Chemistry: analytical and immunological testing – Including titration or ph determination
Reexamination Certificate
1998-12-16
2001-05-15
Alexander, Lyle A. (Department: 1743)
Chemistry: analytical and immunological testing
Including titration or ph determination
C436S001000, C436S165000, C436S166000, C422S067000
Reexamination Certificate
active
06232128
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a bicarbonate-containing medical solution package and more particularly to an improved bicarbonate-containing medical solution package equipped with an indicating device adapted to alert the user to expiration of a medical aqueous solution containing sodium bicarbonate or the like through a change in color.
PRIOR ART
The medical bicarbonate solution, that is a medical aqueous solution containing bicarbonate ions, is broadly in use in such applications as an antidote, an artificial kidney dialysate, a peritoneal dialysate, an infusion, a root canal enlarging agent (for dental use), an artificial cerebrospinal fluid, an intraocular irrigating solution, a cardiac perfusate, a cardioplegic solution, a peritoneal irrigating solution, a solution for organ preservation, etc. In such a medical aqueous solution, bicarbonate ions are in equilibrium as represented by the following expression (1):
2HCO
3
−
CO
2
↑+CO
3
2−
+H
2
O
In an open system, the reaction proceeds to the right as the carbon dioxide gas on the right-hand side of the expression is dissipated, with the result that the bicarbonate ion is decreased and the carbonate ion is increased. As a result, the pH of the aqueous solution rises progressively.
This change with time detracts a great deal from the utility value of the aqueous solution because one of the primary objectives of using such a medical solution is the maintenance or correction of the acid-base balance. Particularly, it is known that injection of the solution with an increased carbonate ion concentration causes necrosis of the subcutaneous tissue [Howland, J. and Marriot, W. M., Am. J. Dis. Child., 11, 309 (1916)] and to avoid this hazard, the carbonate ion concentration of solutions is generally controlled, with Japanese Pharmacopoeia XIII restricting it to the range of 7.9-8.6 and USP 23 to the range of 7.0-8.5.
Furthermore, to prevent aging, aqueous solutions for medical use are conventionally packed in gas-tight containers such as glass ampules or stoppered bottles for preventing evaporation of evolved carbon dioxide gas to thereby maintain the equilibrium essential to the stabilization of bicarbonate ion concentration and solution pH.
However any glass container has the serious disadvantage that it is broken by a slight impact, does not lend itself well to capacity increase, is very heavy, and involves difficulties in disposal. In addition, since the evolution of carbon dioxide gas in the course of sterilization or pasteurization of a medical aqueous solution is unavoidable, the risk for an elevation of internal pressure inducing breakage of the glass container is high.
To overcome the above breakage and other troubles associated with glass containers and provide containers of reduced weight and easier to dispose of, much research has been undertaken in the field of plastic containers in recent years and, for medical use, too, containers made of polyethylene, ethylene-vinyl acetate copolymer, polypropylene, polyvinyl chloride, or the like have been developed. However, as used independently, plastic containers invariably have the disadvantage that the gas permeability of the plastic material itself is so high that when such a container is filled with a bicarbonate ion-containing aqueous solution for medical use, the carbon dioxide gas evolved escapes through the container wall into the atmosphere with the progress of time to inevitably cause an elevation of the solution pH. Therefore, even the use of such a plastic container is still inadequate for obviating the above-mentioned disadvantages associated with aging of the solution. The above-mentioned problems due to dissipation of carbon dioxide gas and consequent rising in pH of the solution are encountered in the sterilization step as well.
As a technology for overcoming the above-mentioned disadvantages of plastic containers, it has been proposed to enshroud a direct container in a gas-impermeable secondary container (outer container or packaging material) and establish a carbon dioxide atmosphere in the space between the two containers [e.g. Japanese Unexamined Patent Publication Nos. 49675/1993, 261141/1993, and 339512/1994].
However, even this double packaging technology is not effective enough to eliminate the gradual loss of carbon dioxide gas due to the incidence of the so-called pinhole in the secondary packaging material or mere prolongation of the storage period and the aqueous solution which has undergone such a time-dependent elevation of pH should be discarded promptly to avoid the above-mentioned risk due to inadvertent administration to a patient.
Regarding the detection of an abnormal pH change of such a double-packaged bicarbonate-containing medical solution, much research has been undertaken and it has been proposed to dispose an oxygen absorber, such as Ageless™ (manufactured by Mitsubishi Gas Chemical Co.), and an oxygen sensor, such as Ageless Eye™ (manufactured by Mitsubishi Gas Chemical Co.), within the secondary package to create an anoxic state and detect the infiltration of atmospheric oxygen in the event of formation of a pinhole. However, this technology does not provide for a direct indication of a pH change but merely senses the infiltration of atmospheric oxygen from a pinhole. In addition, the above-mentioned oxygen absorber and oxygen sensor have the drawback that it requires a special handling procedure for avoiding exposure to oxygen during storage as well as in the packaging operation. Therefore, the advent of a technology that would lend itself well to commercial production and provide for an accurate and timely detection of pH change has been demanded by the industry.
The present invention, therefore, has for its object to overcome all the above-mentioned disadvantages of the prior art and thereby provide a novel medical solution package which is capable of holding a bicarbonate-containing medical solution in stable condition in a plastic container and providing an unmistakable visual indication of pH change due to evolution of carbon dioxide gas.
After intensive studies with the above object in mind, the inventors of the present invention discovered that a novel medical solution package meeting the above object can be provided by the technology of the invention which comprises a step of dispensing a bicarbonate-containing medical solution in a gas-permeable plastic container and sterilizing it by the routine autoclaving, hot-water immersion, or hot-water shower method or, as a alternative, dispensing a bicarbonate-containing medical solution in a plastic container by the aseptic process, a step of packaging the filled container in a gas-impermeable plastic secondary packaging member, a step of establishing a carbon dioxide atmosphere in the space between said container and said secondary packaging member, and a step of disposing a pH indicating device comprising a gas-permeable plastic packet containing a bicarbonate-containing fluid and a specific pH-indicator within said space. The present invention has been developed on the basis of the above finding.
DISCLOSURE OF THE INVENTION
Thus the present invention provides a bicarbonate-containing medical solution package comprising a gas-permeable plastic container filled with a bicarbonate-containing medical solution and a gas-impermeable plastic packaging member enclosing said gas-permeable plastic container, with a carbon dioxide atmosphere having been established in a space between said container and said packaging material, and, as disposed in said space, a pH indicating device comprising a gas-permeable plastic packet containing a bicarbonate-containing fluid and a pH-indicator which undergoes a change in color in response to a change in pH of said fluid.
More particularly, the present invention provides the above-mentioned package wherein said pH-indicator is a substance selected from among cresol red, m-cresol purple, and phenol red, the above-mentioned package wherein the pH-indicator is available in a concentration of
Abe Akiyo
Hamamoto Rika
Iguchi Seiichiro
Inai Masatoshi
Kawakami Keiichi
Alexander Lyle A.
Otsuka Pharmaceutical Factory Inc.
Sughrue Mion Zinn Macpeak & Seas, PLLC
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