JP7190538B2 - Pharmaceutical composition - Google Patents

Description

TECHNICAL FIELD The present invention relates to a pharmaceutical composition having improved stability and excellent formulation stability while containing an azulene derivative and water.

Azulene derivatives have anti-inflammatory, anti-allergic and anti-ulcer effects, and are widely used as active ingredients of oral and throat medicines and gastrointestinal drugs. However, azulene derivatives are easily decomposed by heat, light, or moisture over time, and long-term storage in conventional formulations has been difficult. Examples of methods for stabilizing the azulene derivative include a method of making the azulene derivative stable by making it amorphous by using freeze-drying (Patent Document 1), and a method of sealed packaging together with an oxygen scavenger (Patent Document 2). method requires a lot of equipment and manpower. On the other hand, as stabilizers for azulene derivatives, a method of adding an amino acid and a weakly basic alkali salt (Patent Document 3), a method of adding an aluminum salt (aluminum lactate, aluminum phosphate, etc.) (Patent Document 4) ), a method of adding edetic acid and its salts (Patent Document 5), a method of adding propylene glycol as a polyhydric alcohol (Patent Document 6), and the like have been studied.

JP-A-58-154547 JP-A-59-176247 Japanese Patent Publication No. 49-11219 JP-A-59-157014 JP-A-1-121216 Japanese Patent Publication No. 2-42811

Although various methods for stabilizing azulene derivatives have been investigated, they still do not have sufficient effects, and their use has sometimes been restricted in terms of formulation design. In order to obtain a practical azulene derivative formulation that can maintain stability over a long period of time, the present inventors have developed a pharmaceutical composition containing an azulene derivative, which is an aqueous pharmaceutical composition containing water as a base material, which destabilizes the azulene derivative. The formulation stability of the composition was investigated.

In other words, an object of the present invention is to provide a formulation technique that improves the stability of a pharmaceutical composition containing an azulene derivative and water and provides excellent formulation stability.

The present inventor conducted intensive studies to solve the above problems, and found that a pharmaceutical composition containing ethyl aminobenzoate together with an azulene derivative and water has improved stability and can have excellent formulation stability. I found out. The present invention has been completed through further studies based on this finding.

That is, the present invention provides inventions in the following aspects.
Item 1. A pharmaceutical composition comprising (A) an azulene derivative, (B) water, and (C) ethyl aminobenzoate.
Section 2. Item 2. The pharmaceutical composition according to item 1, wherein the component (A) is at least one selected from the group consisting of azulene sulfonic acid and its salts, and dimethylisopropylazulene.
Item 3. Item 3. The pharmaceutical composition according to Item 1 or 2, further comprising (D) a sugar alcohol.
Section 4. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, which is a solid external preparation for oral mucosa application.
Item 5. A method for improving the stability of the component (A) in a pharmaceutical composition containing (A) an azulene derivative and (B) water, comprising:
A method for improving stability, comprising adding (C) ethyl aminobenzoate to a pharmaceutical composition together with the component (A) and the component (B).

According to the pharmaceutical composition of the present invention, even a pharmaceutical composition containing an azulene derivative and water can have excellent formulation stability.

1. Pharmaceutical composition The pharmaceutical composition of the present invention comprises (A) an azulene derivative (sometimes referred to as component (A)), (B) water (sometimes referred to as component (B)), and (C ) ethyl aminobenzoate (sometimes referred to as component (C)). The pharmaceutical composition of the present invention is described in detail below.

(A) Azulene Derivative The pharmaceutical composition of the present invention contains an azulene derivative as component (A). An azulene derivative is a compound or a salt thereof in which one or more substituents are bonded to an azulene skeleton. Azulene derivatives have actions such as anti-inflammatory action, anti-allergic action and anti-ulcer action, and are known ingredients as active ingredients of oropharyngeal drugs and gastrointestinal drugs.

The azulene derivative used in the present invention is not particularly limited as long as it is pharmaceutically or cosmetically acceptable. Examples include azulene derivatives having at least an acidic functional group bonded to the skeleton. Specific examples of the acidic functional group include a sulfo group and a carboxyl group, preferably a sulfo group.

Specific examples of azulene derivatives used in the present invention include azulene sulfonic acid (guaiazulene sulfonic acid), dimethylisopropylazulene (guaiazulene), dimethylethylazulene (kamaazulene), and 1,4-dimethyl-7-ethylazulene-3. - sulfonic acid (kamaazulene sulfonic acid) and the like.

When the azulene derivative is in the form of a salt, the type of the salt is not particularly limited as long as it is pharmaceutically or cosmetically acceptable. For example, alkali metal salts such as sodium salts and potassium salts; Alkaline earth metal salts such as calcium salts and magnesium salts; other metal salts such as aluminum salts; ammonium salts; acetates, trifluoroacetates, butyrates, palmitates, stearates, fumarates, maleates salts, carboxylates such as succinate, malonate, lactate, tartrate, citrate; organic sulfonates such as methanesulfonate, toluenesulfonate, tosylate; methylamine salt, triethylamine salts, organic amine salts such as triethanolamine salts, morpholine salts, piperazine salts, pyrrolidine salts, tripyridine salts, picoline salts; inorganic acid salts such as hydrochlorides, sulfates, nitrates, hydrobromides, phosphates, etc. is mentioned.

These azulene derivatives may be used singly or in combination of two or more.

Among these azulene derivatives, preferably at least one selected from the group consisting of azulene sulfonic acid and its salts, and dimethylisopropylazulene, from the viewpoint of obtaining a better effect of improving stability in pharmaceutical compositions. be done. Azulene sulfonic acid and/or salts thereof preferably include azulene sulfonic acid and/or alkali metal salts thereof, more preferably sodium azulene sulfonate.

In the pharmaceutical composition of the present invention, the content of component (A) is not particularly limited, and is appropriately determined according to the type of azulene derivative to be used, the degree of action to be imparted, the formulation form and application of the pharmaceutical composition, etc. It may be set, but for example, 0.001 to 10% by weight can be mentioned. From the viewpoint of better obtaining the effect of improving the stability in the pharmaceutical composition, the content of component (A) is preferably 0.005 to 1% by weight, more preferably 0.01 to 0.1% by weight. mentioned. Further, when the pharmaceutical composition of the present invention is a solid external preparation for oral mucosa application, the content of component (A) is preferably 0.01 to 0.1% by weight, more preferably 0.03 to 0.1% by weight. 0.08 weight percent, more preferably 0.04 to 0.07 weight percent.

(B) Water The pharmaceutical composition of the present invention contains water as component (B). Dissolving the azulene derivative in water reduces the stability of the azulene derivative, but in the present invention, the azulene derivative and water are included, and even if the composition is inherently unstable, the stability is effectively improved. can be made

In the pharmaceutical composition of the present invention, the content of component (B) is not particularly limited, and may be appropriately set according to the dosage form and application of the pharmaceutical composition. is 5 to 80% by weight, more preferably 10 to 80% by weight. When the pharmaceutical composition of the present invention is a solid external preparation for oral mucosa, the content of component (B) is preferably 1 to 20% by weight, more preferably 1 to 10% by weight.

In the pharmaceutical 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). The amount of component (B) is, for example, 20 to 4000 parts by weight, preferably 20 to 3600 parts by weight. When the pharmaceutical composition of the present invention is a solid external preparation for oral mucosa application, component (B) is preferably 20 to 300 parts by weight, more preferably 25 to 200 parts by weight per 1 part by weight of component (A). mentioned.

(C) Ethyl Aminobenzoate The pharmaceutical composition of the present invention contains ethyl aminobenzoate as the component (C). Ethyl aminobenzoate, also called ethyl 4-aminobenzoate, benzocaine, etc., is a known local anesthetic. The stability of the azulene derivative in the pharmaceutical composition decreases when it coexists with water. Stability can be effectively improved by blending aminobenzoic acid.

In the pharmaceutical composition of the present invention, the content of component (C) is not particularly limited, and may be appropriately set according to the formulation form and application of the pharmaceutical composition. Preferably 0.05 to 10% by weight, more preferably 0.1 to 5% by weight. When the pharmaceutical composition of the present invention is an external preparation for mucosa, the content of component (C) is preferably 0.1 to 3% by weight, more preferably 0.1 to 2.5% by weight. . Furthermore, when the pharmaceutical composition of the present invention is a solid external preparation for oral mucosa, the content of component (C) is preferably 0.05 to 1% by weight, more preferably 0.05 to 0.05% by weight. 5% by weight, more preferably 0.05 to 2% by weight, and even more preferably 0.05 to 0.2% by weight.

In the pharmaceutical composition of the present invention, the ratio of component (C) to component (A) is determined according to the respective contents of component (A) and component (C). The amount of component (C) is, for example, 0.5 to 80 parts by weight, preferably 25 to 80 parts by weight, more preferably 40 to 80 parts by weight, still more preferably 70 to 80 parts by weight. When the pharmaceutical composition of the present invention is a solid external preparation for oral mucosa application, component (C) is, for example, 0.5 to 3.5 parts by weight, preferably 0.7 to 1 part by weight per 1 part by weight of component (A). 3.5 parts by weight.

(D) Sugar alcohol The pharmaceutical composition of the present invention contains a sugar alcohol as component (D). Sugar alcohols are known ingredients used as bases and corrigents. When sugar alcohol is added to a pharmaceutical composition containing an azulene derivative and water, it further lowers the stability of the azulene derivative. , the stability can be effectively improved even if the composition is unstable.

Sugar alcohols are not particularly limited as long as they are pharmaceutically or cosmetically acceptable. preferably sorbitol, xylitol, isomaltose, erythritol, maltitol and reduced palatinose. These sugar alcohols may be used singly or in combination of two or more.

In the pharmaceutical composition of the present invention, the content of component (D) is not particularly limited, and may be appropriately set according to the formulation form and application of the pharmaceutical composition. 3% by weight or more, more preferably 5% by weight or more. In addition, when the pharmaceutical composition of the present invention is a solid external preparation for oral mucosa application, the content of component (D) is, for example, 10 to 99.5% by weight, preferably 90 to 99.5% by weight, and more 95 to 99% by weight is preferred.

In the pharmaceutical composition of the present invention, the ratio of component (D) to component (A) is determined according to the respective contents of component (A) and component (D). The amount of component (D) is, for example, 90 to 1800 parts by weight, preferably 95 to 300 parts by weight. When the pharmaceutical composition of the present invention is a solid external preparation for oral mucosa application, component (D) is, for example, 100 to 1800 parts by weight, preferably 150 to 1800 parts by weight, more preferably 150 to 1800 parts by weight per 1 part by weight of component (A). is 1000 to 1700 parts by weight.

Other Ingredients The pharmaceutical composition of the present invention may, if necessary, contain other pharmacological ingredients in addition to the ingredients described above. Such pharmacological components include, for example, antihistamines (diphenhydramine, diphenhydramine hydrochloride, etc.), local anesthetics other than ethyl aminobenzoate (procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine, proparacaine, meprilcaine or salts thereof, oxethazaine, , Rohto extract, lidocaine, etc.), fungicides other than quaternary ammonium salts (iodine, povidone iodine, potassium iodide, chlorhexidine gluconate, acrinol, etc.), anti-inflammatory agents (dipotassium glycyrrhizinate, glycyrrhetinic acid, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, etc.), skin protective agents (collodion, castor oil, etc.), blood circulation-promoting ingredients (nonylic acid vanillylamide, benzyl nicotinate, capsaicin, hot pepper extract, etc.), vitamins (vitamin A, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, etc.) and the like.

In addition, the pharmaceutical composition of the present invention may, if necessary, contain base materials and additives other than the components described above in order to obtain a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. , cottonseed oil, peanut oil, lard, squalane, fish oil, etc.), mineral oil (liquid paraffin, paraffin, gelling hydrocarbon, petrolatum, etc.), waxes and waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oils (isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid) , palmitic acid, behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), lower alcohols (ethanol, propanol, isopropanol, butanol, isobutanol, etc.), higher alcohols ( Stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl alcohol, lanolin alcohol, etc.), polyhydric alcohols (propylene glycol, 1,3-butylene glycol, ethylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol, etc.) trihydric alcohol such as glycerin, polyethylene glycol such as macrogol 4000 and macrogol 6000), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone etc.); POE (10-50 mol) phytosterol ether, POE (10-50 mol) dihydrocholesterol ether, POE (10-50 mol) 2-octyldodecyl ether, POE (10-50 mol) decyl Tetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) Polyoxyethylene alkyl ether such as 2-decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether, ether, their phosphoric acids and phosphates (POE cetyl ether sodium phosphate, etc.), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoisostearate, POE (10-80 mol) ) glyceryl monoisostearate, POE (10 to 30 mol) glyceryl monostearate, POE (20 to 100 mol)/polyoxypropylene-modified silicone, POE/alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, Polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20-85) ), surfactants such as glycerin fatty acid esters (glyceryl monostearate, etc.), hydrogenated soybean phospholipids, hydrogenated lanolin alcohol; cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives ( methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-cionell, citronellal, farnesol, etc.), coloring agents (tar pigments (brown No. 201, blue No. 201, yellow No. 4, yellow No. 403, etc.), cacao pigment, chlorophyll, aluminum oxide, etc.), thickening agent (sodium alginate, ethyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, carboxyvinyl polymer, sodium polyacrylate, etc.) , pH adjuster (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agent (dl-sodium pyrrolidone carboxylate solution , D-sorbitol solution, etc.), stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate) , sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidants, ultraviolet rays Additives such as absorbents, chelating agents, adhesives, buffers, solubilizers, solubilizers, and preservatives are included.

Dosage form The dosage form of the pharmaceutical composition of the present invention is not particularly limited, and may be liquid, semi-solid (gel, ointment, paste, etc.), solid, etc., preferably Liquid or solid forms may be mentioned.

In addition, the pharmaceutical composition of the present invention may be either an external drug or an internal drug. External pharmaceuticals include topical preparations for mucous membrane application and topical preparations for skin application, preferably topical preparations for mucous membrane application. Examples of topical preparations for oral mucosa application include topical preparations for oral mucosa application and other topical preparations for application to mucous membranes (eg, suppositories and vaginal preparations), preferably topical preparations for oral mucosa application. Specific examples of topical preparations for skin application include gels, creams, lotions, emulsions, liquids, patches, aerosols, ointments, and packs. agents, creams, lotions, emulsions, liquids, ointments, jellies, solids and the like. Liquid formulations include aqueous formulations. Solid formulations include candy, drops, troches, tablets, chewable formulations, gummy formulations, edible film formulations and the like. Preparation into these formulations can be carried out according to known methods described in the Japanese Pharmacopoeia 17th Edition, General Rules for Formulations, etc., by using additives suitable for the formulations.

Among these dosage forms, liquid topical preparations and solid topical preparations for mucous membrane application are preferred, and more preferred are candy, drops, troches, tablets, chewable preparations, gummy preparations, Examples include solid external preparations for oral mucosa such as edible film preparations.

2. Method for Improving Stability Further, the present invention provides a method for improving the stability of an azulene derivative in a pharmaceutical composition containing an azulene derivative and water. Specifically, the method for improving stability of the present invention is characterized by blending (C) ethyl aminobenzoate together with (A) an azulene derivative and (B) water in a pharmaceutical composition. The improvement in the stability of the azulene derivative is due to the blue coloration of the azulene derivative when the pharmaceutical composition containing the azulene derivative and water is exposed to light, compared to the case where the pharmaceutical composition does not contain the component (C). It can be confirmed by the delay in color fading over time. In the stability-improving method of the present invention, the types and amounts of the components used, the formulation form of the pharmaceutical composition, etc. are as described in the section "1. Pharmaceutical composition" above.

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

A pharmaceutical composition (liquid formulation) having the composition shown in Test Example Table 2 was prepared. 45 ml of the obtained pharmaceutical composition was filled in a glass screw-tube bottle (capacity: 50 ml) and tested under the conditions of 4,000 lux of illumination and 20° C. using a photostability tester (LT-120A, Nagano Science Co., Ltd.). Light was applied for 10 days. After that, the appearance of each pharmaceutical composition was visually observed to evaluate the change in color tone (light stability) of sodium azulene sulfonate. Specifically, the color tone of the obtained pharmaceutical composition is a relative value when the color tone of the pharmaceutical composition of Comparative Example 1 shown in Table 1 is 10 immediately after preparation and 0 after 9 days of light irradiation. evaluated. In addition, in the test examples, the unit of numerical values indicating the compounding amount of each component in the table is % by weight.

Table 2 shows the results obtained. A pharmaceutical composition containing sodium azulene sulfonate in water undergoes large changes in color tone and is unstable, and the extent of this change is greater when the amount of water is larger (Comparative Examples 1 and 2). isomaltose, sorbitol), the color change becomes large and the stability is lowered (Comparative Examples 2 to 5). On the other hand, when sodium azulene sulfonate was contained in water and ethyl aminobenzoate was contained, the degree of suppression of color tone change was remarkably improved, and the stability was effectively improved (Examples 1 to 7). Such an effect of improving stability was also confirmed when sugar alcohol was contained (Examples 5 to 7).

In addition, Example 1 and Comparative Example 1 are cited as representative examples, and Table 3 shows photographs showing changes in color tone of sodium azulene sulfonate.

Formulation Examples Pharmaceutical compositions (solutions, drops, oral ointments, ointments/creams) having compositions shown in Tables 4 to 7 were prepared. All of the obtained pharmaceutical compositions were formulations with excellent photostability, as in the Examples.

Claims (4)

(A) at least one azulene derivative selected from the group consisting of compounds and salts thereof having one or more acidic functional groups bonded to the azulene skeleton, and dimethylisopropylazulene; (B) water; C) ethyl aminobenzoate and
The acidic functional group is at least one selected from the group consisting of a sulfo group and a carboxyl group . (Except when containing gargle preparations containing sodium bicarbonate). 2. The pharmaceutical composition according to claim 1, wherein the compound having one or more acidic functional groups attached to the azulene skeleton is azulene sulfonic acid . 3. The pharmaceutical composition according to claim 1, further comprising (D) a sugar alcohol. The pharmaceutical composition according to any one of claims 1 to 3, which is an external preparation for oral mucosa.