PERITONEAL DIALYSIS SOLUTIONS CONTAINING MALTODEXTRINS AND AMINO ACIDS

Abstract: A peritoneal dialysis solution comprising as osmotic agents approximately 2.0 to about 6.0 % (w/v) maltodextrins and approximately 0.25 to about 2.0 % (w/v) amino acids. The peritoneal dialysis solution will also include other components such as sodium, chloride, lactate, bicarbonate, calcium, and magnesium.

Description: S P E C I F I C A T I O N TITLE PERITONEAL DIALYSIS SOLUTIONS CONTAINING MALTODEXTRINS AND AMINO ACIDS BACKGROUND OF THE INVENTION The present invention relates generally to peritoneal dialysis. More specifically, the present invention relates to peritoneal dialysis solutions- It is known to use dialysis to support a patient whose renal function has decreased to the point where the kidneys no longer sufficiently function. Two principal methods of dialysis are utilized: hemodialysis; and peritoneal dialysis. Hemodialysis utilizes an artificial kidney dialysis machine through which the patient's blood is passed. A membrane in the machine acts as an artificial kidney and cleanses the blood. Hemodialysis is an extracorporeal treatment that requires special machinery. Therefore, there are certain inherent disadvantages with hemodialysis. Peritoneal dialysis was developed to overcome some of the disadvantages associated with hemodialysis. In peritoneal dialysis, a patient's own peritoneum is used as a semi-permeable membrane. The peritoneum is capable of acting as a natural semi-permeable membrane due to the large number of blood vessels and capillaries present in this membranous lining of the body cavity. In peritoneal dialysis, a dialysis solution is introduced into the peritoneal cavity utilizing a catheter. After a sufficient period of time, an exchange of solutes between the dialyεate and the blood is achieved. By providing a suitable osmotic gradient from blood to dialysate, fluid removal is achieved permitting water outflow from the blood. This allows the proper acid-base, electrolyte and fluid balance to be returned to the blood and the dialysis solution is simply drained from the body cavity through the catheter. There are many advantages to peritoneal dialysis. However, one of the difficulties that has been encountered is providing a dialysate that includes a suitable osmotic agent. What is required is that a sufficient osmotic gradient is achieved. To achieve the osmotic gradient, an osmotic agent is used. The osmotic agent maintains the osmotic gradient required to cause transport of water and toxic substances across the peritoneum into the dialysis solution. In order to be suitable, the osmotic agent needs to achieve at least a couple of criteria. First, it needs to be non-toxic and substantially biologically inert. However, the agent should be metabolizable. The agent should not rapidly cross the peritoneum membrane into the blood. By achieving both these criteria, one is able to allow maintenance of the maximum ultrafiltration gradient, and also prevent toxicity or accumulation of unwanted substances in the blood. It is believed that no currently used substances currently satisfy the criteria for an osmotic agent in a dialysis solution. The most widely used osmotic agent today is dextrose. Dextrose is fairly safe and is readily metabolizable if it enters the blood. But, one of the problems encountered with dextrose is that it is rapidly taken up by the blood from the dialysate. Because dextrose crosses the peritoneum so rapidly, the osmotic gradient is dissipated within two to three hours of infusion. This can cause reversal of the direction of ultrafiltration, causing water to be reabεorbed from the dialysate toward the end of the time allowed for the exchange. A further concern with respect to dextrose is that because it is taken up so rapidly by the blood, it can represent a large proportion of the patient's energy intake. In non-diabetic patients, this may not be significant. However, this can represent a severe metabolic burden to a patient whose glucose tolerance is already impaired. Dextrose can also cause problems with respect to patients having hyperglycemia or who are obese. A further problem experienced with dextrose is with respect to the preparation of a dialysis solution. Dialysis'solutions, similar to other medical products and solutions, are typically sterilized by heating. Unfortunately, heat sterilization of dextrose at physiological pHs will cause dextrose to caramelize. To compensate for this problem, it is known to adjust the pH of the dialysate to within the range of 5 to 5.5 - at this low pH, dextrose cara elization will be minimal when heated. However, it is believed that this low pH may be responsible for the pain some patients experience on the in-flow of dialysis solution. Additionally, the low pH of the solution may cause other problems, e.g., may effect peritoneal host defense. To address some of the above concerns, a number of substances have been proposed as alternatives to dextrose. It is believed that none of the proposed materials currently available have proven to be an adequate substitute for dextrose. Dextrans, polyanions, and glucose polymers have been suggested as replacements for dextrose. Because of their high molecular weight, it is believed that their diffusion across the peritoneum and into the blood should be minimized. But, the low osmotic activity per unit mass of these materials dictates the need for larger concentrations (w/v) of these materials in the dialysis fluids in order for them to be effective. Additionally, systemic absorption of these materials, mainly through the lymphatics, along with slow metabolism, raises serious concerns about the long term safety of these agents. Small molecular weight substances have also been explored. These substances include glycerol, sorbitol, xylitol, and fructose. However, these substances are believed to raise a number of safety concerns while offering no substantial advantage over dextrose. An attractive substitute for dextrose appears to be amino acids. Short term studies have indicated that amino acids are well tolerated. But, because of their low molecular weights, they are transported quite rapidly through the peritoneum resulting in a rapid loss of osmotic gradient. Additionally, the rapid uptake of amino acids leads to a considerable nitrogen burden and limits the use of amino acids to one to two exchanges per day. Recently, polypeptides have been explored as a potential class of osmotic agents. It is believed that polypeptides will have a slow transport across the peritoneum and therefore maintain a prolonged osmotic gradient between the dialysate and blood. U.S. Patent No. 4,906,616 to Gilchrist et al and European Patent No. 0218900 to Klein set forth polypeptides as the osmotic agent in the peritoneal dialysis solution. Each of these patents discusses the substitution of polypeptides for dextrose. As disclosed, polypeptides are the only osmotic agents utilized in these formulations. It is believed that the polypeptide solutions proposed by Klein and Gilchrist et al have very limited clinical use. Although larger in size, like amino acids, these polypeptide compositions are absorbed from the peritoneum quite rapidly. This leads to uremic symptoms. In addition, these materials containing polypeptides have the potential of producing allergic reactions. This is due to the size of polypeptides that are used. Glucose polymers have also been explored in peritoneal dialysis solutions. U.S. Patent No. 4,761,237 discloses the use of glucose polymers in a dialysis solution. EP 0 076 355 discloses a dialysis solution comprising the conventional electrolyte combination of sodium, calcium, magnesium, chloride, lactate, and sodium hydroxide with the alleged improvement comprising the use of a glucose polymer as the osmotic agent. EP 0 153 164 discloses a peritoneal dialysis solution having an osmotic agent that is a glucose polymer mixture. U.S. Patent No. 4,886,789 is believed to relate to EP 0 153 164. It is believed that the disclosed solutions do not overcome all of the issues set forth above. There is therefore a need for an improved peritoneal dialysis solution. SUMMARY OF THE INVENTION The present invention provides an improved dialysis solution. The improved dialysis solution provides for the use of a mixture of amino acids and maltodextrins as the osmotic agent in a peritoneal dialysis solution. To this end, the present invention provides, in an embodiment, a peritoneal dialysis solution comprising as osmotic agents approximately 2 to about 6% (w/v) maltodextrins and approximately 0.25 to 2% (w/v) of a mixture of esεential and non-essential amino acids. In an embodiment, the amino acids comprise both esεential and non-essential amino acids. In an embodiment, the solution includes: 120 to about 140 (mEq/L) sodium; 70 to about 110 (mEq/L) chloride; 0 to about 45.00 (mEq/L) of lactate; 0 to about 45.00 (mEq/L) of bicarbonate; 0 to about 4.00 (mEq/L) of calcium; and 0 to about 4.00 (mEq/L) of magnesium. In an embodiment, the maltodextrins are derived from the hydrolysis of starch and have the following composition: Weight Average Mol. Wt. (Mw) 10,000 - 16,000 daltons Number Average Mol. Wt. (Mn) 4,000 - 8,000 daltons Polydisperεity 1.0 - 4.0 Fraction > 100,000 daltons NMT 1.0% Mono, Di, Trisaccharides NMT 5.0% Distribution normal Alpha (1-4) NLT 90% Aluminum (10% solution) <10ppb Aqueous Solubility NLT 10% (w/v) pH (10% solution) 5.0 - 7.0 Heavy Metals <5ppm DP (Degree of polymerization) greater than 20 > 75% DP greater than 50 > 50% DP greater than 100 > 25% In an embodiment, the ami > acids comprise: Amino Acid Cone. fmα%. Leucine 74 - 112 Valine 100 - 151 Threonine 47 - 71 Isoleucine 61 - 92 Lyεine.HCl 55 - 83 Hiεtidine 52 - 78 Methionine 32 - 48 Phenylalanine 42 - 62 Tryptophan 20 - 30 Alanine 68 - 103 Proline 43 - 65 Arginine 60 - 113 Glycine 36 - 55 Serine 48 - 72 Tyrosine 20 - 35 Aεpartate 55 - 83 Glutamate 55 - 83 In an embodiment, the amino acids are chosen so as to have the following ratios: Phenylalanine/Tyroεine 1.3 - 3.0 Essential/Total Amino Acids0.4 - 0.7 In an embodiment, the maltodextrins and amino acids comprise the only osmotic agents in the solution. In another embodiment, a peritoneal dialysis solution is provided that comprises: Maltodextrins (% w/v) 2.0 - 6.0 Amino Acids (% w/v) 0.25 - 2.0 Sodium (mEq/L) 120 - 140 Chloride (mEq/L) 70 - 110 Lactate (mEq/L) 0.0 - 45.0 Bicarbonate (mEq/L) 0.0 - 45.0 Calcium (mEq/L) 0.0 - 4.0 Magnesium (mEq/L) 0.0 - 4.0 pH 6.0 - 7.4 In an embodiment, a method for providing an osmotic agent for a peritoneal dialysis solution is provided comprising the steps of selecting as the osmotic agent two compositions, one having a weight average molecular weight equal to or greater than 10,000 daltons and compriεing approximately 2.0 to about 6.0% (w/v) of the compoεition and a second composition having a molecular weight equal to or less than 300 daltons and comprising approximately .25 to about 2.0% w/v of the compoεition. In an embodiment of the method, the osmotic agent includeε maltodextrin and amino acidε. In another embodiment, a two part peritoneal dialyεiε εolution deεigned to be mixed prior to infusion into a patient is provided compriεing: a first part housed in a first εtructure including approximately 2.0 to about 6.0% (w/v) maltodextrinε and a pH of approxi- mately 4.0 to about 5.5; a εecond part houεed in a εecond structure including amino acids; and including in either the first or the second εtructure a sufficient amount of the following ingredients so that when the first part and second part are mixed the following is provided: 120 to about 140 (mEq/L) sodium; 70.0 to about 110.00 (mEq/L) chloride; 0.0 to about 45.0 (mEq/L) lactate; 0.0 to about 45.0 (mEq/L) bicarbonate; 0.0 to about 4.0 mEq/L) calcium; and 0.0 to about 4.0 (mEq/L) magnesium. In a preferred embodiment, the sum of lactate plus bicarbonate is within the range of 20 to about 45 (mEq/L) An advantage of the present invention is that it provides an improved peritoneal dialysis solution. Still further, an advantage of the preεent invention iε that it provideε an improved osmotic agent for use in a peritoneal dialyεiε εolution. A further advantage of the present invention is that it provides a dialysis solution that allows for sustained ultrafiltration over long dwells. Moreover, an advantage of the preεent invention iε that it provideε a combination of large and εmall molecular weight soluteε. An advantage of the preεent invention is that it provides the option of increasing infusion volume to provide improved efficiency. Another advantage of the present invention iε that it provideε for the combination of osmotic agents to provide improved safety. Furthermore, an advantage of the present invention iε that it provides a balanced peritoneal supplementation of calorie and nitrogen source to improve nutritional status. Further, an advantage of the present invention is that it provideε a solution having a physiological pH to help reduce the pain on infusion experienced by a number of peritoneal dialysiε patientε. Moreover, an advantage of the present invention iε that it provideε reduced oεmolalitieε along with a physiological pH to restore peritoneal cell functions. Additional features and advantages of the preεent invention are described in, and will be apparent from, the detailed description of the preεently preferred embodiments and from the drawings. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates graphically peritoneal volume profiles over time of solutions pursuant to the experiment set forth below. Figure 2 illustrates graphically peritoneal volume profileε over time of εolu ions purεuant to the experiment εet forth below. Figure 3 illustrateε graphically percent absorption of maltodextrins administered alone pursuant to the experiment set forth below. Figure 4 illuεtrates graphically percent absorption for maltodextrinε administered in combination with amino acids pursuant to the experiment set forth below. Figure 5 illustrateε graphically εolution performance purεuant to the experiment set forth below. DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS The present invention provides improved peritoneal dialysiε solutionε that preferably contain maltodextrinε and amino acids aε an oεmotic agent. Preferably, the dialyεiε εolution containε a mixture of well-defined amino acidε and maltodextrins for uεe aε the osmotic agent in peritoneal dialysiε εolutionε. As set forth in detail below, by using amino acids and maltodextrinε in a peritoneal dialyεiε solution as the osmotic agent, the disadvantageε of typical oεmotic agentε can be overcome. The maltodextrinε and amino acids provide an osmotic agent that provides a combination of low and high molecular weight soluteε. Preferably, approximately 0.25% to about 2% (w/v) of a mixture of essential and non-essential amino acids is utilized with approximately 2 to about 6 (w/v) maltodextrins as the osmotic agent. Preferably, the maltodextrinε utilized are derived from the hydrolyεiε of εtarch. Preferably, the maltodextrinε have the following compoεition: Weight Average Mol. Wt. (Mw) 10,000 - 16,000 Number Average Mol. Wt. (Mn) 4,000 - 8,000 Polydispersity 1.0 - 4.0 Fraction > 100,000 daltonε NMT 1.0% Mono, Di, Triεaccharideε NMT 5.0% Diεtribution normal Alpha (1-4) NLT 90% Aluminum (10% solution) <10ppb Aqueouε Solubility NLT 10% (w/v) pH (10% εolution) 5.0 - 7.0 Heavy Metalε <5ppm DP (Degree of polymerization) greater than 20 >75% DP greater than 40 >50% DP greater than 80 >25% In addition to maltodextrinε, preferably, the εolution containε a mixture of essential and noneεεential amino acidε having the following compoεition: Amino Acid Cone. (mq%) Leucine 74 - 112 Valine 100 - 151 Threonine 47 - 71 Iεoleucine 61 - 92 Lyεine.HCl 55 - 83 Hiεtidine 52 - 78 Methionine 32 - 48 Phenylalanine 42 - 62 Tryptophan 20 - 30 Alanine 68 - 103 Proline 43 - 65 Arginine 60 - 113 Glycine 36 - 55 Serine 48 - 72 Tyrosine 20 - 35 Aspartate 55 - 83 Gluta ate 55 - 83 Preferred Ratioε Phenylalanine/Tyroεine 1.3 - 3.0 Eεεential/Total Amino Acids 0.4 - 0.7 Although preferably maltodextrinε and amino acidε are uεed aε the oεmotic agent, other high molecular weight and low molecular weight compositions can be used in combination. It is believed that the high molecular weight composition should have a weight average molecular weight greater than or equal to 10,000 daltons. The low molecular weight compoεition should have a molecular weight less than or equal to 300 daltons. Preferably, the compoεitionε have molecular weightε within the following rangeε, reεpectively: approximately 10,000 to about 16,000 daltons; and approximately 100 to about 300 daltonε. By way of example, and not limitation, an example of a εolution of the present invention is as follows: Maltodextrinε (% w/v) 2.0 - 6.0 Amino Acidε (% w/v) 0.25 - 2.0 Sodium (mEq/L) 120 - 140 Chloride (mEq/L) 70 - 110 Lactate (mEq/L) 0.0 - 45.0 Bicarbonate (mEq/L) 0.0 - 45.0 Calcium (mEq/L) 0.0 - 4.0 Magneεium (mEq/L) 0.0 - 4.0 pH 6.0 - 7.4 In the example above, the components that are not compatible with each other can be separated during sterilization and mixed together prior to infusion. By way of example, and not limitation, the composition can be contained in separate chambers or containers, aε followε: Chamber 1 Chamber 2 Maltodextrin (% w/v) 2-6.0 Amino acidε (% w/v) 0.0 .25-2.0 Sodium (mEq/L) 0-300 0-300 Chloride (mEq/L) 0-250 0-250 Lactate (mEq/L) 0-100 0-100 Bicarbonate (mEq/L) 0-100 0-100 Calcium (mEq/L) 0-10 0-10 Magneεium (mEq/L) 0-5.0 0-5.0 pH 4.0-5. 5 6.0-7.5 Preferably, only maltodextrin is contained in chamber 1. In an embodiment, lactate is contained in chamber 1 along with maltodextrin. The contentε of the two chamberε are mixed prior to infuεion into the peritoneal cavity of the patient. By way of example, and not limitation, an animal model of peritoneal dialyεiε iε εet forth below. Through the animal model, it waε obεerved that εolutionε containing a combination of large solutes (mw 10,000 - 16,000 daltons) and small solutes (molecular weight 100 to 300 daltons) , are ideal for fluid and solute transport for patients on peritoneal dialysiε. The experiment alεo suggests that a solution containing the combined oεmotic agentε iε more effective than a εolution containing either of the oεmotic agentε alone. When maltodextrin of the compoεition defined by the preεent invention waε used as the large solute along with amino acidε, in proportionε outlined above, unexpected benefit in dialyεiε efficiency aε determined by ultrafiltration per gram of osmotic agent absorbed was observed over long dwells. See Figure 5. EXAMPLE NO. 1 INTRODUCTION Maltodextrins of varying molecular weight averages were investigated as alternate osmotic agents to dextrose in peritoneal dialyεiε solutions administered to normal rats. Additional experimentε uεing maltodextrinε/amino acidε in combination were alεo conducted. MATERIAL PREPARATION Maltodextrin powderε, varying in the degree of enzymatic hydrolyεiε, were uεed in theεe experiments. 5% (w/v) solutionε were prepared and aεsayed for molecular weight, os olality, and pH aε εhown below: Weight Oεmolality Sample ID Averaσe Mw (mOsm/kq pH G6 38000 17 5.3 G17 12700 38 5.1 G29 2400 65 5.2 G40 2000 103 5.3 G17D 21600 30 5.1 G29D 3400 44 5.2 Individual amino acidε were prepared on a weight percent baεiε aε followε: Leu 8.45%; Val 12.27%; Thr 5.36%; He 7.00%; Lys 5.45%; His 5.91%; Met 3.64%; Phe 4.73%; Trp 2.27%; Ala 7.73%; Pro 4.91%; Arg 6.82%; Gly 4.18%; Ser 5.45%; Tyr 2.73%; Aεp 6.55%; and Glu 6.55%. The maltodextrinε were formulated alone or in combination with amino acidε as εu marized in Table 1. Following diεεolution of all solution components, solu¬ tions were sterile filled through a 0.22 μm filter unit into Viaflex ® bags. U C dextran in saline waε injected into each εolution bag (lμCi/30ml) aε a dilution marker for meaεuring peritoneal volume. Solutions were analyzed for pH, osmolality, sodium, and chloride. TABLE 1 Composition of Maltodextrin Dialysate Solutions 7.5% G17D 7.5% G17 7.5% G29D Component Maltodextrin (g/L) 75 75 75 Amino Acid Blend (g/L) Target Sodium (mEq/L) 132 132 132 Chloride (mEq/L) 96 96 96 Lactate (mEq/L) 40 40 40 Calcium (mEq/L) 3 5 3 5 3.5 Magnesium (mEq/L) 05 05 05 Electrolyte Total (mEq/L) 272 272 272 Assayed components Osmolality (mOsm/kg) 302 322 352 PH 5 1 5 1 5 1 Sodium (mEq/L) 126 126 126 Chloride (mEq/L) 96 96 96 Maltodextrin GPC Average Molecular Wt 21,500 12,700 3,400 7.5% G29 3% G17D/ 3% G17/ 075% AAs 0.75% AAs Component Maltodextrin (g/L) 75 30 30 Ammo Acid Blend (g/L) 7.5 7.5 Target Sodium (mEq/L) 132 132 132 Chloride (mEq/L) 96 96 96 Lactate (mEq/L) 40 40 40 Calcium (mEq/L) 3 5 3 5 3 5 Magnesium (mEq/L) 0 5 0 5 0 5 Electrolyte Total (mEq/L) 272 272 272 Assayed components Osmolality (mOsm/kg) 374 327 333 PH 5 1 7.0 7.0 Sodium (mEq/L) 126 123 126 Chloride (mEq/L) 96 93 96 Maltodextrin GPC Average Molecular Wt 2,400 21 ,600 12,700 3% G29D/ 1% AA 4% G17D/ 1% 4% G17/ 0.75% AAs AAs 1% AAs Component Maltodextrin (g/L) 30 40 40 Amino Acid Blend (g/L) 7.5 10 10 10 Target Sodium (mEq/L) 132 132 132 132 Chloride (mEq/L) 96 96 96 96 Lactate (mEq/L) 40 40 40 40 Calcium (mEq/L) 3.5 3.5 3.5 3.5 Magnesium (mEq/L) 0.5 0 5 0 5 0.5 Electrolyte Total (mEq/L) 272 272 272 272 Assayed components Osmolality (mOsm/kg) 342 335 360 370 pH 7.0 7.0 7.0 7 0 Sodium (mEq/L) 130 132 131 132 Chloride (mEq/L) 100 99 99 100 Maltodextrin GPC Average Molecular Wt 3,400 21,600 12,700 EXPERIMENTAL PROCEDURE 7.5% Maltodextrins Adminiεtered Alone Male Sprague-Dawley rats (Harlan Sprague Dawley Inc., Indianapolis, Indiana) weighing 300-370 grams were administered 7.5% (w/v) maltodextrin εolutionε (n=6/group) during the courεe of two treatment dayε. Prior to εolution injection, a 1.5 ml baεeline blood sample waε collected via the tail vein. Plasma waε εeparated by centrifugation @ 12,000 xg for 10 inuteε and εtored frozen. On a given treatment day, each rat was weighed, anesthetized by Metafane inhalation, the abdominal area εhaved, and dialyεate solution (90 ml/kg) injected intraperitoneally using a 23 needle. Dialysate solutions were warmed to room temperature prior to injection. The dialysiε solution (25-35 ml) contained approximately lμCi 14 C Dextran as a dilution marker for measuring peritoneal volume. Ratε were allowed to recover and were permitted free accesε to water. Dialyεate εa pleε (0.2 ml) were collected at 2 and 4 hourε during the dwell period and frozen. A 2 hour blood εample waε alεo collected for dialysate to plasma ratios (D/P) of urea and creatinine determinations. At the end of the 8 hr dwell period, a 2 ml blood εample waε collected via the tail artery, and plasma was separated and frozen. Ratε were euthanized by tail vein injection of T-61 εolution. The abdominal cavity waε immediately opened by midline incision, dialysate collected, and volume recorded by weight. A 5 ml dialysate sample was εtored frozen for further analyεeε. 3% Maltodextrinε/0.75% Amino Acids The dialyεiε procedure, aε previously described was performed uεing Sprague-Dawley ratε weighing 270-400 grams. Ratε were adminiεtered either 3% maltodextrin/0.75% amino acid εolutionε or 4.25% Dextroεe Dianeal solution (n=6/group) during the course of two treatment days. 4% Maltodextrins/1% Amino Acids The dialysiε procedure, as previouεly deεcribed waε performed uεing Sprague-Dawley ratε weighing 350-380 grams. Rats were adminiεtered either 4% maltodextrin/1% amino acid solutions or 1% amino acids alone (n=6/group) during the course of one treatment day. SAMPLE ANALYSES Oεmolality All dialysate solutions were aεεayed for oεmolality by freezing point depression. (Oεmometer Advanced Inεtruments Model (3M0) U C Dextran All dialyεate εampleε were aεεayed for radiolabelled dextran. 0.1 or 0.05 ml of dialyεate sample was added to 1 ml of water in 7 ml glass scintillation vials. 3 ml of Ready Gel Scintillation cocktail (Beckman) was added and the vialε εhaken until gelled. Sampleε were counted on Beckman Scintillation Counter Model LS 5000 TD. Maltodextrinε Freεh and spent dialysate εampleε were aεεayed for maltodextrin content by enzymatic hydrolyεiε to free glucoεe. 50 μL of dialyεate εample was incubated with 950 μL of 0.6 mg/ l a yloglucoεidaεe in 0.01M εodium acetate for 1 hour at 55°C. Hydrolyzed solutions were then assayed for glucose by the following method: Glucoεe phoεphorylation is catalyzed by hexokinase. In a coupled reaction, catalyzed by glucose-6-phosphate dehydrogenase, NAD is reduced to NADH. The resulting abεorbance change iε proportional to the glucoεe concentration. BUN/Creatinine Plaεma and dialysate samples were analyzed on a Boehringer Mannheim/Hitachi 704 Analyzer. BUN: Urea iε hydrolyzed by the action of ureaεe. In a coupled reaction, NADH is oxidized to NAD. The resulting absorbance change iε proportional to the concentration of urea. Creatinine/Pap: Creatinine is converted to creatine by creatininase. Creatine is converted to sarcoεine by creatinase. The oxidation of εarcosine by εarcoεine oxidaεe produced hydrogen peroxide which is utilized in an indicator reaction in the formation of red benzoquinoneimine dye. RESULTS The following calculations were performed based on εample analyseε: Net Ultrafiltration Net ultrafiltration following an 8 hour dwell in all ratε waε determined aε a difference between the infuεion volume and the volume at the end of the 8 hour dialyεiε. Peritoneal Volume An eεtimate of dialyεate volumeε at 2 and 4 hourε baεed on U C dextran diεappearance from dialyεate during the dwell period. Intraperitoneal volume estimations at time t are based on the following equation: DPM in - [DPM in - DPM out]*t Vt = 8 Ct/W Where: DPM in = Volume infuεed * Concentration of U C Dextran. DPM out = Volume drained at 8 hrs * Concentration of 1 C Dextran. Ct = Concentration of C Dextran at time t. W = body weight (kg) . Volume profiles are εhown graphically in Figureε 1 and 2. Volume profileε for 2.5% Dextroεe Dianeal (n=ll) from a previouε εtudy is included as a hiεtoric reference. Dialyεate Oεmolalitv Oεmolality reεultε at 2, 4, and 8 hourε were determined. Absorption of Osmotic Agents Absorption (%) at each time interval was determined using the following equation: [Vo* Co]-[Vt* Ct] *100 [Vo* Co] Where: Vo = Volume infuεed (ml) Co = Concentration (g/dl) of osmotic agent at t=0 Vt = Volume (ml) at time t Ct = Concentration (g/dl) at time t Note: Volumes at 2 and 4 hours were estimated based on C Dextran dilution. The percent absorption of maltodextrinε administered in combination waε determined at 8 hourε. RESULTS Tukey'ε statistical analysis of the data generated in this study was performed. Mean group valueε were asseεεed for statistical significance at α = 0.05 as shown. Means under the same line are not significantly different. Parameter Rank (High to Low) Net UF ^ ^^™ ™ " 1 6 4 5 3 2 1 7 Absorption (8 hourε) 7 4 3 2 1 6 5 Net UF/Gra Abεorbed * 6 5 2 1 7 Where: 1 = 7, 5% G17D 2 = 7, 5% G17 3 = 7, 5% G29D 4 = 7 5% G29 5 = 4 G17D + 1% AA 6 = 4 G17 + 1% AA 7 = 2 5% Dextroεe Dianeal CONCLUSIONS The Figureε 1-5 illuεtrate graphically the reεultε. When administered alone, glucose polymers yield increased 8-hour drain volu eε when compared to 2.5% Dianeal ® in εpite of lower initial oεmolality. Addition of 1% amino acidε allowε a 46% reduction in the quantity of glucoεe polymerε required to produce equivalent net UF at 8 hours. The percent adsorption of glucose polymers iε significantly lower than glucose alone at the end of 8 hours. The addition of amino acids doeε not change the percent of glucoεe polymer abεorbed. Combination solutions (GP + amino acidε) provide higher net UF per g of osmotic agent absorbed. It should be understood that various changes and modifications to the presently preferred embodimentε deεcribed herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantageε. It iε therefore intended that such changes and modifications be covered by the appended claims.

Claims: WE CLAIM: 1. A peritoneal dialysis solution comprising as osmotic agents: approximately 2.0 to about 6.0% (w/v) maltodextrins; and approximately 0.25 to about 2.0% (w/v) amino acidε. 2. The peritoneal dialysiε εolution of Claim 1 wherein the amino acidε compriεe both eεεential and non¬ eεεential amino acidε. 3. The peritoneal dialyεiε εolution of Claim 1 including sodium, chloride, lactate, bicarbonate, calcium, and magneεium. 4. The peritoneal dialyεiε εolution of Claim 1 wherein the εolution includeε: 120 to about 140 (mEq/L) εodium; 70 to about 110 (mEq/L) chloride; 0 to about 45.00 (mEq/L) of lactate; 0 to about 45.00 (mEq/L) of bicarbonate; 0 to about 4.00 (mEq/L) of calcium; and 0 to about 4.00 (mEq/L) of magneεium. 5. The peritoneal dialysis εolution of Claim 1 wherein the pH of the εolution iε approximately 6.0 to 7.4. 6. The peritoneal dialyεiε εolution of Claim 1 wherein the maltodextrinε have the following compoεition: Weight Average Mol. Wt. (Mw) 10,000 - 16,000 daltonε Number Average Mol. Wt. (Mn) 4,000 - 8,000 daltonε Polydisperεity 1.0 - 4.0 Fraction > 100,000 daltonε NMT 1.0% Mono, Di, Triεaccharideε NMT 5.0% Diεtribution normal Alpha (1-4) NLT 90% Aluminum (10% εolution) <10ppb Aqueous Solubility NLT 10% (w/v) pH (10% solution) 5.0 - 7.0 Heavy Metals <5ppm DP (Degree of polymerization) greater than 20 > 75% DP greater than 50 > 50% DP greater than 100 > 25% 7. The peritoneal dialysiε εolution of Claim 1 wherein the maltodextrinε are derived from the hydrolyεiε of starch. 8. The peritoneal dialyεiε εolution of Claim 1 wherein the amino acids comprise: Amino Acid Cone. fmg%. Leucine 74 - 112 Valine 100 - 151 Threonine 47 - 71 Iεoleucine 61 - 92 Lyεine.HCl 55 - 83 Hiεtidine 52 - 78 Methionine 32 - 48 Phenylalanine 42 - 62 Tryptophan 20 - 30 Alanine 68 - 103 Proline 43 - 65 Arginine 60 - 113 Glycine 36 - 55 Serine 48 - 72 Tyroεine 20 - 35 Aεpartate 55 - 83 Glutamate 55 - 83 9. The peritoneal dialyεiε εolution of Claim 1 wherein the amino acidε are choεen εo as to have the following ratios: Phenylalanine/Tyrosine 1.3 - 3.0 Essential/Total Amino Acids 0.4 - 0.7 10. The peritoneal dialysis εolution of Claim 1 wherein maltodextrins and amino acidε comprise the only osmotic agents. 11. A peritoneal dialysis solution comprising: Maltodextrinε (% w/v) 2.0 - 6.0 Amino Acids (% w/v) 0.25 - 2.0 Sodium (mEq/L) 120 - 140 Chloride (mEq/L) 70 - 110 Lactate (mEq/L) 0.0 - 45.0 Bicarbonate (mEq/L) 0.0 - 45.0 Calcium (mEq/L) 0.0 - 4.0 Magnesium (mEq/L) 0.0 - 4.0 pH 6.0 - 7.4 12. The peritoneal dialyεiε solution of Claim 11 wherein the maltodextrins are derived from the hydrolysiε of εtarch and have the following compoεition: Weight Average Mol. Wt. (Mw) 10,000 - 16,000 daltonε Number Average Mol. Wt. (Mn) 4,000 - 8,000 daltons Polydisperεity 1.0 - 4.0 Fraction > 100,000 daltonε NMT 1.0% Mono, Di, Triεaccharideε NMT 5.0% Diεtribution normal Alpha (1-4) NLT 90% Aluminum (10% solution) <10ppb Aqueous Solubility NLT 10% (w/v) pH (10% solution) 5.0 - 7.0 Heavy Metals <5ppm DP (Degree of polymerization) greater than 20 > . 75% DP greater than 40 > 50% DP greater than 80 > . 25% 13. The peritoneal dialysiε εolution of Claim 11 wherein the amino acidε compriεe: Amino Acid Cone. fmσ%) Leucine 74 - 112 Valine 100 ■ - 151 Threonine 47 - 71 Iεoleucine 61 - 92 Lyεine.HCl 55 - 83 Hiεtidine 52 - 78 Methionine 32 - 48 Phenylalanine 42 - 62 Tryptophan 20 - 30 Alanine 68 - 103 Proline 43 - 65 Arginine 60 - 113 Glycine 36 - 55 Serine 48 - 72 Tyroεine 20 - 35 Aεpartate 55 - 83 Glutamate 55 - 83 14. The peritoneal dialysiε εolution of Claim 11 wherein the amino acidε are choεen so as to have the following ratios: Phenylalanine/Tyrosine 1.3 - 3.0 Essential/Total Amino Acidε 0.4 - 0.7 15. The peritoneal dialyεis solution of Claim 11 wherein maltodextrins and amino acids comprise the only osmotic agents. 16. A method for providing an osmotic agent for a peritoneal dialysis solution compriεing the εtepε of εelecting aε the oεmotic agent two compoεitionε, one having a molecular weight equal to or greater than 10,000 daltonε and compriεing approximately 2.0 to about 6.0% (w/v) of the compoεition and a second composition having a molecular weight equal to or leεs than 300 daltons and compriεing approximately .25 to about 2.0% w/v of the composition. 17. The method of Claim 16 wherein the oεmotic agent includes maltodextrin and amino acids. 18. The method of Claim 17 wherein the maltodextrinε are derived from the hydrolyεiε of εtarch and have the following compoεition: Weight Average Mol. Wt. (Mw) 10,000 - 16,000 daltonε Number Average Mol. Wt. (Mn) 4,000 - 8,000 daltonε Polydisperεity 1.0 - 4.0 Fraction > 100,000 daltonε NMT 1.0% Mono, Di, Triεaccharideε NMT 5.0% Diεtribution normal Alpha (1-4) NLT 90% Aluminum (10% εolution) <10ppb Aqueous Solubility NLT 10% (w/v) pH (10% εolution) 5.0 - 7.0 Heavy Metalε <5ppm DP (Degree of polymerization) greater than 20 > . 75% DP greater than 50 > 50% DP greater than 100 > 25% 19. The method of Claim 17 wherein the amino acidε compriεe: Amino Acid Cone. fmq%) Leucine 74 - 112 Valine 100 - 151 Threonine 47 - 71 Isoleucine 61 - 92 Lysine.HCl 55 - 83 Hiεtidine 52 - 78 Methionine 32 - 48 Phenylalanine 42 - 62 Tryptophan 20 - 30 Alanine 68 - 103 Proline 43 - 65 Arginine 60 - 113 Glycine 36 - 55 Serine 48 - 72 Tyroεine 20 - 35 Aεpartate 55 - 83 Glutamate 55 - 83 20. A two part peritoneal dialyεiε solution designed to be mixed prior to infuεion into a patient comprising: a first part houεed in a firεt εtructure including approximately 2.0 to about 6.0% (w/v) maltodextrin and a pH of approximately 4.0 to about 5.5; a second part houεed in a εecond εtructure including amino acidε; and including in either the firεt or the εecond εtructure a εufficient amount of the following ingredientε εo when the firεt part and second part are mixed the following is provided: 120 to about 140 (mEq/L) εodium; 70.0 to about 110.00 (mEq/L) chloride; 0.0 to about 5.0 (mEq/L) lactate; 0.0 to about 45.0 (mEq/L) bicarbonate; 0.0 to about 4.0 mEq/L) calcium; and 0.0 to about 4.0 (mEq/L) magnesium. 21. The two part peritoneal dialysis solution of Claim 20 wherein the first and εecond εtructureε are two separate chambers of a εingle container. 22. The two part peritoneal dialysis solution of Claim 20 wherein the pH of a resultant solution, compriεing a mixture of the first part and the εecond part, iε approximately 6.0 to about 7.4.

Inventors: BURKE RON, FALLER BERNARDETTE, HENDERSON LEE W, MARTIS LEO, SHOCKLEY TY, BURKE, RON, FALLER, BERNARDETTE, HENDERSON, LEE, W., MARTIS, LEO, SHOCKLEY, TY
Applicants: BAXTER INT, BAXTER INTERNATIONAL INC.
Application year: 1995
Main classification: A61K31
IPC codes: A61K31, A61K33, A61M1