WO2006137433A1

WO2006137433A1 - Aqueous preparation having levocabastine solubilized therein

Info

Publication number: WO2006137433A1
Application number: PCT/JP2006/312403
Authority: WO
Inventors: Toru Oguma
Original assignee: Wakamoto Pharmaceutical Co., Ltd.
Priority date: 2005-06-21
Filing date: 2006-06-21
Publication date: 2006-12-28
Also published as: JPWO2006137433A1

Abstract

A weakly acidic to almost neutral aqueous preparation containing levocabastine, a cyclodextrin and a water-soluble cellulose derivative. A conventional levocabastine suspension preparation needs to be fully shaken to give a homogenous solution before use. However, the inventive levocabastine preparation does not need such an effort since levocabastine is solubilized in the preparation. The levocabastine preparation can be applied to eyes in the form of an eye drop even when contact lens are worn, and therefore is easy to use for a user.

Description

Specification

Aqueous drug with solubilized levocabastine

Technical field

[0001] The present invention relates to an aqueous drug in which levocabastine is soluble.

Background art

[0002] Levocabastine is a drug that is poorly soluble in water and difficult to dissolve, so allergic conjunctivitis and allergic rhinitis as suspension eye drops (0.025% and 0.05%) and suspension nasal drops (0.025%) Has been used to treat.

When using a suspension, the container must be shaken thoroughly to make a uniform solution before use. Also, doctors should instruct patients not to apply suspension eye drops when wearing contact lenses.

On the other hand, a better aqueous solution can be obtained than the above-mentioned troublesome use, and a water-soluble preparation is desired.

[0003] Against this background, WO95 / 25518, PCT / IB95 / 00143 (CIBA-GEIGY AG) discloses a water-soluble preparation of levocabastine with hydroxypropyl β-cyclodextrin. Hydroxypropyl | 8-cyclodextrin is a novel substance as a pharmaceutical additive, and it is not a single substance. Therefore, it takes a long development period and a large amount of development costs to put it into practical use. Not reached.

JP-A-11-512445 discloses a composition for ophthalmic levocabastine as a pharmaceutically active compound, but there is no specific description of the aqueous drug of the present invention. Cyclodextrins and water-soluble cellulose derivatives There is no description or suggestion that the combined use of the combination produces a synergistic solubilizing action, and makes levocabastine highly soluble.

[0004] Patent Document 1: W095 / 25518

Patent Document 2: Japanese Patent Publication No. 11-512445

Disclosure of the invention

Problems to be solved by the invention

[0005] The present invention is an aqueous solution containing dissolved levocabastine using an existing pharmaceutical additive. The purpose is to provide drugs.

Means for solving the problem

The present invention provides the following aqueous drugs.

1. Antiallergic aqueous drug containing levocabastine, cyclodextrins and water-soluble cellulose derivatives.

2. An aqueous drug containing dissolved levocabastine, wherein levocabastine is dissolved and dissolved by adding cyclodextrins and a water-soluble cellulose derivative.

3. The aqueous drug according to 1 or 2 above, wherein the cyclodextrins are at least one selected from the group force consisting of a, j8, and γ-cyclodextrin.

4. The aqueous drug according to any one of 1 to 3 above, wherein the water-soluble cellulose derivative is at least one selected from the group force consisting of methylcellulose and hydroxypropylmethylcellulose.

5. The aqueous drug according to any one of 1 to 4 above, wherein levocabastine is in a concentration range of 0.01 to 0.5 w / v%.

6. The aqueous drug according to any one of 1 to 5 above, wherein the water-soluble cellulose derivative is in a concentration range of 0.002 to 1.0 w / v%.

7. The aqueous drug according to 3 above, wherein a-cyclodextrin is in a concentration range of 1 to 10 w / v%, β-cyclodextrin and 0.2 to 1.6 w / v%, or γ-cyclodextrin and ¾ to 23 w / v%.

8. The aqueous drug according to 6 above, wherein the water-soluble cellulose derivative is in the concentration range of 0.002 to 0.4 w / v%.

9. The above-mentioned 7 in the concentration range of a-cyclodextrin ¾ to 8w / v%, β-cyclodextrin S 0.3 to 1.4w / v% or _{シクロ} -cyclodextrin ¾ to 18w / v% Aqueous drugs

10. The aqueous drug according to any one of 1 to 9 above, wherein the levocabastine is levocabastine hydrochloride.

The inventor has only a slight soluble effect on levocabastine alone. The combined use of rhodextrins and water-soluble cellulose derivatives produces a synergistic solubilizing action, and can make levocabastine so much soluble, preferably at a slightly acidic to neutral pH. I found. That is, the present invention is an aqueous drug containing levocabastine, cyclodextrins and a water-soluble cellulose derivative, preferably a weakly acidic to neutral aqueous drug.

Further, the present invention is an aqueous drug containing levocabastine dissolved therein, wherein the lepocanstine is solubilized by containing cyclodextrins and a water-soluble cellulose derivative.

[0008] Due to the solubility of levocabastine, the problems of conventional suspension preparations can be solved and preparations can be easily prepared. When using suspension preparations, the container must be shaken well to make a uniform chemical solution, and the force must be used. It can be instilled even when worn, making it a user-friendly formulation.

BEST MODE FOR CARRYING OUT THE INVENTION

[0009] Preferable examples of the cyclodextrins include α, β, and γ-cyclodextrin. The required amount of the cyclodextrins (eg, α, j8 and γ-cyclodextrin) for a given levocabastine can be easily determined by a person skilled in the art from time to time by conducting a simple solubility test according to the method described in the present invention. Can be determined. These cyclodextrins can be used alone or in combination.

The concentration of cyclodextrins used in the present invention is 1 to 10% for a-cyclodextrin, 0.2 to 1.6% for β-cyclodextrin, 6 to 23% for y-cyclodextrin, and more preferably Α-cyclodextrin is 2-8%, β-cyclodextrin is 0.3-1.4%, and y-cyclodextrin is 9-18%. The concentration of cyclodextrin used does not need to be increased as long as levocabastine is sufficiently soluble in relation to the type of cyclodextrin used and the cellulose derivative used in combination. Moreover, since the solubility of cyclodextrins varies depending on the temperature, it is necessary to set a concentration at which cyclodextrins do not precipitate in practice. Each cyclodextrin exhibits the soluble effect of lepocabastin in addition to each other. It is convenient to use together. In particular, it is preferable to use a combination of α-cyclodextrin and j8-cyclodextrin, in which the amount of levocabastine dissolved is large.

[0010] Examples of the water-soluble cellulose derivative used in the present invention include methyl cellulose, hydroxypropinoremethinoresenorelose, hydroxypropinoresenorelose, hydroxyethylcellulose, and hydroxyethylmethylcellulose. Force methylcellulose or hydroxypropylmethylcellulose is preferred.

The methylcellulose used in the present invention is not particularly limited, and even a miscellaneous methylcellulose can be used alone or in combination, but the viscosity of a 2 w / v% aqueous solution at 20 ° C is 3 to 12000 millipascal'second. The thing of the range of is preferable. In addition, methylcellulose is distinguished by the viscosity of its aqueous solution.For example, the commercial product varieties have the indicated viscosity 4, 15, 25, 100, 400, 1500, 8000 (the numbers are millipascals with a 20 ° C viscosity of 2 w / v% aqueous solution). 'S) and are readily available. The outline, specifications, application, use amount and product name of methylcellulose are described in detail in the Pharmaceutical Additives Dictionary (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo).

The concentration of methylcellulose used is effective over a wide range of 0.002 to lw / v%, and more preferably 0.002 to 0.4 w / v%. The concentration of methylcellulose used does not need to be increased as long as levocabastine hydrochloride is sufficiently soluble in relation to the cyclodextrin used together.

[0011] The hydroxypropyl methylcellulose used in the present invention is not particularly limited, and any hydroxypropylmethylcellulose can be used alone or in combination. The viscosity of a 2 w / v% aqueous solution at 20 ° C is 3 ~ 10000 millipascals · Preferably in the range of seconds! /. Furthermore, hydroxypropyl methylcellulose is distinguished by the viscosity of its aqueous solution.For example, for commercial varieties, the indicated viscosity is 3, 4, 4.5, 6, 15, 50, 100, 400, 1500, 4000, 10000 (the number is 2 w / v% aqueous solution with a viscosity of 20 ° C and millipascal.second) and is readily available. The outline, specifications, application, amount used and product name of hydroxypropylmethylcellulose are described in detail in the Pharmaceutical Additives Dictionary (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo).

The concentration of hydroxypropyl methylcellulose used is a wide range of 0.002 to lw / v% And more preferably 0.002 to 0.4 w / v%. As described above with respect to the concentration of methylcellulose, the concentration of hydroxypropylmethylcellulose used does not need to be increased as long as lepocanustin is sufficiently soluble in relation to the cyclodextrin used together.

In the present invention, it is preferable to adjust the pH of the solution to usually 5 to 9, preferably 6 to 8. Examples of such drugs include, but are not limited to, external preparations, eye drops, nasal drops, ear drops and the like.

In addition, the aqueous drug of the present invention may further contain an inorganic salt (for example, sodium chloride, boric acid, potassium chloride, etc.), a polyhydric alcohol (propylene glycol, glycerin, mannitol, sorbitol, etc.) as necessary. ) Isotonic agents, buffers (eg, borate buffer, phosphate buffer, acetate buffer, citrate buffer, tris buffer, etc.), amino acids (eg, glutamate, ε-aminocaproic acid, etc.) ) Buffering agents, chelating agents (eg, sodium edetate, cuenic acid, etc.), quaternary ammonium salts (eg, salted benzalcoum, salted benzethonium), noroxy Benzoic acid esters (for example, methyl noroxybenzoate, ethoxyethyl para-benzoate, propyl noroxybenzoate, butyl noroxybenzoate), sol Phosphate, chlorobutanol, sodium Edeto acid, suitably incorporated preservatives, etc., such as boric acid. Usually, it is used at a ratio of tonicity agent 0.5 to 6.5 w / v%, buffer agent 0.01 to 1.0 w / v%, chelating agent 0.001 to 0.1 w / v% with respect to the total amount of aqueous drug. The term levocabastine includes levocabastine and pharmaceutically acceptable salts thereof. Most preferred is levocabastine hydrochloride.

External preparations, eye drops, and nasal drops can be produced by a known method using the aqueous drug of the present invention. For example, the solubilizing agent (cyclodextrin and water-soluble cellulose derivative), buffer, isotonic agent and preservative of the present invention are added to sterilized purified water and dissolved. A desired solution can be prepared by dissolving levocabastine, for example, levocabastine hydrochloride, in this solution.

Furthermore, the aqueous liquid preparation of the present invention may contain medicinal ingredients other than levocabastine. These medicinal ingredients include analgesics, anti-inflammatory agents, antiallergic agents, wound healing agents And antibacterial agents.

Example 1

[0013] In the following, as an example, test results are shown for the effects of water-soluble cellulose derivatives and cyclodextrins alone and in combination on the solubility [w / v%] of levocabastine hydrochloride. Methyl cellulose [Metroses SM-4 (Shin-Etsu Chemical Co., Ltd.)] and hydroxypropyl methyl cellulose [TC-5 (Shin-Etsu Chemical Co., Ltd.)] were used as water-soluble cellulose derivatives. % Is wZv% unless otherwise specified.

[0014] [Solubilization test]

(1) Solubility change of levocabastine hydrochloride by cellulose derivative alone

1) Change in solubility of levocabastine hydrochloride by methylcellulose alone

At room temperature (21 ° C), 0.4 g of levocabastine hydrochloride is mixed with 1/15 M phosphate buffer (pH 7.0), and 0.00001, 0.0001, 0.001, 0.01, 0.1, 0.2, 0.4, 0.6, 0.8, 1.0 A methylcellulose solution (dissolved in the above-mentioned phosphate buffer) was added and stirred so as to be 100%, and the volume was adjusted to 100 ml with 1 / 15M phosphate buffer (PH7.0). After stirring, these aqueous drugs were filtered with a 0.45 m filter, and the concentration of levocabastine hydrochloride in the filtrate was measured by HPLC.

[0015] 2) Change in solubility of levocacastin by hydroxypropylmethylcellulose alone

At room temperature (21 ° C), 0.4 g of levocabastine hydrochloride is mixed with 1/15 M phosphate buffer (pH 7.0), and this is mixed with hydroxypropylmethylcellulose solution to 0.001, 0.01, 0.1, 0.2, 0.3%. (Dissolved in the above phosphate buffer) was added and stirred, and the volume was made up to 100 ml with 1/15 M phosphate buffer (pH 7.0). After stirring, these aqueous drugs were filtered through a 0.45 μm filter, and the concentration of lepocanastine hydrochloride in the filtrate was measured by HPLC.

[0016] The measurement conditions are as follows.

(a) Detector: UV spectrophotometer (measurement wavelength 225 nm)

(b) Column: Mightysil RP-18 GP 5 m φ 4.6 X 150 mm (manufactured by Kanto Chemical Co., Inc.)

(c) Column temperature: room temperature

(d) Mobile phase: 5mmol / L sodium dihydrogen phosphate solution (adjusted with pH2.5 phosphoric acid): Acetonitrile (6: 4)

(e) Flow rate: 0.55ml / min (revocabastine hydrochloride retention time approx. 5 minutes) [0017] Tables 1 and 2 show the amounts of levocabastine hydrochloride (mg / ml) dissolved in the filtrate for each concentration (w / v%) of methylcellulose and hydroxypropylmethylcellulose. As can be seen from the above, the amount of levocabastine hydrochloride dissolved in combination with methylcellulose or hydroxypropyl methylcellulose was very small, and it was found that levocabastine hydrochloride had a concentration of about 0.09 mg / ml and did not dissolve forcefully. The concentration of levocabastine hydrochloride in the preparation actually used for treatment is 0.27 mg / ml and 0.54 mg / ml (0.25 mg / ml and 0.50 mg / ml as levocabastine), and the amount of levocabastine hydrochloride dissolved by these water-soluble celluloses is It doesn't go far.

[0018] [Table 1]

“Change in solubility of levocabastine hydrochloride by methylcellulose (MC) (21 ° C) I

Dissolved amount of levocabastine hydrochloride (mg / ml)

[0020] (2) Change in solubility of levocabastine hydrochloride by cyclodextrins alone

1) Change in solubility of levocabastine hydrochloride by a-cyclodextrin alone At room temperature (21 ° C), 0.4 g of levocabastine hydrochloride was mixed with 1 / 15M phosphate buffer (pH 7.0). Add α-cyclodextrin to 8%, 10%, 12% and stir.

The volume was made up to 100 ml with Μphosphate buffer (ρΗ7.0). After stirring, add these aqueous drugs to

Filter with a 45 μm filter, and measure the concentration of levocabastine hydrochloride in the filtrate by HPLC.

[0021] 2) Change in solubility of levocabastine hydrochloride by β-cyclodextrin alone At room temperature (21 ° C), 0.4 g of levocabastine hydrochloride is mixed with 1/15 M phosphate buffer (pH 7.0), and this is adjusted to 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6% j8 —Cyclodextrin was added and stirred, and the volume was made up to 100 ml with 1/15 M phosphate buffer (pH 7.0). After stirring, these aqueous drugs were filtered through a 0.45 m filter, and the concentration of levocabastine hydrochloride in the filtrate was measured by HPLC.

[0022] 3) Change in solubility of levocabastine hydrochloride by y-cyclodextrin alone

At room temperature (21 ° C), 0.4 g of levocabastine hydrochloride is mixed with 1/15 M phosphate buffer (pH 7.0), and then γ-cyclodextrin is added to 3, 6, 9, 12, 15%. In addition, the mixture was stirred and made up to 100 ml with 1/15 M phosphate buffer (とした 7.0). After stirring, these aqueous drugs were filtered through a 0.45 μm filter, and the concentration of levocabastine hydrochloride in the filtrate was measured by HPLC.

The measurement conditions are as described in (1) above.

[0023] Tables 3 to 5 show the amount of levocabastine hydrochloride (mg / ml) dissolved in the filtrate for each concentration (w / v%) of various cyclodextrins.

As shown in the table, with any cyclodextrin, the amount of lepocanostine hydrochloride dissolved increases as the concentration of cyclodextrin increases. However, adding OL-cyclodextrin to a concentration of 12 w / v%, adding β-cyclodextrin to a concentration of 1.6 w / v%, and γ-cyclodextrin. Even if dextrin is added to a concentration of 15 w / v%, the dissolved amounts of the repo vastin hydrochloride are 0.477 mg / ml, 0.39 mg / ml and 0.068 mg / ml, respectively. Moreover, since the solubility of cyclodextrin itself in water is temperature-dependent, cyclodextrin itself precipitates as crystals when the room temperature decreases to around 15 ° C, so the practical amount of lepocanostine hydrochloride dissolved in cyclodextrin is further increased. V, which should be estimated low. The concentration of levocabastine hydrochloride, which is actually used for treatment, is 0.25 mg / ml and 0.50 mg / ml as levocabastine, and it is necessary to have at least some allowance for solubles in the production of actual aqueous solutions. Therefore, it is difficult to formulate with only these cyclodextrins.

[0024] [Table 3] Change in solubility of levocabastine hydrochloride by α-cyclodextrin (a-CD) (21 ° C) Dissolution amount of levocabastine hydrochloride (mg / ml)

(a -CD) (%) 0 2. 0 4. 0 6. 0 8. 0 10. 0 12. 0

S solution 0. 008 0. 061 0. 103 0. 1 70 0. 28 1 0. 372 0. 477

[0025] [Table 4]

[0026] [Table 5]

[0027] (3) Change in solubility of levocabastine hydrochloride by combined use of cyclodextrins and water-soluble cellulose derivatives

By the method shown in the above (2), <<, j8 and γ cyclodextrin were adjusted to the concentrations described in Tables 6 to 8. Add methylcellulose or hydroxypropylmethylcellulose to these preparations, and add test solution so that methylcellulose in each preparation is 0.2 w / v% or hydroxypropylmethylcellulose in each preparation is 0.1 lw / v%. Prepared. These aqueous drugs were filtered through a 0.45 μm filter, and the amount of levocabastine hydrochloride dissolved in the filtrate was measured by HPLC.

The measurement conditions are as described in (1) above.

[0028] As shown in Tables 6 to 8 (Figs. 1 to 3), when methylcellulose is contained at a concentration of 0.2 w / v% or hydroxypropylmethylcellulose at a concentration of 0.1 w / _v %, levocabas hydrochloride is used. The amount of tin dissolved increases from the amount of water-soluble cellulose derivatives (MC, HPMC) and cyclodextrins (α, β, γ) alone, as the concentration of cyclodextrins (III, β, γ) increases. It increased rapidly compared to the expected amount of dissolution (predicted amount: additive), indicating these apparent synergistic effects. — A clear increase starts from 2w / v% for CD, 0.2w / v% for β-CD, and 3w / v% for γ-CD, and a CD and | 8-CD are more than twice the predicted amount. In addition, γCD increased more than three times the predicted amount. Due to these synergistic effects, water-soluble salts Acid levocabastine drug (0.05%) can be easily manufactured _c

[Table 6]

[Table 7]

Changes in the solubility of levocapastin hydrochloride by adding water-soluble cellulose derivatives (MC: 0.2% or HPMC: 0.1%) to 3-cyclodextrin (-CD) at various concentrations (21 ° C)

Dissolved amount of levocapastin hydrochloride (mg / ml)

(4) Examination of the amount of water-soluble cellulose that exhibits a synergistic effect

In advance, 0.000002, 0.00002, 0.0002, 0.002, 0.02, 0.2, 0.3, 0.4, 0.5% methylcellulose and hydroxypropylmethylcellulose solutions were prepared using a 1 / 15M phosphate buffer (pH 7.0). At room temperature (21 ° C), these hydrochloric Repokano cystine 0.4g each preparation, a - cyclodextrin 7 ₈ and _| 8- cyclodextrin lg mosquitoes卩Ete, mixed and stirred, preparation of cellulose derivatives of the above And made up to 100 ml.

These aqueous drugs are filtered through a 0.45 μm filter, and levocabastine hydrochloride in the filtrate is filtered. The amount of dissolution was measured by HPLC.

The measurement conditions are as described in (1) above.

[0033] As shown in Table 9 (FIG. 4)! /, A synergistic effect with cyclodextrin was manifested with an applied force of 0.002 w / v% for methylcellulose and hydroxypropylmethylcellulose, and 0.3 to The synergistic effect is maximized with the addition of 0.4 w / v%, and the amount of levocabastine hydrochloride dissolved is 2.7 to 3.8 times the expected amount of dissolution due to the addition of the amount of levocabastine hydrochloride dissolved by cyclodextrin alone and water-soluble cellulose derivative alone. It became. Furthermore, the amount of dissolution does not increase even if the amount of added cellulose in the cellulose derivative is increased.

[0034] [Table 9]

[0035] (5) Change in solubility of levocabastine hydrochloride by combination of a CD and j8-CD

The solution was prepared by the method shown in (2) above so that a and j8-cyclodextrin had the concentrations shown in Table 10. Methyl cellulose was added to these prepared solutions, and test solutions were prepared so that methyl cellulose in each prepared solution was 0.5 w / v%. These aqueous drugs were filtered through a 0.45 μm filter, and the amount of levocabastine hydrochloride dissolved in the filtrate was measured by HPLC.

The measurement conditions are as described in (1) above. The results are shown in Table 10.

[0036] [Table 10]

It can be seen that the combined use of CD and | 8—CD synergistically improves the amount of levocabastine hydrochloride dissolved compared to the case of single use.

Example 2

[0037] The following are typical examples of the present invention applied to the form of eye drops.

[Example 1] Eye drops

The following components were mixed by a conventional method to form a clear solution, which was sterilized by filtration to give an eye drop.

[Example 3] Eye drops

The following components were mixed by a conventional method to form a clear solution, which was sterilized by filtration to give an eye drop. Levocabastine hydrochloride 0. 054 g

α — Cyclodextrins 4 g

γ — cyclodextrins 12 g

Methinoresenorelose 0.02 g

Sodium chloride 0.45 g

Sodium dihydrogen phosphate sodium hydrate 0.1 g

Sodium edetate 0.05 g

Benzalkonium chloride 0.03 g

0.1 N-Sodium hydroxide proper amount (pH 7.0)

Sterile purified water Total volume 100ml

[Example 4] Eye drops

The following ingredients are mixed by a conventional method to make a clear solution, and sterilized by filtration.

Levocapathin hydrochloride 0. 054 g

β — Cyclodextrins 0.8 g

γ —cyclodextrin 12 g

Methinoresenorelose 0.02 g

Sodium chloride 0.45 g

Sodium dihydrogen phosphate sodium hydrate 0.1 g

Sodium edetate 0.05 g

Benzarconium chloride 0.03 g

0.1 N-Sodium hydroxide appropriate amount (pH 7.0)

Sterilized purified water 100ml

[Example 5] Eye drops

The following ingredients were mixed by a conventional method to make a clear solution, and sterilized by filtration to give an eye drop.

[Example 6] Eye drops

Sodium cromoglycate 2 g

ct-cyclodextrin 8 g

β-cyclodextrin 1.3 g

Methinoresenorelose 0.002 g

Sodium chloride 0.4 g

Sodium dihydrogen phosphate Rumuni hydrate 0.1 g

ナ Sodium Detoate 0.005 g

Benzalkonium chloride 0.03 g

0.1 N Sodium hydroxide appropriate amount (pH 7.0)

Sterilized purified water 100ml

[Example 7] Eye drops

Levocabastine hydrochloride 0. 054 g

Off mouth oxacin 0.3 g

α-cyclodextrin 7 g

—Cyclodextrins 1 g

Methinoresenorelose 0.002 g

Sodium chloride 0.45 g

Sodium dihydrogen phosphate Rumuni hydrate 0.1 g

Sodium edetate 0.05 g

Benzalkonium chloride 0.03 g

0.1 N Sodium hydroxide appropriate amount (pH 7.0)

Sterilized purified water 100ml

[0044] Nasal formulation

The method for producing the nasal drops of the present invention is not particularly limited, and can be produced by a known method. For example, after dissolving each of the above components in water or warm water by a conventional method, pH, osmotic pressure, etc. are appropriately adjusted to produce a solution, and further, aseptic filtration is performed as necessary. It can be manufactured by filling a container.

Industrial applicability

[0045] The present invention relates to an aqueous drug in which levocabastine is soluble.

Brief Description of Drawings

FIG. 1 is a diagram showing the synergistic effect of α-CD and cellulose derivatives shown in Table 6.

FIG. 2 is a diagram showing the synergistic effect of 13 CD shown in Table 7 and a cellulose derivative. FIG. 3 is a diagram showing the synergistic effect of γ-CD and cellulose derivatives shown in Table 8.

FIG. 4 is a diagram showing an examination of the addition amount of the cellulose derivative shown in Table 9.

Claims

The scope of the claims

[1] An antiallergic aqueous drug containing levocabastine, cyclodextrins and a water-soluble cellulose derivative.

[2] An aqueous drug containing levocabastine dissolved therein, wherein the levocabastine is soluble by adding a cyclodextrin and a water-soluble cellulose derivative.

[3] The aqueous drug according to claim 1 or 2, wherein the aqueous drug is at least one selected from the group forces consisting of cyclodextrins _α , β, and γ-cyclodextrin.

[4] The aqueous drug according to any one of claims 1 to 3, wherein the water-soluble cellulose derivative is at least one selected from the group force consisting of methylcellulose and hydroxypropylmethylcellulose.

[5] The aqueous drug according to any one of claims 1 to 4, wherein levocabastine is in a concentration range of 0.01 to 0.5 w / v%.

6. The aqueous drug according to any one of claims 1 to 5, wherein the water-soluble cellulose derivative is in a concentration range of 0.002 to 1.0 w / v%.

[7] The concentration according to claim 3, wherein a-cyclodextrin is in a concentration range of 1 to 10 w / v%, β-cyclodextrin-ca 0.2 to 1.6 w / v%, or _{シクロ} -cyclodextrin-ca S6 to 23 w / v%. Aqueous drug

8. The aqueous drug according to claim 6, wherein the water-soluble cellulose derivative is in a concentration range of 0.002 to 0.4 w / v%.

[9] The concentration of a-cyclodextrin ¾ to 8w / v%, β-cyclodextrin S 0.3 to 1.4w / v%, or γ-cyclodextrin 9 to 18w / v%, Aqueous drugs described

10. The aqueous drug according to any one of claims 1 to 9, wherein the levocabastine is levocabastine hydrochloride.