WO2018100290A1 - Novel compounds for peritoneal dialysis - Google Patents

Abstract

The invention relates to a compound of formula (I) in which R' and R'' are independently selected from: a hydrogen; the halogens; the alkyls, preferably with 1, 2 or 3 carbon atoms; and a –CO-R1 function in which R1 is an alkyl preferably with 1, 2 or 3 carbon atoms, for the use thereof in peritoneal dialysis.

Description

 New compounds for peritoneal dialysis

The present invention relates to the use in peritoneal dialysis of compounds selected from anhydrohexitols and their derivatives, or a mixture thereof. The invention also relates to peritoneal dialysis solutions comprising such compounds. The invention also relates to a process for the preparation of peritoneal dialysis solutions using such compounds.

Context of the invention

Dialysis is a procedure to supplement or replace kidney function in some patients. To do this, the methods mainly used today are hemodialysis and peritoneal dialysis. In hemodialysis, the patient's blood passes through a kidney dialysis machine that includes a membrane that acts as an artificial kidney, to filter and purify the blood. Because it is an extracorporeal treatment that requires special equipment, hemodialysis inevitably faces some drawbacks such as the availability of dialysis machines and the possibility of infections and contaminations.

Peritoneal dialysis does not require such equipment, since it advantageously uses the peritoneum of the patient as a filter membrane. The peritoneum is a membranous abdominopelvic wall covering of the body walls that is able to act as a natural semi-permeable membrane, due to its large number of blood vessels and capillaries. The treatment involves introducing via a catheter a peritoneal dialysis solution into the peritoneal cavity. During a given exposure period, fluid and solute exchange occurs between the solution and the blood until it reaches equilibrium. The dialysis solution or dialysate is then removed from the body by a catheter.

Peritoneal dialysis solutions are sterile and typically include water, electrolytes (Na +, Cl-, Ca2 +, Mg2 +), a buffer (lactate and / or carbonate), and an osmotic agent. The role of the osmotic agent is to make the dialysis solution slightly hypertonic. By gradient effect, movements of fluids and solutes are thus effected, from the blood to the dialysate. Conventional solutions use glucose as the osmotic agent, which is an inexpensive compound, and has the advantage of producing high ultrafiltration levels.

However, a major disadvantage is that these solutions are not biocompatible. The main factor causing these bioincompatibility problems is the presence of high levels of glucose and glucose products (GDPs for "glucose degradation product").

The GDPs are molecules of low molecular weight, among which are mainly 5-hydroxymethyl furaldehyde (5-HMF), and also for example furaldehyde and 3,4-didesoxyglucosone-3-ene (3,4-DGE) . The GDPs cause abdominal pain, discomfort during infusion, and are cytotoxic. They inhibit cell proliferation and impair the functions of inflammatory cells. 3,4-DGE, for example, is lethal to leucocytes and mesothelial cells at the concentrations usually found in peritoneal dialysis solutions. GDPs also favor the production of advanced glycation end products (AGEs), which cause dysfunctions of proteins and cellular functions. In order to minimize these defects, one approach relies on the development of new osmotic agents that can be more considered biocompatible. In this regard, mention can be made of the only two glucose alternatives currently available on the market: amino acids and icodextrin, a glucose polymer belonging to the maltodextrin family, obtained by hydrolysis of starch.

The use of glucose polymers such as icodextrin is an attractive alternative to glucose. In addition to limiting exposure to glucose and GDPs, these compounds allow for more sustainable and linear ultrafiltration. However, icodextrin can not be strictly considered biocompatible. Although to a lesser extent, its heat sterilization also leads to the production of toxic GDPs. As for amino acids, they have the particular disadvantage of producing ultrafiltration times too short and cause adverse acidosis in patients.

The present invention aims to provide a new agent for peritoneal dialysis that does not have all these disadvantages. The present invention in particular aims to provide compounds that allow the preparation of peritoneal dialysis solutions with extremely low levels of GDPs. The present invention aims to address the aforementioned problems by providing an agent having good pharmacological and pharmacokinetic properties, in particular that allows to obtain an ultrafiltration level at least as high as those of the prior art, or even higher . Presentation of the invention

 It is to the credit of the Applicant to have succeeded in answering the aforementioned problems, thanks to the new use of compounds having a dianhydrohexitol unit of formula (I), in particular isosorbide. As can be seen from the examples below, these compounds advantageously make it possible to prepare solutions in which, despite the sterilization, the content of GDPs and the reactivity towards proteins are extremely low (Examples B.1 and B.2.). In addition, these substances produce few undesirable metabolites (Example B.3.), And make it possible to obtain high and long-lasting ultrafiltration rates (Examples B.3 and B.4).

The compounds of the invention are therefore very promising candidates as regards their effectiveness, but also as regards their safety. In particular, the results obtained are even better than those obtained with glucose and icodextrin, conventionally used for this application.

Summary of the invention

The present invention thus has for its first object a compound of formula (I) (I)

 OR with R 'and R "independently selected from: hydrogen, halogens, alkyls, preferably having 1, 2 or 3 carbon atoms; a -CO-R1 function, where R1 is alkyl having preferably 1, 2 or 3 carbon atoms for its use in peritoneal dialysis.

The subject of the present invention is also a composition comprising a compound of formula (I) for use in peritoneal dialysis.

The present invention also relates to a peritoneal dialysis solution comprising a compound of formula (I) or such a composition.

The subject of the present invention is also a method for preparing a peritoneal dialysis solution, comprising mixing at least one compound of formula (I) or a composition comprising at least one compound of formula (I), with a solvent.

Detailed description of the invention

A first subject of the invention relates to a compound of formula (I)

 (I)

O with R 'and R "independently selected from: hydrogen, halogens, alkyls, preferably having 1, 2 or 3 carbon atoms, a -CO-R1 function, where R1 is alkyl preferably having 1, 2 or 3 carbon atoms for its use in peritoneal dialysis.

The compounds used according to the invention comprise a dianhydrohexitol unit. For example, the dianhydrohexitol moiety may be selected from dianhydrosorbitol, dianhydro- roitol and dianhydromannitol. Preferably, the compounds of the invention comprise a dianhydrosorbitol unit, in particular dianhydro-D-sorbitol.

Alkyls preferably having 1, 2 or 3 carbon atoms include methyl, ethyl, propryl and isopropyl.

Preferably, at least one of the groups R 'and R "is a hydrogen, preferably both, In the latter case preferably, the compound of the invention is 1, 4, 3, 6-dianhydrosorbitol (also called "Isosorbide", 1, 4,3,6-dianhydro-D-sorbitol or (3R, 3aR, 6S, 6aR) -hexahydrofuro [3,2-b] furan-3,6-diol), CAS No. 652-67 The present invention also relates to a composition comprising at least one compound according to the invention for use in peritoneal dialysis.

Such a composition may quite include different compounds of formula (I). Preferably in the composition useful to the invention, at least 50% by dry weight of compounds of formula (I) comprise a dianhydrosorbitol unit, preferably at least 60%, preferably at least 70%, preferably at least 80% by weight. %, preferably at least 90%. Very preferably, said composition comprises only compounds of formula (I) having a dianhydrosorbitol unit.

Preferably, in the composition useful for the invention, at least 50% by dry weight of the compounds of formula (I) have at least one of the groups R 'and R "which is a hydrogen, preferentially both, preferably isosorbide, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%, Very preferably, said composition comprises only compounds of formula (I) in which at least one of the groups R 'and R "is a hydrogen, preferably both. In the latter case, said composition comprises only isosorbide as compounds of formula (I).

Preferably, the compounds which are useful for the invention exhibit, in particular after heat sterilization, in particular at 121 ° C. for 15 minutes:

 a content of 5-hydroxymethyl furaldehyde (5-HMF) of less than 135 ppb, preferably less than 100 ppb, preferably less than 50 ppb, preferably less than 30 ppb, preferably less than 20 ppb, preferably less than 10 ppb; ppb, preferably less than 8 ppb, preferably less than 6 ppb, preferably less than 4 ppb, preferably less than 2 ppb, preferably less than 1 ppb, preferably 0 ppb; and or,

a furfuraldehyde content of less than 65 ppb, preferably less than 50 ppb, preferably less than 40 ppb, preferably less than 20 ppb, preferably less than 15 ppb; and or,

a content of 3,4-didesoxyglucosone-3-ene (3,4-DGE) of less than 20 ppm, preferably less than 10 ppm, preferably less than 5 ppm, preferably less than 2 ppm, preferably less than 1 ppm, preferably 0 ppm; these contents being expressed by weight relative to the weight of a 4% solution of said compounds of the invention.

The contents of 5-HMF and furaldehyde can be determined by those skilled in the art by liquid chromatography and detection by UV spectrophotometry at 280 nm. The 3,4-DGE content can be determined by those skilled in the art by liquid chromatography, preferably using pyrazinecarboxamide for calibration, and detection by UV spectrophotometry at 230 nm. For example, we can refer to the methods described in the Example in point B.1. below.

Generally, the compounds of the invention have an osmolality of between 200 and 350 mOsm / kg; said osmolality being determined on the basis of a 0.4% solution of said compounds. This osmolality is for example between 250 and 350 mOsm / kg, or even between 260 and 310 mOsm / kg.

This osmolality can conventionally be determined by those skilled in the art by means of an osmometer. For example, one can refer to the method described in Example B.4. below. Preferably, the compounds that are useful for the invention have a reducing sugar content of less than 3.5%, this percentage being expressed as the dry weight of reducing sugars relative to the total dry weight of said compounds. This content is preferably less than 2.5%, preferably less than 1.0%, more preferably less than 0.5%. It is generally greater than 0.001%, or even greater than 0.005%.

This reducing sugar content can conventionally be determined by those skilled in the art by means of the Bertrand method. For example, we can refer to the method described in the Example in point B.3. below.

The present invention also relates to a peritoneal dialysis solution comprising at least one compound of formula (I), said compound of formula (I) being preferably as defined before. The present invention further relates to a peritoneal dialysis solution comprising a composition as defined above.

Generally in this solution, the concentration of compounds of formula (I) is chosen in a range from 1 to 20%, preferably from 1 to 15%, preferably from 1 to 10%. This concentration is preferably at least 2%, preferably at least 3%, preferably at least 4%. It is for example chosen in the range of 4 to 10%, preferably 5 to 9%, preferably 6 to 9%, for example 7 to 8%.

Peritoneal dialysis solutions are typically hypertonic. They thus preferably have an osmolality of greater than 280 mOsm / kg, preferably greater than 320 mOsm / kg.

Preferably, the peritoneal dialysis solutions of the invention have a pH chosen in a range from 6.00 to 9.00, preferably from 7.00 to 8.00, in particular from 7.30 to 7.50, for example from 7.35 to 7.45.

Preferably, the peritoneal dialysis solutions of the invention, in particular after heat sterilization, have:

a content of 5-hydroxymethyl furaldehyde (5-HMF) of less than 135 ppb, preferably less than 100 ppb, preferably less than 50 ppb, preferably less than 30 ppb, preferably less than 20 ppb, preferably less than 10 ppb, preferably less than 8 ppb, preferably less than 6 ppb, preferably less than 4 ppb, preferably less than 2 ppb, preferably less than 1 ppb, preferably 0 ppb; and or,

 a furfuraldehyde content of less than 65 ppb, preferably less than 50 ppb, preferably less than 40 ppb, preferably less than 20 ppb, preferably less than 15 ppb; and or,

 a content of 3,4-didesoxyglucosone-3-ene (3,4-DGE) of less than 20 ppm, preferably less than 10 ppm, preferably less than 5 ppm, preferably less than 2 ppm, preferably less than 1 ppm, preferably 0 ppm; these contents being expressed by weight relative to the weight of said solution when the concentration of compounds of formula (I) is brought to 4%.

Generally, the peritoneal dialysis solutions of the invention comprise other substances, as long as this does not contravene the properties sought in the present invention, particularly in terms of safety and efficacy. These other substances are typically chosen from:

 - Assets other than the compounds of formula (I) of the invention, for example icodextrin, glucose, dextrans, hydroxyethyl starch;

 buffers, for example lactate or citrate buffers;

electrolytes.

However, preferably, the compounds of the invention represent at least 50% by dry weight of the active ingredients of the solution, preferably at least 60%, preferably at least 70%, preferably at least 80%, preferably at least 90%. Very preferably, the compounds of the invention are the only active agents of the peritoneal dialysis solution of the invention.

Thus, preferably, the subject of the present invention is a peritoneal dialysis solution comprising:

 compounds of formula (I), said compounds being preferentially as defined before;

 - a tampon ;

 electrolytes;

a solvent, preferably water. The subject of the invention is also a method for preparing a peritoneal dialysis solution according to the invention, comprising mixing at least one compound of formula (I) with a solvent, preferably water, optionally with at least one least one other substance, such as (s) that defined before. It also relates to a process for preparing a peritoneal dialysis solution according to the invention, comprising mixing a composition comprising at least one compound of formula (I) as described above with a solvent, preferentially some water,

Preferably, this process comprises a step of sterilizing said composition, preferably heat sterilization.

The compounds, compositions or peritoneal dialysis solutions of the invention are typically intended for a patient suffering from renal insufficiency, that is to say having a partial or total loss of renal function, consecutive for example to diabetes or infection. The invention thus also relates to the use of compounds of formula (I) or of a composition comprising such compounds, or of a peritoneal dialysis solution according to the invention, as a medicament, in particular intended for the treatment of chronic renal failure. It also relates to the use of compounds of formula (I) or a composition comprising such compounds, for the manufacture of a peritoneal dialysis solution, in particular for the treatment of chronic renal failure.

The present invention also relates to a method of treatment, comprising the administration of compounds of formula (I) or of a composition comprising such compounds, or of a peritoneal dialysis solution according to the invention, to a subject requiring it . In particular, the present invention relates to a method of treating chronic renal failure by peritoneal dialysis in a subject, comprising administering a peritoneal dialysis solution of the invention to said subject, particularly by injection into the peritoneal cavity. .

The peritoneal dialysis solutions of the invention can be used in addition to or instead of glucose solutions, typically in the context of continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD). Note that in the present invention, it is understood that the expression "between X and Y" covers a range of values excluding the cited boundaries, while the expression "selected in the range from X to Y" covers a range of of values including the mentioned terminals.

In the present invention, it is furthermore understood that when referring to a concentration expressed as a percentage of a substance in solution, this concentration expresses well the number of grams of said substance per 100 ml of said solution. This mass in grams is indeed a dry mass, that is to say it excludes in particular the mass of water possibly present in the substance in its powder form, before solubilization.

The invention will be better understood with the aid of the examples which follow, which are intended to be illustrative and not limiting.

Description of the Figures

 Figure 1: Effect of sterilization on the production of GDPs. GDPs produced after sterilization at 121 ° C for 15 minutes for isosorbide, icodextrin or glucose in 4% solutions.

Figure 2: Effect of sterilization on protein reactivity.

Absorbance at 284 nm, before and after sterilization, in the absence and in the presence of lysine, for a 0.5% solution of isosorbide or icodextrin.

 Figure 3: Reducing sugar levels. Percentage of reducing sugars formed over time for a solution of isosorbide or icodextrin.

Figure 4: Glucose level. Percentage of glucose formed over time for a solution of isosorbide or icodextrin.

 Figure 5: Osmolality. Osmolality over time for a solution of isosorbide or icodextrin at 0.4%. Examples

A. Substances tested

 In the examples that follow, the following substances were compared

 Isosorbide;

Icodextrin; Glucose (anhydrous dextrose).

B. Tests of substances

 1. Effects of sterilization on the production of GDPs

In this example, the inventors have studied the influence of sterilization on the production of GDPs, namely 5-hydroxymethyl furaldehyde (5-HMF), furaldehyde, and 3,4-didesoxyglucosone-3-ene (3, 4-DGE), solutions using different substances. 20 ml to 4% solutions of each of the test substances were prepared in osmosis water. The GDPs content was measured after sterilization at 121 ° C for 15 minutes.

The content of 5-HMF and furaldehyde was determined by liquid chromatography (using standards of 5-HMF (Merck - Ref.8.206.78.001) or furaldehyde for calibration respectively), and detection by UV spectrophotometry at 280 nm . For chromatography, a column with a particle size of 9 μιη, 8% crosslinking, an internal diameter of 7.8 mm and a length of 300 mm (HPX 87H column - Biorad - Ref.125.0140) was used. The conditions were as follows: eluent H2SO4 5mN (1 N sulfuric acid), flow rate 0.8 mL / min.

The 3,4-DGE content was determined by liquid chromatography (using pyrazinecarboxamide (Sigma - Ref P7136) for calibration), and detection by UV spectrophotometry at 230 nm. For chromatography, a column with a particle size of 5 μιη, a pore size of 120 Å, an internal diameter of 4.6 mm and a length of 15 cm (Supelcosil LC-18 - Supelco - Ref 58230) has been used. The conditions were as follows: Elution solvent H ₂ O / MeOH, flow rate 1.0 mL / min.

The results are shown in Figure 1.

As expected, glucose produces a very high content of GDPs. The icodextrin glucose polymer has lower but still high contents. For isosorbide, however, very small amounts of furfuraldehyde were produced, and the presence of 5-HMF and 3,4-DGE was not detected. It can be deduced that the compound of the invention has a markedly lower propensity to induce undesirable side effects.

2. Effect of sterilization on protein reactivity

In this example, the inventors have studied the influence of sterilization on the reactivity towards proteins, solutions using isosorbide or icodextrin.

0.5% solutions of each of the substances to be tested were prepared in a phosphate buffer (pH 7, 200 mM), in the absence or in the presence of 0.5% of L-lysine.

The absorbance of the solutions at 284 nm was measured before and after sterilization at 121 ° C for 45 minutes. The phosphate buffer used for the realization of the solutions was used as a negative control, and a glucose solution as a positive control (results not shown).

The results obtained are shown in Figure 2. The difference in absorbance observed between the substance to be tested alone before and after sterilization (dashed histograms) can be attributed to the production of degradation products. The results confirm that the compound of the invention exhibits excellent resistance to degradation during sterilization. The difference in absorbance observed between the substance to be tested in the presence and absence of lysine after sterilization (gray histograms) can be attributed to the reactions that occur between the test substance and lysine, thus reflecting the reactivity of these substances. against proteins (Maillard reaction). The greater the difference in absorbance, the more the substance can be judged to be reactive with respect to proteins. The results indicate that the substance of the invention is the least reactive towards proteins. This very low reactivity suggests an excellent tolerance of the substance of the invention.

3. Digestibility

In this example, the inventors have studied the level of glucose and reducing sugars formed by isosorbide or icodextrin. When these substances are subject to digestion enzymes. The objective is to give an idea of their life time, and thus of action, as well as to give an idea of their propensity to induce undesirable side effects, because of the production of these metabolites. The substances were digested with porcine pancreatin (P7545, SIGMA).

0.6 g of dry substance was introduced into 150 ml of sodium maleate buffer (pH 7, 0.1 mol / l). The mixture was stirred until the substance dissolved, and then the flasks were placed on a water bath for 15 minutes, so that the solution had a temperature of 37 ° C. 1.5 mL of the resulting solution was taken to obtain a sample at t = 0. Then, 0.15 g of pork pancreatin was added. The mixture was incubated at 37 ° C. in a thermostated bath with stirring for 5 hours. Samples of 0.75 ml were taken at time t = 15; 30 ; 45; 60; 90; 120; 180; 240; 300 minutes. The enzymatic reaction was stopped by placing the specimens in a dry bath at 100 ° C for 10 minutes. The glucose and reducing sugar contents were determined on the initial solutions at times t = 0 to t = 300 minutes.

Glucose was used as a positive control (results not shown). The reducing sugar content was determined by the Bertrand method. Specifically, in a 250 mL conical flask was introduced: 20 mL of titrant containing the equivalent of 0.5 to 5.0 mg glucose per mL; 20 mL of cupric solution (4% copper sulfate pentahydrate); 20 mL sodium tartrate solution (20% sodium and potassium double tartrate and 15% sodium hydroxide); some glass balls. The whole was heated to moderate boiling for 3 minutes and then left to settle for 2 minutes. The supernatant was removed, and the Cu ₂ 0 precipitate was dissolved with 20 mL of ferric liquor (5% ferric sulfate and 20% sulfuric acid). The resulting solution was titrated with 0.1 N potassium permanganate solution and using the Bertrand table.

The results are shown in Figures 3 and 4.

Advantageously, and in comparison with icodextrin, isosorbide subjected to digestive enzymes does not lead to the formation of glucose over time, and produces very little reducing sugars. It can be deduced that the substance of the invention may act longer on the body, with a lower propensity to induce undesirable side effects. 4. Osmolality

The osmolality was determined on the basis of an aqueous solution made of osmosis water comprising 0.4% of substance to be tested. The osmolality measurement of this solution was performed using an osmometer (FISKE® ASSOCIATES MARK 3), following the manufacturer's instructions.

The results are shown in Figure 5.

The osmolality of isosorbide is higher than that of icodextrin. It can be deduced that the substance of the invention, in particular isosorbide, produces higher levels of ultrafiltration for the same content by weight.

Claims

claims 1. Compound of formula (I)

 with R 'and R "independently selected from: hydrogen, halogens, alkyls, preferably having 1, 2 or 3 carbon atoms, a -CO-R1 function, where R1 is alkyl preferably having 1, 2 or 3 carbon atoms for its use in peritoneal dialysis. 2. Compound according to claim 1, characterized in that it comprises a dianhydrosorbitol unit. 3. Compound according to any one of claims 1 or 2, characterized in that at least one of the groups R 'and R "is a hydrogen. 4. Compound according to claim 3, characterized in that the groups R 'and R "are hydrogens. 5. Compound according to any one of claims 1 to 4, characterized in that it is isosorbide. 6. Composition comprising at least one compound as defined in any one of claims 1 to 5, for use in peritoneal dialysis. 7. Peritoneal dialysis solution comprising at least one compound as defined in any one of claims 1 to 5 or a composition according to claim 6. 8. A process for preparing a peritoneal dialysis solution, comprising mixing at least one compound as defined in any one of claims 1 to 5 or a composition according to claim 6, with a solvent.