JP2009029779A - Aqueous pharmaceutical composition containing levocabastine and/or salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an aqueous pharmaceutical composition reducing cytotoxicity of a vasoconstrictor, inhibiting rupture of pollens, suppressing increase in particle size of levocabastine and/or a salt thereof or intensifying cooling sensation. <P>SOLUTION: The aqueous pharmaceutical composition is prepared by combining and compounding (a) levocabastine and/or a salt thereof with (b) an imidazoline vasoconstrictor and (c) menthol. Particularly, an imidazoline compound is used as (b) the vasoconstrictor, or a thickening agent is further added to the aqueous pharmaceutical composition. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an aqueous pharmaceutical comprising levocabastine and / or a salt thereof, which can reduce cytotoxicity, inhibit pollen rupture, inhibit the increase in particle size of levocabastine and / or a salt thereof, and impart an excellent refreshing feeling. Relates to the composition.

  In addition to histamine H1 antagonism, levocabastine has a chemical mediator release inhibitory effect and eosinophil migration inhibitory action, and is used as a remedy for allergic diseases such as allergic rhinitis and allergic conjunctivitis. Used in combination.

  Furthermore, since levocabastine is hardly soluble in water, it is formulated in a suspended state when it is used as an aqueous pharmaceutical composition. Usually, when a medicinal ingredient is in a suspended state, the bioavailability of the ingredient depends largely on the size of the suspended particles, so it is actually used after production, distribution, sales and storage. It is required that the size of the suspended particles does not change. However, it is known that levocabastine is prone to aggregation, crystal growth, sedimentation, etc. in solution and the size of the suspended particles changes, and in order to incorporate levocabastine into an aqueous pharmaceutical composition, the particle size of levocabastine It is necessary to prevent change and stabilize.

  In addition, vasoconstrictors are used in combination with nasal drops and eye drops for the purpose of removing ocular hyperemia and reducing nasal congestion. Since mucous membranes such as nasal mucosa and ocular mucosa are sensitive to external factors, pharmaceutical compositions applied to mucous membranes are required to have higher levels of safety, pharmacological effects, and feeling of use. Yes. However, vasoconstrictors have a problem that they are cytotoxic to mucosal cells. Therefore, in order to use a pharmaceutical composition containing a vasoconstrictor applied to mucous membranes, it is essential to reduce cytotoxicity and enhance safety.

  In recent years, intensive studies have been made on allergic diseases, and the onset mechanism has been clarified. For example, in the case of allergic rhinitis, which is a type I allergy, specific IgE antibodies are produced by contact with an antigen (eg, a protein released upon cedar pollen rupture), which is received on nasal mucosal mast cells. Sensitization is achieved by binding to the body. Here, when the antigen is exposed again, as a result of the antigen-antibody reaction, mast cell degranulation occurs, and chemical mediators such as histamine are released, thereby causing allergic symptoms. Among type I allergies, hay fever is steadily increasing in number and is a major social problem. Pollen particles, which are the inducing factor of hay fever, are covered with a strong outer wall and inner membrane, and proteins that become allergens are present in the pollen covered with the outer wall surface and inner membrane. Therefore, it is considered effective to suppress the rupture of pollen present on the mucous membrane in order to suppress the allergic action due to hay fever. So far, preparations useful for suppressing pollen rupture include compositions containing lower alcohols and water-swellable clay minerals (see Patent Document 1), water-soluble compounds having an alkylene moiety having 3 to 18 carbon atoms in the molecule. (For example, see Patent Document 2). However, there is no known technique for suppressing pollen rupture using levocabastine or a vasoconstrictor.

  In the mucosa-applied pharmaceutical composition, imparting a refreshing feeling is important, and a particularly strong refreshing feeling tends to be preferred. A refreshing agent such as menthol can increase the refreshing feeling by increasing the amount, but the problem is that the feeling of irritation increases with the increase in menthol. Conventionally known methods of suppressing menthol and other stimuli include thickeners and chlorobutanol. Levocabastine and a vasoconstrictor, which are the only active ingredients, do not increase the amount of menthol. There is no known way to enhance it.

However, in a pharmaceutical composition containing levocabastine and a vasoconstrictor, it is possible to achieve a reduction in cytotoxicity, suppression of pollen rupture, or stable maintenance of the particle size of levocabastine and / or its salt, and an even better refreshing feeling. If it can be given, its usefulness can be said to be extremely high, but its technical means have not been clarified.
JP 2002-316925 A JP 2000-109425 A

  Accordingly, an object of the present invention is to provide an aqueous pharmaceutical composition that can reduce the cytotoxicity of a vasoconstrictor, suppress the pollen rupture, suppress the increase in the particle size of levocabastine and / or its salt, or enhance the excellent refreshing feeling. Is to provide.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have formulated levocabastine and / or a salt thereof, an imidazoline-based vasoconstrictor, and menthol as a unit in an aqueous pharmaceutical composition, thereby reducing cytotoxicity. It has been found that suppression of pollen rupture, suppression of increase in levocabastine and / or a salt thereof, or provision of an excellent refreshing feeling can be achieved. Furthermore, the reduction of cytotoxicity, the suppression of pollen rupture, the suppression of the increase in the particle size of levocabastine and / or its salt, or the excellent refreshing sensation can be achieved with a thickener (preferably a cellulosic thickener, particularly preferably hydroxypropylcellulose). ) Was found to be more prominent when further blended. The present invention has been completed by making further improvements based on such findings.

That is, this invention is the aqueous | water-based pharmaceutical composition hung up below.
Item 1. An aqueous pharmaceutical composition comprising (a) levocabastine and / or a salt thereof, (b) an imidazoline vasoconstrictor, and (c) menthol.
Item 2. Item 4. The aqueous pharmaceutical composition according to Item 1, further comprising a thickening agent.
Item 3. Item 3. The aqueous pharmaceutical composition according to Item 2, wherein the thickener is a cellulosic thickener.
Item 4. Item 3. The aqueous pharmaceutical composition according to Item 2, wherein the thickening agent is hydroxypropylmethylcellulose.
Item 5. The aqueous pharmaceutical composition according to any one of claims 1 to 4, which is a composition applied to mucosa.
Item 6. Item 6. The aqueous pharmaceutical composition according to any one of Items 1 to 5, which is an ophthalmic composition or an otolaryngological composition.
Item 7. Item 7. The aqueous pharmaceutical composition according to any one of Items 1 to 6, which is a nasal drop or an eye drop.
Item 8. Item 8. The aqueous pharmaceutical composition according to any one of Items 1 to 7, which is a composition for suppressing pollen rupture.
Item 9. Item 8. The aqueous pharmaceutical composition according to any one of Items 1 to 7, which is a composition for treating or alleviating nasal inflammation.

That is, this invention is the method hung up below.
Item 10. A method for inhibiting pollen rupture, comprising a step of bringing an aqueous pharmaceutical composition containing (a) levocabastine and / or a salt thereof, (b) an imidazoline vasoconstrictor, and (c) menthol into contact with pollen.
Item 11. In the aqueous pharmaceutical composition, (a) levocabastine and / or a salt thereof, (b) an imidazoline vasoconstrictor, and (c) menthol are coexisted, and the aqueous pharmaceutical composition has an effect of inhibiting pollen rupture. How to grant.
Item 12. An aqueous pharmaceutical composition containing an imidazoline-based vasoconstrictor, wherein (a) levocabastine and / or a salt thereof, and (c) menthol coexist in an aqueous pharmaceutical composition containing an imidazoline-based vasoconstrictor Method for reducing the cytotoxicity of a product.
Item 13. A refreshing sensation of an aqueous pharmaceutical composition containing menthol, characterized in that (a) levocabastine and / or a salt thereof and (b) an imidazoline vasoconstrictor coexist in an aqueous pharmaceutical composition containing menthol. How to strengthen.
Item 15. Stabilization of the particle size of levocabastine and / or a salt thereof characterized by coexisting (b) an imidazoline vasoconstrictor and (c) menthol in an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof Method.

  According to the aqueous pharmaceutical composition of the present invention, by including levocabastine and / or a salt thereof, an imidazoline vasoconstrictor, and menthol, cytotoxicity is reduced and higher safety can be provided.

  Moreover, since the aqueous | water-based pharmaceutical composition of this invention has the outstanding destruction destruction-inhibiting effect | action and can suppress the bursting of pollen, it can improve the allergic symptom by pollen effectively.

  Furthermore, the aqueous pharmaceutical composition of the present invention can exhibit an excellent refreshing feeling that cannot be achieved by using menthol alone.

  Furthermore, since the increase in the particle size of levocabastine and / or its salt is suppressed in the aqueous pharmaceutical composition of the present invention, the bioavailability of levocabastine and / or its salt is stably maintained, Also, dispersion stabilization of the salt thereof is expected.

  Hereinafter, in the present specification for explaining the present invention in detail, the aqueous pharmaceutical composition means a pharmaceutical composition containing at least 50 wt% or more, more preferably 70 wt% 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 also referred to as (-)-(3S, 4R) -1- [cis-4-cyano-4- (4-fluorophenyl) cyclohexyl] -3-methyl-4-phenylpiperidine-4-carboxylic acid It is a known compound.

  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 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, the effects of the present invention described above can be exhibited more effectively.

  The aqueous pharmaceutical composition of the present invention contains an imidazoline vasoconstrictor (hereinafter sometimes simply referred to as component (B)). An imidazoline-based vasoconstrictor is a drug with an imidazoline skeleton that contracts expanded peripheral blood vessels, relieves conjunctival congestion in the ophthalmic area, and nasal congestion associated with nasal mucosal congestion in the otolaryngological area. A drug used to relieve. The imidazoline-based vasoconstrictor is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specifically, naphazoline, tetrahydrozoline, oxymetazoline, and These salts are mentioned. Examples of the salt of the above compound include inorganic acid salts such as hydrochloride and nitrate. Further, the above compound and its salt may be in the form of a hydrate. Furthermore, the compound may be any of d-form, l-form, and dl-form. Of these, naphazoline, tetrahydrozoline, and salts thereof are preferable in order to make pollen bursting suppression and excellent refreshing feeling more remarkable. In the present invention, as component (B), one of these imidazoline vasoconstrictors may be selected and used alone, or two or more may be used in any combination.

  In the aqueous pharmaceutical composition of the present invention, the blending ratio of the imidazoline-based vasoconstrictor is not particularly limited, and can be appropriately set according to the use, formulation form, etc. of the composition. As an example of the mixing ratio of the imidazoline vasoconstrictor in the aqueous pharmaceutical composition, a ratio in which the total amount is 0.00001 to 1 w / v%, preferably 0.00005 to 0.5 w / v% is exemplified. More specifically, the blending ratio of the imidazoline-based vasoconstrictor is preferably 0.0005 to 0.5 w / v%, particularly preferably 0.001 to 0.1 w / v when the aqueous pharmaceutical composition is an eye drop or nasal drop. %: When the aqueous pharmaceutical composition is an eye wash or nasal wash, it is preferably 0.00005 to 0.02 w / v%, particularly preferably 0.0001 to 0.01 w / v%. By including the imidazoline-based vasoconstrictor at such a ratio, the effects of the present invention described above can be exhibited more effectively.

  Furthermore, the aqueous pharmaceutical composition of the present invention contains menthol (hereinafter sometimes simply referred to as component (C)). The menthol used in the present invention may be any of d-form, l-form and dl-form, but is preferably l-form. In the present invention, an essential oil containing menthol may be used as the component (C). Examples of such essential oils include mint oil, mint water, cool mint oil, spearmint oil, and peppermint oil.

  In the aqueous pharmaceutical composition of the present invention, the blending ratio of menthol is not particularly limited, and can be appropriately set according to the use or formulation form of the composition. As an example of the blending ratio of menthol in the aqueous pharmaceutical composition, a ratio in which the total amount is 0.00005 to 1 w / v%, preferably 0.0001 to 0.5 w / v% is exemplified. More specifically, the menthol content is preferably 0.0001 to 0.5 w / v%, particularly preferably 0.0002 to 0.05 w / v% when the aqueous pharmaceutical composition is eye drops or nasal drops; 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 menthol at such a ratio, the effects of the present invention described above can be achieved more effectively.

  In the aqueous pharmaceutical composition of the present invention, the ratio of the above components (A) to (C) is not particularly limited, but by satisfying the following range, the destruction of pollen, levocabastine and / or its salt particles The suppression of the increase in size and the enhancement of the refreshing feeling can be made more remarkable: the total amount of the component (A) is 100 parts by weight and the component (B) is 1 to 1900 parts by weight in total, and (C) The total amount of the components is 0.1 to 3800 parts by weight; preferably the component (B) is 3 to 400 parts by weight in total; and the component (C) is 0.3 to 1900 parts by weight in total; more preferably the component (B) is 10 in total ~ 380 parts by weight, and (C) component is 0.5 to 190 parts by weight in total.

  The aqueous pharmaceutical composition of the present invention preferably contains a thickener in addition to the components (A) to (C). The viscous agent that can be blended in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such thickeners include cellulose-based thickeners such as hydroxypropylmethylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxyethylcellulose, nitrocellulose; gum arabic, Examples include Karaya gum, xanthan gum, carob gum, guar gum, dull man gum, tragacanth gum, benzoin gum, locust bean gum, casein, agar, alginic acid, carrageenan, gelatin, pectin, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, carboxyvinyl polymer, etc. Is done. Among these, a cellulose-based thickener is preferable, and hydroxypropylmethylcellulose is particularly preferable from the viewpoint of more effectively acquiring reduction in cytotoxicity and suppressing increase in particle size of levocabastine and / or a salt thereof. The type of hydroxypropylmethylcellulose used in the present invention is not particularly limited, and examples thereof include hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, and hydroxypropylmethylcellulose 2910. Particularly preferred are hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910 and the like. The said thickener may be used individually by 1 type, and may be used in combination of 2 or more type.

When a thickener is blended in the aqueous pharmaceutical composition of the present invention, the blending ratio of the thickener can be appropriately set according to the type of the thickener used, the expected effect, and the like. As an example of the blending ratio of the thickener in the aqueous pharmaceutical composition, a ratio in which the total amount is 0.001 to 3 w / v%, preferably 0.005 to 1 w / v% is exemplified. More specifically, the blending ratio of the viscous agent is preferably 0.05 to 0.35 w / v%, particularly preferably 0.1 to 0.3 w / v% when the aqueous pharmaceutical composition is an eye drop or nasal drop; When the aqueous pharmaceutical composition is an eye wash or a nasal wash, it is preferably 0.05 to 0.35 w / v%, particularly preferably 0.1 to 0.3 w / v%. By containing a thickener (preferably a cellulosic thickener, particularly preferably hydroxypropylmethylcellulose) at such a ratio, it is more effective in reducing cytotoxicity and suppressing the increase in particle size of levocabastine and / or its salts. Can be demonstrated.

  In addition, when a cellulosic thickener, particularly hydroxypropylmethylcellulose, is blended in the aqueous pharmaceutical composition of the present invention as a thickening agent, useful effects such as reduction of cytotoxicity and suppression of increase in particle size of levocabastine and / or a salt thereof. From the viewpoint of more effectively expressing the cellulose-based thickener, it is desirable that the cellulosic thickener satisfies the following range as a ratio to the component (A): (A) Cellulosic thickener per 100 parts by weight of the component The adhesive is 15 to 4000 parts by weight, preferably 150 to 1300 parts by weight, and more preferably 350 to 1200 parts by weight.

  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, in an aqueous pharmaceutical composition, the ratio in which the buffering agent is 0.01 to 5 w / v%, preferably 0.1 to 4 w / v%, more preferably 0.3 to 3 w / v% is exemplified. .

  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). Specific examples of the components used in ophthalmic drugs or rhinitis nasal drops include the following components.

  Neostigmine methyl sulfate, zinc sulfate, zinc lactate, allantoin, pranoprofen, ε-aminocaproic acid, lysozyme chloride, sodium azulenesulfonate, dipotassium glycyrrhizinate, berberine chloride, berberine sulfate, diphenhydramine hydrochloride, chlorpheniramine maleate, acetic acid Retinol, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, aminoethylsulfonic acid (taurine), potassium aspartate, magnesium aspartate, magnesium aspartate Potassium mixture, sulfamethoxazole, sulfaisoxazole, sulfamethoxazole nato Sulfaisomidine sodium, glucose, sodium hyaluronate, chondroitin sulfate sodium, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, methyl salicylate, iproheptin hydrochloride, acrinol, benzalkonium chloride, lidocaine hydrochloride, lidocaine, chloride Benzethonium etc.

  In addition, in the aqueous pharmaceutical composition of the present invention, various additives are appropriately selected according to conventional methods according to the use and formulation form within a range that does not impair the effects of the invention, and one or more of them are selected. An appropriate amount may be contained in combination. 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.

  Macrogol, poloxamer, poloxamine, polysorbate 80, polyoxyethylene (60) hydrogenated castor oil, alkyldiaminoethylglycine, benzalkonium chloride, parabens, sorbic acid, potassium sorbate, polyhexamethylene biguanide, potassium chloride, sodium chloride , Calcium chloride, magnesium sulfate, glycerin, propylene glycol, camphor, geraniol, borneol, fennel oil, bergamot oil, eucalyptus oil, rose oil, sodium edetate, benzethonium chloride, citric acid, trometamol, chlorhexidine gluconate, chlorobutanol, acetic acid Sodium, acetic acid, sodium bicarbonate, sodium carbonate and the like.

  Since the aqueous pharmaceutical composition of the present invention is liquid and fluid, it is easy to apply to mucous membranes. In a conventional aqueous composition containing 50% by weight or more of water, levocabastine and / or a salt thereof has an effect on bioavailability, dispersion stability, etc., as the particle size increases with the passage of storage time. In the aqueous pharmaceutical composition of the present invention, although it is a liquid containing 50% by weight or more of water, such disadvantages are solved and the increase in the particle size of levocabastine and / or its salt is suppressed. .

  Since the aqueous pharmaceutical composition of the present invention can exhibit useful effects based on the above components (A) to (C), it is used as a pharmaceutical or quasi-drug preparation. Specifically, the aqueous pharmaceutical composition of the present invention includes eye drops (however, eye drops include eye drops that can be applied while wearing contact lenses), eye wash (however, for eye wash) Ophthalmic compositions such as eyewashes that can be washed while wearing contact lenses; otolaryngological compositions such as nasal drops, nasal rinses, and ear drops; contact lens care agents (contact lens disinfectants, contacts) Examples include contact lens compositions such as lens preservatives, contact lens cleaners, and contact lens cleaner preservatives; and oral compositions such as oropharyngeal drugs and gargles (mouth rinses). Among these preparation forms, preferred are mucosa-applied compositions such as ophthalmic compositions and otolaryngological compositions, and more preferred are eye drops or nasal drops.

  In addition, the said composition for contact lenses can be applied to all types of contact lenses, regardless of whether they are hard contact lenses or soft contact lenses.

  The aqueous pharmaceutical composition of the present invention can suppress the rupture of pollen and can effectively suppress the occurrence of allergic symptoms caused by pollen. In view of such effects, the aqueous pharmaceutical composition of the present invention is useful as a pollen burst inhibiting composition or an antiallergic composition, particularly as a composition for preventing or treating hay fever. The aqueous pharmaceutical composition of the present invention is also useful as a composition for treating or alleviating nasal inflammation.

  The aqueous pharmaceutical composition of the present invention can be produced by using purified water as a base, adding and mixing the above-described ingredients, and formulating it according to the intended dosage form.

(II) Method for reducing cytotoxicity, method for inhibiting pollen rupture, method for enhancing refreshment, and method for stabilizing the particle size of levocabastine and / or a salt thereof As described above, in the aqueous pharmaceutical composition, levocabastine and / or Alternatively, the cytotoxicity of an aqueous pharmaceutical composition containing an imidazoline vasoconstrictor can be reduced by the coexistence of a salt thereof, an imidazoline vasoconstrictor and menthol. Therefore, the present invention is characterized in that (a) levocabastine and / or a salt thereof, and (c) menthol coexist in an aqueous pharmaceutical composition containing an imidazoline vasoconstrictor from another viewpoint. The present invention provides a method for reducing cytotoxicity of an aqueous pharmaceutical composition containing an imidazoline vasoconstrictor.

  Further, as described above, pollen rupture can be suppressed by allowing levocabastine and / or a salt thereof, an imidazoline vasoconstrictor, and menthol to coexist in an aqueous pharmaceutical composition. Therefore, the present invention provides a step of bringing an aqueous pharmaceutical composition containing (a) levocabastine and / or a salt thereof, (b) an imidazoline-based vasoconstrictor, and (c) menthol into contact with pollen from yet another viewpoint. A method for suppressing pollen rupture is provided. Further, the present invention provides an aqueous pharmaceutical composition characterized by coexisting (a) levocabastine and / or a salt thereof, (b) an imidazoline vasoconstrictor, and (c) menthol in an aqueous pharmaceutical composition. A method for imparting a pollen rupture inhibitory action to a pollen.

  In addition, as described above, in the aqueous pharmaceutical composition containing menthol, it is possible to provide a refreshing feeling by coexisting levocabastine and / or a salt thereof and an imidazoline vasoconstrictor. Therefore, the present invention is characterized in that (a) levocabastine and / or a salt thereof, and (b) an imidazoline vasoconstrictor coexist in an aqueous pharmaceutical composition containing menthol, from another viewpoint. A method for enhancing the refreshing feeling of an aqueous pharmaceutical composition containing menthol is provided.

  Furthermore, as described above, the particle size of levocabastine and / or a salt thereof in the aqueous pharmaceutical composition by coexisting levocabastine and / or a salt thereof, an imidazoline vasoconstrictor, and menthol in the aqueous pharmaceutical composition. Can be suppressed. Therefore, the present invention is characterized in that (b) an imidazoline-based vasoconstrictor and (c) menthol are coexisted in an aqueous pharmaceutical composition containing levocabastine and / or a salt thereof from still another viewpoint. The present invention provides a method (stabilization method) for stabilizing the particle size of levocabastine and / or a salt thereof.

  In these methods, the type and concentration of levocabastine and / or its salt to be used, the type and concentration of an imidazoline vasoconstrictor, the type and concentration of menthol, the type and concentration of other ingredients, the formulation of an aqueous pharmaceutical composition The use and the like are as described in the column “(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 Test liquids (composition test liquid 1 and comparative test liquid 1-4) having the composition shown in Table 1 were prepared, and the cytotoxicity of these test liquids was measured using Cornepack (normal rabbit corneal epithelial cells). : NRCE2, serum-free liquid medium for rabbit corneal epithelial cell proliferation: RCGM2, both manufactured by Kurabo Industries) and NR reagent set (for NRCE2, manufactured by Kurabo Industries) were used for the test. 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 were inoculated in a 96-well multiplate at 100 μL to 2000 cells / well and cultured at 37 ° C. under 5% CO 2 for 3 days. 100 μL of the test solution shown in Table 1 was added to each well containing the corneal epithelial cells thus cultured, and cultured for 2 days at 37 ° C. and 5% CO 2. (n = 3)
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 37 ° C. and 5% CO 2 for 2 hours. Incubated.

  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. As a control, a test was performed in the same manner with a medium added instead of the test solution, and the absorbance of neutral red at 540 nm was measured. According to the following formula, cell viability when each test solution was added was calculated.

  The obtained results are shown in FIG. As can be seen from FIG. 1, when the test solution 1 was added, the cell viability was significantly higher than when the comparative test solution 1-4 was added. From these results, it was confirmed that the aqueous pharmaceutical composition containing levocabastine hydrochloride, naphazoline hydrochloride, and menthol as a unit can reduce cytotoxicity and have high safety.

  Furthermore, when cytotoxicity was evaluated in the same manner as described above using the same amount of camphor instead of menthol in the above test solution, the test solution 4 containing levocabastine hydrochloride, naphazoline hydrochloride, and camphor was effective in reducing cytotoxicity. Was not recognized.

Test Example 2 Evaluation of Pollen Bursting Inhibitory Effect An aqueous pharmaceutical composition (Example 1, Comparative Example 1-6 and control) having the composition shown in Table 2 was prepared, and the cedar pollen burst inhibiting effect of these aqueous pharmaceutical compositions The following tests were conducted and evaluated.

  Specifically, 5 mg of cedar pollen was mixed with 1 mL of each aqueous pharmaceutical composition and left at 37 ° C. for 1 hour. The degree of subsequent cedar pollen rupture was observed under a microscope. The percentage of pollen rupture (%) was determined by measuring the ratio of the number of ruptured pollen to the total number of pollen per unit area with a microscope. Furthermore, based on the following formula, the pollen rupture rate of each aqueous pharmaceutical composition relative to the pollen rupture rate of the control aqueous pharmaceutical composition was calculated as a pollen rupture inhibition rate (%).

  The results are shown in FIG. As is clear from FIG. 2, the pollen rupture inhibition rate showed a high value only when levocabastine hydrochloride, tetrahydrozoline hydrochloride and menthol were combined together (Example 1). On the other hand, in Comparative Example 1-6, the tendency which promotes pollen rupture was recognized.

  From the above results, it was found that the pollen rupture inhibitory effect was obtained by using menthol together with levocabastine hydrochloride and tetrahydrozoline hydrochloride, and could not be obtained using other terpenoids. That is, according to the aqueous | water-based pharmaceutical composition of this invention, since the burst of pollen was suppressed, it became clear that release | release of allergen by burst to a pollen can be suppressed effectively.

Test Example 3 Evaluation of Usability A nasal drop (Example 2 and Comparative Example 7-9) having the composition shown in Table 3 was prepared and filled in a nasal drop container made of polypropylene. A usability evaluation test was conducted by two monitors. Specifically, the nasal drop of Example 2 was dropped on both noses by two pushes, and the refreshing feeling felt was evaluated immediately after the nasal drop. After 6 hours, the nasal drop of Comparative Example 8 was dropped on both noses in two pushes in the same manner. Similarly, the nasal drop of Example 2 and Comparative Example 8 were compared immediately after nasal drop. On another day, the comparison between Example 2 and Comparative Example 9, the comparison between Comparative Example 7 and Comparative Example 8, and the comparison between Comparative Example 7 and Comparative Example 9 were performed in the same procedure. In addition, all this tests were implemented by n = 2.

  The results are shown in Table 4. From these results, the nasal preparation containing menthol, tetrahydrozoline hydrochloride and levocabastine hydrochloride (Example 2) is more stigmatic than the nasal preparation containing two components of menthol and tetrahydrozoline hydrochloride, menthol and levocabastine hydrochloride (Comparative Example 8-9) A refreshing feeling immediately after the nose was felt more strongly, and it was confirmed that the feeling of use was good. Moreover, in the comparison between the comparative example 7 and the comparative example 8, and the comparison between the comparative example 7 and the comparative example 9, a result that the refreshing feeling was the same was obtained.

  From these results, it was confirmed that levocabastine and tetrahydrozoline alone have no effect of improving the refreshing feeling of menthol, but when these three components are combined, the refreshing feeling can be enhanced.

Test Example 4 Stability Evaluation Aqueous pharmaceutical compositions (Example 3 and Comparative Examples 10-12) having the compositions shown in Table 5 were prepared, and each 5 mL was filled in a 10 mL glass screw vial, and each week at 60 ° C. for 1 week. The particle size of levocabastine in each aqueous pharmaceutical composition after storage was measured using a laser diffraction / scattering particle size distribution analyzer HORIBA LA-920. The particle diameter is shown as the particle diameter (μm) at the apex on the frequency graph where the frequency distribution value is the largest, that is, the mode diameter.

  The results are also shown in Table 5. From this result, when tetrahydrozoline hydrochloride and menthol were blended together with levocabastine hydrochloride (Example 3), the particle diameter after storage was fine and stable as a dispersion system. From these results, it was revealed that tetrahydrozoline hydrochloride and menthol contribute to the suppression of the increase in particle size of levocabastine hydrochloride.

Formulation Examples Eye drops (Example 4-13) and nasal drops (Examples 14-23) are prepared according to the formulations shown in Tables 6 and 7 below.

In Test example 1, it is the result of having evaluated the cytotoxicity of the test liquid (The implementation test liquid 1 and the comparative test liquid 1-4). In Test example 2, it is the result of evaluating the burst suppression effect of the pollen of an aqueous | water-based pharmaceutical composition (Example 1, Comparative Example 1-6).

Claims (8)

  An aqueous pharmaceutical composition comprising (a) levocabastine and / or a salt thereof, (b) an imidazoline vasoconstrictor, and (c) menthol.   The aqueous pharmaceutical composition according to claim 1, further comprising a thickening agent.   The aqueous pharmaceutical composition according to claim 2, wherein the thickener is a cellulosic thickener.   The aqueous pharmaceutical composition according to claim 2, wherein the thickening agent is hydroxypropylmethylcellulose.   The aqueous pharmaceutical composition according to any one of claims 1 to 4, which is a composition applied to mucosa.   The aqueous pharmaceutical composition according to any one of claims 1 to 5, which is an ophthalmic composition or an otolaryngological composition.   The aqueous pharmaceutical composition according to any one of claims 1 to 6, which is a nasal drop or an eye drop.   A method for inhibiting pollen rupture, comprising a step of bringing an aqueous pharmaceutical composition containing (a) levocabastine and / or a salt thereof, (b) an imidazoline vasoconstrictor, and (c) menthol into contact with pollen.

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