Peritoneal dialysis fluid

Details Peritoneal dialysis fluid Peritoneal dialysis fluid

2000-06-08

2002-12-10

Pak, John (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S024000

Reexamination Certificate

active

06492336

ABSTRACT:

The present invention relates to novel peritoneal dialysis fluids and to the use thereof for performing peritoneal dialysis.
BACKGROUND TO THE INVENTION
In the human body, the transfer of solutes and toxins from one body fluid compartment to another occurs by a variety of chemical and physical processes which include diffusion, osmosis and active transport. In this respect, toxins, excess of water and solutes are transferred from the tissues to the blood stream and then via the arteries to the kidneys. In the kidneys substances to be eliminated may be metabolised and eliminated in the urine.
In renal disease, kidney function is not sufficient to maintain an adequate degree of clearance, thus the accumulation of water and uremic toxins occurs in the body. Today, the medical treatments available for patients suffering from a malfunction of the kidney are kidney transplantation, extracorporeal hemodialysis, or alternatively intracorporeal peritoneal dialysis. Treatment by kidney transplantation. remains the preferred therapy as the patients may lead a near normal life. Hemodialysis (an extracorporeal procedure) and peritoneal dialysis (an intracorporeal procedure) are the alternative therapies to treat end stage renal disease (ESRD) patients.
Peritoneal dialysis is a well established intracorporeal procedure which is used today as an alternative to the extracorporeal hemodislysis. In fact, in many instances, peritoneal dialysis is preferred to the extracorporeal therapy.
However, in some medical centers, hemodialysis technology is not available and the cost of peritoneal dialysis in general may be lower when other medical complementary care procedures are excluded, For some patients, the surgery required to prepare for permanent blood access has been unsuccessful. Finally, some nephrologist prefer peritoneal dialysis as a hemodialysis procedure, because it uses a natural membrane and residual (resting) kidney function may be maintained for a long period after starting the therapy.
In peritoneal dialysis, a dialysis fluid is introduced with the aid of a catheter into the peritoneal cavity in the abdomen of the patient. This catheter is permanently implanted by surgery through the abdominal wall. The peritoneal cavity is flooded with the dialysis fluid, left for an appropriate lapse of time, and then drained.
Peritoneal dialysis relies on the physiological activity of the peritoneum. The peritoneum is a layer of mesothelial cells which contains large numbers of blood vessels and capillaries. These facilitate use of the peritoneal cavity as a semipermeable membrane. The peritoneal dialysis procedure involves the introduction of a fluid into the peritoneal cavity for a suitable period of residence time. This allows an exchange of solutes between the dialysate and the blood during the residence time of the dialysate in the peritoneum. This residence time (also called dwell time) varies from patient to patient and can be about five hours. Accordingly, the frequency with which the dialysate has to be exchanged is on average, four to five times per day.
The removal of uremic toxins takes place across the peritoneal membrane by diffusion, and excess water in the body is removed by an osmotic pressure induced by an osmotic agent such as glucose. Glucose is currently the standard osmotic agent and is generally used in a concentration in the dialysis fluid (% weight by volume) of from 1.36 to 4.25.
As indicated, glucose is currently included in the dialysis fluid to impart the necessary osmotic gradient, i.e., it is the standard osmotic agent for dialysis solutions. However, because it is introduced into the peritoneal cavity, it will find its way into the bloodstream during therapy. In fact, glucose crosses the peritoneum so rapidly that the magnitude of the osmotic gradient falls within 2-3 hours after the injection of the dialysate. This causes the unwanted result of water being reabsorbed from the dialysate toward the end of the dialysis period, i.e. before the dialysis fluid is replaced with fresh fluid.
Further, the amount of glucose which is absorbed represent a large portion of the patient's energy uptake, possibly being as high as 15-40%. The clinical consequences are hypoglycemia and obesity. In addition, the sugar has a long term undesirable effects, especially for diabetic patients, for whom there is an additional requirement to increase the injection of the insulin doses or to introduce additional insulin in the dialysis fluid.
A further negative effect of using glucose is the formation of advanced glycation of proteins in diabetic and uremic patients, due to a high concentration of glucose, which is not quickly metabolized. This disadvantage may be the cause of peritoneal membrane damage during therapy and may be also responsible for membrane scelerosis which decreases the salt clearance.
The reduction of advanced glycated end product (AGE) uremia in the peritoneal membrane is today a new considerable factor in assessing the performance of dialysis therapy
1
. Glycation of the protein matrix of the peritoneum membrane has been demonstrated in CAPD patients. The local biological effects of AGE on peritoneal cells, has been demonstrated in vitro and involves activation of mesotheial cells and the pathological change of the peritoneal cell matrix which may cause scelorosis.
One of the most important and difficult aspects of peritoneal dialysis, is finding a suitable osmotic agent for the preparation of the dialysate, by which the required osmotic pressure can be achieved without the secondary problems referred to above. An appropriate osmotic agent should have the following properties: it should satisfy the needs for peritoneal dialysis; be a non-toxic substance: the accumulation of unacceptable derivatives or metabolites in the peritoneum or in the circulation should be avoided; it should not rapidly cross the peritoneal membrane into the blood and in this respect it should allow maintenance of the required ultrafiltration; it should not react with the peritoneum or with proteins, leading to secondary reactions involving pathology of the peritoneal membrane, of peritoneal cells, or of cells from the circulation; it should not alter cell function which can reduce natural local phagocytosis, and the ability of the immune system to kill bacteria.
To date, several osmotic agents such as dextran
2
, fructose
3
, xylitol
4
, sorbitol
5
, polyglucose
7,8
, amino acids
9
, glycerol
10
, peptides
11
, and plasma substitutes
12
, have been proposed, but most of these have not completely satisfied the medical needs.
In Dolkart R. E WO 82/03987, the use of a monosaccharide sugar alcohol such as glycerol has been suggested as an alternative osmotic agent to overcome glucose overloading, mainly in diabetic patients. In addition, xylitol and sorbitol have also been proposed in the 1970's. However when given in their pure form and in an amount sufficient to exert transperitoneal ultrafiltration, all these sugar alcohols have a high transperitoneal absorption and lead to their accumulation in the blood at a rate over the rate of their metabolic clearance, thus causing several adverse reactions.
In U.S. Pat. No. 3,911,915 by Seifter et al, a disaccharide in the form of maltose has been proposed for intraperitoneal use. Although maltose has been demonstrated to have beneficial effects following intravenous administration
14
in respect to the insulin need and glucose overloading when compared to glucose, this substance was not provided a suitable osmotic agent in peritoneal dialysis.
The use of high molecular weight polyglucose have been proposed by Milner in the U.S Pat. No. 3,928,135 for the use as ingredients for oral or intravenous administration, and by Alexander in No. WO 83/00087 for the special use as osmotic agent in peritoneal dialysis. This proposal by Alexander is based on the concept that an iso-osmotic solution containing polyglucose exercises transperitoneal ultrafiltration. Although glucose polymers seem to be well tolerable by patients, plasma oligosaccharide concentrati

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