JP7190537B2 - 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.

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

A method of adding a liquid additive such as a polyhydric alcohol, particularly propylene glycol, as a stabilizer for the azulene derivative is preferable from the viewpoint of simplicity. However, the inventor of the present invention has conducted studies to put a pharmaceutical composition containing an azulene derivative into practical use, and found that even if a polyhydric alcohol is used as an additive, its stabilizing effect is such that the long-term stability that can withstand practical use was insufficient to maintain , and the formulation stability was poor.

Accordingly, an object of the present invention is to further improve the stability of a pharmaceutical composition containing an azulene derivative and a polyhydric alcohol, and to provide a formulation technique that 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 a polyhydric alcohol has improved stability and excellent formulation stability. I found what I could prepare for. The present invention has been completed through further studies based on this finding.

That is, the present invention provides inventions in the following aspects.
Section 1. A pharmaceutical composition comprising (A) an azulene derivative, (B) a polyhydric alcohol, and (C) ethyl aminobenzoate.
Section 2. Item 1. The pharmaceutical composition according to Item 1, further comprising (D) a sugar alcohol.
Item 3. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the component (A) is at least one selected from the group consisting of azulene sulfonic acid and its salts, and dimethylisopropylazulene.
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. In a pharmaceutical composition containing (A) an azulene derivative and (B) a polyhydric alcohol, the above (A)
A stability improvement method for improving the stability of a component,
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 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)) and (B) a polyhydric alcohol (sometimes referred to as component (B)), (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. are 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) Polyhydric Alcohol The pharmaceutical composition of the present invention contains a polyhydric alcohol as component (B). Polyhydric alcohols are known as stabilizers for azulene derivatives in pharmaceutical compositions, but their stabilizing action is insufficient. In the pharmaceutical composition of the present invention, the stability can be effectively improved even if the composition contains a polyhydric alcohol and originally has insufficient stability.

Polyhydric alcohols are not particularly limited as long as they are pharmaceutically or cosmetically acceptable. Examples include propylene glycol, 1,3-butylene glycol, ethylene glycol, isoprene glycol, diethylene glycol, and dipropylene glycol. trihydric alcohols such as glycerin; and polyethylene glycols such as Macrogol 4000 and Macrogol 6000. These polyhydric alcohols may be used singly or in combination of two or more.

Among these polyhydric alcohols, dihydric alcohols, more preferably propylene glycol, and glycerin are preferred.

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 type of polyhydric alcohol used, the formulation form and application of the pharmaceutical composition, etc. For example, 1 to 90% by weight, preferably 3 to 80% 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, 1500 to 5000 parts by weight, preferably 1800 to 5000 parts by weight, more preferably 1900 to 4500 parts by weight.

(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. In a pharmaceutical composition, the azulene derivative has insufficient stability even when it coexists with a polyhydric alcohol. Even if the composition is insufficient, the 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 0.3% 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 may contain a sugar alcohol as component (D). Sugar alcohols are known ingredients used as bases and corrigents. A sugar alcohol tends to lower the stability of an azulene derivative when incorporated into a pharmaceutical composition containing an azulene derivative and a polyhydric alcohol. Even if the composition contains a sugar alcohol and is originally less stable, the stability can be effectively improved.

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.

When component (D) is contained in the pharmaceutical composition of the present invention, the content is not particularly limited and may be appropriately set according to the formulation form and application of the pharmaceutical composition, for example 2% by weight. Above, preferably 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.

When the pharmaceutical composition of the present invention contains component (D), the ratio of component (D) to component (A) is determined according to the contents of component (A) and component (D). For example, 90 to 1800 parts by weight, preferably 95 to 300 parts by weight, of component (D) can be used per 1 part by weight of component (A). 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.), cholesterol, glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.) Oil base such as 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 (10-50 mol) oleyl ether, POE (2-50 mol) cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) 2- Polyoxyethylene alkyl ethers such as decyltetradecyl ether, POE (10-50 mol) polyoxypropylene (2-30 mol) cetyl ether, their phosphoric acid/phosphate (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 (10-30 mol) glyceryl mono Stearate, POE (20-100 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), glycerin fatty acid ester (glyceryl monostearate, etc.), hydrogenated soybeans Surfactants such as phospholipids and 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-cioneal, citronellal, farnesol, etc.), coloring agents (tar pigments (brown No. 201, blue No. 201, yellow No. 4, yellow No. 403, etc.), cocoa pigments, chlorophyll, aluminum oxide etc.), thickeners (sodium alginate, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, xanthan gum, carrageenan, carboxyvinyl polymer, sodium polyacrylate, etc.), pH adjusters (phosphoric acid, hydrochloric acid, citric acid, sodium citrate , succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (dl-sodium pyrrolidonecarboxylate solution, D-sorbitol solution, etc.), stabilizers (dibutylhydroxytoluene, Butyl hydroxyanisole, 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 absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives and other additives.

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., but is preferably Liquid, semi-solid, or solid aqueous preparations, more preferably liquid or solid.

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 formulation forms, liquid topical preparations that are aqueous preparations or solid topical preparations for mucous membrane application are preferred, and candy, drops, troches, tablets, and chewable preparations are more preferred. , gummies, edible film agents, and other solid external preparations for oral mucosa application.

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 a polyhydric alcohol. Specifically, the method for improving stability of the present invention is characterized by blending (C) ethyl aminobenzoate with (A) an azulene derivative and (B) a polyhydric alcohol in a pharmaceutical composition. The improvement in the stability of the azulene derivative is exhibited by the azulene derivative when the pharmaceutical composition containing the azulene derivative and the polyhydric alcohol is exposed to light, compared to the case where the pharmaceutical composition does not contain the component (C). It can be confirmed by delaying blue 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 expressed as a relative value when the color tone immediately after preparation of the pharmaceutical composition of Reference Example 1 shown in Table 1 is 10 and the color tone 10 days after light irradiation is 0. 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. Even if sodium azulene sulfonate is blended with a polyhydric alcohol (propylene glycol, glycerin), the degree of suppression of color tone change is slight compared to Reference Example 1, which does not contain a polyhydric alcohol, so the stability is only slightly improved. (Comparative Examples 1 and 4). Furthermore, when sugar alcohols (isomaltose, sorbitol) are added, the degree of suppression of color tone change is further reduced, and the stability is lowered (Comparative Examples 2 and 3). On the other hand, when sodium azulene sulfonate contains a polyhydric alcohol and contains ethyl aminobenzoate, the degree of suppression of color tone change is significantly improved, and the stability is effectively improved (Examples 1 to 7). ). Such an effect of improving stability was also confirmed when sugar alcohol was contained (Examples 4 to 6).

As representative examples, Example 3 and Comparative Example 1 are shown, and Table 3 shows photographs showing changes in color tone of sodium azulene sulfonate.

Pharmaceutical compositions (solutions, drops, lozenges, oral ointments, ointments/creams) having compositions shown in Formulation Examples Tables 4 to 8 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 having one or more acidic functional groups bonded to the azulene skeleton, salts thereof, and dimethylisopropylazulene; and (B) a polyhydric alcohol (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 used as a 2. The pharmaceutical composition according to claim 1, further comprising (D) a sugar alcohol. 3. The pharmaceutical composition according to claim 1 or 2, wherein the compound having one or more acidic functional groups bonded to the azulene skeleton is azulene sulfonic acid . The pharmaceutical composition according to any one of claims 1 to 3, which is an external preparation for oral mucosa.