JP7106852B2 - Suspension-type topical solution - Google Patents

Description

TECHNICAL FIELD The present invention relates to a suspension-type external preparation containing a poorly water-soluble drug.

In order to increase drug absorption efficiency and drug efficacy, preparations for direct application to mucous membranes, such as nasal drops for treating allergic rhinitis and eye drops for treating dry eye, have been developed. These topical preparations use an aqueous base to avoid irritation to tissues, but are often used as suspension-type topical solutions because the drug, which is the active ingredient, generally has low solubility. .
Suspension-type external preparations usually contain crystalline cellulose/carmellose sodium, carboxymethylcellulose sodium, and polyacrylic acid as dispersants for stably dispersing drugs, which are water-insoluble or poorly water-soluble active ingredients, over a long period of time. A water-soluble or water-swellable polymer such as sodium is added. For example, an aqueous suspension containing a sparingly water-soluble medicinal ingredient, a polyhydric alcohol, crystalline cellulose/carmellose sodium, and a cooling agent (Patent Document 1), a water-insoluble or sparingly water-soluble drug, and microgel and water-soluble A sterile aqueous suspension preparation (Patent Document 2) containing an ionic polymer is known.
Such topical preparations are often used for symptomatic treatment because of their immediate effects, but their poor staying power has prevented sufficient sustained effects from being obtained. Therefore, there has been a demand for a formulation that provides sustained effects.

On the other hand, a gel formulation with a thickening agent such as carboxyvinyl polymer adheres to the administration site when administered, and is expected to have a sustained effect because the utilization rate of the active ingredient is increased. However, gel formulations have the drawback that they cannot be administered to the affected area satisfactorily in containers commonly used for nasal drops, eye drops, and the like.

Conventionally, at least one kind of cationic response selected from gellan gum, pectin and sodium alginate has been used as a topical preparation which is liquid before application and gels on the affected area after application to increase adhesion to the affected area and improve drug retention. A nasal drop composition containing a type polymer (Patent Document 3), a mucous membrane application solution containing at least one selected from gellan gum and pectin and polyethylene glycol in an aqueous solvent (Patent Document 4), dissolved in the formulation, and , a semi-solid preparation for rectal, urethral and vaginal applications (Patent Document 5) characterized by containing non-gelled gellan gum is known.

JP-A-2004-67614 JP-A-2008-179623 Patent No. 4457422 Patent No. 5200365 Patent No. 5217136

When gellan gum is added to a suspension-type topical solution containing a poorly water-soluble drug in a stable dispersion to improve adhesion to the affected area, the poorly water-soluble drug settles, resulting in a decrease in dispersion stability. I found out the problem.

Accordingly, the present inventors have made intensive studies to solve the above problems, and as a result, it is possible to obtain a suspension-type external preparation in which a poorly water-soluble drug can be stably dispersed over a long period of time by adding a monovalent metal salt. The inventors have found that and completed the present invention.

Such aspects of the present invention are as follows.
(1) (a) poorly water-soluble drug, (b) at least one selected from the group consisting of crystalline cellulose/carmellose sodium, carboxymethylcellulose and salts thereof, (c) gellan gum, and (d) monovalent metal salt and a monovalent metal hydroxide containing at least one selected from the group consisting of,
(2) (a) the poorly water-soluble drug is beclomethasone ester derivative and its salt, fluticasone ester derivative and its salt, prednisolone, prednisolone ester derivative and its salt, mometasone ester derivative and its salt, fluorometholone, and The suspension-type external preparation according to (1), which is at least one selected from the group consisting of triamcinolone acetonide;
(3) The suspension-type topical liquid preparation according to (1), wherein the metal contained in (d) the monovalent metal salt or monovalent metal hydroxide is sodium or potassium;
(4) suspension-type topical liquid preparations of (1) to (3), which are preparations for application to mucous membranes;
(5) The suspension-type external solution according to any one of (1) to (4), which is a nasal drop,
(6) the suspension-type topical liquid preparation according to any one of (1) to (5), which exhibits thixotropic properties;
(7) The suspension-type topical liquid preparation according to any one of (1) to (6), which is a shakeable preparation before use,
(8) (b) crystalline cellulose/carmellose sodium, at least one selected from the group consisting of carboxymethylcellulose and salts thereof, (c) gellan gum, and (d) monovalent metal salt and monovalent metal hydroxide a method for producing a suspension-type external liquid preparation, comprising the step of adding (a) a dispersed poorly water-soluble drug to a liquid containing at least one selected from the group consisting of
is.

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a suspension-type liquid preparation for external use that is highly adhesive to the affected area and in which a poorly water-soluble drug can be stably dispersed over a long period of time.

In the present invention, the poorly water-soluble drug refers to a drug that is almost insoluble or extremely poorly soluble in water according to the Japanese Pharmacopoeia solubility notation. , hydrocortisone and/or salts thereof, ester derivatives of beclomethasone and/or salts thereof, ester derivatives of mometasone and/or salts thereof, clobetasol and/or salts thereof, dexamethasone and/or salts thereof, diflucortolone, clobetasone and/or Salts thereof, ester derivatives of fluticasone and/or salts thereof, triamcinolone acetonide, fluocinolone acetonide, fluorometholone, halcinonide, deprodone propionate, etc., are of the quality usually used as pharmaceuticals. can do. Also, these poorly water-soluble drugs can be used singly or in combination of two or more.
Among these poorly water-soluble drugs, preferred are beclomethasone ester derivatives and/or salts thereof, fluticasone ester derivatives and/or salts thereof, prednisolone ester derivatives and/or salts thereof, and mometasone ester derivatives and/or salts thereof. , fluorometholone, triamcinolone acetonide. Among them, preferred are beclomethasone propionate, fluticasone propionate, fluticasone furoate, prednisolone, prednisolone acetate, mometasone furoate, fluorometholone, triamcinolone acetonide, more preferably beclomethasone propionate. is an ester.
The content of the poorly water-soluble drug is a general amount blended as a drug, specifically 0.01 to 0.3% by weight of the total suspension-type external application liquid preparation of the present invention.

Examples of the component (b) used in the present invention include crystalline cellulose/carmellose sodium, carboxymethylcellulose, and salts of carboxymethylcellulose. Among the salts of carboxymethylcellulose, sodium carboxymethylcellulose is preferred. These are dispersants and components that impart thixotropic properties to suspension-type external preparations. As the crystalline cellulose/carmellose sodium of the present invention, Ceolus RC-A591NF manufactured by Asahi Kasei Chemicals Co., Ltd. and the like can be used. The preferred blending amount of component (b) of the present invention is 0.1 to 10% by weight, more preferably 0.1 to 3% by weight, and most preferably 1 to 2% by weight, based on the total weight of the suspension type external preparation. %. Crystalline cellulose/carmellose sodium is preferable as the component (b).

In the present invention, gellan gum, the component (c), is a polysaccharide that Shpingomonas elodea calculates extracellularly, and because it gels in response to cations such as calcium ions and sodium ions, it is blended in various pharmaceuticals and foods. It is A preferable amount of gellan gum used in the present invention is 0.01 to 2% by weight, and a more preferable range is 0.01 to 0.1% by weight, based on the total suspension type external preparation.

Examples of the metal contained in the monovalent metal salt or monovalent metal hydroxide of the component (d) used in the present invention include sodium and potassium. Examples of acids contained in metal salts include citric acid, malic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid, acetic acid, nitric acid, succinic acid, and maleic acid. The monovalent metal salt and monovalent metal hydroxide of the present invention may be used singly or in combination of two or more.
Among these monovalent metal salts and monovalent metal hydroxides, preferred are sodium citrate, potassium citrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, diphosphate Potassium hydrogen, sodium lactate, potassium lactate, sodium edetate, sodium chloride, sodium hydroxide, potassium hydroxide, more preferably sodium citrate.
A preferred blending amount of the monovalent metal salt and monovalent metal hydroxide used in the present invention is 0.01 to 5% by weight, more preferably 0.1 to 1% by weight, of the total suspension-type external preparation. %.

The suspension-type external liquid preparation of the present invention contains bactericides, anti-inflammatory agents, antihistamines, local anesthetics, vasoconstrictors, antiallergic agents, vitamins, amino acids, focus adjusters, astringents, cooling agents, and thickeners. , stabilizers, preservatives, tonicity agents, solubilizers, and other active ingredients and additives that can be usually incorporated can be appropriately incorporated within a range that does not impair the effects of the present invention.

The suspension-type external preparation of the present invention can be prepared by a conventional method by adding a sparingly water-soluble drug, crystalline cellulose/carmellose sodium and/or carboxymethylcellulose sodium, gellan gum, a monovalent metal salt and, if necessary, others to purified water. The most convenient manufacturing method is to mix the components of (1), adjust the pH with an acid and/or base as necessary, and finally adjust the volume with purified water.

The suspension-type external application liquid preparation of the present invention can be used as a preparation for application to mucosa or a preparation for skin, etc., but preparation for application to mucosa is preferred. Specifically, eye drops, nasal drops, oral cavity preparations, pharynx preparations, rectal preparations, urethral preparations, and vaginal preparations are preferred, and nasal drops are more preferred. Moreover, the suspension-type external application liquid preparation of the present invention is preferably a ready-to-use shake-type preparation that is shaken immediately before use.

In addition, the suspension-type liquid preparation for external use of the present invention is preferably a liquid preparation exhibiting thixotropic properties. In the present invention, the thixotropic property indicates the property that the apparent viscosity decreases when a certain shearing force is applied, and the apparent viscosity recovers by standing still. In the present invention, the thixotropic suspension-type topical liquid preparation has a certain viscosity when left standing before use, so that the poorly water-soluble drug is easily maintained in a uniformly dispersed state, and a constant shearing force is applied during use. Applying force (eg, lightly shaking a container containing the liquid agent of the present invention) lowers the viscosity, making it easier to discharge from the container. When the suspension-type external preparation of the present invention is ejected by spraying or the like and adheres to the affected area, the viscosity increases due to the properties of gellan gum and gelation occurs. Therefore, retention in the affected area is good, and as a result, the effect of the poorly water-soluble drug can be exhibited more effectively.

EXAMPLES The present invention will be described in more detail below with reference to Examples, Comparative Examples and Test Examples, but the present invention is not limited to these. In addition, % means the weight% in an Example. In addition, centrifugation in the test examples was performed as a method of evaluating dispersion stability during long-term storage. In general, when a suspension such as a suspension-type topical solution is stored for a long period of time, both the liquid (solvent) and solid (dispersoid) in the suspension are subjected to the gravity of the earth, so substances with high density settle. For example, if the suspension is allowed to stand for one year, the integrated value of gravity is 1 (years)×365 (days)×24 (hours)×1 (×g). This is equivalent to the integrated value when a force of 8760 (x g) is applied for 1 hour, and by applying a large force in one direction such as by centrifugation, the sedimentation behavior of the suspension agent can be predicted in a short time. can be done. If the weight of the sediment after centrifugation is small, the suspending agent is less likely to settle even after long-term storage, and it can be said that the dispersion stability is high. If the drug concentration in the suspension does not change before and after centrifugation, it can be said that the drug is uniformly dispersed in the suspension even after long-term storage.

Example 1
Beclomethasone propionate 0.1g
Crystalline cellulose/carmellose sodium 2.0 g
Gellan gum 0.025g
Sodium citrate 0.2g
Benzalkonium chloride 0.015 g
Purified water total 100g
Add 2.0 g of crystalline cellulose/carmellose sodium to 60.0 g of purified water, stir with a homomixer at 8000 rpm for 30 minutes to disperse, and add 0.025 g of gellan gum and 0.2 g of sodium citrate dissolved in 17.66 g of purified water. After stirring at 4500 rpm for 15 minutes, 0.015 g of benzalkonium chloride dissolved in 20.0 g of purified water and 0.1 g of beclomethasone propionate dispersed therein were added and stirred at 5000 rpm for 10 minutes with a homomixer to obtain a suspension. .
The viscosity of Example 1 was measured under two conditions with a B-type rotational viscometer (TVB-10M/Toki Sangyo Co., Ltd.). The viscosity was 1637 mPa·s (M2 probe, after 1 minute) at 6 rpm, and 278 mPa·s (M3 probe, after 1 minute) at 60 rpm. It was confirmed that the viscosity decreased as the number of revolutions increased (the shear force applied increased), and Example 1 exhibited thixotropic properties.

Examples 2-3 and Comparative Examples 1-3 produced according to Example 1 are shown in Table 1 below.

(Test example 1)
A transparent glass tube was filled with 8.5 g of the liquid preparations prepared in Examples 1, 2 and 3 and Comparative Examples 1 and 3 to prepare samples. After the sample was centrifuged at 1000 rpm for 10 minutes in a centrifuge, all the supernatant was removed. After the sediment was dried at 50°C for 2 days, the weight of the sediment was measured. The ratio of the weight of the sediment to the components other than purified water in the sample filled in the glass tube was calculated and defined as the sedimentation rate. In Comparative Example 2, the preparation was separated into two layers immediately after preparation, and the drug could not be uniformly dispersed, so the test was not conducted.

(Test example 2)
A transparent glass tube was filled with 8.5 g of the liquid preparations prepared in Examples 1, 2 and 3 and Comparative Examples 1 and 3 to prepare samples. After this sample was centrifuged at 1000 rpm for 10 minutes, 1 g of suspension was collected. The concentration of the poorly water-soluble drug in the suspension was measured using liquid chromatography (LC-2010CHT/Shimadzu Corporation). Taking the concentration of the poorly water-soluble drug in the suspension before centrifugation as 100%, the drug concentration in the upper portion of the liquid after centrifugation was calculated. In Comparative Example 2, the preparation was separated into two layers immediately after preparation, and the drug could not be uniformly dispersed, so the test was not conducted.

Table 2 shows the results.

A liquid formulation containing crystalline cellulose/carmellose sodium and gellan gum as a poorly water-soluble drug had poor dispersion stability (Comparative Example 1). Examples 1-2). In addition, the liquid preparation containing the sparingly water-soluble drug, gellan gum and sodium citrate immediately separated into two layers, and the sparingly water-soluble drug could not be stably dispersed (Comparative Example 2). Furthermore, the dispersion stability was poor in a liquid preparation containing a poorly water-soluble drug, crystalline cellulose/carmellose sodium, and sodium citrate (Comparative Example 3). From the above results, it is considered that the liquid formulation of the present invention has high dispersion stability even when stored for a long period of time (Examples 1 to 3).

The formulations of Examples 4 to 10 and Comparative Example 4 produced according to Example 1 and the results of Test Example 1 are shown in Table 3 below. Comparative Example 4 was not tested because the formulation separated into two layers on the day after preparation and the drug could not be uniformly dispersed.

The liquid preparations (Examples 4 to 10) in which crystalline cellulose/carmellose sodium, gellan gum, and sodium citrate were blended with poorly water-soluble drugs had the same results in Test Example 1 as in Examples 1 to 3, and could be stored for a long period of time. It is considered that the dispersion stability is high even in the case of In addition, the liquid formulation containing a divalent metal salt instead of a monovalent metal salt separated into two layers on the next day, and the poorly water-soluble drug could not be stably dispersed (Comparative Example 4).

Formulation examples of the present invention are shown below.

Formulation example 1
Beclomethasone propionate 0.1g
Crystalline cellulose/carmellose sodium 2.0 g
Gellan gum 0.025g
Sodium citrate 0.2g
Benzalkonium chloride 0.015 g
Polysorbate 80 0.005g
0.4 g of glycerin
Propylene glycol 0.4g
Citric acid 0.03g
Menthol 0.004g
Purified water total 100g
Add 2.0 g of crystalline cellulose/carmellose sodium to 59.5 g of purified water, stir with a homomixer at 8000 rpm for 30 minutes to disperse, and add 0.025 g of gellan gum and 0.2 g of sodium citrate dissolved in 17.51 g of purified water. After stirring at 4500 rpm for 15 minutes, 0.015 g of benzalkonium chloride dissolved in 19.8 g of purified water and 0.1 g of beclomethasone propionate dispersed therein were added and stirred at 5000 rpm for 10 minutes with a homomixer to obtain a suspension. . 0.005 g of polysorbate 80, 0.4 g of glycerin, 0.4 g of propylene glycol, 0.03 g of citric acid and 0.004 g of menthol were added to this suspension and dissolved.

Formulation example 2
Beclomethasone propionate 0.1g
Crystalline cellulose/carmellose sodium 2.0 g
Gellan gum 0.025g
Sodium citrate 0.2g
Benzalkonium chloride 0.015 g
Polysorbate 80 0.05g
3.0 g of glycerin
Propylene glycol 15g
0.1 g of citric acid
Menthol 0.01g
Purified water total 100g
2.0 g of crystalline cellulose/carmellose sodium was added to 60.0 g of purified water and dispersed by stirring at 8000 rpm for 30 minutes with a homomixer. After stirring at 4500 rpm for 15 minutes, 0.015 g of benzalkonium chloride dissolved in 10.0 g of purified water and 0.1 g of beclomethasone propionate dispersed therein were added and stirred at 5000 rpm for 10 minutes with a homomixer to obtain a suspension. . To this suspension, 0.05 g of polysorbate 80, 3.0 g of glycerin, 15 g of propylene glycol, 0.1 g of citric acid and 0.01 g of menthol were added and dissolved.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a poorly water-soluble drug-containing suspension-type external preparation with good dispersibility and good patient compliance.

Claims (8)

(a) a sparingly water-soluble drug, (b) at least one selected from the group consisting of crystalline cellulose/carmellose sodium and carboxymethylcellulose sodium , (c) gellan gum, and (d) a monovalent metal salt . Suspension-type external solution characterized by: (a) the poorly water-soluble drug is beclomethasone ester derivative and its salt, fluticasone ester derivative and its salt, prednisolone, prednisolone ester derivative and its salt, mometasone ester derivative and its salt, fluorometholone, and triamcinolone acetonide The suspension-type external preparation according to claim 1, which is at least one selected from the group consisting of: 3. The suspension-type external liquid preparation according to claim 1, wherein the metal contained in (d) the monovalent metal salt is sodium or potassium. 4. The suspension-type external liquid preparation according to any one of claims 1 to 3, which is a mucosa-applicable preparation. The suspension-type external preparation according to any one of claims 1 to 4, which is a nasal drop. The suspension-type external preparation according to any one of claims 1 to 5, which exhibits thixotropic properties. 7. The suspension-type external application liquid preparation according to any one of claims 1 to 6, which is a shaking-type preparation before use. (b) at least one selected from the group consisting of crystalline cellulose/carmellose sodium and sodium carboxymethylcellulose; (c) gellan gum; A method for producing a suspension-type liquid preparation for external use, comprising the step of adding a water-soluble drug.