JPH11246393A - Powder for preparing sparingly soluble medicament into quickly soluble formulation and production of the powder - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject powder having good solubility and useful as a gargle through dissolving itself in water, by coating the surface of particles comprising a sparingly soluble medicament and a thickening agent with a dispersant. SOLUTION: This powder is obtained by coating the surface of particles comprising (A) a sparingly soluble medicament [pref. allopurinol, 2-(3-cyano-4- isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid, salicylic acid, or aspirin] and (B) a thickening agent (pref. sodium polyacrylate, carboxymethylcellulose or the like) in the weight ratio A/B of pref. (1:20) to (1:2) with (C) a dispersant (pref. xylitol, sorbitol or the like) and pref. (D) a dissolving auxiliary (pref. polyvinylpyrrolidone or macrogol). It is preferable that the surface of the particles is filmily coated with a layer comprising the components C and D, or both the components C and D are made to adhere in particulate form to the surface of the above particles.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a powder for rapidly dissolving a poorly soluble drug to be used as a gargle when dissolved in water, and a method for producing the powder.

[0002]

2. Description of the Related Art Up to now, preparation of a gargle for a poorly soluble drug containing a thickener or the like requires a great deal of labor and time due to the low dispersibility and solubility of the thickener itself. Met. For example, in the preparation of an allopurinol gargle containing a thickener, the thickener and allopurinol are pulverized and mixed in a mortar, mixed with a small amount of water to form a gel.
While stirring for 3 hours.
(For example, Vol. 13, No. 6, 1997, PHA
The gargle produced in this way had to be stored in small doses that could be used at one time, or had to be added with a preservative in order to prevent the growth of bacteria and the like.

[0003]

Thus, for example,
To prepare an allopurinol gargle containing a thickener, it is necessary to first grind and mix the thickener and the active ingredient (allopurinol) in a mortar, and to dissolve this into a liquid gargle, Since it is necessary to add water to the mixture of the thickener and the main agent and to stir for 3 hours while heating at 60 ° C., there is a problem that much time and labor are required for preparation. In addition, it is usual to prepare an amount that can be used over several days in advance due to the complexity of preparation, but in such a case, the stability of the preparation is maintained because the main drug precipitates out in a few days. There was a problem that it was not possible.

[0004]

DISCLOSURE OF THE INVENTION The present invention is directed to a method for rapidly dissolving a particle comprising a poorly soluble drug and a thickener, which shows good solubility and can be easily prepared at the time of use by coating the surface of the particle with a dispersant. A powder for preparation is provided to solve the above problems. In the present invention, the following aspects are also suitably adopted as means for solving the above-mentioned problems.

(1) The surface of the particles is coated with a dispersant and a solubilizing agent. (2) The surface of the particles is coated with a mixture of a dispersant and a solubilizer in a film form. (3) The particles are coated by adhering a dispersant and a solubilizing agent on the surface of the particles. (4) The particles contain at least one selected from the group consisting of sodium polyacrylate, carboxymethylcellulose, hydroxypropylmethylcellulose, gelatin and sucrose fatty acid ester as a thickener. (5) At least one selected from the group consisting of xylitol, sorbitol and D-mannitol is contained in the coating on the surface of the particles as a dispersant. (6) At least one selected from the group consisting of polyvinylpyrrolidone, D-mannitol and macrogol is contained as a dissolution aid together with a dispersant in the coating on the surface of the particles. (7) After granulating a mixture of a thickener and a poorly soluble drug by spraying, coating the surface of the obtained particles (granulated material) with a dispersant (or with a dispersant and a solubilizer). Thus, a powder for quick-dissolution preparation at the time of use is produced. (8) After granulation by a method in which a thickener and a poorly soluble drug are brought into close contact with each other by centrifugal force, the surface of the obtained particles (granulated material) is treated with a dispersant (or a dispersant and a dissolution aid). ) By coating, a powder for quick dissolving preparation is prepared. (9) A solution obtained by dissolving a thickener and a poorly soluble drug in a solvent is concentrated and dried, and then pulverized into particles, and the surface of the obtained particles (powder) is dispersed with a dispersant (or a dispersant). And a dissolution aid) to produce a powder for quick dissolving preparation. (10) After a solution obtained by dissolving a thickener and a poorly soluble drug in a solvent is spray-dried and granulated, the surface of the obtained particles (powder) is treated with a dispersant (or a dispersant and a dissolution aid). ) By coating, a powder for quick dissolving preparation is prepared.

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The powder of the present invention is readily dissolved in water or another suitable liquid medium each time it is used to give a good preparation, and therefore, it can be prepared for use at the time of preparation which does not need to be dissolved in advance. A powder, in which a sparingly soluble drug and a thickener such as sodium polyacrylate and carboxymethyl cellulose are made into particles, and the surface of the particles is made of at least one dispersant of xylitol and sorbitol; And a dissolution aid such as polyvinylpyrrolidone and macrogol.

The poorly soluble drug of the present invention is not particularly limited as long as it does not dissolve or uniformly suspend in a short time, such as floating on the water surface or becoming lumpy because of poor dispersibility in a solvent containing a thickener. But not allopurinol, 2- (3-cyano-4-isobutoxyphenyl) -4-methyl-5-thiazolecarboxylic acid, salicylic acid (o-hydroxybenzoic acid),
Aspirin, azulene, sodium azulene sulfonate sodium hydrogencarbonate, domiphen bromide, popidone iodine, amphotericin B and the like are mentioned, and among them, allopurinol is preferable.

[0008] As a method of forming the hardly soluble drug and the thickener into particles, for example, (a) agitated tumbling fluidized bed granulation method (spray bonding while stirring the powder with air while stirring with a stirring blade); (B) a high-speed stirring granulation method (a method of spraying a binder liquid with a spray while stirring the powder at a high speed with a stirring blade, and spraying the binder liquid) (Agitation may be performed without stirring), (c) Fluidized bed granulation (a method of spraying a binding liquid by spraying while powder is fluidized with air), (d) ) Spray dry method (a method in which a solution in which a main drug and a thickener are dissolved is sprayed into a dry atmosphere and dried to form particles), and (e) dry granulation method (powder is compressed into a pellet by a roller. (F) Method of pulverizing by post-grinding), (f) Dissolving the active ingredient in water, ethanol, or aqueous ethanol solution The solution dissolved in the medium is concentrated, dried,
Pulverization method or (g) high-speed airflow impact method (a method of forming particles by colliding powders in an airflow)
Is adopted.

The shape and size of the particles differ depending on which of the above methods is employed.
In the method (c), the particles become particles having a poorly soluble drug attached to the surface of the thickener. On the other hand, in the above method (b), the thickener and the poorly soluble drug become particles that are very tightly bound, and in the above methods (d) and (f), the thickener and the poorly soluble drug are mixed. The resulting particles are uniformly agglomerated. Further, in the method (e), a fine flake is formed in which a thickener and a poorly soluble drug are mixed.

In the present invention, any of the above particles may be used, and the size of the particles can be arbitrarily selected as long as the solubility at the time of use is not impaired.
m, particularly preferably 500 to 1000 μm. In this range, particles having a small average particle diameter are in the form of a powder or a shape close thereto, and such particles can also achieve the object of the present invention.

In the present invention, the ratio of the poorly soluble drug to the thickener is generally expressed as 1 weight ratio of the poorly soluble drug to the thickener.
The range of / 20 to 1/2 is appropriate because the formation of particles is easy.

The particles may contain, if necessary, suitable auxiliary components such as a coloring agent and a dispersing agent in addition to the poorly soluble drug and the thickener.

In the present invention, it is essential that the particles are coated with a dispersing agent such as xylitol and sorbitol (preferably with a dispersing agent and a solubilizing agent). The particles are allowed to flow in air or an inert gas, and a solution in which a dispersant (preferably, a dispersant and a solubilizing agent) is dissolved in a solvent such as water or ethanol is sprayed onto the surface of the fluidized particles. A method of forming a film-like film composed of a dispersant (preferably, a dispersant and a solubilizing agent); (2) powder by spraying water, ethanol, or the like on the surface of the particles fluidized with air or an inert gas; A method is adopted in which the adhesion of the dispersant (or the dispersant and the solubilizing agent) is directly adhered to the powder in a powder form.

In the present invention, it is not necessary to completely coat the entire surface of the particles with the dispersant (or the dispersant and the solubilizing agent), and the dispersant is partially coated in the form of a powder or a film on the surface of the particles. There is no problem even if it is done.

The amount of the dispersant relative to the particles comprising the poorly soluble drug and the thickener is preferably 1/2 to 4 times by weight. The amount of the solubilizer is preferably 1/20 to 1/2 times the weight of the particles.

That is, the powder of the present invention comprising particles coated with a dispersant or the like is used in an amount of 100 to 2000 parts by weight, preferably 500 to 1000 parts by weight, per 100 parts by weight of the poorly soluble drug.
Parts by weight of a thickener and 0 to 1300 parts by weight, preferably 5 parts by weight.
Those containing 100 to 1000 parts by weight of a solubilizer are suitable.

The powder according to the present invention as described above rapidly dissolves in water at the time of use, so that it is prepared and used by dissolving in water each time. The amount of water used for dissolution is preferably 150 to 300 times the weight of the powder.

[0018]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments of the present invention will be described below, but it goes without saying that the present invention is not limited to these embodiments. In addition, "%" in the examples is unless otherwise specified.
% By weight.

[Example 1] 10
00% by weight of sodium polyacrylate (thickener),
Xylitol (dispersant) of 3000% by weight with respect to allopurinol is sprayed into air at room temperature with water as a binding liquid by a stirring tumbling fluidized bed granulator, and the average particle diameter is 1000 μm
Until granulated. Observation of these particles with a microscope confirmed that the surfaces of the particles composed of allopurinol and sodium polyacrylate were coated with xylitol. When these particles were dissolved in water at room temperature to prepare a gargle, a stable gargle was obtained in about 8 minutes.

Example 2 10 parts of allopurinol
By stirring 00% by weight of sodium polyacrylate (thickener) together with allopurinol in a high-speed stirring granulator, allopurinol was converted into particles adhered to sodium polyacrylate.
00% by weight of sorbitol (dispersant) and 500% by weight of D-mannitol (dissolution aid) with respect to allopurinol Particles composed of allopurinol and sodium polyacrylate and water as a binder liquid by a high-speed stirring granulator. It was sprayed into air at room temperature and granulated until the average particle diameter became 1000 μm. Observation of these particles with a microscope confirmed that the surfaces of the particles composed of allopurinol and sodium polyacrylate were coated with xylitol. When these particles were dissolved in water at room temperature to prepare a gargle, a stable gargle was obtained in about 8 minutes.

Example 3 500% by weight of sodium polyacrylate (thickener) based on aspirin and 1500% by weight of xylitol (dispersant) based on aspirin were stirred by a tumbling fluidized bed granulator. Water was sprayed into the air at room temperature as a binding liquid, and granulated until the average particle diameter became 1000 μm. Observation of these particles with a microscope confirmed that the surfaces of the particles composed of aspirin and sodium polyacrylate were coated with xylitol. The particles were dissolved in water at room temperature to prepare a gargle, and a stable gargle was obtained in about 7 minutes.

Comparative Example Allopurinol and 1000% by weight of sodium polyacrylate (thickener) based on allopurinol were mixed in a mortar, and a small amount of sterilized purified water was added to form a gel. For 3 hours to dissolve, and then sterilized in an autoclave. It took almost 8 hours to perform all of these steps.

[0023]

According to the present invention, conventionally, a time-consuming and time-consuming preparation due to poor solubility and cohesion of a thickener, for example, a preparation at the time of use of a poorly soluble drug such as allopurinol gargle, The preparation can be performed in a short time without any trouble. Therefore, since the preparation can be prepared and used immediately by using the powder of the present invention when necessary, there is no need to worry about the proliferation of bacteria and precipitation of the main drug as in the conventional allopurinol gargle. In addition, since the preparation method is simple, preparation and carrying by the patient himself are possible.

Claims (19)

[Claims] 1. A fast-dissolving powder for use at the time of fast-dissolving, wherein the surface of particles comprising a poorly soluble drug and a thickener is coated with a dispersant. 2. The powder according to claim 1, wherein the surface of the particles is coated with a dispersant and a solubilizing agent. 3. The powder according to claim 2, wherein the surface of the particles is coated with a layer containing a dispersant and a solubilizing agent in a film form. 4. The powder according to claim 2, wherein a dispersant and a solubilizing agent are attached to the surface of the particles in the form of particles. 5. The method according to claim 1, wherein the thickener comprises at least one selected from sodium polyacrylate, carboxymethylcellulose, hydroxypropylmethylcellulose, gelatin and sucrose fatty acid ester. The powder for quick-dissolution preparation according to claim 1. 6. A dispersant comprising at least one selected from xylitol, sorbitol and D-mannitol.
The powder according to any one of claims 1 to 4, which comprises a seed. 7. The powder according to claim 2, which contains at least one selected from polyvinylpyrrolidone and macrogol as a solubilizing agent. . 8. The sparingly soluble drug includes allopurinol and 2-
2. The composition according to claim 1, further comprising at least one selected from (3-cyano-4-isobutoxyphenyl) -4-methyl-5-thiazolecarboxylic acid, salicylic acid (o-hydroxybenzoic acid) and aspirin. The powder for quick-dissolution preparation according to any one of Items 1 to 4. 9. Forming particles containing a poorly soluble drug and a thickener, and then coating at least a part of the surface of the obtained particles with a dispersant and / or a solubilizing agent. A method for producing a powder for sexual preparation. 10. The method according to claim 9, wherein the mixture of the poorly soluble drug and the thickener is formed into particles by spraying the binding liquid with a spray while stirring with a stirring blade while flowing in air. The method for producing a powder for quick dissolution preparation according to the above. 11. The mixture according to claim 9, wherein the mixture of the poorly soluble drug and the thickener is granulated by bringing the poorly soluble drug and the thickener into close contact with each other by centrifugal force and granulating the mixture. A method for producing a powder for quick dissolving preparation. 12. The powdery preparation for quick dissolution according to claim 9, wherein the mixture of the poorly soluble drug and the thickener is sprayed while spraying the binding liquid into particles while flowing the mixture with air. Manufacturing method. 13. The preparation according to claim 9, wherein the solution obtained by dissolving the poorly soluble drug and the thickener in a solvent is re-particled by spray drying. Powder manufacturing method. 14. The preparation according to claim 9, wherein the mixture of the poorly soluble drug and the thickener is compressed by a roller into pellets and then crushed into particles. Powder manufacturing method. 15. The quick-dissolving solution according to claim 9, wherein a solution obtained by dissolving the poorly-soluble drug and the thickener in a solvent is concentrated, dried, and then pulverized into particles. Production method of powder for preparation. 16. The method according to claim 9, wherein the mixture of the poorly soluble drug and the thickener is made into particles by colliding the mixture with air or an inert gas stream by a rotary plate. Manufacturing method of powder for preparation. 17. The powder according to claim 9, wherein the surface of the particles comprising the sparingly soluble drug and the thickener is sprayed with a solution containing a dispersant to coat the surface of the particles. Manufacturing method. 18. The method according to claim 9, wherein particles comprising a poorly soluble drug and a thickener are caused to flow, and a powder containing a dispersant is adhered to the particles. Law. 19. The powder according to claim 1, which is a gargle.