JP5252846B2 - Aqueous pharmaceutical composition - Google Patents

Description

  The present invention relates to a highly safe aqueous pharmaceutical composition containing levocabastine and / or a salt thereof, in which expression of cytotoxicity is suppressed.

  Type I allergic diseases, including allergic rhinitis and allergic conjunctivitis, are broadly divided into immediate phase reactions and late phase reactions. In the immediate phase reaction, it is known that sneezing, runny nose and nasal congestion are induced immediately after antigen induction, while in the late phase reaction, nasal congestion occurs again several hours after antigen induction. Therefore, in order to effectively treat or improve allergic diseases, it is important to suppress not only the immediate phase reaction but also the late phase reaction.

  Levocabastine is known as an H1 blocker with high affinity and specificity for the histamine H1 receptor and a long duration of action, and as a remedy for allergic diseases such as allergic rhinitis and allergic conjunctivitis And used in eye drops. However, levocabastine cannot sufficiently suppress the delayed phase reaction even though it is effective for suppressing the immediate phase reaction. That is, levocabastine can strongly improve the symptoms of sneezing and runny nose in the immediate phase reaction, but has a drawback that the effect of improving nasal congestion symptoms, particularly in the late phase reaction, is weak.

  On the other hand, flunisolide is a synthetic corticosteroid having an antiallergic action, and is used in aqueous pharmaceutical compositions applied to allergic rhinitis, vasomotor rhinitis and the like. As an action of a steroid, it is known that the number of mast cells is decreased in the immediate phase, and the suppression of inflammatory cytokines produced from T cells and the number of eosinophils are decreased in the late phase. Due to these actions, flunisolide is known to be effective not only for immediate phase reaction but also for late phase reaction.

So far, it has been clarified that allergy symptoms can be improved quickly and more effectively by combining flunisolide and levocabastine (see Patent Document 1). More specifically, it has been clarified that the combined use of flunisolide and levocabastine not only shortens the delay in the onset of effects, but also improves symptoms associated with seasonal or perennial allergic rhinitis. In addition, by using flunisolide and levocabastine in combination, the amount of levocabastine used is expected to be reduced, and troublesome side effects such as drowsiness possessed by levocabastine are expected to be solved.
Japanese Patent Publication No.11-511758 JP 2004-339213 A

  With the background of such prior art, the present inventors proceeded with studies, and in an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof and flunisolide, cytotoxicity that was not observed with these components alone was developed. It has been found. Furthermore, the inventors' investigations have revealed that cytotoxicity is expressed even when terpenoids used as a refreshing agent in an aqueous pharmaceutical composition are combined with levocabastine and / or a salt thereof. Mucous membranes such as ocular mucosa and nasal mucosa are particularly sensitive to cell damage. Therefore, in the practical use of aqueous pharmaceutical compositions containing levocabastine and / or its salts, the occurrence of cytotoxicity is suppressed and safety is enhanced. To be prepared.

  Therefore, an object of the present invention is to provide a highly safe aqueous pharmaceutical composition containing levocabastine and / or a salt thereof and suppressing the expression of cytotoxicity.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have surprisingly found that in aqueous pharmaceutical compositions containing levocabastine and / or a salt thereof, by blending flunisolide and terpenoids in combination, It has been found that the cytotoxicity of the composition can be effectively suppressed. The present invention has been completed by making further improvements based on such findings.

That is, the present invention is an aqueous pharmaceutical composition listed below:
Item 1. An aqueous pharmaceutical composition comprising (A) levocabastine and / or a salt thereof, (B) flunisolide, and (C) a terpenoid.
Item 2. (C) The terpenoid is at least one selected from the group consisting of menthol, camphor, borneol, geraniol, cineol, limonene, linalool, eugenol, bergamot oil, mint oil, eucalyptus oil, fennel oil, rose oil and cool mint oil. Item 4. The aqueous pharmaceutical composition according to Item 1, wherein
Item 3. (C) The aqueous pharmaceutical composition according to Item 1, wherein the terpenoid is menthol or a derivative thereof.
Item 4. Item 4. The aqueous pharmaceutical composition according to any one of Items 1 to 3, which is a composition applied to mucosa.
Item 5. Item 4. The aqueous pharmaceutical composition according to any one of Items 1 to 3, which is a nasal drop or an eye drop.

That is, the present invention is the following method:
Item 6. A method for suppressing the expression of cytotoxicity of an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof, comprising: (A) levocabastine and / or a salt thereof, (B) flunisolide, and (C ) A method for inhibiting the expression of cytotoxicity, characterized by coexisting terpenoids.
Item 7. A method for inhibiting cytotoxicity of an aqueous pharmaceutical composition comprising levocabastine and / or a salt thereof and flunisolide, wherein (A) levocabastine and / or a salt thereof, (B) flunisolide, and (C) A method for suppressing cytotoxicity, characterized by coexisting terpenoids.
Item 8. A method for suppressing cytotoxicity of an aqueous pharmaceutical composition comprising levocabastine and / or a salt thereof and a terpenoid, comprising: (A) levocabastine and / or a salt thereof, (B) flunisolide, and (C) A cytotoxicity-suppressing method comprising coexisting a terpenoid.

  According to the aqueous pharmaceutical composition of the present invention, the expression of cytotoxicity is suppressed, and it can be used with high safety even for mucous membranes that react sensitively to cell injury.

  Furthermore, the aqueous pharmaceutical composition of the present invention can effectively exert an inhibitory effect on allergic symptoms of both immediate phase reaction and late phase reaction by including levocabastine and / or a salt thereof and flunisolide.

  Further, according to the aqueous composition of the present invention, since the sensory characteristics are also improved, a satisfactory feeling of use can be obtained even when applied to mucous membranes sensitive to external factors (eg, ocular mucosa, nasal mucosa). Can do.

In this specification, the aqueous pharmaceutical composition refers to a pharmaceutical composition containing at least 50% by weight or more, more preferably 70% by weight or more of water in the composition.
I. Aqueous Pharmaceutical Composition The aqueous pharmaceutical composition of the present invention contains levocabastine and / or a salt thereof (hereinafter sometimes simply referred to as component (A)). Levocabastine is a known compound, and may be synthesized by a known method or obtained as a commercial product.

  The salt of levocabastine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such salts include acid addition salts, salts with organic bases, salts with inorganic bases, and the like. More specifically, examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide and phosphate; monocarboxylate (acetate, trifluoroacetate, Organic acid salts such as butyrate, palmitate, stearate; polyvalent carboxylates such as fumarate, maleate, succinate, malonate; lactate, tartrate, citrate, etc. Examples thereof include organic sulfonates such as methanesulfonate, toluenesulfonate (ortho-type, meta-type, para-type), etc. Examples of salts with organic bases include methylamine and triethylamine. And salts with organic amines such as triethanolamine, morpholine, piperazine, pyrrolidine, tripyridine, picoline, etc. Examples of salts with inorganic bases include ammonium salts; Examples include salts with alkali metals such as salts, salts with alkaline earth metals such as calcium salts and magnesium salts, salts with metals such as aluminum salts, etc. Among these, acid addition salts are preferable, and more preferable. These salts of levocabastine may be used alone or in any combination of two or more.

  In the aqueous pharmaceutical composition of the present invention, one of these levocabastine and a salt thereof may be selected and used alone, or two or more may be used in any combination. Levocabastine hydrochloride, that is, levocabastine hydrochloride is preferred.

  In the aqueous pharmaceutical composition of the present invention, the blending ratio of levocabastine and / or a salt thereof is not particularly limited, and can be appropriately set according to the use, formulation form and the like of the aqueous pharmaceutical composition. As an example of the blending ratio of levocabastine and / or a salt thereof in the aqueous pharmaceutical composition, the total amount of the aqueous pharmaceutical composition is 0.0001 to 0.1 w / v%, preferably 0.0005 to 0.05 w / v%. The ratio is illustrated. More specifically, the blending ratio of levocabastine and / or a salt thereof is preferably 0.006 to 0.05 w / v%, particularly preferably 0.0125 to 0.027 w /% when the aqueous pharmaceutical composition is an eye drop or nasal drop. v%; When the aqueous pharmaceutical composition is an eye wash or a nasal wash, it is preferably 0.0006 to 0.005 w / v%, particularly preferably 0.00125 to 0.0027 w / v%. By including levocabastine and / or a salt thereof at such a ratio, it becomes possible to more effectively exhibit the antiallergic effect.

  Further, the aqueous pharmaceutical composition of the invention contains flunisolide (hereinafter sometimes simply referred to as component (B)). Flunisolide is a known compound and may be synthesized by a known method or obtained as a commercial product. In the present invention, flunisolide may be used in the form of a hydrate such as 1/2 hydrate.

  The blending ratio of flunisolide in the aqueous pharmaceutical composition of the present invention is not particularly limited, and can be appropriately set according to the use and formulation form of the aqueous pharmaceutical composition. As an example of the blending ratio of flunisolide, the total amount is 0.0001 to 0.1 w / v%, preferably 0.001 to 0.05 w / v%, based on the total amount of the aqueous pharmaceutical composition. More specifically, the blending ratio of flunisolide is preferably 0.005 to 0.05 w / v%, particularly preferably 0.0125 to 0.025 w / v% when the aqueous pharmaceutical composition is an eye drop or nasal drop; When the composition is an eye wash or a nasal wash, it is preferably 0.0005 to 0.005 w / v%, particularly preferably 0.00125 to 0.0025 w / v%. By including flunisolide at such a blending ratio, it becomes possible to more effectively suppress the expression of cytotoxicity and to exhibit an antiallergic effect more remarkably.

  Further, the aqueous pharmaceutical composition of the invention contains a terpenoid (hereinafter sometimes simply referred to as the component (C)) in addition to the components (A) and (B).

  The terpenoid used in the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such terpenoids include menthol, menthone, camphor, borneol, geraniol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, linalyl acetate and the like. These compounds may be d-form, l-form or dl-form. In the present invention, an essential oil containing the above compound may be used as a terpenoid. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, and rose oil. These terpenoids may be used alone or in any combination of two or more.

  Of these terpenoids, menthol, camphor, borneol, geraniol, cineol, limonene, linalool, eugenol are preferable from the viewpoint of more effectively suppressing cytotoxicity caused by the coexistence of levocabastine and / or a salt thereof and flunisolide. Examples of preferable essential oils containing these include bergamot oil, cool mint oil, peppermint oil, eucalyptus oil, fennel oil, and rose oil. More preferably, mention may be made of menthols such as l-menthol, d-menthol and dl-menthol or derivatives thereof, and examples of essential oils containing these include cool mint oil.

  The blending ratio of the terpenoid in the aqueous pharmaceutical composition of the present invention is not particularly limited, and can be appropriately set according to the use and formulation form of the aqueous pharmaceutical composition. As an example of the mixing ratio of the terpenoid, the total amount of the aqueous pharmaceutical composition is 0.00005 to 1 w / v%, preferably 0.0001 to 0.5 w / v%. More specifically, the blending ratio of the terpenoid is preferably 0.0001 to 0.5 w / v%, particularly preferably 0.0002 to 0.05 w / v% when the aqueous pharmaceutical composition is an eye drop or nasal drop; When the composition is an eye wash or a nasal wash, it is preferably 0.0001 to 0.1 w / v%, particularly preferably 0.0002 to 0.01 w / v%. By including the terpenoid at such a blending ratio, the expression of cytotoxicity can be more effectively suppressed.

In the aqueous pharmaceutical composition of the present invention, the ratio of the components (A) to (C) is not particularly limited, but by satisfying the following range, suppression of the expression of cytotoxicity and excellent antiallergic effect Can be noticeable:
The total amount of component (A) is 100 parts by weight and the total amount of component (B) is 4 to 400 parts by weight, and the total amount of component (C) is 0.185 to 8000 parts by weight; preferably the total amount of component (B) is 19 -400 parts by weight, and the total amount of the component (C) is 0.4-4000 parts by weight; more preferably, the component (B) is 47-200 parts by weight in total, and the component (C) is 0.7-400 parts by weight in total.

  The aqueous pharmaceutical composition of the present invention may further contain a buffer in addition to the above components. The buffer that can be incorporated into the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such buffers include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer, ε-aminocaproic acid, aspartic acid, aspartate and the like. These buffering agents may be used alone or in any combination of two or more. Among the above buffering agents, borate buffer and phosphate buffer are suitable.

  When blending a buffering agent in the aqueous pharmaceutical composition of the present invention, the blending ratio of the buffering agent differs depending on the type of buffering agent used and expected effects, etc., and cannot be defined uniformly, For example, the ratio in which the total amount of the buffering agent is 0.001 to 10 w / v%, preferably 0.005 to 5 w / v%, based on the total amount of the aqueous pharmaceutical composition.

  In addition, the aqueous pharmaceutical composition of the present invention can be adjusted to a pH within the range acceptable to the living body within the range where the chemical stability of the compounding components is not significantly impaired. The appropriate pH varies depending on the application site, formulation form and the like of the aqueous pharmaceutical composition, but is usually 6 to 9, preferably 6.5 to 8.5, more preferably 6.8 to 8.2, particularly preferably. It is about 7-8. The pH can be adjusted by a method known in the art using the buffer, a pH adjuster, an isotonic agent, a salt or the like usually used in the art.

  If necessary, the aqueous pharmaceutical composition of the present invention can be adjusted to an osmotic pressure ratio within a range acceptable to the living body. The appropriate osmotic pressure ratio varies depending on the application site, formulation form, etc., but is usually about 0.3 to 4.2, preferably about 0.5 to 4.0, and more preferably about 0.8 to 3.8. The adjustment of the osmotic pressure can be performed by a method known in the art using inorganic salts, polyhydric alcohols, sugar alcohols, saccharides and the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution with reference to the 15th revised Japanese pharmacopoeia. Measure with reference to the descent method. The standard solution for measuring the osmotic pressure ratio was sodium chloride (Japanese Pharmacopoeia standard reagent) dried at 500 to 650 ° C. for 40 to 50 minutes, then allowed to cool in a desiccator (silica gel), and 0.900 g was accurately weighed. Dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

The aqueous pharmaceutical composition of the present invention may contain an appropriate amount of various pharmacologically active ingredients and physiologically active ingredients in addition to the above-mentioned ingredients as long as the effects of the present invention are not hindered. Such an ingredient is not particularly limited, and examples thereof include active ingredients in various pharmaceuticals described in the over-the-counter drug manufacturing (import) approval standard 2000 edition (supervised by the Pharmaceutical Affairs Research Committee). Specifically, the following components can be used as components used in otolaryngological or ophthalmic drugs.
Antihistamine: for example, iproheptin, diphenhydramine, chlorpheniramine and the like.
Vasoconstrictor: For example, naphazoline, tetrahydrozoline, oxymetazoline, epinephrine, ephedrine, phenylephrine, methylephedrine and the like.
Bactericides: for example, acrinol, cetylpyridinium, benzalkonium, benzethonium, chlorhexidine and the like.
Anti-inflammatory agents: for example, glycyrrhetinic acid, glycyrrhizic acid, methyl salicylate, glycol salicylate, allantoin, azulene, azulenesulfonic acid, guaiazulene, tranexamic acid, ε-aminocaproic acid, berberine, lysozyme, licorice, etc.
Astringent: For example, zinc white, zinc lactate, zinc sulfate and the like.
Others: for example, indomethacin, ibuprofen, ibuprofen piconol, bufexamac, butyl flufenamate, bendazac, piroxicam, ketoprofen, felbinac, purple root, horse chestnut, and salts thereof.

Further, in the aqueous pharmaceutical composition of the present invention, various additives are appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired, and one or more are used in combination. Thus, an appropriate amount may be contained. Examples of such additives include various additives described in Pharmaceutical Additives Encyclopedia 2005 (edited by Japan Pharmaceutical Additives Association). Typical additives include the following additives.
Carrier: An aqueous solvent such as water or hydrous ethanol.
Thickeners: for example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate and the like.
Sugars: for example, glucose, cyclodextrin and the like.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form or dl-form.
Surfactant: For example, polyoxyethylene (hereinafter abbreviated as POE) -polyoxypropylene (hereinafter abbreviated as POP) block copolymer (specifically, poloxamer 407, etc.), ethylenediamine POE-POP block copolymer adduct ( Specifically, poloxamine, etc.), POE sorbitan monooleate, POE hydrogenated castor oil (specifically, POE (60) hydrogenated castor oil, etc.), nonionic surfactants such as polyoxyl stearate; alkyldiaminoethyl Glycine-type amphoteric surfactants such as glycine; alkyl quaternary ammonium salts (specifically, cationic surfactants such as benzalkonium chloride and benzethonium chloride. The numbers in parentheses indicate the number of moles added.
Chelating agents: for example, ethylenediaminetetraacetic acid disodium (sodium edetate), ethylenediaminetetraacetic acid tetrasodium, ethylenediaminetetraacetic acid barium, ethylenediaminetetraacetic acid cobalt, ethylenediaminetetraacetic acid cobalt ethylenediaminetetraacetic acid copper, ethylenediaminetetraacetic acid diammonium, ethylenediaminetetraacetic acid Dilithium, ethylenediaminetetraacetic acid dipotassium, ethylenediaminetetraacetic acid iron, ethylenediaminetetraacetic acid lanthanum, ethylenediaminetetraacetic acid magnesium, ethylenediaminetetraacetic acid nickel, ethylenediaminetetraacetic acid nickel, ethylenediaminetetraacetic acid tripotassium, ethylenediaminetetraacetic acid trisodium, ethylenediaminetetraacetic acid zinc, etc. .
Preservatives, bactericides or antibacterial agents: for example, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxy Methyl benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glowyl (manufactured by Rhodia) Name) etc.
pH adjuster: for example, hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate, boro Sand, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, ammonium acetate etc.
Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.
Stabilizer: Dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.
Base: Octyldodecanol, olive oil, sesame oil, titanium oxide, potassium bromide, soybean oil, camellia oil, corn oil, rapeseed oil, cottonseed oil, paraffin, castor oil, plastibase, peanut oil, lanolin, petrolatum, propylene glycol and the like.

  The aqueous pharmaceutical composition of the present invention may be liquid or semi-solid such as ointment. When the aqueous pharmaceutical composition of the present invention is used as a composition for applying to mucosa, liquid is preferably used from the viewpoint of easy application to mucosa.

  In addition, the preparation form of the aqueous pharmaceutical composition of the present invention is not particularly limited. For example, otolaryngological compositions such as nasal drops, nasal washings, and ear drops; eye drops [however, the eye drops are contacted Including eye drops that can be instilled while wearing a lens], artificial tears, eye wash [however, the eye wash contains an eye wash that can be washed while wearing a contact lens], eye ointment, and contact lens composition [ Ophthalmic compositions such as contact lens mounting solution, contact lens care composition (contact lens disinfectant, contact lens preservative, contact lens cleaner, contact lens cleaner, etc.); Examples include compositions for applying to mucous membranes such as compositions for oral cavity such as drugs (an agent for gargle). Among them, preferred are otolaryngological compositions or ophthalmic compositions, more preferred are nasal drops, nasal rinses, eye drops, or eyewashes, and particularly preferred are nasal drops or eye drops. The contact lens composition can be applied to all contact lenses including hard contact lenses and soft contact lenses.

  The aqueous pharmaceutical composition of the present invention exhibits an excellent antiallergic effect due to the coexistence of the components (A) and (B), and thus is useful for the prevention or treatment of allergic symptoms, particularly for the prevention or treatment of allergic rhinitis. .

  The aqueous pharmaceutical composition of the present invention is produced according to a known method. For example, the above components (A) to (C), and other components as necessary may be added to an aqueous solvent such as purified water and physiological saline, etc. so as to obtain a desired concentration, and prepared according to a conventional method. That's fine.

II. Method for suppressing expression of cytotoxicity, method for reducing cytotoxicity As described above, in an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof, by coexisting levocabastine and / or a salt thereof, flunisolide, and a terpenoid, The expression of cytotoxicity of the aqueous pharmaceutical composition can be suppressed. Accordingly, the present invention, from yet another aspect, is a method for inhibiting the expression of cytotoxicity of an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof, wherein (A) levocabastine and / or Alternatively, the present invention provides a method for inhibiting the expression of cytotoxicity, characterized by coexisting a salt thereof, (B) flunisolide, and (C) a terpenoid.

  In addition, in the aqueous pharmaceutical composition containing levocabastine and / or a salt thereof and flunisolide, the cytotoxicity of the aqueous pharmaceutical composition can be suppressed by coexisting levocabastine and / or a salt thereof with flunisolide and a terpenoid. . Accordingly, the present invention provides a method for inhibiting cytotoxicity of an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof and flunisolide from still another aspect, wherein (A) levocabastine is contained in the aqueous pharmaceutical composition. And / or a salt thereof, (B) flunisolide, and (C) a method for inhibiting cytotoxicity, comprising coexisting a terpenoid.

  Furthermore, in the aqueous pharmaceutical composition containing levocabastine and / or a salt thereof and a terpenoid, the cytotoxicity of the aqueous pharmaceutical composition can be suppressed by making levocabastine and / or a salt thereof and flunisolide and terpenoid coexist. . Accordingly, the present invention, from yet another viewpoint, is a method for inhibiting cytotoxicity of an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof and a terpenoid, wherein (A) levocabastine is used in the aqueous pharmaceutical composition. And / or a salt thereof, (B) flunisolide, and (C) a terpenoid coexisting is provided.

  In these methods, the type and concentration of levocabastine and / or its salt to be used, the type and concentration of flunisolide, the type and concentration of terpenoids, the type and concentration of other ingredients, the formulation and use of aqueous pharmaceutical compositions, etc. Is as described in the column of “I. Aqueous pharmaceutical composition”.

  Hereinafter, the present invention will be described in detail based on examples, test examples, and the like, but the present invention is not limited thereto.

Test Example 1 Evaluation Test for Cytotoxicity Aqueous pharmaceutical compositions (Example 1 and Comparative Example 1-3) having the composition shown in Table 1 were prepared, and the cytotoxicity of these aqueous pharmaceutical compositions was measured using Cornepack (normal rabbit cornea). Tests were performed using epithelial cells: NRCE2, serum-free liquid medium for rabbit corneal epithelial cell proliferation: RCGM2, both from Kurabo Industries) and NR reagent set (for NRCE2, from Kurabo Industries). This test was conducted according to the instruction manual attached to the NR reagent set, “Neutral Red Method Using Normal Rabbit Corneal Epithelial Cells (NR Method)”.

Normal rabbit corneal epithelial cells (secondary cultured cells) were inoculated into a 96-well multiplate at 100 μL each at 2000 cells / well and cultured at 37 ° C. under 5% CO ₂ for 3 days. 100 μL of each aqueous pharmaceutical composition was added to each well containing corneal epithelial cells thus cultured, and cultured for 3 days at 37 ° C. and 5% CO ₂ (tertiary culture). Next, 100 μL of a neutral red aqueous solution (5 mg / mL) diluted 33-fold with physiological saline (neutral red concentration of about 150 μg / mL) was added to each well at ₂ ° C. and 5% CO 2. Incubated for hours. After removing the supernatant, the cells were fixed and washed for 1 minute with 200 μL of 1 wt% formalin aqueous solution (containing 1 wt% calcium chloride). Subsequently, the supernatant was removed, neutral red was extracted from the cells for 20 minutes using 100 μL of 50 wt% ethanol aqueous solution (containing 1 wt% acetic acid), and the number of surviving cells was neutral red at 540 nm using a microplate reader. It was calculated | required by measuring the light absorbency of. In addition, as a control, instead of an aqueous pharmaceutical composition, a formulation containing only a base (a composition having the same composition as in Example 1 except that it does not contain levocabastine hydrochloride, flunisolide and l-menthol) was added. In the same manner, the neutral red absorbance at 540 nm was measured. The absorbance is corrected by subtracting the average absorbance of the blank (measured value obtained by the same treatment in the absence of neutral red after culturing the cells under the same conditions as the control), and further according to the following formula. The cell viability when the aqueous pharmaceutical composition was added was calculated.

  The results are shown in FIG. From this result, the combined use of levocabastine hydrochloride and flunisolide or l-menthol (Comparative Example 2-3) showed a decrease in cell viability compared to the case of levocabastine hydrochloride alone (Comparative Example 1), It became clear that injury toxicity was caused. On the other hand, by combining levocabastine hydrochloride, flunisolide and l-menthol (Example 1), the cell viability was the same as that of levocabastine hydrochloride alone, and no cytotoxicity was observed.

Formulation Example An aqueous pharmaceutical composition (Example 2-18) was prepared according to the formulation described in Table 2-4 below.

It is the result in which the cytotoxicity of each aqueous pharmaceutical composition (Example 1 and Comparative Example 1-3) was evaluated in Test Example 1.

Claims (7)

An aqueous pharmaceutical composition comprising (A) levocabastine and / or a salt thereof, (B) flunisolide, and (C) 1-menthol . A nose drops or eye drops, aqueous pharmaceutical composition according to claim 1. The aqueous | water-based pharmaceutical composition of Claim 1 or 2 whose compounding ratio of a component (A) is 0.0001-0.1 w / v%. The aqueous | water-based pharmaceutical composition in any one of Claims 1 thru | or 3 whose compounding ratio of a component (B) is 0.0001-0.1 w / v%. Relative to 100 parts by weight of the total amount of the components (A), 19 to 400 parts by weight of component (B) in total, and component (C) is 0.4 to 4000 parts by weight in total, to any one of claims 1 to 4 The aqueous pharmaceutical composition as described. The aqueous pharmaceutical composition according to any one of claims 1 to 5 , further comprising a buffer. A method for inhibiting cytotoxicity of an aqueous pharmaceutical composition comprising levocabastine and / or a salt thereof and flunisolide, wherein (A) levocabastine and / or a salt thereof, (B) flunisolide, and (C) A method characterized by coexisting l-menthol .

Images