AU2013207545B2 - Nutritive compositions and methods of using same - Google Patents

Abstract

The invention provides intradialytic parenteral nutrition (IDPN) solutions with low carbohydrate for the treatment of malnutrition in dialysis patients. THE IDPN solutions of the invention are particularly advantageous for the treatment of malnutrition in patients who are diabetic or suffer from other glucose management pathologies or patients who require strict fluid management.

Description

WO 2010/005961 PCT/US2009/049800 NUTRITIVE COMPOSITIONS AND METHODS OF USING SAME FIELD OF THE INVENTION The invention pertains to nutrition supplement compositions for patients receiving 5 dialysis treatment and methods of using the nutrition supplement compositions. The nutrition supplement compositions include reduced levels of carbohydrates and lower volume to reduce complications in patients who are diabetic or suffer from other glucose management related pathologies, or patients who require strict fluid management. 10 BACKGROUND OF THE INVENTION Severe malnutrition remains a problem for patients receiving maintenance hemodialysis (MHD). Dialysis patients often have poor appetites and low energy. This malnutrition is reflected in low serum albumin concentrations, a strong predictor of increased morbidity and mortality. (Moore and Lindenfield, Support Line 29(5):7-16 (Oct. 2007)). 15 Patients are often treated using diet liberalization, oral supplements and enteral feeding. When these methods are not effective intradialytic parenteral nutrition (IDPN) may be utilized for more aggressive nutrition repletion efforts. IDPN is infused during the hemodialysis procedure. IDPN has been used for decades and has resulted in weight gain and improved protein levels in patients. (U.S. Publication 20 No. 2005/0148647). The typical IDPN treatment delivers 4-6 mg/kg/minute of glucose for patients in need of carbohydrate control and 6-8 mg/kg/minute for patients who do not need carbohydrate control. Blood glucose must be monitored to avoid problems associated with insulin resistance, hyperglycemia and hypoglycemia. In some cases, insulin is also administered either in the IDPN solution or more typically separately administered 25 subcutaneously to modulate blood glucose levels. IDPN generally contains 1.2-1.4 g/kg of amino acids. However, these amounts can be lowered for patients who do not tolerate protein well. Monitoring of serum bicarbonate and carbon dioxide levels must be monitored to check for acidosis caused by administration of amino acids. Lipids are provided in IDPN at a rate between 4 mg/kg/minute and 12-12.5 g/hour depending on tolerance of the lipids by the 30 patient. Generally, these lipids are emulsions of purified vegetable oil from soybean (Intraliipid@ from Kabi Vitrum or Travamulsion@ from Travenol) or safflower oil (Liposyn@ from Abbott). (Powers, Contemporary Dialysis and Nephrology:29-31 (Feb. 1990).

WO 2010/005961 PCT/US2009/049800 IDPN is usually administered in one liter of solution, and occasionally micronutrients, like vitamins and minerals are co-administered in or with IDPN. IDPN has proved effective in decreasing morbidity and mortality in MHD patients, leads to increased levels of serum albumin and creatine levels, and increased body weight. (Moore and Celano, Nutrition in 5 Clinical Practice, 20(2):202-212 (2005)). Hypoglycemia is another potential dangerous result of the administration of insulin during IDPN with symptoms of nervousness, sweating, intense hunger, trembling, weakness, palpitations, and trouble speaking. Problems associated with IDPN include hyperglycemia, complications in patients with insulin resistance or other problems associated with glucose management, as well as 10 complications in patients who require strict fluid management. The glucose concentrations administered with IDPN can cause hyperglycemia and hypoglycemia in some patients. The administration of insulin can sometimes successfully treat this hyperglycemia, but some patients demonstrate insulin resistance, and may not respond to insulin treatment. (Goldstein and Strom, Journal ofRenal Nutrition 1(l):9-22 (Jan. 1991)). Hyperglycemia is a major 15 barrier to effective nutrition support even outside the context of hemodialysis. Many studies report associations between hyperglycemia and increased morbidity and mortality. (McCowen and Bistrian, Nutrition in Clinical Practice, 19(3):235-244 (Jun. 2004)). Moreover, the amount of fluid in typical IDPN treatment is a barrier to use in patients with strict fluid management. Thus, a need exists for an improved IDPN composition for 20 administration to patients that diminishes hyperglycemia associated with IDPN administration and decreases the need for the administration of insulin with IDPN. Moreover, a need exists for a lower volume IDPN dosage form. SUMMARY OF THE INVENTION 25 The invention provides intradialytic parenteral nutrition (IDPN) solutions with low carbohydrate content and low volume. The IDPN solutions of the invention are effective in the treatment of malnutrition in patients receiving dialysis treatment. These solutions also reduce the need for insulin administration when administered to patients undergoing maintenance hemodialysis (MHD) patients. Moreover, patients with metabolic conditions 30 that impair their glucose tolerance and metabolism would also benefit from the IDPN solutions of the invention. Also, patients with strict fluid management would benefit from the IDPN solutions of the invention. The IDPN solutions of the invention also include amino acids and, optionally, lipids and/or micronutrients such as vitamins, trace elements and/or minerals. In certain preferred embodiments the IDPN solutions are lipid free. In other WO 2010/005961 PCT/US2009/049800 preferred embodiments, the IDPN solutions of the invention are kept in containers for administration to patients, such as bags appropriate for parenteral administration. In one embodiment, each bag contains one dose of IDPN for a patient. In other embodiments, these doses are supplemented with pharmaceuticals, such as insulin. These doses are often 5 administered subcutaneously using a separate administration system. DETAILED DESCRIPTION The invention provides intradialytic parenteral nutrition (IDPN) solutions with low carbohydrate and low volume. The IDPN solutions of the invention allow medical personnel 10 to engage in reduced carbohydrate management for MHD patients when they receive IDPN. Moreover, the IDPN solutions of the invention are particularly effective for treating malnutrition in MHD patients who have glucose management difficulties including patients that are insulin resistant, who have type I diabetes or pancreatitis. Also, the reduction of carbohydrate in the IDPN solutions of the invention favors anabolism over catabolism, thus 15 effectively treating malnutrition. In preferred embodiments, the IDPN solutions of the invention have reduced volume, so as to reduce side effects associated with high infusion volumes including dyspnea, increased respiratory rate, rhonchi edema, hypertension, and anxiety. The IDPN solutions of the invention are especially appropriate for patients that have adequate caloric intake but not protein intake. Further, the IDPN solutions of the invention 20 can be administered to normal weight or obese patients. Preferably, the IDPN solutions of the invention contain carbohydrate and amino acids. In some embodiments of the IDPN solution of the invention, the solution also contains lipids. In other embodiments of the IDPN solution of the invention, the solution also contains micronutrients such as vitamins, trace elements and/or minerals. In other embodiments of the 25 IDPN solution of the invention, the solution also contains pharmaceuticals such as insulin. In preferred embodiments, of the IDPN solution of the invention, pharmaceuticals are coadministered with the IDPN, but are not part of the IDPN solution. For example, insulin can be administered subcutaneously in a separate injection. Preferably, the carbohydrate contained in the IDPN solutions of the invention dextrose (D-glucose). The amino acids 30 contained in the IDPN solutions of the invention include combinations of two or more of the standard 20 amino acids. Preferably, all 20 of the amino acids are administered in the IDPN solutions of the invention. More preferably, 17 amino acids are used. Preferably, the solution of amino acids used to make the IDPN solution of the invention is a concentrated solution and is used in the invention due to the benefits of low volume. Preferably the WO 2010/005961 PCT/US2009/049800 concentrated solution contains 15 g/mL of amino acids. More preferably, the concentrated solution contains 20 g/mL of amino acids. Preferably, the IDPN solutions of the invention contain between 0.02 and 0.10 g/mL of dextrose in solution. Preferably, the IDPN solutions of the invention contain between 0.04 5 and 0.08 g/mL of dextrose in solution. More preferably, the IDPN solutions of the invention contain between 0.05 and 0.07 g/mL of dextrose in solution. More preferably the IDPN solutions of the invention contains between 0.055 and 0.065 g/mL of dextrose in solution. In various embodiments of the IDPN solutions of the invention, the solutions contain 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 0.10 g/mL of dextrose in solution. In other embodiments 10 of the IDPN solutions of the invention, the solutions contain 0.055, 0.056, 0.057, 0.058, 0.059, 0.060, 0.061, 0.062, 0.063, 0.064 or 0.065 g/mL of dextrose in solution. Preferably, the IDPN solutions of the invention are packaged in sterile containers for administration to patients. Preferably, the sterile containers are bags used for parenteral administration of IDPN solutions to a patient. Preferably the bags hold between 100 mL of 15 IDPN solution and 2 liters of IDPN solution. More preferably, the bags hold between 300 mL or 1 liter of IDPN solution. More preferably, the bags hold between 419 mL of IDPN solution and 809 mL of IDPN solution. More preferably, the bags hold between 350 mL and 635 mL of solution. Preferably, the IDPN solutions of the invention are packaged in sterile containers so 20 that the sterile container holds one dose of IDPN solution for administration to a patient. Preferably the dose of IDPN solution has a volume between 100 mL of IDPN solution and 2 liters of IDPN solution. More preferably, the dose of IDPN solution has a volume between 350 mL or 635 mL of IDPN solution. More preferably, the dose of IDPN solution has a volume of 300, 342, 350, 383, 400, 419, 427, 450, 483, 500, 540, 550, 600, 613, 635, 700 or 25 809 mL. In conjunction with a volume associated with the IDPN solution of the invention, the term "about" means +/- 10 mL per dose. Preferably, a dose of the IDPN solution of the invention contains between 10 and 50 g of dextrose. More preferably, a dose of the IDPN solution contains between 20 and 45g of dextrose. More preferably, a dose of the IDPN solution contains 20, 23, 26, 30, 35 and 41 g 30 of dextrose. In conjunction with an amount of dextrose associated with the IDPN solution of the invention, the term "about" means +/- 1 g per dose. In some embodiments of the IDPN solution of the invention, the amount of dextrose in the IDPN solution is dependent upon the mass of the patient receiving the IDPN treatment. Generally, the IPDN solution of the invention contains a dose of dextrose less than 1 g/kg of 11 WO 2010/005961 PCT/US2009/049800 body mass of the patient. For example, a patient with a mass between 34 and 39 kg would receive an IDPN solution containing 20 g of dextrose, a patient with a body mass between 40 and 44 kg would receive an IDPN solution containing 23 g of dextrose, a patient with a body mass between 45 and 51 kg would receive an IDPN solution containing 26 g of dextrose, a 5 patient with a body mass between 52 and 59 kg would receive an IDPN solution containing 30 g of dextrose, a patient with a body mass between 60 and 69 kg would receive an IDPN solution containing 35 g of dextrose, and a patient with a body mass of 70 kg, or greater, would receive an IDPN solution containing 41 g of dextrose Preferably, the IDPN solutions of the invention contain between 0.10 and 0.20 g/mL 10 of amino acids in solution. Preferably the IDPN solutions of the invention contain between 0.12 and 0.18 g/ml of amino acids in solution. More preferably the IDPN solutions of the invention contains between 0.15 and 0.17 g/mL of amino acids in solution. In various embodiments of the IDPN solutions of the invention, the solutions contain 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.20 g/mL of dextrose in solution. In other 15 embodiments of the IDPN solutions of the invention, the solutions contain 0.150, 0.151, 0.152, 0.153, 0.154, 0.155, 0.156, 0.157, 0.158, 0.159, 0.160, 0.161, 0.162, 0.163, 0.164, 0.165, 0.166, 0.167, 0.168, 0.169 or 0.170 g/mL of amino acids in solution. Preferably, a dose of the IDPN solution of the invention contains between 30 and 120 g of amino acids. More preferably, a dose of the IDPN solution contains between 51 and 110 20 g of amino acids. More preferably, a dose of the IDPN solution contains 50, 52, 52.5, 55, 60, 65, 68, 70, 75, 78, 80, 85, 90, 95, 100, 105 and 110 g of amino acids. In conjunction with an amount of amino acids associated with the IDPN solution of the invention, the term "about" means +/- 3 g per dose. In some embodiments of the IDPN solution of the invention, the amount of amino 25 acids in a dose of the IDPN solution is dependent upon the mass of the patient receiving the IDPN treatment. For example, a patient with a body mass between 34 and 39 kg would receive an IDPN solution containing 51 g of amino acids, a patient with a body mass between 40 and 44 kg would receive an IDPN solution containing 60 g of amino acids, a patient with a body mass between 45 and 51 kg would receive an IDPN solution containing 68 g of amino 30 acids, a patient with a body mass between 52 and 59 kg would receive an IDPN solution containing 78 g of amino acids, a patient with a body mass between 60 and 69 kg would receive an IDPN solution containing 90 g of amino acids, and a patient with a body mass of 70 kg, or greater, would receive an IDPN solution containing 105 g of amino acids.

WO 2010/005961 PCT/US2009/049800 In some embodiments of the IDPN solution of the invention, the solution also contain lipids. Preferably the lipids are emulsions of purified vegetable oil from soybean (Intraliipid@ from Kabi Vitrum or Travamulsion@ from Travenol) or safflower oil (Liposyn@ from Abbott). IDPN solutions of the invention with lipids contain 5-30% lipid by 5 volume. Preferably, IDPN solutions of the invention with lipids contain 10-20% lipid by volume. Lipids should not be added to IPDN solutions administered to patients with hyperlipemia, acute pancreatitis, lipid nephrosis or allergic reactions to eggs. In preferred embodiments of the IDPN solution of the invention, the solution is lipid free. 10 In some embodiments of the IDPN solution of the invention, the solution also contains micronutrients such as vitamins, trace elements and/or minerals. Vitamins and minerals that are optionally added to the IDPN solutions of the invention include water soluble vitamins such as vitamin C, folic acid, vitamin B 1 , and vitamin B 6 , as well as multivitamins lacking vitamin K, and trace elements such as zinc, selenium, copper, 15 chromium, and manganese. Minerals also include mineral salts such as sodium phosphate, and magnesium sulfate. In some embodiments of the IDPN solution of the invention, the solution also contains pharamaceutical compositions. One example of a pharmaceutical composition appropriate for inclusion in the IPDN solution of the invention is insulin. In some 20 embodiments, insulin is added to the IDPN solution just prior to administration to the patient, because many solution container materials will absorb insulin. Preferably, insulin is coadministered independent of the IDPN solution. For example, the insulin can be subcutaneously injected during treatment with IDPN. Preferably 5-20 units of insulin is added with one dose of IDPN. 25 Preferably, the IDPN solution of the invention is administered to dialysis patients who are suffering from malnutrition. A dialysis patient suffering from malnutrition can be identified by detecting evidence of protein or energy malnutrition and inadequate dietary protein intake, evidence of the inability to administer or tolerate adequate oral nutrition inclusive of supplements and tube feeding, and evidence that the combination or oral and/or 30 enteral intake when combined with IDPN will meet the patient's nutritional needs. Administration of the IDPN solution of the invention generally coincides with the start of hemodialysis on a patient. During IDPN solution administration the patient should be monitored for glucose tolerance, protein status and/or fat status. Glucose monitoring includes blood glucose level before, during and after IDPN administration and monitoring the patient WO 2010/005961 PCT/US2009/049800 for symptoms of hyper or hypoglycemia. The symptoms of hyperglycemia include nausea, thirst, headache, vomiting and weakness. The symptoms of hypoglycemia include headache, dizziness, tremors, cold sweat, confusion, and faintness. The presence of hyper or hypoglycemia can then be confirmed through blood sugar analysis, such as via a fingerstick 5 or arterial glucose level. To treat hyperglycemia, insulin is administered. To treat hypoglycemia the patient should receive 20-30 g of simple carbohydrates orally. Protein monitoring includes the monitoring of blood urea nitrogen (BUN) prior to dialysis and Kt/V which is a measure of dialysis adequacy. Fat monitoing includes a pre-dialysis triglyceride test prior to lipid infusion and then 10 another following first lipid infusion to ensure that the patient is clearing lipids from the bloodstream. Also, sodium, potassium, phosphorus and magnesium levels should be monitored for the presence of refeeding syndrome. Generally, the IDPN solution of the invention is administered through a port post dialyzer of the dialysis machine being used to perform hemodialysis on the patient. In a 15 preferred embodiment, the IDPN infusion is performed through the venous chamber of the dialysis machine. Examples of routes of parenteral administration include intravenous, intradermal, subcutaneous, and intraperitoneal administration. Any pharmaceutically acceptable carrier can be used in conjunction with the IDPN solution of the invention. The IDPN solution of the invention can be administered in the same manner prior art IDPN 20 solutions have been administered. EXAMPLES Protein Repletion Formulas The following IDPN formulas were developed. These formulas are administered to a 25 MHD patient requiring 3.25 hours or longer dialysis treatment time. The formulas are fat free and micronutrient free, but these components could easily be added. 7 WO 2010/005961 PCT/US2009/049800 Table 1 WEIGHT CHO AA VOL Total Kcals FINAL (g/dl) 34-39 Kg 29ml 255ml (Approx. 50cc 272kcals D5.9 20gm 51gm fill) 15.3AA 334ml 40-44 Kg 33ml 300m] 383ml 318kcals D6.0 23gm 60gm 15.7AA 45-51 Kg 37ml 340ml 427ml 360kcals D6.1 26gm 68 gm 15.9AA 52-59 Kg 43ml 390ml 483ml 414kcals D6.2 30gm 78gm 16.1AA 60-69 Kg 50ml 450ml 550ml 479kcals D6.4 35gm 90 gm 16.4AA 70+Kg 59ml 525ml 635ml 560kcals D6.5 41gm 105gm 16.6AA The infusion rate schedule for subjects of each weight class are shown in Table 2, below. 5 Table 2 Weight class Week 1 Infusion Rate Week 2 Infusion Rate 34-39 kg 50 mL/hour 105 mL/hour 40-44 kg 60 mL/hour 120 mL/hour 45-51 kg 65 mL/hour 135 mL/hour 52-59 kg 75 mL/hour 150 mL/hour 60-69 kg 85 mL/hour 170 mL/hour 70+ kg 100 mL/hour 195 mL/hour The following formulations were made with a more dilute commercially available 10 source of amino acids.

WO 2010/005961 PCT/US2009/049800 Table 3 WEIGHT CHO AA VOL Total Kcals FINAL (g/dl) 34-39 Kg 29ml 340ml (Approx. 50cc D4.8 20gm 51gm fill) 272 kcals 12.2AA 419ml 40-44 Kg 33ml 400ml 483ml 318 kcals D4.8 23gm 60gm 12.4AA 45-51 Kg 37ml 453ml 540ml 360 kcals D4.8 26gm 68 gm 12.6AA 52-59 Kg 43m] 520ml 613ml 414 kcals D4.9 30gm 78gm 12.7AA 60-69 Kg 50ml 600ml 700ml 479 kcals D5.0 35gm 90 gm 12.9AA 70+Kg 59m1 700ml 809ml 560 kcals D5.1 41gm 105gm 13.OAA

Claims (18)

1. A sterile product suitable to provide a IDPN solution for use in haemodialysis, which comprises a package containing 300 ml to 2000 ml of an aqueous solution of dextrose at a concentration between 0.04 and 0.08 g/ml and amino acids at a concentration between 0.12 and 0.18 g/ml.

2. A product as claimed in claim I wherein i) the concentration of dextrose is between 0.05 and 0.07 g/ml; and ii) the concentration of amino acids is between 0.12 and 0.18 g/mi.

3. A product as claimed in claim 1 or 2 wherein i) the concentration of dextrose is between 0.055 and 0.065 g/ml; and ii) the concentration of amino acids is between 0.15 and 0.17 g/ml.

4. A product according to any of claims 1 to 3 containing 350 ml to 635 ml of the specified aqueous solution.

5. A product according to any claims 1 to 3 containing about 300 ml, about 342 ml. about 350 ml, about 383 ml, about 400 ml, about 419 ml, about 427 ml, about 450 ml, about 483 ml, about 500 ml, about 540 ml, about 550 ml, about 600 ml, about 613 ml, about 635 ml. about 700 ml, or about 809 ml of the specified aqueous solution.

6. A product as claimed in any preceding claim containing two or more of the 20 standard amino acids.

7. A product as claimed in any preceding claim containing a mixture of 17 of the 20 standard amino acids.

8. A product as claimed in any preceding claim containing a mixture of all of the 20 standard amino acids.

9. A product as claimed in any preceding claim which is lipid free. 11

10. A product as claimed in claims 1 to 8, wherein the solution further comprises lipids.

11. A product as claimed in claim 10, wherein the lipids comprise purified vegetable oil from soybean or safflower oil.

12. A product as claimed in claims 10 or 11, wherein the lipids comprise 5 to 30% of the aqueous solution by volume.

13. A product as claimed in claims 10 or 11, wherein the lipids comprise 10 to 20% of the aqueous solution by volume.

14. A product as claimed in any preceding claim, wherein the solution further comprises a pharmaceutical agent.

15. A product as claimed in claim 14, wherein the pharmaceutical agent is insulin.

16. A product as claimed in claim 15, containing 5-20 units of insulin.

17. A product according to any preceding claim wherein the aqueous solution further comprises a vitamin selected from vitamin C, folic acid, vitamin BG and vitamin K.

18. A product according to any preceding claim wherein the aqueous solution further comprises minerals selected from zinc, selenium and magnesium.