terpene, salt-form antihistamine, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, and surfactants HLB 10-13. Emulsified preparations have been found to have a problem that the viscosity increases with time, particularly under low temperature conditions, and the viscosity is not constant, and a method for solving this problem has been studied. It has been found that, by blending, the increase in viscosity over time can be suppressed, and the stability over time of an emulsion preparation containing at least one of salicylic acid ester and terpene and a salt form of an antihistamine can be further improved.

  The present invention has been completed based on these findings and has the following embodiments.

(I) Emulsified pharmaceutical composition (I-1) Emulsified pharmaceutical composition comprising the following components:
(A) at least one salt selected from the group consisting of salicylic acid esters and (b) terpenes (c) an antihistamine in salt form,
(D) polyethylene glycol fatty acid ester,
(E) sorbitan fatty acid ester,
(F) HLB 10-13 surfactant.
(G) thickener,
(I-2) The emulsified pharmaceutical according to (I-1), wherein (d) is a polyethylene glycol fatty acid ester of HLB17 or higher and / or (e) is a sorbitan fatty acid ester of HLB3-5 Composition.
(I-3) The emulsified pharmaceutical composition according to (I-1) or (I-2), wherein the component (f) is at least one of polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether.
(I-4) The emulsified pharmaceutical composition according to (I-1) or (I-2), wherein the component (f) is polyoxyethylene hydrogenated castor oil.
(I-5) The emulsified pharmaceutical composition according to any one of (I-1) to (I-4), which is an anti-inflammatory analgesic external composition.

(II) Emulsification stabilization method (II-1) An emulsified pharmaceutical composition comprising (a) at least one selected from the group consisting of salicylic acid ester and (b) terpene, and (c) a salt form of an antihistamine. And (g) surfactants of (e) sorbitan fatty acid ester, (f) HLB 10-13, and (g) ) Emulsification stabilization method characterized by using a thickener together.
(II-2) Emulsification stabilization according to (II-1), wherein (d) is a polyethylene glycol fatty acid ester of HLB 17 or higher and / or (e) is a sorbitan fatty acid ester of HLB 3-5 Method.
(II-3) The emulsion stabilization method according to (II-1) or (II-2), wherein the component (f) is at least one of polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether.
(II-4) The emulsion stabilization method according to (II-1) or (II-2), wherein the component (f) is polyoxyethylene hydrogenated castor oil.

(III) Method for inhibiting viscosity increase (III-1) (a) At least one selected from the group consisting of salicylic acid ester and (b) terpene, (c) salt form antihistamine, (d) polyethylene glycol fatty acid ester , (E) a sorbitan fatty acid ester, and (f) a method for suppressing the increase in viscosity of an emulsion composition containing HLB 10-13 surfactant, wherein (g) increase is further added to the components (a) to (f). A method characterized by using a sticking agent in combination.
(III-2) Viscosity increase suppression according to (III-1), wherein (d) is a polyethylene glycol fatty acid ester of HLB 17 or higher and / or (e) is a sorbitan fatty acid ester of HLB 3-5 Method.
(III-3) The method for suppressing the increase in viscosity according to (III-1) or (III-2), wherein the component (f) is at least one of polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether.
(III-4) The method for suppressing the increase in viscosity according to (III-1) or (III-2), wherein the component (f) is polyoxyethylene hydrogenated castor oil.

  The emulsified pharmaceutical composition of the present invention comprises (a) at least one selected from the group consisting of a salicylic acid ester and (b) a terpene, (c) a salt form of an antihistamine, (d) a polyethylene glycol fatty acid ester, ( e) a sorbitan fatty acid ester, and (f) a surfactant of HLB 10-13, comprising at least one of components (a) and (b), and component (c) In this way, the emulsified state can be stably maintained over time. In addition, the emulsified pharmaceutical composition of the present invention is characterized by containing (g) a thickener together with the components (a) to (f), and when the composition is provided with no thickener. Can be significantly suppressed over time (viscosity increase under low temperature conditions), and an emulsion composition having good viscosity stability can be provided.

(I) Emulsified pharmaceutical composition The emulsified pharmaceutical composition of the present invention has an emulsified form and is at least one selected from the group consisting of at least (a) a salicylic acid ester and (b) a terpene, and (c) a salt. In the form of antihistamine, (d) polyethylene glycol fatty acid ester, (e) sorbitan fatty acid ester, (f) HLB 10-13 surfactant and (g) thickener. Hereinafter, each component will be described.

(A) Salicylic acid ester Salicylic acid ester is an ester formed by dehydration condensation of salicylic acid and alcohol. Examples of such salicylic acid esters include, but are not limited to, for example, glycol salicylate, methyl salicylate, ethyl salicylate, salicin, n-propyl salicylate, isopropyl salicylate, n-butyl salicylate, isoamyl salicylate, salicylic acid-tert-octyl, nonyl salicylate, Examples include dodecyl salicylate, cyclohexyl salicylate, benzyl salicylate, salicylic acid-α-methylbenzyl, and phenyl salicylate. Of these, preferred are glycol salicylate and methyl salicylate, and more preferred is glycol salicylate. These salicylic acid esters may be used singly or in combination of two or more.

  The blending ratio of the salicylic acid ester in the emulsified pharmaceutical composition of the present invention can be appropriately set from the range of usually 0.5 to 15% by weight. Although it does not restrict | limit, Preferably it is 1 to 12 weight%, More preferably, it is 1 to 5 weight%.

(B) The terpene terpene includes monoterpene, hemiterpene, sesquiterpene and the like. Specific examples include terpene hydrocarbons, terpene alcohols, terpene aldehydes, and terpene ketones. Examples of terpene hydrocarbons include monoterpene hydrocarbons such as limonene, pinene, and camphor; and sesquiterpene hydrocarbons such as lysine. Examples of the terpene alcohol include monoterpene alcohols such as citronellol, geraniol, linalool, menthol, terpineol, and borneol; sesquiterpene alcohols such as farnesol; and diterpene alcohols. Examples of the terpene aldehyde include monoterpene aldehydes such as citronellal, citral, and safranal; and diterpene aldehydes such as retinal. Examples of the terpene ketone include monoterpene ketones such as menthone, carbomenton, and yonon. These terpenes may be any of d-, l- and dl-forms. The terpene used in the present invention is preferably a monoterpene, more preferably a monoterpene hydrocarbon and a monoterpene alcohol. More preferred are cyclic monoterpenes, and specific examples of such cyclic monoterpenes include l-menthol and dl-camphor. In addition, although these terpenes may be used individually by 1 type, they can also be used in combination of 2 or more types arbitrarily.

  The blending ratio of the terpene in the emulsified pharmaceutical composition of the present invention is appropriately set in consideration of the blending amount of the salicylic acid ester described above, but the total amount with the salicylic acid ester is within 20% by weight, preferably within 18% by weight. More preferably, it can be appropriately set from the range of 1 to 20% by weight within the range of 15% by weight or less. Preferably it is 1 to 18 weight%, More preferably, it is 1 to 15 weight%.

(C) Salt-form antihistamine The salt-form antihistamine targeted by the present invention is a salt-form compound having an antihistamine action. Here, the salt forms include salts with inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; and formic acid, oxalic acid, citric acid, acetic acid, maleic acid, pamoic acid, fumaric acid, besylic acid, tannic acid, and lauryl sulfuric acid. The form of the salt with organic acids, such as, can be mentioned.

  Antihistamines in the form of salts include clemastine fumarate, diphenhydramine hydrochloride, diphenhydramine lauryl sulfate, diphenhydramine tannate, chlorpheniramine maleate, promethazine hydrochloride, promethazine methylenedisalicylate, hydroxyzine pamoate, homochlorcyclidine hydrochloride Azelastine hydrochloride, oxatomide pamoate, ketotifen fumarate, emedastine fumarate, fexofenadine hydrochloride, pseudoephedrine hydrochloride, epinastine hydrochloride, olopatadine hydrochloride, cetirizine hydrochloride, bepotastine besylate, and levocetirizine hydrochloride are known. Preferably, it is an antihistamine used by blending in a composition for external use, specifically, an inorganic acid salt or organic acid salt of diphenhydramine such as diphenhydramine hydrochloride, diphenhydramine lauryl sulfate, and diphenhydramine tannate; and maleic acid Mention may be made of inorganic or organic acid salts of chlorpheniramine such as chlorpheniramine. In addition, the antihistamine which has these salt forms may be used individually by 1 type, However, 2 or more types can also be used in arbitrary combinations.

  The blending ratio of the antihistamine in the salt form in the emulsified pharmaceutical composition of the present invention can be appropriately set within the range of usually 0.1 to 5% by weight. Although not limited, it is preferably 0.1 to 3% by weight, more preferably 0.1 to 2% by weight.

(D) Polyethylene glycol fatty acid ester The polyethylene glycol fatty acid ester is obtained by esterifying a fatty acid and polyethylene glycol. In other words, a plurality of moles of ethylene oxide (hydrophilic group) derived from polyethylene glycol is added to a lipophilic group derived from fatty acid.

  The fatty acid constituting the polyethylene glycol fatty acid ester (hereinafter, also simply referred to as “PEG fatty acid ester”) is preferably, but not limited to, a saturated or unsaturated fatty acid having 12 to 18 carbon atoms. Examples of saturated fatty acids having 12 to 18 carbon atoms include lauric acid (12: 0), myristic acid (14: 0), pentadecylic acid (15: 0), palmitic acid (16: 0), and margaric acid (17: 0) And stearic acid (18: 0). As unsaturated fatty acids having 12 to 18 carbon atoms, double bonds such as palmitoleic acid (16: 1), oleic acid (18: 1 (9)), and vaccenic acid (18: 1 (11)) are included. Unsaturated fatty acids having two double bonds such as linoleic acid (18: 2 (9,12)); and (9,12,15) -linolenic acid (18: 3), (6 , 9,12) -linolenic acid (18: 3) and unsaturated fatty acids having three double bonds such as eleostearic acid (18: 3 (9,11,13)). Saturated fatty acids are preferred, and specific examples include lauric acid, myristic acid, palmitic acid, and stearic acid. More preferred are saturated fatty acids having 16 to 18 carbon atoms such as palmitic acid and stearic acid. The PEG fatty acid ester may be a mono fatty acid ester having 1 molecule of fatty acid per molecule, or may be a di fatty acid ester having 2 molecules of fatty acid per molecule. Mono fatty acid esters are preferred.

  In addition, although said PEG fatty acid ester may be used individually by 1 type, it can also be used in combination of 2 or more types arbitrarily.

  The PEG fatty acid ester used in the present invention preferably has an HLB of 17 or more. If it is HLB17 or more, the upper limit is not particularly limited, but 20 can be mentioned as the upper limit. HLB is an abbreviation for hydrophile-lipophile balance, and is one of the indexes representing the effect of the surfactant. The larger the HLB value, the higher the hydrophilicity. In the present invention, HLB refers to a value calculated by HLB = 7 + Σ (the number of hydrophilic groups) −Σ (the number of lipophilic groups) which is the Davies equation (hereinafter the same). Moreover, when containing 2 or more types of surfactant, a weighted average value is said.

  In addition, the number of moles of ethylene oxide (PEG) added to the PEG fatty acid ester is not particularly limited as long as it is described above, but can usually be selected from a range of 5 to 250 moles. Preferably it is 10-200 mol, More preferably, it is 10-150 mol.

  A preferable PEG fatty acid ester used in the present invention is PEG monostearic acid having an HLB of 17 or more and an ethylene oxide (PEG) addition mole number of 40 to 100.

  The blending ratio of the PEG fatty acid ester in the emulsified pharmaceutical composition of the present invention can be appropriately set within the range of usually 0.1 to 10% by weight. Although not limited, it is preferably 0.3 to 7.5% by weight, more preferably 0.5 to 5% by weight.

(E) Sorbitan fatty acid ester A sorbitan fatty acid ester is a fatty acid ester-bonded to at least one of the four hydroxyl groups of sorbitan.

  Although it does not restrict | limit as a fatty acid which comprises sorbitan fatty acid ester, Preferably C16-C18 saturated or unsaturated fatty acid can be mentioned. Examples of the saturated fatty acid having 16 to 18 carbon atoms include palmitic acid (16: 0), margaric acid (17: 0), and stearic acid (18: 0). As unsaturated fatty acids having 16 to 18 carbon atoms, double bonds such as palmitoleic acid (16: 1), oleic acid (18: 1 (9)), and vaccenic acid (18: 1 (11)) are included. Unsaturated fatty acids having two double bonds such as linoleic acid (18: 2 (9,12)); and (9,12,15) -linolenic acid (18: 3), (6 , 9,12) -linolenic acid (18: 3) and unsaturated fatty acids having three double bonds such as eleostearic acid (18: 3 (9,11,13)). Saturated fatty acids are preferred, and specific examples include palmitic acid and stearic acid.

  The sorbitan fatty acid ester may be a mono fatty acid ester having 1 molecule of fatty acid per molecule, or a di fatty acid ester, a tri fatty acid ester, and a tetra fatty acid ester having 2 to 4 molecules of fatty acid per molecule. May be. Mono fatty acid esters are preferred. In the present invention, sorbitan fatty acid esters may be used singly or in combination of two or more.

  The sorbitan fatty acid ester used in the present invention preferably has an HLB of 3-5. More preferably, it is HLB4-5.

  A preferred sorbitan fatty acid ester used in the present invention is sorbitan monostearic acid ester (= sorbitan monostearate) having an HLB of 3 to 5.

  The blending ratio of the sorbitan fatty acid ester in the emulsified pharmaceutical composition of the present invention can be appropriately set within the range of usually 0.1 to 10% by weight. Although not limited, it is preferably 0.3 to 7.5% by weight, more preferably 0.5 to 5% by weight.

(F) Surfactant of HLB 10-13 In the emulsified pharmaceutical composition of the present invention, a hydrophilic surfactant of HLB 10-13 can be suitably used as the surfactant.

  The hydrophilic surfactant is not particularly limited as long as it is usually used in pharmaceuticals, quasi drugs, cosmetics, etc. From the viewpoint of thermal stability and fluidity, a nonionic hydrophilic surfactant is used. preferable. Nonionic hydrophilic surfactants include polyglycerin fatty acid esters and polyoxyethylene (hereinafter referred to as POE) addition type surfactants, among which POE addition type surfactants are preferred, POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyltetradecyl ether, POE (10-10 mol) 50 mol) oleyl ether, POE (10-50 mol) cetyl ether, POE (10-50 mol) lauryl ether, POE (10-50 mol) stearyl ether, POE (10-50 mol) behenyl ether, POE (10-10 mol) 50 moles) alkyl (12-14) Polyoxyethylene alkyl ethers such as POE (5-30 mol) polyoxypropylene (5-30 mol) 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether These phosphates and phosphates (such as POE cetyl ether sodium phosphate); POE (20-100) hydrogenated castor oil; POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoiso; Stearate, POE (10 to 80 mol) glyceryl monoisostearate, POE (10 to 30 mol) glyceryl monostearate, POE (20 to 100) POE / polyoxypropylene-modified silicone, POE / alkyl-modified silicone, etc. It is done. These hydrophilic surfactants may be used alone or in any combination of two or more. Preferable are polyoxyethylene alkyl ether and polyoxyethylene hydrogenated castor oil, and more preferable is polyoxyethylene hydrogenated castor oil.

  In the present invention, the hydrophilic surfactants HLB10 to 13 may be used alone or in combination of two or more.

  The blending ratio of the hydrophilic surfactants of HLB 10 to 13 in the emulsified composition of the present invention can be appropriately set from the range of usually 0.1 to 10% by weight. Preferably it is 0.3 to 7.5 weight%, More preferably, it is 0.5 to 5 weight%.

(G) Thickener In the present invention, the thickener includes carrageenan gum, guar gum, gellan gum, locust bean gum, xanthan gum, gum arabic, tragacanth gum, galactan, carob gum, karaya gum, tamarind gum, pectin, agar, quince seed, algae Colloid, starch (rice, wheat, corn), dextran, succinoglucan, pullulan, collagen, casein, albumin, gelatin; starch polymers such as carboxymethyl starch and methylhydroxypropyl starch; methylcellulose, nitrocellulose, methylhydroxypropyl Cellulose, sodium cellulose sulfate, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystals Cellulose polymers such as roulose and cellulose powder; Alginate polymers such as sodium alginate and propylene glycol alginate; Vinyl polymers such as polyvinyl alcohol, polyvinyl methyl ether, polyvinyl pyrrolidone and carboxyvinyl polymer; Polyethylene glycol 20,000 , 40,000, 60,000, etc .; polyoxyethylene polymer such as polyoxyethylene polyoxypropylene copolymer; acrylic polymer such as sodium polyacrylate, polyethyl acrylate, polyacrylamide; Examples thereof include polyethyleneimine, cationic polymer, bentonite, AlMg silicate (beegum), laponite, hectorite, and silicic anhydride.

  These thickeners may be naturally derived or synthetically derived, and the origin is not particularly limited. Moreover, even if it is 1 type individual, the mixture which combined 2 or more types arbitrarily may be sufficient. Xanthan gum, carboxyvinyl polymer, carboxymethyl cellulose (CMC), alginic acid, and salts thereof are preferable. In addition, although it does not restrict | limit especially as a salt here, Alkali metal salts, such as sodium and potassium, Alkaline earth metal salts, such as magnesium and calcium, can be mentioned. An alkali metal salt such as sodium is preferable.

  In order to more effectively exhibit the effects of the present invention (emulsification stability and viscosity stability), particularly viscosity stability, it is preferable to use two or more thickeners in combination. Although not limited, it is preferred to use at least one thickener selected from the group consisting of xanthan gum, carboxyvinyl polymer, carboxymethylcellulose (CMC), alginic acid, and salts thereof for such combinations. More preferably, it is an embodiment formed by combining two or more thickeners belonging to these groups. Specific examples include combinations of xanthan gum and one or more other thickeners (carboxyvinyl polymer, CMC, alginic acid, and salts thereof).

  The blending ratio of the thickener in the emulsified pharmaceutical composition of the present invention (the total amount when two or more kinds are used in combination) can be appropriately set in the range of usually 0.1 to 10% by weight. Preferably it is 0.1 to 5 weight%, More preferably, it is 0.1 to 3 weight%.

(H) Other components blended in the emulsified pharmaceutical composition The emulsified pharmaceutical composition of the present invention further includes components necessary for emulsification in addition to the above components. An example of such a component is water.

  Water is not particularly limited. For example, purified water, distilled water, ionic water, sterilized water, physiological saline, deep sea water and the like can be used without limitation. Preferably it is purified water. The mixing ratio of the water in the emulsified pharmaceutical composition of the present invention can be appropriately set in the range of usually 20 to 90% by weight. Preferably it is 30 to 80 weight%, More preferably, it is 40 to 80 weight%.

(I) Arbitrary component In the emulsified pharmaceutical composition of the present invention, other components are appropriately selected according to the form and the like as long as the effects of the present invention are not impaired. Can be used in combination. For example, various additives such as stabilizers, preservatives, buffers, pH adjusters and the like generally used in the preparation of pharmaceutical preparations can be mentioned, and specific examples include the following.

  (I-1) Examples of the oil component include higher alcohols. Examples of the higher alcohol include aliphatic alcohols having 6 or more carbon atoms, more preferably 6 to 30 carbon atoms. The oil component is preferably solid at room temperature (25 ° C.). Specific examples include cetanol, behenyl alcohol, myristyl alcohol, cetyl alcohol, oleyl alcohol, stearyl alcohol, hexadecyl alcohol, lanolin alcohol and the like. These higher alcohols may be used alone or in combination of two or more.

  (I-2) As an example of a pH adjuster, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid; lactic acid, acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, Organic acids such as fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon-aminocaproic acid, glutamic acid, aminoethylsulfonic acid; sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, etc. Inorganic bases: organic salts such as monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, and lysine.

  (I-3) Examples of preservatives include butyl paraben, methyl paraben, propyl paraben, ethyl paraben, sodium benzoate, phenol and benzyl alcohol.

  (I-4) Examples of stabilizers include dibutylhydroxytoluene, sodium edetate, sodium sulfite, and dry sodium sulfite.

  (I-5) Examples of buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, epsilon-aminocaproic acid, aspartic acid, and aspartate. Can do.

  (I-6) As other ingredients, sodium carboxymethyl starch, magnesium stearate, cellulose, lactose, hard fat, self-emulsifying glyceryl monostearate, glyceryl stearate, D-sorbitol, medium chain fatty acid triglyceride, corn starch, Examples include propylene glycol, dipropylene glycol, propylene glycol fatty acid ester, 1,3-butylene glycol, glycerin, polyethylene glycol, and glyceryl monostearate.

  (I-7) Furthermore, the following medicinal ingredients can be blended in the emulsified pharmaceutical composition of the present invention within a range not impairing the effects of the present invention, preferably antiphlogistic analgesia. For example, steroid drugs (dexamethasone, dexamethasone hydrochloride, dexamethasone acetate, hydrocortisone hydrochloride, prednisolone valerate, prednisolone acetate, etc.), local anesthetics (lidocaine, dibucaine, procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilucaine or these Salts, benzoic acid alkyl esters (for example, ethyl aminobenzoate, parabutylaminohydrochloric acid diethylaminoethyl hydrochloride), orthocaine, oxesasein, oxypolyentoxydecane, funnel extract, percamamine ase, tesitdecitine, etc., anti-inflammatory agents (glycyrrhetinic acid, glycyrrhizin) Dipotassium acid, monoammonium glycyrrhetinate, allantoin, indomethacin, felbinac, diclofenac Thorium, loxoprofen sodium, etc.), bactericides (benzalkonium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, phenol, etc.), antipruritic agents ( Crotamiton, thianthol, etc.), skin protectants (collodion, castor oil, etc.), blood circulation promoting ingredients (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, pepper extract, etc., vitamin E), vitamins (vitamins A, B, C, D), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.).

(J) Preparation Method and Use Method of Emulsion Composition The emulsion type pharmaceutical composition of the present invention comprises the above components (a) to (h) and, if necessary, at least one of the components described in (i). The ingredients are mixed, heated to a temperature of about 75 to 85 ° C., and then emulsified by a known method such as emulsifying under a predetermined condition using a mixer such as a homogenizer, a homomixer, or a stirrer. be able to.

  Here, the viscosity of the emulsified pharmaceutical composition of the present invention is not particularly limited, but is usually adjusted to 1000 to 150,000 cp, preferably 1500 to 130,000 cp, more preferably 2000 to 100000 cp. The viscosity is a value measured by the following method using a viscometer “model: LVDV-II + (manufactured by BROOK FIELD, Inc., spindle E type)”.

(Method)
35 g of a sample (emulsified composition) is put in a sample container of a marem screw tube (No. 7 or No. 8), measured at 3 rpm at room temperature (around 25 ° C.), and an intermediate value between the maximum value and the minimum value is measured. Adopt as.

  The emulsified pharmaceutical composition of the present invention is a liquid to semi-solid oil-in-water emulsified composition and can be suitably used at the time of use as a skin external preparation. Specifically as a form of the said external preparation for skin, liquid-semisolid emulsion and cream can be illustrated. Thus, since the emulsified pharmaceutical composition of the present invention has a liquid to semi-solid state, it is easy to take in use, has good spreadability, has little stickiness, is easy to adjust to the skin, and has an excellent usability. .

  Since the emulsified pharmaceutical composition of the present invention contains a salicylic acid ester (eg, glycol salicylate, methyl salicylate, phenyl salicylate, or salicin) as an active ingredient, it can be suitably used particularly as an analgesic. Specifically, as an anti-inflammatory analgesic, specifically an anti-inflammatory analgesic external composition, neuralgia, joint pain, low back pain, muscle pain, stiff shoulder pain, fracture pain, bruise pain, sprain pain, trauma pain, headache, or surgery This can be improved by applying to later pain and the like. Preferred are neuralgia, low back pain, muscle pain, stiff shoulder pain, and joint pain caused by aging, poor posture, long working hours, etc., and more preferred are low back pain, muscle pain, stiff shoulder pain, and joint pain. Moreover, in addition to analgesia, it can be used for the purpose of anti-inflammation (anti-inflammatory) and / or fatigue and fatigue. Such anti-inflammatory analgesic composition for external use is usually used by applying it to the affected area and the surrounding skin once and multiple times a day. In this case, the amount of salicylic acid ester contained in the single application amount of the anti-inflammatory analgesic external composition is not limited, but may be about 15 to 200 mg / ml.

(II) Emulsification Stabilization Method The present invention is an emulsified pharmaceutical composition comprising (a) at least one selected from the group consisting of salicylic acid esters and (b) terpenes, and (c) a salt form of an antihistamine. An emulsion stabilization method is provided. In the preparation of the emulsified pharmaceutical composition, in addition to the above components, the method further comprises (d) a polyethylene glycol fatty acid ester, (e) a sorbitan fatty acid ester, (f) a surfactant of HLB 10-13, and (g ) It can be carried out by blending a thickener.

  (A) salicylic acid ester used in the method of the present invention, (b) terpene, (c) salt form antihistamine, (d) polyethylene glycol fatty acid ester, (e) sorbitan fatty acid ester, (f) HLB 10-13 The types of the surfactant and (g) thickener, and the blending ratio thereof are as described in (I) above. Therefore, in the said invention, the description of (a), (b), (c), (d), (e), (f), and (g) in said (I) can be used.

  In the emulsion stabilization method of the emulsion type pharmaceutical composition of the present invention, the preparation method of the target emulsion type pharmaceutical composition is also as described in (j) of (I) above. Therefore, in the invention, the description of (j) in (I) above can be used. In preparation of the emulsified pharmaceutical composition, the above components (a) to (g) and (i) water necessary for emulsification are used. The type of water and the amount of water used are also as described in (i) (i) above. Therefore, in the invention, the description of (i) in (I) above can be used.

  The emulsion type composition to be emulsion-stabilized is generally used for the preparation of pharmaceutical preparations as optional components in addition to the above (a) to (g) and (i), as long as the effects of the present invention are not hindered. Various additives such as buffering agents, pH adjusting agents, stabilizers, preservatives and the like may be blended. Specific examples of each component are as described in (I) (h) above. Therefore, in the invention, the description of (h) in (I) above can be used.

  According to the emulsion stabilization method of the present invention, it is possible to stably maintain the emulsified state (emulsion) of the emulsion composition over a long period of time, as shown in the experimental examples described later.

(III) Method for inhibiting increase in viscosity The present invention comprises (a) at least one selected from the group consisting of salicylic acid esters and (b) terpenes, (c) salt-form antihistamines, (d) polyethylene glycol fatty acid esters, The present invention provides a method for suppressing the increase in viscosity of an emulsion composition containing (e) a sorbitan fatty acid ester and (f) a surfactant of HLB 10-13. In the preparation of the emulsion composition, the method can be carried out by further blending a thickener in addition to the above components.

  (A) at least one selected from the group consisting of salicylic acid ester and (b) terpene, (c) salt form antihistamine, (d) polyethylene glycol fatty acid ester, (e) sorbitan The types of fatty acid esters, (f) surfactants of HLB 10 to 13, and (g) thickeners, and the blending ratios thereof are as described in (I) above. Therefore, in the said invention, the description of (a)-(g) in said (I) can be used.

  In the method for suppressing the increase in viscosity of the emulsion composition of the present invention, the preparation method of the target emulsion composition is also as described in (j) of (I) above. Therefore, in the invention, the description of (j) in (I) above can be used. In preparing the emulsified composition, water necessary for emulsification is further used in addition to the components (a) to (g). The type of water and the amount of water used are also as described in (i) (i) above. Therefore, in the invention, the description of (i) in (I) above can be used.

  The emulsion composition to be viscosity-stabilized is generally used for the preparation of pharmaceutical preparations as optional components in addition to the above (a) to (g) and (i) as long as the effects of the present invention are not hindered. Various additives such as stabilizers, preservatives, buffers and pH adjusters may be blended. Specific examples of each component are as described in (I) (h) above. Therefore, in the invention, the description of (h) in (I) above can be used.

  According to the method for suppressing the increase in viscosity according to the present invention, as shown in the experimental examples to be described later, the instability of the viscosity of the emulsion composition over time (especially the increase in viscosity under low temperature conditions) is suppressed and the viscosity is stabilized. Is possible.

  Hereinafter, the present invention will be specifically described based on experimental examples and examples. However, the present invention is not limited by these.

Experimental example Emulsification stability evaluation and viscosity change evaluation
(1) Preparation of emulsion type pharmaceutical compositions (Examples 1 to 11 and Comparative Examples 1 to 7) Oil-in-water type emulsion compositions were prepared according to the formulation described in Table 1. Specifically, among each compounding component described in Table 1, an oil component (in Table 1, components a, b, d, e, f, etc.) and an aqueous component (in Table 1, components c, g, i) Etc.) were weighed and dissolved by heating at about 80 ° C. to prepare an oil phase and an aqueous phase. While stirring at the same temperature, the aqueous phase was gradually added to the oil phase prepared above, and then cooled to 40 ° C. or lower to prepare an oil-in-water emulsion type pharmaceutical composition. In addition,% in a table | surface shows weight%.

(2) Evaluation of emulsification stability of emulsified pharmaceutical composition The emulsified pharmaceutical composition prepared above was allowed to stand at 25 ° C for 1 day or longer and then stored in a thermostatic bath at 50 ° C. The number of days until the property of the type pharmaceutical composition changed (separation of the water phase and the oil phase [occurrence of a fault]) was measured and evaluated according to the following criteria.

[Evaluation criteria]
A: No separation is observed for 8 days or more.
○: Separation is not observed until 7 days, or water is slightly separated, but the emulsified state is stable as a whole.
X: Separation occurred before 7 days (an oil phase or a water phase appears in the upper or lower part, and a fault occurs).

(3) Evaluation of Viscosity Change of Emulsion Composition After the emulsion-type pharmaceutical composition prepared above was allowed to stand for 1 day or more at 25 ° C., after measuring the viscosity at room temperature (25 ° C.) (initial viscosity), It preserve | saved in the cycle of 5 to -20 degreeC / 12 hours in a cycle type thermostat. After 10 cycles, the viscosity was measured again at room temperature (25 ° C.), and the change in viscosity of the emulsified pharmaceutical composition was evaluated according to the following criteria.

[Evaluation criteria]
A: There is no change in viscosity, or even small (initial value is less than 2 times)
○: Some change in viscosity (2 to 3 times the initial value)
X: Viscosity change is large (more than 3 times the initial value).

  The viscosity was measured under the following conditions.

[Viscosity measurement conditions]
Using a viscometer “model: LVDV-II + (BROOK FIELD, Spindle T type), put 80 g of sample into a sample container of a Marem screw tube (No. 8) and measure at 3 rpm at room temperature (25 ° C.). The intermediate value between the maximum and minimum values is taken as the measurement value.

(4) The results of evaluation results are shown in Tables 1 and 2 together. The blank in the table indicates that no component is added (0%).

  As can be seen from the comparison between the examples shown in Table 1 and the comparative examples shown in Table 2, (a) at least one selected from the group consisting of salicylic acid ester and (b) terpene, (c) antihistamine in salt form Emulsion stability is maintained over a long period of time by combining a drug, (d) polyethylene glycol fatty acid ester, (e) sorbitan fatty acid ester, (f) surfactant of HLB 10-13, and (g) thickener. It turns out that you can. Moreover, it turned out that emulsification stability improves further by using POE hydrogenated castor oil as a component (f) (Examples 1-9).

  (A) at least one selected from the group consisting of salicylic acid esters and (b) terpenes, (c) salt-form antihistamines, (d) polyethylene glycol fatty acid esters, (e) sorbitan fatty acid esters, and ( f) The emulsion composition containing the surfactants of HLB 10 to 13 has a tendency to increase in viscosity over time (Comparative Examples 2 and 4 to 7), and a thickener is used in combination with this. It was found that the increase in the viscosity can be suppressed (Examples 1 to 11). Moreover, it turned out that the said viscosity raise inhibitory effect is obtained by using a thickener together 2 or more types rather than 1 type (Examples 1-6).

Claims (5)

An emulsified pharmaceutical composition comprising the following ingredients:
(A) at least one salt selected from the group consisting of salicylic acid esters and (b) terpenes (c) an antihistamine in salt form,
(D) polyethylene glycol fatty acid ester,
(E) sorbitan fatty acid ester, and (f) a surfactant of HLB 10-13,
(G) Thickener. The emulsified pharmaceutical composition according to claim 1, wherein (d) is a polyethylene glycol fatty acid ester of HLB 17 or higher and / or (e) is a sorbitan fatty acid ester of HLB 3-5.   The emulsified pharmaceutical composition according to claim 1 or 2, wherein the component (f) is at least one of polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether.   The emulsified pharmaceutical composition according to claim 1 or 2, wherein the component (f) is polyoxyethylene hydrogenated castor oil.   The emulsified pharmaceutical composition according to any one of claims 1 to 4, which is an anti-inflammatory analgesic external composition.