Link:  Pharm/Biotech Resources

Title:  Solid preparation for dialysis and process for producing the same

United States Patent:  6,923,987

Issued:  August 2, 2005

Inventors:  Kai; Toshiya (Osaka, JP); Yamamoto; Kazuyuki (Osaka, JP); Fujiki; Kazutaka (Osaka, JP); Sato; Makoto (Osaka, JP)

Assignee:  Nipro Corporation (Osaka, JP)

Appl. No.:  963570

Filed:  September 27, 2001

A solid preparation for dialysis for preparing a double preparation type sodium bicarbonate solid preparation for dialysis in which there is no fear that a sugar component is decomposed or colored, and which can maintain stability and is also excellent in content homogeneity and a process for producing the same. The solid preparation for dialysis is a mixture of a first composition composed of core particles including sodium chloride and a coating layer containing one or more electrolytes, a second composition composed of core particles including a sugar that is covered with a coating layer comprising the same sugar or a different sugar, and an acid.

SUMMARY OF THE INVENTION

In view of the above circumstances, it is an object of the present invention to provide a double preparation type sodium bicarbonate solid preparation for dialysis containing electrolytes (except for sodium bicarbonate), an acid and a sugar. The preparation can maintain stability equal to a sodium bicarbonate solid preparation for dialysis comprising three preparations where a sugar is separately provided, is excellent in content homogeneity and there is no fear that the sugar is decomposed or colored.

In order to solve the above problems, the present inventors have wholeheartedly investigated. They found that the desired object can be achieved by granulating a composition containing electrolytes except for sodium bicarbonate and a composition containing a sugar separately and subsequently mixing them with an acid to produce an A preparation of a double preparation type sodium bicarbonate solid preparation for dialysis, and attained the present invention.

That is, the present invention is a solid preparation for dialysis comprising a mixture of particles of a first composition containing one or more electrolytes selected from the group consisting of sodium chloride, calcium chloride, magnesium chloride, potassium chloride, and sodium acetate, particles of a second composition containing a sugar, and an acid.

Further, the present invention is a process for producing a solid preparation for dialysis comprising the following steps (1) to (3):

(1) a step of spraying an aqueous solution containing one or more electrolytes selected from the group consisting of calcium chloride, magnesium chloride, potassium chloride and sodium acetate onto core particles containing sodium chloride, and drying the coated particles to obtain a first composition;
(2) a step of spraying, onto core particles containing a sugar, an aqueous solution into which the same sugar or a different sugar is dissolved, and drying the coated particles to obtain a second composition; and
(3) a step of mixing the first composition obtained in step (1) and the second composition obtained in step (2), and further mixing them with an acid to obtain a solid preparation for dialysis.

Moreover, the present invention is a process for producing a solid preparation for dialysis comprising the following steps (1) to (3):

(1) a step of spraying an aqueous solution containing one or more electrolytes selected from the group consisting of calcium chloride, magnesium chloride, potassium chloride and sodium acetate onto core particles containing sodium chloride, and drying the coated particles to obtain a first composition;
(2) a step of spraying, onto core particles containing a sugar, an aqueous solution of the same sugar or a different sugar, and drying the coated particles to obtain a second composition; and
(3) a step of mixing an acid with the first composition obtained in step (1), and subsequently mixing the resultant mixture with the second composition obtained in step (2) to obtain a solid preparation for dialysis.

DETAILED DESCRIPTION OF THE INVENTION

The first composition of the solid preparation for dialysis preferably has a characteristic feature that core particles containing sodium chloride are covered with a coating layer containing one or more electrolytes selected from the group consisting of calcium chloride, magnesium chloride, potassium chloride and sodium acetate.

Moreover, the second composition of the solid preparation for dialysis preferably has a characteristic feature that core particles containing a sugar are covered with a coating layer consisting of the same sugar or a different sugar.

Sodium chloride of the core particles forming the first composition may be any one as long as it is in the solid state and forms core particles, and sodium chloride having a particle diameter of about 75 to 1,700 μm and which is in a crystalline state is preferable.

The core particles may include particles of an electrolyte such as magnesium chloride, calcium chloride, potassium chloride, sodium acetate or the like in addition to sodium chloride. The content of the electrolyte particles in the core particles is at most 15% by weight. On producing the first composition of the present invention, the electrolyte may be used as it is without being pulverized. Also, in advance, the electrolyte may be pulverized into particles having a particle diameter of 75 to 1,700 μm by a pulverizer or a particle size selector, or may be granulated into granules having a similar size by wet or dry granulation.

The coating layer of the core particles forming the above first composition contains one or more electrolytes selected from the group consisting of calcium chloride, magnesium chloride, potassium chloride and sodium acetate. Moreover, the electrolytes may contain sodium chloride in addition to the above components. The content of sodium chloride included in the coating layer is at most 50% by weight.

As the calcium chloride, calcium chloride dihydrate, calcium chloride monohydrate, calcium chloride anhydride or the like is used. As the magnesium chloride, magnesium chloride hexahydrate or the like is preferably used. As the sodium acetate, sodium acetate anhydride, sodium acetate trihydrate or the like is preferably used.

The electrolytes contained in the coating layer of the first composition are used to form a coating layer on the core particles by dissolving the electrolytes in water to prepare an aqueous solution, spraying the solution onto the core particles of the first composition, and drying the particles. The concentration of the electrolytes in the aqueous solution is preferably 15 to 50% by weight and, more preferably, 25 to 40% by weight. If the concentration of the aqueous solution is lower than 15% by weight, it takes a longer time to coat the core particles since the quantity of the aqueous solution becomes greater. If the concentration of the aqueous solution is higher than 50% by weight, the electrolytes are not fully dissolved into the water and there is a fear that a suspension will be formed.

As the sugar contained in the core particles and the coating layer of the above second composition, glucose, maltose, xylitol, trehalose or the like is used. Glucose is preferably used. The sugar is preferably a powder having a particle diameter of about 45 to 1,700 μm.

The core particles of the second composition may also include particles of an electrolyte such as sodium chloride, magnesium chloride, calcium chloride, potassium chloride, sodium acetate or the like in addition to the particles of the sugar. The content of the particles of the electrolytes in the core particles is at most 50% by weight. On producing the second composition of the present invention, the electrolyte may be used as it is without being pulverized. Moreover, in advance, the electrolyte may be pulverized into particles having a particle diameter of 75 to 1,700 μm by a pulverizer or a particle size selector, or may be granulated into granules having a similar size by wet or dry granulation.

The sugar forming the coating layer is the same or a different sugar than the sugar of the above core particles. The sugar is used to form a coating layer on the core particles by dissolving it into water to prepare an aqueous solution, spraying the solution onto the core particles containing the sugar, and drying them. The concentration of the sugar in the aqueous solution is preferably 1 to 60% by weight and, more preferably, 15 to 40% by weight.

The first composition of the solid preparation for dialysis of the present invention can be obtained by granulation according to a centrifugal fluidized bed granulation method, a fluidized bed granulation method, an agitating fluidized bed granulation method or the like. For the second composition of the present invention, the dry compressed granulation method can also be used in addition to the above granulation methods. For both the first composition and the second composition, an agitating fluidized bed granulation method is preferably used. The first composition and the second composition are granulated by the above granulation methods into granules having an average particle diameter of 300 to 1,700 μm. By this process, the first composition and the second composition can be mixed homogeneously, and a solid preparation for dialysis that is excellent in homogeneity can be obtained.

An agitating fluidized bed granulation apparatus is used for the agitating fluidized bed granulation method. The agitating fluidized bed granulation apparatus is an apparatus in which the core particles are agitated and fluidized by a fluidizing action of an airflow from the vicinity of the wall and an agitating action by rotation of a rotator in the bottom of the apparatus, and an aqueous solution containing a component forming the coating layer is sprayed to form a homogeneous coating layer on the core particles.

The flow rate of the airflow is preferably 0.2 to 300 m³/min, more preferably, 0.5 to 200 m³/min. If the flow rate is less than 0.2 m³/min, the core particles are likely to form aggregates with one another. Moreover, if the flow rate is greater than 300 m³/min, the components in the aqueous solution are apt to cause a spray dry phenomenon and, furthermore, fine powders are likely to be formed since impact of particles becomes greater.

Furthermore, the rate of revolution of the rotor is preferably 20 to 1,000 rpm and, more preferably, 50 to 500 rpm. If the rate of revolution is smaller than 20 rpm, the thickness of the coating layer becomes nonhomogeneous. Moreover, if the rate of revolution is greater than 1,000 rpm, there is a fear that the coating layer will be scraped off because of mutual collision of the coated particles and friction of the coated particles with the inner wall of the apparatus.

Drying is carried out continuously during the above spraying at an exhaust gas temperature of 25 to 70° C.; preferably, 30 to 60° C. The water content of the granulated product after drying is preferably 0 to 10%.

The granules of the first composition and the second composition are charged into a V-type mixer or the like, and an acid is further added and the components are mixed to form a solid preparation for dialysis. Examples of the above acid include acetic acid, hydrochloric acid, lactic acid or the like. Acetic acid is most preferably used among them. The above acid may include a solid acid such as citric acid, oxalic acid or the like, if necessary (for example, for a patient using the preparation of the present invention who develops acetate intolerance).

The order of mixing is preferably (1) mixing the first composition and the second composition, and further mixing the acid, or (2) mixing the first composition and the acid, and further mixing the second composition, for the purpose of preventing volatilization of the acid, and in order to react the acid and sodium acetate rapidly when sodium acetate is present in the first and/or second composition. When mixing is carried out in the above order (1), the acid is preferably added simultaneously when the first composition and the second composition are mixed, or is added just after mixing of the first composition and the second composition.

The solid preparation for dialysis of the present invention is prepared to form a dialysate by mixing it with a solid preparation containing sodium bicarbonate at a predetermined mixing ratio and subsequently dissolving the mixture into water. Moreover, after the above solid preparation for dialysis and sodium bicarbonate are respectively dissolved into water to make two aqueous solutions, the two solutions may be mixed to prepare a dialysate. Furthermore, after the above solid preparation for dialysis or sodium bicarbonate is dissolved into water to make an aqueous solution, the remaining preparation may be dissolved into the solution to prepare a dialysate.

When the solid preparation for dialysis of the present invention is dissolved together with sodium bicarbonate into water to prepare a dialysate, the dialysate has, for example, the following composition.

The dialysate having the above composition preferably has a pH of 7.2 to 7.4.
 

Claim 1 of 15 Claims

1. A solid preparation for dialysis comprising a mixture of (1) granules of a first composition comprising core particles comprising particles of sodium chloride, and a coating layer covering the core particles and containing (a) 0 to 50% by weight of sodium chloride and (b) 100 to 50% by weight of one or more electrolytes selected from the group consisting of calcium chloride, magnesium chloride, potassium chloride and sodium acetate, the granules having an average particle diameter of 300 to 1,700 μm, (2) granules of a second composition comprising core particles comprising particles of a sugar, the core particles being covered with a coating layer consisting of said sugar or a different sugar, the granules having an average particle diameter of 300 to 1,700 μm, the granules of the first composition having about the same average particle diameter as the particles of the secong composition, and (3) an acid, said solid preparation not containing sodium bicarbonate.

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