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EP-4153264-B1 - PERITONEAL DIALYSIS SOLUTION

EP4153264B1EP 4153264 B1EP4153264 B1EP 4153264B1EP-4153264-B1

Inventors

  • ARDUINI, ARDUINO
  • Bonomini, Mario
  • MASOLA, Valentina
  • GAMBARO, GIOVANNI

Dates

Publication Date
20260506
Application Date
20210512

Claims (19)

  1. A solution comprising: carnitine from 0.02% to 0.05% w/v, and xylitol from 0.50% to 2.50% w/v, and and at least one further active ingredient selected from the group consisting of: glucose in an amount from 0 to 2.90% w/v, polydextrin in an amount from 0 to 8.0% w/v of and glycerol in an amount from 0 to 1.30% w/v for use in the treatment of end-stage renal disease and/or congestive heart failure wherein the solution is administered by peritoneal dialysis to maintain or restore the removal of small solutes and fluids and restore depurative efficacy and/or ultrafiltration.
  2. The solution for use of claim 1, wherein the restoration of depurative efficacy is an increase of the parameter Kt/V to a value of at least 1.5±0.1, preferably to a value comprised between 1.7±0.1 and 1.8±0.1.
  3. The solution for use of claim 1, wherein said restoration of the depurative efficacy is an increase of the parameter Kt/V.
  4. The solution for use of anyone of the preceding claims, wherein the residual kidney function is preserved.
  5. The solution for use of anyone of the preceding claims, wherein the solution comprises 0.02% w/v of carnitine.
  6. The solution for use of anyone of the preceding claims, wherein the solution comprises from 0.50% to 1.50% w/v of glucose.
  7. The solution for use of anyone of the claims 1-4, wherein the solution comprises: 0.7% w/v xylitol, 0.5% w/v glucose and 0.02% w/v carnitine; 0.7% w/v xylitol, 1.45% w/v glucose and 0.02% w/v carnitine; 0.7% w/v xylitol, 2.9% w/v glucose and 0.02% w/v carnitine; 1.0% w/v xylitol, 2.5% w/v glucose and 0.02% w/v carnitine; 0.7% w/v xylitol, 0.5% w/v glucose and 0.025% w/v carnitine; 1.5% w/v xylitol, 0.5% w/v glucose and 0.025% w/v carnitine; 2.0% w/v xylitol, 1.5% w/v glucose and 0.025% w/v carnitine; 0.7% w/v xylitol, 0.5% w/v glucose and 0.03% w/v carnitine; 1.5% w/v xylitol, 0.5% w/v glucose and 0.03% w/v carnitine; 2.0% w/v xylitol, 1.5% w/v glucose and 0.03% w/v carnitine; 0.7% w/v xylitol, 0.11% w/v glycerol, 0.3% w/v glucose and 0.02% w/v carnitine; 1.0% w/v xylitol, 0.44% w/v glycerol, 0.3% w/v glucose and 0.02% w/v carnitine; 1.0% w/v xylitol, 1.15% w/v glycerol, 0.3% w/v glucose and 0.02% w/v carnitine; 0.7% w/v xylitol, 0.58% w/v glycerol, 0.3% w/v glucose and 0.02% w/v carnitine; 0.7% w/v xylitol, 1.30% w/v glycerol, 0.3% w/v glucose and 0.02% w/v carnitine; 0.7% w/v xylitol, 0.11% w/v glycerol, 0.3% w/v glucose and 0.025% w/v carnitine; 1.0% w/v xylitol, 0.44% w/v glycerol, 0.3% w/v glucose and 0.025% w/v carnitine; 1.5% w/v xylitol, 4.0 w/v polydextrin and 0.02% w/v carnitine, 1.5% w/v xylitol, 7.0 w/v polydextrin and 0.02% w/v carnitine, 1.5% w/v xylitol, 4.0 w/v polydextrin and 0.025% w/v carnitine, 1.5% w/v xylitol, 7.0 w/v polydextrin and 0.03% w/v carnitine.
  8. The solution for use of anyone of the preceding claims further comprising one or more ingredients selected from the group consisting of: sodium, calcium, magnesium, chloride, lactate, citrate and bicarbonate.
  9. The solution for use of claim 8, which comprises: - Sodium from 128 to 134 mmol/l, preferably 132 mmol/l; - Calcium from 1.2 to 1.8 mmol/l, preferably 1.3 mmol/l; - Magnesium from 0.25 to 0.75 mmol/l, preferably 0.5 mmol/l; - Chloride from 90 to 120 mmol/l, preferably 103.5 mmol/l; - Lactate from 25 to 40 mmol/l, preferably 35 mmol/l; - Bicarbonate from 0 to 40 mmol/l; - Citrate from 0 to 10 mmol/l, preferably 2 or 4 mmol/l.
  10. The solution for use of anyone of the preceding claims having a pH comprised between 5.5 and 7.5, preferably a pH of 5.5 or 7.1.
  11. The solution for use of anyone of any of claims 1-4, having one of the following compositions: (a) Xylitol mmol/I 46 (0.7% w/v) Glucose mmol/l 27.7 (0.5% w/v) L-Carnitine mmol/l 1,24 (0.02% w/v) Sodium mmol/l 132 Calcium mmol/l 1.3 Magnesium mmol/l 0.5 Chloride mmol/l 103.5 and Lactate mmol/l 35; (b) Xylitol mmol/l 98.6 (1.5% w/v) Glucose mmol/l 27.7 (0.5% w/v) L-Carnitine mmol/l 1.24 (0.02% w/v) Sodium mmol/l 132 Calcium mmol/l 1.3 Magnesium mmol/l 0.5 Chloride mmol/l 103.5 and Lactate mmol/l 35; (c) Xylitol mmol/l 125 (2.0% w/v) Glucose mmol/l 83 (1.5% w/v) L-Carnitine mmol/l 1,24 (0.02% w/v) Sodium mmol/l 132 Calcium mmol/I 1.3 Magnesium mmol/I 0.5 Chloride mmol/I 103.5 and Lactate mmol/I 35; (d) Xylitol mmol/l 46 (0.7% w/v) Glucose mmol/l 80.3 (1.45% w/v) L-Carnitine mmol/l 1,24 (0.02% w/v) Sodium mmol/l 132 Calcium mmol/l 1.3 Magnesium mmol/l 0.5 Chloride mmol/l 103.5 and Lactate mmol/l 35; (e) Xylitol mmol/l 46 (0.7% w/v) Glucose mmol/l 162 (2.9% w/v) L-Carnitine mmol/l 1.24 (0.02% w/v) Sodium mmol/l 132 Calcium mmol/l 1.3 Magnesium mmol/l 0.5 Chloride mmol/l 103.5 and Lactate mmol/l 35; or (f) Xylitol mmol/ l 98.6 (1.5% w/v) Glucose mmol/ l 83 (1.5% w/v) L-Carnitine mmol/ l 1,24 (0.02% w/v) Sodium mmol/ l 132 Calcium mmol/ l 1.3 Magnesium mmol/ l 0.5 Chloride mmol/ l 103.5 and Lactate mmol/ l 35.
  12. The solution for use of anyone of the preceding claims, wherein said solution is used for continuous ambulatory peritoneal dialysis (CAPD) or for automatic peritoneal dialysis (APD).
  13. The solution for use of anyone of the preceding claims, wherein said solution is used for the nocturnal exchange and/or for one or more diurnal exchanges.
  14. The solution for use of anyone of the preceding claims, wherein the solution is contained, stored and/or delivered in a bag, such as a single-, dual- or multi-chamber bag.
  15. The solution for use of any of claims 1-4 wherein the solution is contained in a double-chamber bag and the composition of each chamber has one of the following compositions: (a) Compartment A Compartment B Compartment A+B (after reconstitution) Xylitol mmol/l 92 (1.4% w/v) 0 46 (0.7% w/v) Glucose mmol/l 55,4 (1% w/v) 0 27.7 (0.5% w/v) L-Carnitine mmol/l 2,48 (0.04% w/v) 0 1,24 (0.02% w/v) Sodium mmol/l 0 264 132 Calcium mmol/l 2.6 0 1,3 Magnesium mmol/l 1 0 0,5 Chloride mmol/l 0 207 103.5 Lactate mmol/l 0 70 35 pH 2.6-3.2 8.0-8.5 7.1-7.4 (b) Compartment A Compartment B Compartment A+B (after reconstitution) Xylitol mmol/ l 197,2 (3% w/v) 0 98.6 (1.5% w/v) Glucose mmol/ l 55,4 (1% w/v) 0 27.7 (0.5% w/v) L-Carnitine mmol/ l 2,48 (0.04% w/v) 0 1,24 (0.02% w/v) Sodium mmol/l 0 264 132 Calcium mmol/ l 2.6 0 1.3 Magnesium mmol/l 1 0 0,5 Chloride mmol/l 0 207 103.5 Lactate mmol/l 0 70 35 pH 2.6-3.2 8.0-8.5 7.1-7.4 (c) Compartment A Compartment B Compartment A+B (after reconstitution) Xylitol mmol/l 250 (4% w/v) 0 125 (2.0% w/v) Glucose mmol/l 166 (3% w/v) 0 83 (1.5% w/v) L-Carnitine mmol/l 2,48 (0.04% w/v) 0 1,24 (0.02% w/v) Sodium mmol/l 0 264 132 Calcium mmol/l 2,6 0 1,3 Magnesium mmol/l 1 0 0,5 Chloride mmol/l 0 207 103,5 Lactate mmol/l 0 70 35 pH 2.6-3.2 8.0-8.5 7.1-7.4 (d) Compartment A Compartment B Compartment A+B (after reconstitution) Xylitol mmol/l 92 (1.4% w/v) 0 46 (0.7% w/v) Glucose mmol/l 160,6 (2.9% w/v) 0 80.3 (1.45% w/v) L-Carnitine mmol/l 2,48 (0.04% w/v) 0 1,24 (0.02% w/v) Sodium mmol/l 0 264 132 Calcium mmol/l 2.6 0 1.3 Magnesium mmol/l 1 0 0.5 Chloride mmol/l 0 207 103.5 Lactate mmol/l 0 70 35 pH 2.6-3.2 8.0-8.5 7.1-7.4 (e) Compartment A Compartment B Compartment A+B (after reconstitution) Xylitol mmol/ l 92 (1.4% w/v) 0 46 (0.7% w/v) Glucose mmol/ l 324 (5.8% w/v) 0 162 (2.9% w/v) L-Carnitine mmol/l 2,48 (0.04% w/v) 0 1,24 (0.02% w/v) Sodium mmol/l 0 264 132 Calcium mmol/l 2.6 0 1,3 Magnesium mmol/l 1 0 0.5 Chloride mmol/ l 0 207 103.5 Lactate mmol/ l 0 70 35 pH 2.6-3.2 8.0-8.5 7.1-7.4 (f) Compartment A Compartment B Compartment A+B (after reconstitution) Xylitol mmol/l 92 (1.4% w/v) 0 98.6 (1.5% w/v) Glucose mmol/l 166 (5.8% w/v) 0 83 (1.5% w/v) L-Carnitine mmol/l 2,48 (0.04% w/v) 0 1,24 (0.02% w/v) Sodium mmol/l 0 264 132 Calcium mmol/l 2.6 0 1,3 Magnesium mmol/l 1 0 0.5 Chloride mmol/l 0 207 103.5 Lactate mmol/l 0 70 35 pH 2.6-3.2 8.0-8.5 7.1-7.4
  16. The solution for use of anyone of the preceding claims, wherein said solution is in the form of a concentrate.
  17. The solution for use of claim 15, wherein said solution is for use in a peritoneal dialysis home machine.
  18. The solution for use of anyone of the preceding claims, wherein the treatment is for prevention of kidney and/or peritoneal damage in a subject in which the ability of the kidney and/or of the peritoneal membrane to remove small solutes and fluids is not yet compromised, in particular in a subject who has not yet undergone a peritoneal dialysis treatment.
  19. The solution for use of anyone of the preceding claims, wherein the subject to be treated is affected by severe congestive heart failure resistant to diuretic therapy.

Description

FIELD OF THE INVENTION The present invention relates to the field of peritoneal dialysis. In particular, it relates to solutions for peritoneal dialysis able to maintain or even restore the removal of small solutes and fluid. BACKGROUND OF THE INVENTION Peritoneal dialysis (PD) is a viable but under-prescribed method of treating uremic patients and patients with severe congestive heart failure resistant to diuretic therapy (International comparison of peritoneal dialysis prescriptions from the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS). Wang AY, Zhao J, Bieber B, Kanjanabuch T, Wilkie M, Marshall MR, Kawanishi H, Perl J, Davies S; PDOPPS Dialysis Prescription and Fluid Management Working Group. Perit Dial Int. 2020 Jan 17:896860819895356; The use of peritoneal dialysis in heart failure: A systematic review. Chionh CY, Clementi A, Poh CB, Finkelstein FO, Cruz DN. Perit Dial Int. 2020 Jan 13:896860819895198). Treatment-related failure remains a major limitation to the long-term success of peritoneal dialysis therapy. Concerns about its use centre around the bio-incompatibility of peritoneal dialysis fluids due to their potential for altering the functional and anatomical integrity of the peritoneal membrane. Most of these effects are due to the high glucose content of these solutions, with attendant issues of glucose degradation products (GDPs) generated during heat treatment of glucose-containing solutions and the metabolic effects of the very high glucose concentrations per se. Glucose is the standard osmotic agent used in PD solutions to induce water flow, and thereby peritoneal ultrafiltration across the peritoneal capillaries in order to remove excess fluid and solutes from the patient's body. The progressive damage to the peritoneal membrane is evidenced by faster peritoneal solute transport rate and by a decline of ultrafiltration capacity eventually resulting in ultrafiltration failure, which is often characterized by impaired osmotic conductance (Krediet RT, Struijk DG (2013) Peritoneal changes in patients on long-term peritoneal dialysis. Nat Rev Nephrol 9: 419-429). The observation that these deleterious changes occur upon exposure to conventional glucose-based PD solutions fuels the search for a more biocompatible PD solution. Glucose-based PD solutions developed using multi-chamber bags and characterized by neutral or physiological-pH and low-GDP fluids as compared to conventional predecessors have been labeled as "biocompatible". However, after over a two decades of investigating the potential benefits of neutral pH low-GDP solutions, limited evidence supporting their true biocompatibility exists (Misra PS, Nessim SJ, Perl J. "Biocompatible" Neutral pH Low-GDP Peritoneal Dialysis Solutions: Much Ado About Nothing? Semin Dial. 2017 Mar;30(2):164-173; Bartosova M, Schmitt CP (2019) Biocompatible peritoneal dialysis: the target is still way off. Frontiers Physiol 2019; 9:1853). Given the evidence for the peritoneal membrane toxicity of glucose and its metabolites, many attempts have been made to identify other suitable osmotic agents. Two such candidate agents are represented by L-carnitine and xylitol. Peritoneal dialysis solutions containing L-carnitine and glucose (Bonomini M, Pandolfi A, Di Liberato L, Di Silvestre S, Cnops Y, Di Tomo P, D'Arezzo M, Monaco MP, Giardinelli A, Di Pietro N, Devuyst O, Arduini A (2011) L-carnitine is an osmotic agent suitable for peritoneal dialysis. Kidney Int 80: 645-654; Bonomini M, Di Liberato L, Del Rosso G, Stingone A, Marinangeli G, Consoli A, Bertoli S, De Vecchi A, Bosi E, Russo R, Corciulo R, Gesualdo L, Giorgino F, Cerasoli P, Di Castelnuovo A, Monaco MP, Shockley T, Rossi C, Arduini A (2013) Effects of an L-carnitine-containing peritoneal dialysate on insulin sensitivity in patients treated with CAPD: a 4-month, prospective, multicentre randomized trial. Am J Kidney Dis 62(5): 929-938; WO0126649), or solutions containing L-carnitine, low-dose glucose and xylitol (Bonomini M, Di Silvestre S, Di Tomo P, Di Pietro N, Mandatori D, Di Liberato L, Sirolli V, Chiarelli F, Indiveri C, Pandolfi A, Arduini A (2016) Effect of peritoneal dialysis fluid containing osmo-metabolic agents on human endothelial cells. Drug Des Develop Ther 10: 3925-3932; WO2006094900) have been evaluated. In particular, the combination of L-carnitine, low-dose glucose and xylitol has been tested in vitro on endothelial cells (Bonomini, 2016) or on mesothelial cells (WO2006094900) and the effects, respectively, on vascular inflammation and on mesothelial cells growth have been observed. While considerable evidence in support of the biocompatibility of novel solutions has emerged from cell culture and animal studies, the clinical benefits, especially in terms of removal of small solutes and fluids, as compared to conventional PD solutions are not disclosed nor foreseeable. Indeed, the use of biocompatible fluids is unsupported by high level clinical evidence. There w