Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-09-05
2002-06-18
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S400000, C424S490000, C514S023000, C514S784000
Reexamination Certificate
active
06407070
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a solid pharmaceutical composition for preparing a dialysate containing sodium bicarbonate and a process for producing the same.
BACKGROUND OF THE INVENTION
When blood dialysis is performed on patients suffering from decreased kidney function, the blood of the patient is cleaned in an artificial kidney. In the inside of the artificial kidney, generally, a dialysate is perfused to allow waste materials in the blood to be transferred through a dialysis membrane to the dialysate. As the dialysate, acetic acid-containing dialysate has been used. Recently, the acetic acid-containing dialysate has come to be increasingly replaced by those in which sodium bicarbonate, which alleviates unpleasant symptoms during the dialysis, is used.
The dialysate which contains sodium bicarbonate usually is prepared from two kinds of dialysis preparation, one being a preparation containing electrolyte components other than sodium bicarbonate (for example, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate) and a pH adjusting agent (for example, acetic acid) (hereinafter, referred to as agent A) and the other being a preparation containing sodium bicarbonate (hereinafter, referred to as agent B). The dialysate preparations may sometimes contain sugars such as glucose or may be mixed with another preparation containing a sugar.
Conventionally, agents A and B have been available in the state of concentrated solutions adjusted to predetermined concentrations. However, since about 300 L of dialysate is required for one dialysis operation for a single patient, large amounts of concentrated solutions are used and diluted with water when many patients are subjected to dialysis therapy in a medical ward. Accordingly, to reduce the loads imposed on persons who prepare dialysate and to save space, agent B in the form of a powdered preparation has been increasingly used. In accordance therewith, a solid pharmaceutical preparation for dialysate containing sodium bicarbonate that is composed of two agents including agent A in the form of a powder has been developed. Furthermore, a solid pharmaceutical preparation for dialysate containing sodium bicarbonate as a “one-pack” has been reported but no commercial product has been put on the market.
As solid pharmaceutical preparations for dialysate containing sodium bicarbonate there have been disclosed dialysis compositions composed of two preparations, one being powdery agent A composed of electrolytes (other than sodium bicarbonate), glucose and liquid acid and the other being powdery agent B composed of sodium bicarbonate alone or of sodium bicarbonate and sodium acetate or glucose (Japanese Patent No. 2749375, Japanese Patent No. 2751933, and JP-A-3-38527). However, these dialysis compositions are such that the agents A and B are separately stored and, immediately before use, are dissolved into water and mixed together and then used for the blood dialysis. When the agent A and agent B are mixed in advance, the sodium bicarbonate contained in the agent B and the calcium salt and magnesium salt contained in the agent A react due to the crystal water contained in the salts or moisture in the air to form sparingly soluble salts. Also, the sodium bicarbonate contained in the agent B and the acetic acid contained in the agent A react with each other to generate carbon dioxide gas so that the pH of the dialysate after it is dissolved in a predetermined amount of water cannot be maintained in an appropriate range.
As a one-pack dialysis preparation developed taking the above defects into consideration, a mixture of a granulated product consisting of electrolytes including a calcium component but not sodium bicarbonate and another granulated product consisting of eletrolytes including sodium bicarbonate but not a calcium component is disclosed (JP-A-3-74331). Also, a granulated dialysis composition is disclosed which comprises separate granulated compositions, one being composed of electrolytes other than sodium bicarbonate and a acid and the other being composed of glucose and sodium bicarbonate (JP-A-5-70357, Japanese Patent No. 2809971). Further, a dialysis composition which comprises a powdery preparation containing electrolytes (other than sodium bicarbonate) and acetic acid, and a powdery preparation containing sodium bicarbonate in which the acetic acid is contained as sodium diacetate (JP-A-7-59846) are disclosed. However, these dialysis compositions have been prepared merely by granulating substances that are reactive separately from each other and then mixing. Therefore, it is difficult to prevent production of salts or generation of carbon dioxide gas after the mixing. Since the dialysis compositions are prepared by a wet granulation method, there is the fear that sodium bicarbonate will be colored due to the heat during a drying step or coloring and decomposition of glucose will occur. Furthermore, if the dialysis composition is prepared by use of sodium diacetate in which acetic acid is adsorbed with sodium acetate, it is difficult to have the total amount of acetic acid adsorbed completely so that there is the possibility that the non-adsorbed acetic acid will react with sodium bicarbonate.
On the other hand, there has been disclosed a mixture of a dialysis preparation composed of a first agent containing electrolytes (other than sodium bicarbonate) and acid, and a second agent containing sodium bicarbonate and remaining electrolytes not used in the first agent (JP-A-8-92070). The first agent and/or the second agent are covered with a coating layer composed of at least one substance selected from the group consisting of sodium chloride, potassium chloride and glucose, and citric acid is used as the acid in the embodiment of this patent application. The dialysis preparation is free of the fear that sparingly soluble salts will be produced since the coating layer prevents the reaction of sodium bicarbonate with calcium salt and magnesium salt.
However, when the acid contained in the first agent is acetic acid, the covering layer alone cannot prevent a reaction between the acetic acid contained in the first agent and the sodium bicarbonate contained in the second agent after the mixing of the first and second agents. If the first agent contains sodium acetate as an electrolyte and when the sodium acetate adsorbs acetic acid, there is a fear that the non-adsorbed acetic acid will react with the sodium bicarbonate contained in the second agent. Also, when the sodium acetate is contained in the second agent but is not contained in the first agent, it is difficult to stop evaporation of acetic acid during the process of preparing the first agent. Even if the first agent could be produced, there is the possibility that acetic acid will react with sodium bicarbonate before it is adsorbed by sodium acetate since the second agent is a simple mixture of sodium acetate and sodium bicarbonate. Furthermore, since the dialysis composition is prepared by a wet granulation method, there is the possibility that coloring of sodium bicarbonate and coloring and decomposition of glucose will occur.
SUMMARY OF THE INVENTION
Under the above circumstances, an object of the present invention is to provide a one-pack solid pharmaceutical composition for dialysate containing sodium bicarbonate without reaction between sodium bicarbonate and acetic acid and without reaction between sodium bicarbonate and electrolytes such as calcium chloride or magnesium chloride, and which is excellent in long term storage stability.
The present inventors have made extensive research with a view to solving the above problems. And as a result, they found that the above object can be attained by adding sodium acetate to both of agent A containing electrolytes (other than sodium bicarbonate) and acetic acid and agent B containing sodium bicarbonate, and furthermore coating the sodium bicarbonate contained in the agent B with the sodium acetate, thus completing the present invention.
That is, the present invention
Fujiki Kazutaka
Kai Toshiya
Kato Hiroaki
Sato Makoto
Yamamoto Kazuyuki
Gitomer Ralph
Khare Devesh
Kubovcik & Kubovcik
Nipro Corporation
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