Bicarbonate-based solution in two parts for peritoneal...

Details Bicarbonate-based solution in two parts for peritoneal... Bicarbonate-based solution in two parts for peritoneal...

1999-09-10

2001-10-30

Dees, Jose′ G (Department: 1616)

Drug, bio-affecting and body treating compositions

Inorganic active ingredient containing

Carbonate

C424S677000, C424S678000, C424S679000, C424S680000, C424S681000, C424S682000, C424S686000, C424S722000, C514S002600, C514S025000, C514S054000, C514S060000, C514S557000, C514S561000, C514S738000, C514S773000, C514S777000, C514S778000, C514S784000, C514S788000

Reexamination Certificate

active

06309673

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates generally to peritoneal dialysis and renal replacement therapies, such as hemofiltration and hemodiafilitration. More specifically, the present invention relates to manufacturing and storing bicarbonate-based solutions for peritoneal dialysis and hemofiltration.
To overcome the disadvantages often associated with classical hemodialysis, other techniques were developed, such as peritoneal dialysis and hemofiltration. Peritoneal dialysis utilizes the patient's own peritoneum as a semipermeable membrane. The peritoneum is the membranous lining of the body cavity that, due to the large number of blood vessels and capillaries, is capable of acting as a natural semipermeable membrane.
In peritoneal dialysis, a sterile dialysis solution is introduced into the peritoneal cavity utilizing a catheter. After a sufficient period of time, an exchange of solutes between the dialysate and the blood is achieved. Fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate to permit water outflow from the blood. This allows a proper acid-base, electrolyte and fluid balance to be returned to the blood. The dialysis solution is simply drained from the body cavity through the catheter.
Hemofiltration is a convection-based blood cleansing technique. Blood access can be venovenous or arteriovenous. As blood flows through the hemofilter, a transmembrane pressure gradient between the blood compartment and the ultrafiltrate compartment causes plasma water to be filtered across the highly permeable membrane. As the water crosses the membrane, it convects small and large molecules across the membrane and thus cleanses the blood. An excessive amount of plasma water is eliminated by filtration. Therefore, in order to keep the body water balanced, fluid must be substituted continuously by a balanced electrolyte solution (replacement or substitution fluid) infused intravenously. This substitution fluid can be infused either into the arterial blood line leading to the hemofilter (predilution) or into the venous blood line leaving the hemofilter.
In addition to the removal of metabolic products, one of the most important problems of every kidney replacement therapy, such as hemodialysis, hemofiltration and peritoneal dialysis, lies in the correction of metabolic acidosis. For this reason, the dialysis solutions used in each of these processes contain a buffer.
Three common buffers often used in dialysis solutions are bicarbonate, lactate, and acetate. While initially bicarbonate was the primary buffer used in dialysis solutions, over time lactate and acetate were used as substitutes for bicarbonate. This was due to the difficulty in preparation and storage of bicarbonate-buffered dialysis solutions. Lactate and acetate buffers were found to provide greater stability in use over the previous bicarbonate-buffered solutions. See U.S. Pat. No. 5,211,643.
However, since bicarbonate ions provide advantages over acetate or lactate ions, bicarbonate is again surfacing as the primary buffer used in dialysis solutions. Tests have been conducted that indicate patients exhibit a better tolerance for bicarbonate dialysis solutions. In patients with a multiple organ failure, bicarbonate-buffered solutions are preferred because of the lack of metabolic interference. Further, certain treatments require sterile dialysis solutions containing bicarbonate, calcium and magnesium.
For example, one may have to dialyze a uremic patient who has developed hypotension and lactate acidosis. In such a patient, the lactate or acetate in conventional dialysates may not be metabolized to bicarbonate because of tissue hypoxia, and acidosis may be further worsened because bicarbonate is removed during dialysis. Using bicarbonate-containing dialysates in such a patient will add bicarbonate to the blood and also remove lactate. For these reasons, some researchers have recommended bicarbonate-buffered dialysis as adjunctive treatment for severe lactate acidosis. T. S. Ing. et al,
Bicarbonate-buffered peritoneal dialysis
, The International Journal of Artificial Organs, Volume 8, No. 3, p. 121-124 (1985).
Another potential application of bicarbonate-buffered solutions may be for patients who experience abdominal pain or discomfort when conventional acetate- or lactate-buffered dialysates are infused. The abdominal pain may be related to the unphysiologically high acidity of acetate- and lactate-buffered dialysates. Conceivably, bicarbonate-buffered dialysate, with its more physiologic pH, might decrease the incidence of such symptoms. Id.
The use of medical bicarbonate solutions for injection or for dialysis treatment is known. However, due to the difficulty in preparation and storage of these solutions, a vast array of literature is dedicated to attempts to remedy the stability problem of bicarbonate solutions. Three main problems need to be addressed when manufacturing and storing medical bicarbonate solutions.
First, in solution, bicarbonate is in equilibrium with CO
2
gas, which easily escapes from the solution. As a result, carbonate, a potential irritant, may form, and the pH of the solution is thereby increased. To avoid these phenomena from occurring, the bicarbonate can be stored in a powder form until just before use as described in U.S. Pat. No. 4,489,535 and Jonsson et al, European Patent Application 0 278 100 for machine-controlled dialysis.
Alternatively, an impermeable gas barrier can be used to protect the solution. Or, for hemodialysis, the CO
2
content of the solution can be controlled as described in Murphy et al,
Use of An Artificial Kidney
, J Lab. Clin. Med., Volume 40, pp. 436-444 (1952). U.S. Pat. No. 4,584,176 and European Patent No. 0 209 607 describe controlling the CO
2
content of a bicarbonate-based solution. Moreover, the addition of buffers, such as glycylglycine, has been proposed to further stabilize the bicarbonate solution. See U.S. Pat. No. 4,959,175.
Still further, another approach focuses on generating carbon dioxide within a container to stabilize bicarbonate solutions. See U.S. Pat. No. 5,383,324. In the '324 patent, a device can be used to generate and maintain carbon dioxide pressure within a container. The device can either be positioned within a container that houses the bicarbonate solution or within an overpouch that surrounds the container filled with the bicarbonate solution. The device can be used before, during or after steam sterilization.
Second, bicarbonate solutions for injection and for dialysis generally contain calcium and/or magnesium ions. In the presence of bicarbonate, these ions form calcium carbonate and magnesium carbonate, respectively, which at increased pHs typically precipitate from the solution. To initially remedy this problem, bicarbonate solutions are often made from concentrates, ranging from slightly concentrated, two-fold or less, to much more concentrated solutions. Bicarbonate on the one hand and calcium and/or magnesium on the other hand are included in separate concentrates. These concentrates are then mixed to obtain a ready-to-use solution. Alternatively, the concentrates are mixed and diluted or diluted and mixed.
In order to avoid the precipitation of carbonate salts, some have suggested the bicarbonate concentrate should be acidified when manufactured. See U.S. Pat. No. 5,211,643. Specifically, the '643 patent propos bicarbonate concentrate to less than 7.6 by addition of a physiologically tolerable acid.
Alternatively, others have proposed to leave the pH of the bicarbonate concentrate unadjusted. See U.S. Pat. No. 4,489,535. Left unadjusted, the pH of the bicarbonate concentrate is about 8.0-8.4. The Merck Index, 12
th
Ed., Merck Research Laboratories, Whitehouse Station, N.J., p. 1472 (1996); Boen ST,
A clinical study of factors governing its effectiveness, Peritoneal Dialysis
, p. 76, Van Gorcum & Comp, Assen, The Netherlands (1959); Odel HM et al.,
Peritoneal lavage as an effective means of extrarenal excretion. A clinical appraisal, America

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