Sugar – starch – and carbohydrates – Processes – Carbohydrate manufacture and refining
Reexamination Certificate
1998-12-04
2004-08-03
Wilson, James O. (Department: 1623)
Sugar, starch, and carbohydrates
Processes
Carbohydrate manufacture and refining
C536S045000, C514S060000, C514S054000
Reexamination Certificate
active
06770148
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates generally to peritoneal dialysis and solutions for the same. More specifically, the present invention relates to the use of modified icodextrins in peritoneal dialysis solutions as an osmotic agent and as an alternative to the use of glucose as an osmotic agent. The present invention also relates to methods of preparing peritoneal dialysis solutions that are stable under autoclaving conditions.
Dialysis provides a method for supplementing or replacing renal function in certain patients. Principally, hemodialysis and peritoneal dialysis are the two methods that are currently utilized.
In hemodialysis, the patient's blood is passed through an artificial kidney dialysis machine. A membrane in the machine acts as an artificial kidney for cleansing the blood. Because it is an extracorporeal treatment that requires special machinery, hemodialysis is fraught with certain inherent disadvantages such as the availability of dialysis machines and the possibility of infection and contamination.
To overcome the disadvantages associated with hemodialysis, peritoneal dialysis was developed. Peritoneal dialysis utilizes the patient's own peritoneum as a semi-permeable membrane. The peritoneum is a membranous lining of the abdominopelvic walls of the body. The peritoneum is capable of acting as a natural semi-permeable membrane because of its large number of blood vessels and capillaries.
In operation, a peritoneal 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 blood is achieved. Fluid removal is achieved by providing a suitable osmotic gradient from the dialysate to the blood to permit water outflow from the blood. This allows the proper acid-base, electrolyte and fluid balance to be achieved in the blood. After an appropriate dwell period, the dialysis solution or dialysate is drained from the body through a catheter.
Conventional peritoneal dialysis solutions contain glucose as an osmotic agent to maintain the osmotic pressure of the solution higher than the physiological osmotic pressure (about 285 mOsmol/kg). Glucose is a preferred osmotic agent because it provides rapid ultrafiltration rates. However, certain disadvantages have become associated with the use of glucose.
For example, glucose is known to decompose to 5-hydroxymethyl-furfural (5-MHF) in an aqueous solution during autoclaving or steamed sterilization. Smith, et al.
AM. J. Hosp. Pharm
., 34:205-206 (1977). Because 5-HMF is considered to be harmful for the peritoneum (Henderson, et al.,
Blood Purif
., 7:86-94 (1989)), it would be desirable to have a peritoneal dialysis solution with an osmotic agent as effective as glucose but which does not produce 5-HMF or other harmful decomposition products during autoclaving or sterilization. In short, a substitute osmotic agent for glucose is needed.
One family of compounds capable of serving as osmotic agents in peritoneal dialysis solutions is icodextrins, including maltodextrins. However, while these compounds are suitable for use as osmotic agents, they are also known to degrade during heat sterilization to aldonic acids and formaldehyde. Because the presence of formaldehyde in peritoneal dialysis solutions is inappropriate due to its poor biocompatibility, the use of icodextrins, including maltodextrins as a substitute for glucose as an osmotic agent is unsatisfactory.
Accordingly, there is a need for an improved peritoneal dialysis solution which utilizes an osmotic agent other than glucose and which is stable under autoclaving or steam sterilization conditions.
SUMMARY OF THE INVENTION
The present invention provides a solution to the aforenoted need by providing a sterilized peritoneal dialysis solution comprising a glucose polymer linked predominately by &agr;-1,4 bonds. The term “predominately” is used because it is anticipated that within polymer molecules, other bonds such as &agr;-1,6 bonds will be present as well, but in lesser amounts. Accordingly, as used herein, the term “predominately” means at least 85%. Thus, a glucose polymer linked predominately by &agr;-1,4 bonds includes at least 85%, by number, &agr;-1,4 bonds.
In an embodiment, the glucose polymer linked predominately by &agr;-1,4 bonds is selected from the group consisting of D-glucitol having the formula
gluconic acid having the formula
and alkylglycoside having the formula
wherein R is selected from the group consisting of CH
3
, CH
3
CH
2
and (CH
2
OH)
2
CH, CH
2
(OH)CH(OH)CH
2
, and (CH
2
OH) (CHOHCH
2
OH)CH.
In an embodiment, the glucose polymers, linked predominately by &agr;-1,4 linkages, of the peritoneal dialysis solution may include up to 10% of other linkages including, but not limited to, &agr;-1,6 linkages.
In an embodiment, the peritoneal dialysis solution of the present invention is substantially free of formaldehyde.
In an embodiment, the peritoneal dialysis solution of the present invention is substantially free of furfurals.
In an embodiment, starch utilized as the osmotic agent is substantially free of terminal aldehyde groups.
In an embodiment, the present invention provides a method of preparing a stabilized osmotic agent of a peritoneal dialysis solution comprising the steps of providing a solution of starch dissolved in water and adding NaBH
4
to the solution of partially hydrolyzed starch to reduce the starch.
In an embodiment, the method of the present invention further comprises the step of purifying the reduced starch solution by passing the reduced starch solution through an anionic exchange resin.
In an embodiment, the dissolving and adding steps of the method of the present invention are carried out at room temperature.
In an embodiment, the method of the present invention further comprises the step of allowing the solution to scan for approximately 10 hours after the NaBH
4
is added to the starch solution to reduce the starch.
In an embodiment, the starch of the present invention is maltodextrin.
In an embodiment, the method of the present invention reduces maltodextrin to D-glucitol linked predominately by &agr;-1,4 bonds and having the formula
In an embodiment, the present invention provides a method for preparing a stabilized osmotic agent of a peritoneal dialysis solution which comprises the steps of providing a solution of starch dissolved in water, providing a solution of NaOCl, and adding the NaOCl solution to the starch solution to oxidize the starch.
In an embodiment, the method of the present invention further comprises the step of purifying the oxidized starch solution by passing the oxidized starch solution through a gel permeation chromatograph.
In an embodiment, the oxidation of the starch is carried out at room temperature.
In an embodiment, the combined solutions are allowed to stand for approximately 2 hours.
In an embodiment, the starch is maltodextrin.
In an embodiment, the method of the present invention oxidizes the maltodextrin to a gluconic acid linked predominately by &agr;-1,4 bonds and having the formula
In an embodiment, the maltodextrin can be oxidized electrochemically.
In an embodiment, the present invention provides a method of preparing a stabilized osmotic agent for a peritoneal dialysis solution which comprises the steps of dissolving the starch in an acid and an alcohol selected from the group consisting of methanol, butanol, glycerol or other alcohols.
In an embodiment, the method further comprises the step of stirring the starch, alcohol and acid for 2-16 hours.
In an embodiment, the method further comprises the step of stirring the starch, alcohol and acid at a temperature of about 100° C.
In an embodiment, the starch is maltodextrin.
In an embodiment, the acid is hydrochloric acid or other acids such as sulfuric acid.
In an embodiment, the method of the present invention hydrolysizes and alkylates the starch to an alkylglycoside linked predominately by &agr;-1,4 bonds and having the formula
and wherein R is selected from the group consisting of CH
3
Casu Benito
Naggi Annamaria
Petrella Enrico
Torri Giangiacomo
Baxter International Inc.
Bell Boyd & Lloyd LLC
Kelly Paula J. F.
Owens, Jr. Howard V.
Reagen Joseph P.
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