Biocompatible aqueous solution for use in continuous ambulatory peritoneal dialysis

 

(57) Abstract:

The invention can be used in the treatment of end-stage renal failure. Proposed solution for peritoneal dialysis. It contains at least one osmotically active agent selected from the acetylated amino sugar, deacetylating of amino sugar and combinations thereof. Agent is present in the form of monomer or oligomer of 2-12 carbohydrate chains. For example, as such an agent may be N-acetylglucosamine, N-atsetilgalaktozamin, N-acetimenophen, glucosamine, galactosamine or mannosamine. The solution may additionally contain electrolytes: Na, CL, CA, Mg lactate, malate, acetate, succinate, and combinations thereof. It has a pH of 5.0 to 7.4. The method of peritoneal dialysis includes the introduction of the claimed solution in the peritoneal cavity of the patient. The method of treatment of a patient suffering from renal insufficiency, includes the introduction of the solution into the peritoneal cavity of the patient. The invention provides greater biocompatibility of the solution from the peritoneal membrane, preventing or slowing thus morphological or functional disorders of the peritoneal membrane and increasing the time of treatment of patients by the method of the RNA peritoneal dialysis (NIPD) used in the treatment of end-stage renal failure (command) by introducing a solution with osmotic activity in the peritoneal cavity. Toxic products allocation and excess liquid received from the blood into the dialysis solution by diffusion and ultrafiltration through the peritoneum. Osmotic ultrafiltration occurs due to the addition into dialyzing solution of glucose in hypertensive concentration. Due to the osmotic gradient between the blood and the solution for NAPD glucose draws water from the circulatory system into the peritoneal cavity. This osmotic effect exists and temporarily weakened as glucose is absorbed and/or metabolized.

In the process NAPD dialysis solution is injected by infusion of soft plastic containers in the peritoneal cavity, where it remains for some period of time (hereinafter called the retention time), then its output by drainage and drop. As a rule, daily 3-5 procedures or "exchanges" with the introduction of 1-3 solution for NAPD for each hold during the night. The glucose concentration range from 1.5 to 5% (wt./about.) using commercially available solutions for NAPD that contain 1,5%, 2,5% or 4.5% glucose at high lactate content, as well as various electrolytes present in concentrations of more or less nl is the cue solutions for NAPD usually have the osmolarity 300-700 mosmol/l, preferably 350-450, mosmol/l, as follows from the U.S. Patent 5011826.

Although peritoneal dialysis has several advantages compared with hemodialysis, including significantly lower cost, with this procedure, there are a number of potential complications. In this series include the loss of protein through the relatively highly permeable peritoneal membrane, absorption and metabolism of injected glucose that lead to weight gain and hyperlipidemia, which is especially undesirable for patients-diabetics, which often develops command (Ong-Ajyooth, L., Transp Proc 26:2077, 1994).

In an average day, the patient absorbs from dialysate about 150 g of glucose, which for many is a redundant source of carbohydrates and results in patients without diabetes, hyperinsulinemia and hypertriglyceridemia, which promote the occurrence of atherosclerosis. Probably such a series of events contributes to the development of cardiovascular disease, which most often are the cause of death of patients with the command.

Chronic effects on the peritoneum hypertonic solution for NAPD, having an acid reaction (pH 5 to 6.2), can lead to the loss of its function ultrafiltrate membrane, which causes higher as well as the loss of ability to ultrafiltration (Breborowicz et al. Advances in Peritoneal Dialysis 8: 11, 1992; Breborowicz et al, Nephron 67: 350, 1994). In peritoneal biopsies taken from patients with long-term subjected to dialysis using solutions for NAPD, visible typical epithelial response to stimulation, cell proliferation of mesothelia, as well as reducing the number of microversion that normally cover the surface mesothelial cells (Dobbie, J. W., Lloid, J. K., Gall, C. A. In R. Khamma, K. D. et al Eds. Advances in peritoneal dialysis. Toronto. U of Toronto Press, 3, 1990; Friedlander, M. J. Lab Clin Med 122:639, 1993). The consequence of long-term treatment method NAPD is a chronic inflammation of the peritoneum, which is connected, possibly with acidic properties solution for NAPD (Lewis, S & Holmes, C. , Periton Dial Int 11:14; Beelen, R. H. J. et al In J. F. Maher, Winchester, J. F. Eds. Frontiers in peritoneal dialysis. New York: Field, Richj and Associates, 524, 1986; Bos, H. J. et al, Nephorn 59:508, 1991), play a leading role in the cure (Weiczorowska, K., et al Short Reports). With long-term therapy method NAPD also develop morphologic changes in the peritoneal structure, including fibrosis of the peritoneum (Chaimovitz, C. , Kidney Int 45:1226, 1994). In addition, the use of modern relatively acidic and hypertonic glucose solutions for NPD leads to a decrease in the function of peritoneal macro-phages, which again points to the need for more physiological biocompatible solutions of DL is lose glycosaminoglycans (GAGS), resulting in a sharp decrease in filtration efficiency. It was assumed that the loss of GAG peritoneal membrane is a consequence of the enhanced production of free radicals activated peritoneal leukocytes (Breborowicz, A. et al, Periton Dial Int II (Suppl): 35a, 1991) or destructive actions interstitial proteins (Fligiel, S. E. G. et al, Amer J Pathol 115:418, 1984). Supplementation in dialysis fluid glycosaminoglycan chondroitin sulphate increases net ultrafiltration by slowing down the absorption of glucose and fluid from the peritoneal cavity (Advances in Peritonael Dialysis 8:11, 1992; Nephron 67: 346, 1994), possibly because of their ability to remove free radicals. In the literature there is also evidence that other GAGS, such as heparin and dermatan, remove free radicals (Hiebert, L., Liu, J. M., Semin Thromb Hemost 17:42, 1991; Fracasso, A. et al, J. Amer Soc Neph 5:75p, 1994). It was also reported that hyaluronan (formerly known as hyaluronic acid), which also removes free radicals, protects the peritoneum from damage resulting from NILD therapy (Wieczorowska, K. et al, Perit. Dial. Int. 15: 81, 1995). This is confirmed by the discovery of the fact that the dialysis fluid collected per night, contains hyaluronan in a higher concentration than syvertsen, when peritonitis or without it, the levels of hyaluronan is increased, but a possible source of hyaluronan was mesothelial cells of the peritoneum. Hyaluronan plays an important role in regulating cell proliferation during the healing process. Hyaluronan is a polymer of repeating molecules of N-acetylglucosamine and glucuronic acid; dermatan consists of repeating units of N-acetylglucosamine and iduronovoy acid and chondroitin built of glucuronic acid and N-atsetilgalaktozamin.

Breborowicz and Oreopoulos (Breborowicz and Oreopulos) gave a PCT patent application (EP-555087-A1) (priority 92US - 830721) to be added to the solutions for NPD in cases of peritonitis acceptors of free radicals, such as EIDERS, including degradation products of hyaluronic acid for the prevention of related peritonitis inflammatory reactions.

As described above, N-acetylglucosamine (N-AG) is a component of many GAG. N-AG is formed in almost all the cells from glucose through a series of biochemical reactions that involve the transfer of an amino group from glutamine to glucose with the formation of glucosamine and synthesis of N-acetylglucosamine using acetyl-KoA. Then N-AG is transformed into N-AG-6-phosphate (which goes into the epimer N-AG, N - atsetilenovykh acids, of gangliosides and glycoproteins) and N-AG-1-phosphate (which turns into UDF-N-acetylglucosamine (UDF-N-AG), which are involved in such GAGS as chondroitin and glycoproteins). UDF-N-AG turned into such GAGS as hyaluronan and glycoproteins. Thus, the N-AG is the primary building block of many vital components of tissues, regardless of whether they include directly N-AG or related amino sugar N-acetylcarnosine and N-atsetilgalaktozamin.

It was shown that the oral administration of glucosamine and N-acetylglucosamine (N-AG) is rapidly absorbed and distributed throughout the body, penetrating into tissue, preferably in GAG body. These substances are introduced into the GAG peritoneal membrane that prevents depletion and provides thus the integrity of the peritoneal membrane, preventing or at least slowing the loss of membrane it ultrafiltrate actions. Thus, in the treatment of end-stage renal failure (command) method NAPD the replacement of the entire glucose or part of it available at the moment solutions for NAPD aminosugars, in particular N-AG, should provide a more biocompatible solution for peritoneally, and to remove waste products by the entrainment of the solvent from patients with a command exposed NAPD. Unlike glucose, which as a source of energy absorbed almost all microorganisms, amino sugar metabolismus are relatively less and probably do not support microbial growth, thereby reducing in patients undergoing long-term treatment method NAPD, predisposition to the development of peritonitis, common and serious adverse complications associated with treatment NAPD. Due to the rapid excretion of N-AG and other amino sugars from the systemic circulation by introducing them to GAG and various components of tissue containing the amino sugar, the extent of metabolic conversion to lipids is significantly reduced, which reduces the risk of obesity, protein deficiency, dyslipidemia and hypertriglyceridemia, hyperinsulinemia, and so on, as well as related adverse metabolic consequences.

For N-AG and related amino sugar can be used as osmotic agents in solutions for NAPD, they must have a chemical purity in a high degree, i.e. in the same, which is required for use of the yen in two ways. The first is acid biological processing of crude chitin, representing a linear polymer of repeating units of N-AG and derived from the shells of crabs, shrimps and other crustaceans, after which individual parts of N-AG allocate and dezazetiliruetsa to glucosamine. Glucosamine is isolated and crystallized to a high degree of purity, and then with acetic anhydride re acetimidoyl to N-acetylglucosamine, which precipitated and recrystallized from alcohol so that its purity is higher than 98.5 per cent. The second production method of N-AG, and preferred, is to obtain N-AG from the dried shells of crustaceans or from untreated chitin by direct enzymatic cleavage by a set of enzymes including chitinase and chitobiase that breaks down chitin is a polymer of N-AG to disaccharide glycosides links chitobiose, and then directly to the monomer N-AG, without the need for any stages of organic synthesis. N-AG is recrystallized from ethyl alcohol to a high degree of purity. The enzymes required for this process are highlighted in culture medium for many microorganisms, in particular of Serratia marcescens. So obrazovaniya in solutions NAPD, but also allows N-AG is relatively cheap, since chitin or crustacean shells can be added directly to not containing cells of microorganism growth medium from a culture of S. marcescens, and after the required reaction period can easily be distinguished from that environment N-AT. Changing the duration of the enzymatic reaction, it is possible to obtain polymers with different number of links N-AT, which can be further purified and identified as a molecular particles with a specific molecular weight using available chromatographic separation methods, and which can be isolated, crystallized, and optionally purified by recrystallization using methods known qualified specialists in the field of methods of isolation and purification of carbohydrate chemistry.

In U.S. Patent 5011826 argues that in solutions for NAPD you can use galactose, individually or together with glucose in different ratios, as osmotically active agents, at that time, as in U.S. Patent 4879280 argues that similarly can be used disaccharides, such as lactose, sucrose, cellobiose, etc. together with suitable electrolyte additives. To the th weight less than 400000, such as raffinose, starch, inulin, pectin, dextrans, gidroksietilirovanny starch (HES) and similar substances. For example, colloidal polymers of glucose with chain length in 4-250 links and with an average weight molecular weight of about 16200 and srednekamennogo molecular weight of 5800 passed clinical trials as a component of the solution for NAPD (Kidney Int 46: 496, 1994; US Patent 4886789). The solution of this polymer of glucose, called Icodextrin (Icodextrin), at a concentration of 7.5% had osmollnosti 282, mosmol/kg and a pH of 5.3. However, in the available scientific literature, nor in the published patent does not mention the use of polymers or oligomers of amino sugars such as N-acetylglucosamine, N-acetimenophen or N-atsetilgalaktozamin and the like, as osmotically active components solutions for NPD that is the subject of the present invention.

Since the efficiency intraperitoneal dialysis depends on the presence of a hypertonic solution, and osmolarity depends on the number of molecules in solution, large molecules, such as glycosaminoglycans (GAG), is a small contributor to the osmotic effect of solution for NPD and dialysis solution should contain and the excess glucose is leaving GAG, have a molecular mass similar to the mass of the glucose they need to be osmotically active. Therefore, the inclusion of amino sugars, in particular, N-acetylglucosamine, solutions for NPD in concentrations from 0.5 to 5%, together with glucose or without, will ensure effective dialysis solution with greater biocompatibility with peritoneal membrane, preventing or slowing thus morphological or functional disorders of the peritoneal membrane and increasing the time during which patients with a command can be successfully treated by the method NAPD. This provides several benefits, including significant cost savings in the healthcare system by reducing the need for expensive dialysis, reduction in the number of peritoneal infections in patients undergoing NAPD, a lower risk of cardiovascular disease by reducing lipid changes that are typical when using the currently available solutions for NPD, and improving the quality of life for these patients.

Coming on the market today solutions for NAPD have the following typical composition per 100 ml of solution. Dextrose anhydrous 1,5, 2,5 or 4,25 plus chloride sodium 567 mg, lactate into three which is 132 mEq Na/l; 3,24 mEq Ca/l; 1.5 mEq Mg/l; 101,75 mEq Cl/l and 36 mEq lactate/L. Alternatively, such a solution may contain, instead of lactate, malate, acetate or succinate. Typically, the solution has an osmotic pressure 347, mosmol/L.

The solution for NAPD of the present invention is designed to provide levels of electrolytes, similar to their levels in currently available solutions for NPD, but different in another part of osmotically active carbohydrates, including acetylated and diacetylmorphine of amino sugar, including N-acetylglucosamine, glucosamine, N-atsetilgalaktozamin, galactosamine, N-acetimenophen, mannosamine individually or in combination at various concentrations, or in combination with glucose in different concentrations, or oligomers of N-acetylglucosamine, N-acetyl-mannosamine, N-atsetilgalaktozamin, galactosamine, mannosamine and glucosamine, which consist of at least 2 carbohydrate units and not more than 12 units. This composition may be a mixture of oligomers with different amounts of each oligomer, either separately or in combination with one another. Advanced solutions for NAPD of the present invention may contain various ratios with acetylic evade, also included in the tissue glycosaminoglycans (GAGS), such as glucuronic acid and Euronova acid.

In the simulation of inflammatory bowel disease in animals the colon becomes fibrotic, the same thing happens with the peritoneum as a result of long intraperitoneal dialysis. The introduction of a solution of N-AT in the intestines of rats that have existed caused by chemical inflammatory reaction of the intestine with thickening of the walls of the intestine or fibrosis, reduces fibrotic response to an inflammatory stimulus in the degree of dose-dependent (table 1). You should expect similarly N-AT will to prevent the development of peritoneal fibrosis in patients undergoing NAPD.

In addition to glucose, typical solutions for NPD also contain the appropriate quantity and quality of electrolytes in order to obtain a more or less acceptable saline solution. For example, as a substitute includes lactate. Its absorption and metabolism will be to correct metabolic acidosis. Sodium is usually injected at a concentration slightly lower than its concentration in plasma, or 132-137 mm/l, in order to expedite the removal of sodium. Similarly usually include solutions for listello 280 mosmol/l, so the solution for NPD should have a greater value osmolarity than that, to be effective as a dialysis solution, and preferably it should have an osmotic pressure of 300-700 mosmol/l, and more specifically 310-560, or in a more narrow range, from 350 to 450 mosmol/l (patent 4879280).

In experiments on rats dialysis for 4 hours was performed using a balanced salt solution Hanks (Hanks Balances salt solution), which was added either glucose or N-acetylglucosamine in concentrations of 75 mm or 214 mm at a pH of 7.35 to 7.4. The value of net ultrafiltration was calculated as the difference between the volume extracted by drainage dialysate after a 4-hour retention time in the peritoneal cavity and the volume of dialysis fluid (20 ml). Additionally, we measured the concentration of urea and creatinine in the blood and dialysis fluid, the permeability of the peritoneal membrane to urea and creatinine expressed in the form of surface mass transfer coefficient was calculated according to the method of Krediet and drew (Krediet et al, Blood Purif 4: 194, 1986). The results, shown below in table 2 clearly show that N-AG provides a statistically significant increase in net ultrafiltration, and peryite is about, the inclusion of N-AG in the dialysis fluid in rats stimulates the synthesis of hyaluronic acid, as shown by the increase in the number guluronate acid selected in dialysate, more than 100%, compared to animals that received glucose, such in vivo experiments clearly show that when used for peritoneal dialysis N-AG is more effective osmotic agent than glucose.

Stimulation of the production of hyaluronic acid N-acetylglucosamine was confirmed in tissue culture mesothelial human cells.

Since the implementation of the present invention can be made many changes, not beyond the scope of claims of this invention, it is hereby declared, that all the materials for this invention should not be interpreted in a restrictive sense but only as illustrative.

1. Solution for peritoneal dialysis containing an effective amount of at least one osmotically active agent selected from the group consisting of acetylated amino sugar, deacetylating of amino sugar and combinations thereof, wherein said at least one osmotically active agent prisutstvennye an amino sugar selected from the group consisting of N-acetylglucosamine, N-atsetilgalaktozamin and N-acetylcarnosine.

3. The solution under item 1 or 2, in which deacetylating an amino sugar selected from the group consisting of glucosamine, galactosamine and mannosamine.

4. The solution according to any one of paragraphs.1, 2 or 3, in which acetylated amino sugar is a N-acetylglucosamine.

5. The solution according to any one of paragraphs.1, 2, 3, or 4, optionally containing electrolytes selected from the group consisting of sodium, chloride, calcium, magnesium, lactate, malate, acetate, succinate, and combinations thereof, and these electrolytes are present in the form of pharmaceutically acceptable compositions.

6. The solution on p. 5, in which the solution is a pharmaceutically acceptable pH and the pH is within ~ of 5.0 to 7.4, sodium is present at a concentration in the range of 115 to 140 mEq/l, calcium at a concentration in the range of 0.6 - 5.0 mEq/l, chloride concentrations in the range of 100 - 145 mEq/l, magnesium at a concentration in the range of 0 to 2.0 mEq/l and lactate, malate, acetate or succinate in concentrations in the range of 30 - 45 mEq/L.

7. The solution according to any one of paragraphs.1, 2, 3, 4, 5 or 6, in which at least one osmotically active agent is present in a concentration of 0.5 to 5.0% (wt/about).

8. the RCM active agent, selected from the group consisting of glucose, iduronovoy acid, glucuronic acid, and combinations thereof.

9. The solution on p. 8, in which at least one osmotically active agent together with at least one additional osmotically active agent is present in a concentration of from 0.5 to 5.0% (wt/about).

10. The method of peritoneal dialysis, introducing a solution for peritoneal dialysis in peritoneal cavity of the patient, and this solution contains an effective amount of at least one osmotically active agent selected from the group consisting of acetylated amino sugar, deacetylating of amino sugar and combinations thereof, and the specified at least one osmotically active agent is present in the form of monomer or oligomer of 2 - 12 carbohydrate units, and where this solution reduces complications associated with peritoneal dialysis.

11. The method according to p. 10, in which acetylated amino sugar selected from the group consisting of N-acetylglucosamine, N-atsetilgalaktozamin and N-acetylcarnosine.

12. The method according to p. 10 or 11, in which deacetylating an amino sugar selected from the group consisting of glucosamine, galacto dstanley a N-acetylglucosamine.

14. The method according to any of paragraphs.10, 11, 12 or 13, in which the solution further comprises an electrolyte selected from the group consisting of sodium, chloride, calcium, magnesium lactate, malate, acetate, succinate, and combinations thereof, and these electrolytes are present in the form of pharmaceutically acceptable compositions.

15. The method according to p. 14, in which the solution is a pharmaceutically acceptable pH and the pH is within ~ of 5.0 to 7.4, sodium is present at a concentration in the range of 115 to 140 mEq/l, calcium at a concentration in the range of 0.6 - 5.0 mEq/l, chloride concentrations in the range of 100 - 145 mEq/l, magnesium at a concentration in the range of 0 to 2.0 mEq/l and lactate, malate, acetate or succinate in concentrations in the range of 30 - 45 mEq/L.

16. The method according to any of paragraphs.10, 11, 12, 13, 14 or 15, in which at least one osmotically active agent is present at a concentration of ~ 5,0-5,0% (wt/about).

17. The method according to any of paragraphs.10, 11, 12, 13, 14, 15 or 16, in which the solution further comprises at least one additional osmotically active agent selected from the group consisting of glucose, iduronovoy acid, glucuronic acid, and combinations thereof.

18. The method according to p. 17, in which at least one osmotically active agent in the SAR of 5.0% (wt/about).

19. The method according to any of the p. 10, 11, 12, 13, 14, 15, 16, 17 or 18, in which the solution reduces at least one of the following complications associated with peritoneal dialysis: morphological and functional damage to the peritoneal membrane, peritonitis, adverse metabolic consequences and associated cardiovascular disease and protein deficiency.

20. The method of treatment of a patient suffering from renal failure, including the introduction of solution for peritoneal dialysis in peritoneal cavity of the patient, and this solution contains an effective amount of at least one osmotically active agent selected from the group consisting of acetylated amino sugar, deacetylating of amino sugar and combinations thereof, and the specified at least one osmotically active agent is present in the form of monomer or oligomer of 2 - 12 carbohydrate chains.

21. The method according to p. 20, in which acetylated amino sugar selected from the group consisting of N-acetylglucosamine, N-atsetilgalaktozamin and N-acetylcarnosine.

22. The method according to p. 20 or 21, in which deacetylating an amino sugar selected from the group consisting of glucosamine, galactose the hat is N-acetylglucosamine.

24. The method according to any of the p. 20, 21, 22 or 23, in which the solution further comprises an electrolyte selected from the group consisting of sodium, chloride, calcium, magnesium, lactate, malate, acetate, succinate, and combinations thereof, and these electrolytes are present in the form of pharmaceutically acceptable compositions.

25. The method according to p. 24, in which the solution is a pharmaceutically acceptable pH and the pH is within ~ of 5.0 to 7.4, sodium is present at a concentration in the range of 115 to 140 mEq/l, calcium at a concentration in the range of 0.6 - 5.0 mEq/l, chloride concentrations in the range of 100 - 145 mEq/l, magnesium at a concentration in the range of 0 to 2.0 mEq/l and lactate, malate, acetate or succinate in concentrations in the range of 30 - 45 mEq/L.

26. The method according to any of paragraphs.20, 21, 22, 23, 24 or 25, in which at least one osmotically active agent is present at a concentration of ~ 0.5 to 5.0% (wt/about).

27. The method according to any of paragraphs.20, 21, 22, 23, 24, 25 or 26, in which the solution further comprises at least one additional osmotically active agent selected from the group consisting of glucose, iduronovoy acid, glucuronic acid, and combinations thereof.

28. The method according to p. 27, in which at least one osmotically active agent WMO of 5.0 (wt/V).

 

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