Methylated cyclodextrins and methods for the production thereof

Abstract

The invention relates to a novel methylated cyclodextrin and to a novel method used for the production thereof. The invention also relates to the use of said methylated cyclodextrin for the solubilisation of lipophilic compounds, or carriers of at least one lipophilic group. The invention further relates to a composition comprising said methylated cyclodextrin, particularly a pharmaceutical composition.

Claims

1. A process for preparing a methyl cyclodextrin having a MS of between 0.05 and 1.50, comprising the step of decreasing ionic species of the methyl cyclodextrin, such that the conductivity of said methyl cyclodextrin, when it is in the form of a solution of distilled water at a concentration of 10%, is reduced to a value of less than or equal to 50 μS/cm, wherein the step of decreasing the ionic species is carried out by subjecting the methyl cyclodextrin in solution to: an operation (b.1) of nanofiltration of the methyl cyclodextrin solution, said solution having a solids content by weight of less than or equal to 20%; an operation (b.2) of demineralization on an ion-exchange column; and an operation (b.3) of decoloring with active carbon.

2. A process for preparing a methyl cyclodextrin having a degree of molar substitution (MS) of between 0.05 and 1.50, comprising the steps of: (a) etherification of a cyclodextrin with a methylation reagent, said etherification being carried out in basic medium, at a temperature of between 100 and 200° C. and at a pressure between 1 and 10 bar; (b) decreasing ionic species of the methyl cyclodextrin obtained in step (a), such that the conductivity of said methyl cyclodextrin, when it is in the form of a solution of distilled water at a concentration of 10%, is reduced to a value of less than or equal to 50 μS/cm; (c) drying the methyl cyclodextrin obtained in step (b); and (d) recovering the methyl cyclodextrin obtained in step (c); wherein the step of decreasing the ionic species is carried out by subjecting the methyl cyclodextrin in solution to: an operation (b.1) of nanofiltration of the methyl cyclodextrin solution, said solution having a solids content by weight of less than or equal to 20%; an operation (b.2) of demineralization on an ion-exchange column; and an operation (b.3) of decoloring with active carbon.

3. A composition comprising a methyl cyclodextrin having a degree of molar substitution (MS) of between 0.05 and 1.50 and a conductivity of less than or equal to 50 μS/cm when it is in the form of a solution of distilled water at a concentration of 10%, and also comprising a compound bearing at least one lipophilic group selected from hypoglycemic agents and mixtures thereof.

4. A medicament comprising the composition of claim 3.

5. A process of treatment and/or prevention of type 2 diabetes and/or complications thereof, and/or diseases able to be treated and/or prevented by an increase in the HDL cholesterol level and/or by a reduction in or prevention of atheromatous plaques, and/or diseases of the central nervous system comprising administering the composition of claim 3.

6. A method comprising administering a methyl cyclodextrin obtained according to the process of claim 1 to a subject, for at least one of the solubilization of one of lipophilic compounds or compounds bearing at least one lipophilic group, improving the chemical stability thereof, improving the delivery thereof at and through biological membranes, increasing the physical stability thereof, converting them from a liquid form to a pulverulent form, preventing interactions with other compounds, reducing local irritation after a topical or oral administration of these lipophilic compounds or compounds bearing lipophilic groups, preventing the absorption thereof at certain tissues obtaining prolonged release of these compounds, masking the taste thereof, and modifying the bioavailability thereof, wherein the lipophilic compound or compound bearing at least one lipophilic group is selected from hypoglycemic agents and mixtures thereof.

7. A composition comprising the methyl cyclodextrin prepared according to the process as defined in claim 1, and also comprising at least one lipophilic compound or compound bearing at least one lipophilic group selected from hypoglycemic agents and mixtures thereof.

8. A composition comprising the methyl cyclodextrin prepared according to the process as defined in claim 2, and also comprising at least one lipophilic compound or compound bearing at least one lipophilic group selected from hypoglycemic agents and mixtures thereof.

9. A method for the solubilization in aqueous medium of lipophilic compounds or compounds bearing at least one lipophilic group selected from hypoglycemic agents and mixtures thereof comprising combining with said the methyl cyclodextrin prepared according to the process as defined in claim 1 with said lipophilic compounds or compounds bearing at least one lipophilic group selected from hypoglycemic agents and mixtures thereof.

10. A method for the solubilization in aqueous medium of lipophilic compounds or compounds bearing at least one lipophilic group selected from hypoglycemic agents and mixtures thereof comprising combining with said the methyl cyclodextrin prepared according to the process as defined in claim 2 with said lipophilic compounds or compounds bearing at least one lipophilic group selected from hypoglycemic agents and mixtures thereof.

Description

FIGURE

(1) FIG. 1 describes the ratio of improvement in solubility as a function of the concentration of methyl cyclodextrin for several samples of methyl cyclodextrin (“MβCD-IN”, “MβCD-CP1”, “MβCD-CP2” and “MβCD-CP3”).

EXAMPLE

(2) In the following tests, a methyl-β-cyclodextrin according to the invention (“MβCD-IN”) was compared to methyl-β-cyclodextrins using processes of the prior art (“MβCD-CP1”, “MβCD-CP2” and “MβCD-CP3”).

(3) The inventors proceeded such that these MβCDs all have an MS of 0.7, so as to be able to effectively compare these MβCDs on the basis of the criterion of conductivity.

(4) A. Methyl-β-Cyclodextrins (MβCDs) Used

(5) 1. Preparation of an MβCD According to the Invention (MβCD-IN)

(6) A native β-cyclodextrin was etherified in dimethyl sulfate, in aqueous medium and in the presence of calcium hydroxide, under the following temperature and pressure conditions: 140° C./4 bar. The reaction medium was then neutralized with sulfuric acid.

(7) The reaction product was then spin-dried (Dorr-Oliver BW630H spin dryer) and washed, in order to eliminate the calcium sulfate formed during the reaction. The washing was in particular carried out by spray nozzle with demineralized water heated to 70° C. 3.5 tons of reaction product with 23% dry matter content were thus obtained.

(8) The ionic species of the reaction product obtained in this way were separated by the following operations: nanofiltration of the solution adjusted to 20% dry matter content; demineralization on ion-exchange column; decoloring with active carbon.

(9) The nanofiltration step was in particular carried out under the following conditions: use of AFC30 membranes; use of two 1.7 m.sup.2 tubes in parallel (3.4 m.sup.2 in total); 2.7 m.sup.2/h high-pressure pump; counter-pressure set at 20 bar module inlet; solution of MβCD adjusted to 20% dry matter content, brought to a temperature of 55° C. and to a pH of 5.5; permeate flow rate of from 70 to 85 l/h/m.sup.2; outlet pressure of 18 bar. 6 filtrations were thus carried out.

(10) The demineralization step was in particular carried out under the following conditions: treatment at a temperature of less than 40° C., 50 l/h, at 20% dry matter content: cationic (Amberlite 252); 25 liters; 1.8 eq/l; anionic (Amberlite IRA 910); 40 liters; 1.1 eq/l; mixed bed; 30 liters;
2 700 l tanks were demineralized before regeneration.

(11) The step of decoloring with active carbon (NORIT SX plus) was in particular carried out under the following conditions: solution of MβCD at 20% dry matter content, treated with 1% black; stirring for 1 hour; pH 5-5.5; room temperature; filtration on 11 μm sleeve, then 8 μm, and finally 0.22 μm.

(12) The MβCD obtained in this way was then concentrated so as to have a dry matter content by weight of 30%, by means of an evaporator (NIRO), in particular under the following conditions: supply flow rate of 100 l/h; product temperature of 62° C.; pressure of 200 mbar.

(13) The solution obtained in this way was dried by single-stage spray drying (NIRO spray dryer). The conditions were in particular the following: solution to be spray dried adjusted to a temperature of 70° C. and to a pH of 6.5-7; filtration of the solution (0.22 μm); temperature of the inlet air of 250° C.; temperature of the outlet air regulated to 115° C.; air flow rate of 120 Nm.sup.3/h; negative pressure adjusted to 35 mm of water; flow rate of the spray-dried product of 6.8 to 7 kg/h.

(14) The pulverulent MβCD obtained in this way (MβCD-IN) had a moisture content of 3.5%, a content of reducing sugars of 0.3% and a content of residual native β-cyclodextrin of less than 0.1%.

(15) 2. Comparative MβCDs (MβCD-CP1, -CP2 and -CP3)

(16) The comparative methyl cyclodextrin “MβCD-CP1” corresponds to that used in U.S. Pat. No. 7,259,153 B2 and designated “Cryst. Methylated β-CD” in this patent. Although no process for preparing this MβCD is described in this patent, and this product is not commercially available, the inventors worked on the assumption that it was prepared according to U.S. Pat. No. 5,935,941 A. Indeed, this patent is cited as a promising basis for preparing the MβCD of U.S. Pat. No. 7,259,153 B2. The inventors based this in particular on example 15 of U.S. Pat. No. 5,935,941 A, the only example illustrating the preparation of methylated cyclodextrins. The reaction product was in particular treated according to the methods described in example 1 of this document.

(17) The comparative methyl cyclodextrin “MβCD-CP2” was prepared according to U.S. Pat. No. 6,602,860 B1. The reaction product was in particular treated according to the methods described in example 1 of this document.

(18) The comparative methyl cyclodextrin “MβCD-CP3” corresponds to the product sold under the name KLEPTOSE® Crysmeb, used in patent application WO 2015/087016 A1. This product is in particular obtained according to the U.S. Pat. No. 9,935,941 A, except for the fact that it is dried by spray drying.

(19) B. Characterization

(20) The characteristics of the methyl cyclodextrins MβCD-IN, MβCD-CP1, MβCD-CP2 and MβCD-CP3 were determined according to the following methods.

(21) 1. Determination of the Degree of Molar Substitution (MS) and the Substitution Profile

(22) The MS was determined by proton NMR (on a DPX 250 MHz Advance apparatus (Bruker, Rheinstetten, Germany)). The measurements were taken at 25° C. The calibration was carried out with the D.sub.2O signal. The samples of MβCD, and of native cyclodextrin, i.e. non-methylated cyclodextrin, were prepared at a concentration of 5 mg in 0.75 ml of D.sub.2O. The solutions were evaporated to dryness under a nitrogen stream and then reconstituted in 0.75 ml of D.sub.2O. This operation was repeated twice in order to ensure total exchange of the protons of the hydroxyl functions. The MS was calculated from the difference in integration between the spectrum of the native cyclodextrin and that of the methyl cyclodextrin in accordance with the invention. The NMR spectrum also made it possible to calculate the substitution profile.

(23) 2. Determination of the Conductivity

(24) The conductivity was determined at 25° C. according to the method recommended by the European Pharmacopoeia, reference “2.2.38. Conductivity, January 2008: 20238” on the basis of a 100 ml solution at 10% of MβCD. In particular, 10 dry grams of MβCD were placed in a 100 ml volumetric flask. Distilled water having a resistivity of greater than 500 000 ohms.Math.cm was added (q.s. 100 ml).

(25) The conductivity of this solution was in particular determined by means of an electronic conductivity meter (KNICK 703) fitted with a measurement cell and verified according to the procedure described in the related instructions.

(26) The results obtained are given in Table 1.

(27) TABLE-US-00001 TABLE 1 MβCD MβCD-IN MβCD-CP1 MβCD-CP2 MβCD-CP3 Degree of 0.67 0.67 0.68 0.67 molar substitution (MS) Substitution 75% of the ND ND ND profile substitutions borne by C2 carbons Conductivity 9 μS/cm 89 μS/cm 62 μS/cm 102 μS/cm ND: not determined
C. Test of Solubilization of Glipizide

(28) The methyl cyclodextrin MβCD-IN according to the invention and the comparative methyl cyclodextrins MβCD-CP1, MβCD-CP2 and MβCD-CP3 were evaluated for their ability to solubilize glipizide in distilled water, according to the following method: 6 solutions at 0, 1, 2, 10 and 15% of MβCD were prepared, for each MβCD. Distilled water was used as control solution. These solutions were stirred at room temperature. Glipizide was added milligram by milligram until it no longer dissolved. The limit amount of glipizide dissolving was noted for each solution, which made it possible to calculate the number of mg of glipizide dissolved per ml of solution.

(29) The ratio of improvement in solubility gives the factor by which the solubility is increased in the presence of a defined concentration of methyl cyclodextrin. It is calculated as follows:

(30) $\mathrm{Solubility}\mathrm{ratio}=\frac{S_{\mathrm{MCD}}}{S_{H2O}}$
with: “S.sub.MCD” expressed in mg of glipizide solubilized per ml of solution of methyl cyclodextrin; “S.sub.H2O” expressed in mg of glipizide solubilized per ml of water.

(31) The results are shown in FIG. 1.

(32) It is observed that the ratio of improvement in solubility is much higher as regards the methyl cyclodextrin MβCD-IN according to the invention compared to the methyl cyclodextrins MβCD-CP1, MβCD-CP2 and MβCD-3, not in accordance with the invention.

(33) It may be deduced that at low MSs, a methyl cyclodextrin having a conductivity less than or equal to 50 μS/cm, such as the methyl cyclodextrin MβCD-IN according to the invention, is a much better solubilizer of lipophilic compounds or compounds bearing lipophilic groups.