JP6908448B2 - Pharmaceutical composition - Google Patents

Description

The present invention relates to a pharmaceutical composition containing an azulene derivative but having improved stability and excellent pharmaceutical stability.

Azulene derivatives have anti-inflammatory, anti-allergic, and anti-ulcer effects, and are widely used as active ingredients in oropharyngeal and gastrointestinal drugs. However, the azulene derivative is easily decomposed over time by heat, light or moisture, and it is difficult to store it for a long period of time with a normal preparation. Examples of the method for stabilizing the azulene derivative include a method of asolubilizing and stabilizing by using freeze-drying (Patent Document 1), a method of sealing and packaging with an oxygen scavenger (Patent Document 2), and the like. This method requires a lot of equipment and manpower. On the other hand, as a stabilizer for the azulene derivative, a method of adding an amino acid and a weakly basic alkaline salt (Patent Document 3) and a method of adding an aluminum salt (aluminum lactate, aluminum phosphate, etc.) (Patent Document 4). ), A method of adding edetic acid and salts thereof (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 Special Publication No. 49-11219 JP-A-59-157014 Japanese Unexamined Patent Publication No. 1-121216 Special Fair 2-42811 Gazette

The 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 convenience. However, the present inventor has proceeded with 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 long-term stability that can withstand practical use. It was insufficient to maintain the drug, and faced the problem of poor formulation stability.

Therefore, an object of the present invention is to provide a formulation technique for further improving the stability of a pharmaceutical composition containing an azulene derivative and a polyhydric alcohol to provide excellent formulation stability.

As a result of diligent studies to solve the above problems, the present inventor has 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 that I could prepare. The present invention has been completed by further studies based on this finding.

That is, the present invention provides the inventions of the following aspects.
Item 1. A pharmaceutical composition comprising (A) an azulene derivative, (B) a polyhydric alcohol, and (C) ethyl aminobenzoate.
Item 2. Item 2. The pharmaceutical composition according to Item 1, further comprising (D) a sugar alcohol.
Item 3. Item 2. 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 a salt thereof, and dimethylisopropylazulene.
Item 4. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, which is a solid oral mucosal application external preparation.
Item 5. A method for improving the stability of the component (A) in a pharmaceutical composition containing an azulene derivative (A) and a polyhydric alcohol (B).
A method for improving stability, in which ethyl (C) aminobenzoate is blended together with the component (A) and the component (B) in a pharmaceutical composition.

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

1. 1. Pharmaceutical Composition The pharmaceutical composition of the present invention includes (A) azulene derivative (sometimes referred to as (A) component), (B) polyhydric alcohol (sometimes referred to as (B) component), and It is characterized by containing (C) ethyl aminobenzoate (sometimes referred to as component (C)). Hereinafter, the pharmaceutical composition of the present invention will be described in detail.

(A) Azulene derivative The pharmaceutical composition of the present invention contains an azulene derivative as a component (A). The azulene derivative is a compound having one or more substituents bonded to the azulene skeleton and a salt thereof. The azulene derivative has an anti-inflammatory effect, an anti-allergic effect, an anti-ulcer effect, and the like, and is a known ingredient as an active ingredient of an oropharyngeal drug and a gastrointestinal drug.

The azulene derivative used in the present invention is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, but from the viewpoint of better obtaining the effect of improving stability in the pharmaceutical composition, azulene is used. Examples thereof include azulene derivatives in which at least an acidic functional group is bonded to the skeleton. Specific examples of the acidic functional group include a sulfo group, a carboxyl group and the like, and a sulfo group is preferable.

Specific examples of the azulene derivative 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 can be mentioned.

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, but for example, an alkali metal salt such as a sodium salt or a potassium salt; Alkaline earth metal salts such as calcium salt, magnesium salt; other metal salts such as aluminum salt; ammonium salt; acetate, trifluoroacetate, butyrate, palmitate, stearate, fumarate, maleic acid Carborates such as salts, succinates, malonates, lactates, tartrates and citrates; organic sulfonates such as methanesulfonates, toluenesulfonates and tosylates; methylamine salts, triethylamine Organic amine salts such as salts, triethanolamine salts, morpholin salts, piperazine salts, pyrrolidine salts, tripyridine salts, picolin salts; inorganic acid salts such as hydrochlorides, sulfates, nitrates, hydrobromates, phosphates, etc. Can be mentioned.

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

Among these azulene derivatives, at least one selected from the group consisting of azulene sulfonic acid and a salt thereof, and dimethylisopropylazulene is preferably mentioned from the viewpoint of obtaining a better stability improving effect in a pharmaceutical composition. Be done. Examples of the azulene sulfonic acid and / or a salt thereof include azulene sulfonic acid and / or an alkali metal salt thereof, and more preferably sodium azulene sulfonic acid.

In the pharmaceutical composition of the present invention, the content of the 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 use of the pharmaceutical composition, and the like. It may be set, and examples thereof include 0.001 to 10% by weight. From the viewpoint of better obtaining the effect of improving stability in the pharmaceutical composition, the content of the component (A) is preferably 0.005 to 1% by weight, more preferably 0.01 to 0.1% by weight. Can be mentioned. When the pharmaceutical composition of the present invention is a solid external preparation for oral mucosa, the content of the component (A) is preferably 0.01 to 0.1% by weight, more preferably 0.03 to 0. It is .08% by weight, more preferably 0.04 to 0.07% by weight.

(B) Polyhydric alcohol The pharmaceutical composition of the present invention contains a polyhydric alcohol as a 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, even a composition containing a polyhydric alcohol and originally having insufficient stability can effectively improve the stability.

The polyhydric alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and for example, propylene glycol, 1,3-butylene glycol, ethylene glycol, isoprene glycol, diethylene glycol, dipropylene glycol and the like. Divalent alcohols; trihydric alcohols such as glycerin, polyethylene glycols such as macrogol 4000 and macrogol 6000, and the like. These polyhydric alcohols may be used alone or in combination of two or more.

Among these polyhydric alcohols, a dihydric alcohol is preferable, and propylene glycol and glycerin are more preferable.

In the pharmaceutical composition of the present invention, the content of the component (B) is not particularly limited and may be appropriately set according to the type of polyhydric alcohol used, the formulation form and use of the pharmaceutical composition, and the like. For example, 1 to 90% by weight, preferably 3 to 80% by weight can be mentioned.

In the pharmaceutical composition of the present invention, the ratio of the component (B) to the component (A) is determined according to the contents of the component (A) and the component (B). For example, 1 part by weight of the component (A). The component (B) is, for example, 1500 to 5000 parts by weight, preferably 1800 to 5000 parts by weight, and more preferably 1900 to 4500 parts by weight.

(C) Ethyl Aminobenzoate The pharmaceutical composition of the present invention contains ethyl aminobenzoate as a component (C). Ethyl aminobenzoate is a known local anesthetic also referred to as ethyl 4-aminobenzoate, benzocaine and the like. In the pharmaceutical composition, the azulene derivative has insufficient stability even when coexisting with the polyhydric alcohol, but the pharmaceutical composition of the present invention contains the azulene derivative and the polyhydric alcohol, and is inherently stable. Even if the composition is insufficient, the stability can be effectively improved by adding aminobenzoic acid.

In the pharmaceutical composition of the present invention, the content of the component (C) is not particularly limited and may be appropriately provided depending on the formulation form and use of the pharmaceutical composition, but 0.01 to 10% by weight. It is 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 mucosal application, the content of the component (C) is preferably 0.1 to 3% by weight, more preferably 0.1 to 2.5% by weight. .. Further, when the pharmaceutical composition of the present invention is a solid oral mucosal external preparation, the content of the component (C) is preferably 0.05 to 1% by weight, more preferably 0.05 to 0. 5% by weight, more preferably 0.05 to 0.3% by weight, still more preferably 0.05 to 0.2% by weight.

In the pharmaceutical composition of the present invention, the ratio of the component (C) to the component (A) is determined according to the contents of the component (A) and the component (C). For example, 1 part by weight of the component (A). The 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, and even more preferably 70 to 80 parts by weight. When the pharmaceutical composition of the present invention is a solid oral mucosa-applied external preparation, the 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 the component (A). 3.5 parts by weight is mentioned.

(D) Sugar alcohol The pharmaceutical composition of the present invention may contain a sugar alcohol as a component (D). Sugar alcohol is a known component used as a base or a flavoring agent. When sugar alcohol is added to a drug composition containing an azulene derivative and a polyhydric alcohol, it tends to reduce the stability of the azulene derivative. However, in the pharmaceutical composition of the present invention, in addition to the azulene derivative and the polyhydric alcohol. Even if the composition contains a sugar alcohol and originally has a reduced stability, the stability can be effectively improved.

The sugar alcohol is not particularly limited as long as it is pharmaceutically or cosmetically acceptable, and examples thereof include sorbitol, xylitol, isomaltose, erythritol, maltitol, mannitol, lactitol, palatinose, and reduced palatinose. And preferably, sorbitol, xylitol, isomaltose, erythritol, maltitol, and reduced palatinose are mentioned. These sugar alcohols may be used alone or in combination of two or more.

When the component (D) is contained in the pharmaceutical composition of the present invention, the content thereof is not particularly limited and may be appropriately set according to the formulation form and use of the pharmaceutical composition, for example, 2% by weight. As mentioned above, preferably 3% by weight or more, more preferably 5% by weight or more. When the pharmaceutical composition of the present invention is a solid oral mucosa-applied external preparation, the content of the component (D) is, for example, 10 to 99.5% by weight, preferably 90 to 99.5% by weight. Preferably, it is 95 to 99% by weight.

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

Other Ingredients The pharmaceutical composition of the present invention may contain other pharmacological ingredients in addition to the above-mentioned ingredients, if necessary. Examples of such pharmacological components include antihistamines (difenhydramine, difenhydramine hydrochloride, etc.) and local anesthetics other than ethyl aminobenzoate (procaine, tetracaine, bupipacaine, mepipacine, chloroprocaine, proparacaine, meprilcaine or salts thereof, oxesazein). , Rohto extract, lidocaine, etc.), bactericides other than quaternary ammonium salts (iodine, popidone iodine, potassium iodide, chlorhexidine gluconate, acrinol, etc.), anti-inflammatory agents (dipotassium glycyrrhizinate, glycyrrhetinic acid, indomethacin, fervinac, etc.) Diclofenac sodium, loxoprofen sodium, etc.), skin protectants (corodione, castor oil, etc.), blood circulation promoting components (nonylate vanillylamide, nicotinic acid benzyl ester, capsaicin, capsicum 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 contain a base material or an additive other than the above-mentioned components, if necessary, in order to obtain a desired pharmaceutical composition. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable, but for example, oils (olive oil, saflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil). , Cotton seed oil, peanut oil, lard, squalane, fish oil, etc.), mineral oil (liquid paraffin, paraffin, gelled hydrocarbon, vaseline, etc.), waxes / waxes (mitsurou, carnauba wax, candelilla wax, ceresin, rice wax, etc. Microcrystalin 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, etc.) , Palmitic acid, bechenic 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 tri2-ethylhexanoate, cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic silicone, etc.) Oily bases 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- Decyltetradecyl ether, polyoxyethylene alkyl ethers such as POE (10 to 50 mol) polyoxypropylene (2 to 30 mol) cetyl ether, their phosphates and phosphates (POE cetyl ether sodium phosphate, etc.), POE (20-60 mol) sorbitan monoolate, POE (10-60 mol) sorbitan monoisostearate, POE (10-80 mol) glyceryl monoisostearate, POE (10-30 mol) glyceryl mono Steerate, 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 (Glycerin monostearate, etc.), Hydrogenated soybean Surfactants such as phospholipids and hydrogenated lanolin alcohol; refreshing agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives (methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.) , Fragrance (citral, 1,8-cyonel, citronellal, farnesol, etc.), colorant (tar pigment (brown 201, blue 201, yellow 4, yellow 403, etc.), cocoa pigment, chlorophyll, aluminum oxide, etc.) Etc.), viscous agent (sodium alginate, ethyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, carboxyvinyl polymer, sodium polyacrylate, etc.), pH adjuster (phosphate, hydrochloric acid, citrate, sodium citrate, etc.) , Succinic acid, tartrate acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agent (dol-pyrrolidone sodium carboxylate solution, D-sorbitol solution, etc.), stabilizer (dibutylhydroxytoluene, etc.) Butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbinate, propyl gallate, sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract Etc.), antioxidants, UV absorbers, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives and other additives.

Formulation 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 preferable. Examples thereof include liquid, semi-solid, and solid forms, which are aqueous preparations, and more preferably liquid and solid forms.

In addition, the pharmaceutical composition of the present invention may be either an external drug or an internal drug. Examples of the external preparation include mucosal-applicable external preparations and skin-applicable external preparations, and preferably mucosal-applicable external preparations. Examples of the external preparation for mucosa include oral external preparations for oral mucosa and other external preparations for mucous membranes (for example, suppositories and vaginal preparations), and preferably external preparations for oral mucosa. Specifically, examples of external preparations for skin use include gels, creams, lotions, emulsions, liquids, patches, patches, aerosols, ointments, packs, etc., and examples of external preparations for mucous membranes include gels. Examples thereof include agents, creams, lotions, emulsions, liquids, ointments, jellies, and solids. Examples of the liquid preparation include an aqueous preparation. Examples of the solid agent include candy, drop agent, troche agent, tablet agent, chewable agent, gummy agent, edible film agent and the like. Preparation of these formulations can be carried out by formulating them with additives according to the formulations according to the known method described in the 17th revised Japanese Pharmacopoeia General Regulations for Formulations.

Among these pharmaceutical forms, preferably, a liquid external preparation which is an aqueous preparation or a solid mucosal application external preparation can be mentioned, and more preferably, a candy agent, a drop agent, a troche agent, a tablet agent, and a chewable agent. , Gummy agent, edible film agent and other solid oral mucosal application external preparations.

2. Stability Improving Method 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 together with (A) azulene derivative and (B) 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 as compared with the case where the component (C) is not added to the pharmaceutical composition. It can be confirmed by delaying the fading of blue over time. The types and amounts of the ingredients used in the method for improving the stability of the present invention, the formulation form of the pharmaceutical composition, and the like are as described in the column of "1. Pharmaceutical composition" above.

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

Test Example A pharmaceutical composition (liquid preparation) having the composition shown in Table 2 was prepared. 45 ml of the obtained pharmaceutical composition is filled in a glass screw tube bottle (capacity 50 ml), and an optical stability test device (LT-120A Nagano Science Co., Ltd.) is used under the conditions of an illuminance of 4,000 lux and 20 ° C. It was irradiated with light for 10 days. Then, the appearance of each pharmaceutical composition was visually observed, and the color change (photostability) of sodium azulene sulfonate was evaluated. Specifically, the color tone of the obtained pharmaceutical composition is a relative value when the color tone of the pharmaceutical composition of Reference Example 1 shown in Table 1 is 10 immediately after preparation and 0 is 10 days after light irradiation. evaluated. In the test example, the unit of the numerical value indicating the blending amount of each component in the table is% by weight.

The results obtained are shown in Table 2. Even if a polyhydric alcohol (propylene glycol, glycerin) is added to sodium azulene sulfonate, the degree of suppression of color change is slight as compared with Reference Example 1 which does not contain the polyhydric alcohol, so that the stability is only slightly improved. (Comparative Examples 1 and 4). Further, when a sugar alcohol (isomaltose, sorbitol) is further added, the degree of suppression of color tone change is further lowered, and the stability is lowered (Comparative Examples 2 and 3). On the other hand, when sodium azulene sulfonate contains a polyhydric alcohol and ethyl aminobenzoate, the degree of suppression of color tone change is remarkably improved, and the stability is effectively improved (Examples 1 to 7). ). Such a stability improving effect could be confirmed even when sugar alcohol was contained (Examples 4 to 6).

In addition, Example 3 and Comparative Example 1 are given as representative examples, and the photograph showing the color tone change of sodium azulene sulfonate is shown in Table 3.

Formulation Examples Pharmaceutical compositions (liquids, drops, troches, oral ointments, ointments / creams) having the compositions shown in Tables 4 to 8 were prepared. All of the obtained pharmaceutical compositions were formulations having excellent photostability, as in the examples.

Claims (4)

(A) and azulene derivative, (B) a polyhydric alcohol, it viewed including the a (C) ethylamino benzoic acid, solid oral transmucosal external preparation, pharmaceutical compositions. The pharmaceutical composition according to claim 1, further comprising (D) a sugar alcohol. The pharmaceutical composition according to claim 1 or 2, wherein the component (A) is at least one selected from the group consisting of azulene sulfonic acid and a salt thereof, and dimethylisopropylazulene. A method for improving the stability of the component (A) in a pharmaceutical composition containing an azulene derivative (A) and a polyhydric alcohol (B).
A method for improving stability, in which ethyl (C) aminobenzoate is blended together with the component (A) and the component (B) in a pharmaceutical composition.