Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Carbonate
Reexamination Certificate
2000-04-27
2002-06-04
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Carbonate
C424S715000, C424S665000, C604S410000, C604S408000, C604S416000, C206S219000
Reexamination Certificate
active
06399110
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a glucose-containing preparation, and more specifically, it relates to a neutral glucose-containing preparation with a near physiological pH, and particularly to preparations for peritoneal perfusion, including perfusates for Continuous Ambulatory Peritoneal Dialysis (CAPD).
BACKGROUND ART
Peritoneal perfusates, represented by CAPD perfusates, are perfusates used for dialysis that is carried out in renal failure patients that have lost kidney function, for excretion of wastes through the peritoneum and for maintenance of the balance of a various body fluid components. Such perfusates contain electrolyte components such as sodium chloride, calcium chloride, magnesium chloride and the like and salts of lactic acid, acetic acid, carbonic acid, bicarbonic acid, citric acid, pyruvic acid and the like as alkalizing agents, while containing glucose as an osmotic substance to ensure ultrafiltration of the perfusate.
Incidentally, transfusion preparations containing glucose as an osmotic substance are associated with a number of pharmaceutical problems. For example, when a glucose-containing aqueous solution from neutral to basic pH is heated, the glucose in the aqueous solution is thermally denatured, causing caramelization and further promoting degradation of the glucose itself.
On the other hand, the pH of transfusion perfusate preparations must be a nearly physiological pH, i.e. a pH from neutral to basic. Formulation and heat sterilization of glucose-containing perfusate preparations prepared with such pH values promotes degradation of the glucose in the preparations and is undesirable in terms of stability of the perfusate preparations. These same problems are also inherent in preparations containing glucose polymers such as polyglycol.
In order to overcome these problems there have been proposed perfusates with a near physiological pH, prepared by using two different packages as perfusate preparations, one package filled with a glucose-containing aqueous solution under specific conditions and the other package filled with an aqueous solution of electrolyte components and the like, and these are heat sterilized and then mixed together at the time of use.
For example, in Japanese Patent Application Laid-open No. 3-195561 there is disclosed a glucose-containing solution for various transfusions, peritoneal dialysis fluids or blood preservation solutions, wherein a first solution containing glucose and a second solution containing a component that promotes thermal degradation of glucose are housed separately from each other and steam sterilized.
In Japanese Patent Public Inspection No. 7-500992 there is disclosed a separately packaged and sterilized peritoneal perfusate preparation, comprising a small aqueous amount of an aqueous solution containing glucose at a high concentration, and a glucose-free solution containing a large liquid amount of a salt or the like.
The glucose-containing perfusate preparations provided by these publications are either based on the concept of separating the thermal degradation-promoting components from the glucose solution during heat sterilization of the glucose-containing aqueous solution to avoid thermal degradation of the glucose, and filling them into a separate solution to avoid degradation of the glucose (Japanese Patent Application Laid-open No. 3-195561), or attempt to inhibit production of glucose degradation products by using a glucose-containing aqueous solution in a small liquid amount and at high concentration (Japanese Patent Public Inspection No. 7-500992).
However, since the separately housed glucose-containing aqueous solutions in the perfusate preparations provided by these publications have high pH values, it still cannot be said that they are satisfactory in terms of stability. That is, long-term storage presents the problem of gradual degradation of the glucose contained in the aqueous solution, shifting the glucose-containing aqueous solution to its stable pH range of 3-5, and causing the fluid property of the solution itself to undergo alteration toward the acidic end. Consequently, preparations that exhibit altered fluid properties with storage cannot be considered desirable products from the standpoint of stability.
In order to overcome these problems there has recently been. proposed a solution set for formulation of peritoneal dialysis fluids (Japanese Patent Application Laid-open No. 8-131542) that comprises an aqueous solution at pH 4-5 containing glucose and containing no lactic acid ion, as a first solution, with a second solution containing sodium lactate, wherein after mixing the first and second solutions the glucose concentration of the solution is 5-50 g/L, and the pH is adjusted to be in the range of 6-7.3, and the volume ratio of the first and second solutions is 5:5-9:1.
The solution set described in this publication is characterized in that the glucose and the lactic acid ion are filled separately so that the lactic acid ion is not present with the glucose to be sterilized, in order to avoid promoting glucose degradation by lactic acid ion during the heat sterilization, while the pH is also low, and in that the volume ratio of the glucose-containing solution and the glucose-free solution, i.e. the volume of the glucose-containing solution, is increased. This solution set gives peritoneal dialysis fluids at near physiological pH even when the mixture is carried out after heat sterilization.
However, while the first solution in the solution set proposed by this publication is a glucose-containing aqueous solution with a pH in the acidic range (pH 4-5) in order to avoid thermal degradation of the glucose by heat sterilization, it cannot be said that degradation of the glucose in the first solution is completely prevented, and the result is therefore still unsatisfactory.
Incidentally, it is known that glucose-containing aqueous solutions in a pH range of neutral to basic have a poor stability since the glucose gradually undergoes degradation by heat or long-term storage, producing such degradation products as 5-hydroxymethylfurfuranol (5-HMF) and formic acid. In particular, formic acid which has a rather high acidity causes the fluid property of the solution itself to shift toward the stable acidic range of pH 3-5 with accumulating degradation products. Its toxicity is also a problem to be dealt with.
It has therefore been strongly desired to develop a pharmaceutically stable glucose-containing transfusion preparation that minimizes this degradation of glucose, and particularly the by-production of formic acid under long-term storage conditions.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to overcome the aforementioned problems by providing a transfusion preparation that allows greater stabilization of glucose-containing aqueous solutions, and particularly a transfusion preparation with minimal by-products of glucose degradation and extremely low formic acid contents in neutral glucose-containing preparations at near physiological pH.
It is a related object of the present invention to provide a glucose-containing transfusion preparation for use as a peritoneal perfusate, such as a perfusate for Continuous Ambulatory Peritoneal Dialysis (CAPD).
As the means therefor, the present invention provides a glucose-containing preparation comprising separately housed first and second solutions, the first and second solutions satisfying the following conditions:
(a) the first solution contains 2-50% glucose, and its pH is adjusted to 3-5 with an organic acid buffer solution;
(b) the second solution contains an alkalizing agent, and has a pH value of 8-13 as a pH adjustor for the first solution; and
(c) the glucose concentration is 1-15% in the preparation solution that is obtained by mixing the first solution and second solution, and the pH of the solution is in a range of 6-8.
According to a concrete embodiment of the invention, the organic acid buffer solution of the glucose-containing first solution in the glucose-containing preparation is a lactic
Hirano Kouichi
Kikuchi Takumi
Ghali Isis
Page Thurman K.
Shimizu Pharmaceutical Co., Ltd.
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