Multi-use torasemide composition

Abstract

An aqueous composition including torasemide and at least one organic solvent, to a bottle or container including the composition, and to a kit including the bottle or container and a device for delivery of the composition (for example a syringe). A use of at least one organic solvent for increasing the stability and/or the antimicrobial properties of a composition including torasemide. A method for preparing the composition.

Claims

1. An aqueous composition comprising: torasemide; a buffer or an alkalizing agent; and an organic solvent that is an alcohol derived from propane, wherein a concentration of the organic solvent by weight is greater than or equal to 30% relative to a total weight of the aqueous composition, wherein the aqueous composition is physically, chemically, and antimicrobially stable for at least 24 months when stored at a temperature between 25 and 30° C.

2. The aqueous composition according to claim 1, wherein a concentration of the torasemide by weight is between 0.01% and 5% relative to the total weight of the composition.

3. The aqueous composition according to claim 1, wherein the buffer or alkalizing agent is selected from the group consisting of tromethamine (TRIS), triethanolamine, diethanolamine, monoethanolamine, sodium hydroxide, potassium hydroxide, ammonium hydroxide and meglumine, wherein a concentration of the buffer or of the alkalizing agent by weight is between 1 and 5% relative to the total weight of the aqueous composition.

4. The aqueous composition according to claim 1, further comprising a rheology modifier, selected from the group consisting of synthetic hydrophilic polymers of acrylic acid, polysaccharides, gums, polyvinyl povidone, poloxamers, hydrophilic silica and poly(meth)acrylates, wherein a concentration of rheology modifier by weight is between 0.01 and 10% relative to the total weight of the aqueous composition.

5. The aqueous composition according to claim 1, further comprising a sweetener.

6. The aqueous composition according to claim 1, wherein a viscosity of the aqueous composition is between 0.001 and 5 Pa.Math.s.

7. The aqueous composition according to claim 1, further comprising a pharmaceutically acceptable excipient.

8. The aqueous composition according to claim 1, wherein a pH of the aqueous composition is between 7.5 and 10.

9. A method of treatment, comprising: determining the existence of clinical signs associated with congestive heart failure, treatment of kidney diseases and hypertension are present in a subject; and applying a composition to the subject based on the determining, wherein the composition comprises: torasemide; a buffer or an alkalizing agent; and an organic solvent that is an alcohol derived from propane, wherein a concentration of the organic solvent by weight is greater than or equal to 30% relative to a total weight of the composition, wherein only the torasemide is an active ingredient of the composition that treats the congestive heart failure, treatment of kidney diseases and/or hypertension present in the subject.

10. A method of manufacturing a composition, the method comprising: providing an aqueous composition comprising torasemide; and applying an organic solvent to the aqueous composition, wherein the organic solvent is an alcohol derived from propane, at a concentration by weight greater than or equal to 30%, wherein a composition defined by the aqueous composition and the organic solvent applied to the aqueous composition is physically, chemically, and antimicrobially stable for at least 24 months when stored at a temperature between 25 and 30° C.

11. A method for preparing a composition, comprising: (a) adding a buffer or an alkalizing agent to water at room temperature and stirring to obtain mixture 1, (b) adding torasemide to mixture 1 and stirring to obtain mixture 2, (c) gradually adding a rheology modifier, with stirring, to obtain mixture 3, (d) stirring until a clear solution is obtained, to obtain mixture 4, (e) adding an organic solvent that is an alcohol derived from propane, wherein a concentration of the organic solvent by weight is greater than or equal to 30% relative to a total weight of the composition and stirring until a clear solution is obtained, to obtain mixture 5, wherein mixture 5 is physically, chemically, and antimicrobially stable for at least 24 months when stored at a temperature between 25 and 30° C.

12. A containment system comprising: a container; and a composition comprising: torasemide; a buffer or an alkalizing agent; and an organic solvent that is an alcohol derived from propane, wherein a concentration of the organic solvent by weight is greater than or equal to 30% relative to a total weight of the composition, wherein the composition is physically, chemically, and antimicrobially stable for at least 24 months when stored at a temperature between 25 and 30° C.; wherein the composition is present within the container.

13. A kit-comprising: a containment system comprising: a container; and a composition comprising: torasemide; a buffer or an alkalizing agent; and an organic solvent that is an alcohol derived from propane, wherein a concentration of the organic solvent by weight is greater than or equal to 30% relative to a total weight of the composition, wherein the composition is physically, chemically, and antimicrobially stable for at least 24 months when stored at a temperature between 25 and 30° C.; wherein the composition is present within the container; and a system for administering the composition.

14. The aqueous composition according to claim 1, wherein the alcohol is selected from the group consisting of propylene glycol, glycerol, propane-1,3-diol, propanol, isopropanol and mixtures thereof.

15. The method of treatment according to claim 9, wherein the alcohol is selected from the group consisting of propylene glycol, glycerol, propane-1,3-diol, propanol, isopropanol and mixtures thereof.

16. The method of treatment according to claim 9, wherein the subject is a human.

17. The method of treatment according to claim 9, wherein the subject is an animal.

18. The method according to claim 10, wherein the organic solvent endows the aqueous composition with antimicrobial properties.

19. The method according to claim 10, wherein the alcohol is selected from the group consisting of propylene glycol, glycerol, propane-1,3-diol, propanol, isopropanol and mixtures thereof.

20. The method according to claim 11, wherein the alcohol is selected from the group consisting of propylene glycol, glycerol, propane-1,3-diol, propanol, isopropanol and mixtures thereof.

21. The method according to claim 11, wherein the method is performed under an inert atmosphere.

22. The method according to claim 11, wherein process (d) comprises adding a pharmaceutically acceptable excipient.

23. The method according to claim 11, further comprising adjusting the volume, with stirring.

24. The method according to claim 11, further comprising adjusting the pH.

25. The containment system according to claim 12, wherein the alcohol is selected from the group consisting of propylene glycol, glycerol, propane-1,3-diol, propanol, isopropanol and mixtures thereof.

26. The containment system according to claim 12, wherein the container is a bottle.

27. The kit according to claim 13, wherein the alcohol is selected from the group consisting of propylene glycol, glycerol, propane-1,3-diol, propanol, isopropanol and mixtures thereof.

28. The kit according to claim 13, wherein the container is a bottle.

29. The aqueous composition according to claim 1, wherein only the torasemide is an active ingredient of that composition that treats congestive heart failure, treatment of kidney diseases and/or hypertension present in a subject.

30. The method of treatment according to claim 9, wherein the composition is physically, chemically, and antimicrobially stable for at least 24 months when stored at a temperature between 25 and 30° C.

31. The method of treatment according to claim 30, wherein a pH of the composition is between 7.5 and 10.

32. The method of manufacture according to claim 10, wherein only the torasemide is an active ingredient of that composition that treats congestive heart failure, treatment of kidney diseases and/or hypertension present in a subject.

33. The method of manufacture according to claim 10, wherein a pH of the composition is between 7.5 and 10.

34. The method of preparing a composition according to claim 11, wherein only the torasemide is an active ingredient of mixture 5 that treats congestive heart failure, treatment of kidney diseases and/or hypertension present in a subject.

35. The method of preparing a composition according to claim 11, wherein a pH of mixture 5 is between 7.5 and 10.

36. The containment system according to claim 12, wherein only the torasemide is an active ingredient of that composition that treats congestive heart failure, treatment of kidney diseases and/or hypertension present in a subject.

37. The containment system according to claim 12, wherein a pH of the composition is between 7.5 and 10.

38. The kit according to claim 13, wherein only the torasemide is an active ingredient of that composition that treats congestive heart failure, treatment of kidney diseases and/or hypertension present in a subject.

39. The kit according to claim 13, wherein a pH of the composition is between 7.5 and 10.

Description

BRIEF DESCRIPTION OF THE FIGS.

(1) FIG. 1 shows a solubility curve of torasemide (in mg.Math.ml.sup.−1) as a function of pH.

(2) FIG. 2 shows a cap and a system from administering the composition (syringe).

(3) FIG. 3 shows two examples of kits according to the present invention (left and right) including a bottle provided with a cap and a system for administration (syringe) of the composition and a reducer (center).

EXAMPLES

Example 1

Preparation of a Composition According to the Invention

(4) Preparation of a Mixture 1:

(5) Water and tromethamine (buffer) are introduced at room temperature (18-25° C.) with stirring by means of a deflocculating turbine (speed: 200-600 rpm, duration: about 15 min).

(6) Preparation of a mixture 2:

(7) Torasemide is added to mixture 1, with stirring by means of a deflocculating turbine (speed: 200-600 rpm, duration: about 15 min).

(8) Preparation of a mixture 3:

(9) The polymer is added gradually to mixture 2, with stirring by means of a deflocculating turbine and mechanical stirring (speed: 200-600 rpm, duration: about 15 min).

(10) Preparation of a mixture 4:

(11) The remaining excipients (apart from the organic solvent) are added to mixture 3, maintaining stirring until a clear solution is obtained.

(12) Preparation of a mixture 5:

(13) Then the organic solvent (propylene glycol) is added to mixture 4, maintaining stirring until a clear solution is obtained.

(14) Optionally, the volume is adjusted with water, with magnetic stirring, for a minimum time of 15 min.

(15) Optionally, the pH is adjusted to the desired value.

(16) The composition is obtained in the form of a colorless liquid of low viscosity.

(17) The compositions in Table 1 below are prepared according to the above protocol, with the amounts indicated in the table.

(18) TABLE-US-00001 TABLE 1 compositions, comparative example and according to the invention. Composition No. Comparative 1 Composition 1 Composition 2 Torasemide 0.30% 0.20% 0.20% Tromethamine 1.50% 1.50% (TRIS) Meglumine 1.00% PEG 400 10.00% Propylene glycol 40.00% 40.00% Carbopol 971P 0.20% Natrosol 250G 1.00% Pharm Saccharin sodium 0.20% Hydrochloric acid Q.S. pH 8.0-10 Q.S. pH 9.3-9.7 Q.S. pH 9.3-9.7 WFI Q.S. 100% Q.S. 100% Q.S. 100% Q.S. = quantity sufficient for. WFI = water for injection.

Example 2

Optimized Stability of the Compositions According to the Invention

(19) The stability of compositions 1 and 2 was evaluated in accelerated harsh storage conditions: at a temperature of 40° C., at a relative humidity of 75% and for a time T=2 months.

(20) For each of the compositions tested, the level of impurities is measured by the method corresponding to the active ingredient, described in the monographs of the European or American Pharmacopeia.

(21) The results are presented in Table 2 below:

(22) TABLE-US-00002 TABLE 2 stability tests of compositions 1 and 2. Composition No. Comparative 1 Composition 1 Composition 2 Macroscopic turbid clear clear appearance Torasemide content 100.30 99.10 100.00 (per dose, 95-105%) Each unknown 0.31 0.02 0.01 impurity (≤0.3%) Total unknown 0.41 0.07 0.04 impurities (≤1.0%)

(23) “Unknown impurity” means the impurities, degradation products and chemical impurities classified as “B” and “A” in the European Pharmacopeia and “A” and “E” in the American Pharmacopeia (USP). The results obtained demonstrate that the compositions according to the invention are more stable than the compositions of the prior art. The compositions according to the invention thus meet the criteria required by the American and European pharmacopeias in terms of stability.

Example 3

Antimicrobial Properties of the Compositions According to the Invention

(24) Antimicrobial efficacy was evaluated according to the European monograph.

(25) The following compositions (A to I according to the invention and CE1 to CE7 counter-examples) were prepared according to the procedure of example 1.

(26) TABLE-US-00003 TABLE 3 Efficacy of antimicrobial storage of different batches with 0.2% of carbomer and with different amounts of propylene glycol. Percentage composition (in % w/w) CE1 CE2 A Ingredients (0% PG) (20% PG) (40% PG) Torasemide 0.20 0.20 0.20 Tromethamine 1.50 1.50 1.50 Carbomer 0.20 0.20 0.20 Propylene glycol 0.00 20.00 40.00 Purified water 98.10 78.10 58.10 q.s. w/w Total (% w/w) 100.00 100.00 100.00 Efficacy of NC NC C antimicrobial storage (Ph Eur) S. aureus C C C E. coli C C C Ps. aeruginosa C C C C. albicans C C C A. brasiliensis NC NC C NC = not compliant, C = compliant.

(27) TABLE-US-00004 TABLE 4 Efficacy of antimicrobial storage of different batches with 1% of HEC and with different amounts of propylene glycol. Percentage composition (in % w/w) CE3 CE4 B Ingredients (0% PG) (20% PG) (40% PG) Torasemide 0.20 0.20 0.20 Tromethamine 1.50 1.50 1.50 Hydroxyethylcellulose 1.00 1.00 1.00 Propylene glycol 0.00 20.00 40.00 Purified water 97.30 77.30 57.30 q.s. w/w Total (% w/w) 100.00 100.00 100.00 Efficacy of NC NC C antimicrobial storage (Ph Eur) S. aureus NC C C E. coli C C C Ps. aeruginosa C NC C C. albicans NC C C A. brasiliensis NC NC C NC = not compliant, C = compliant.

(28) TABLE-US-00005 TABLE 5 Efficacy of antimicrobial storage of different batches with 0.3% of xanthan gum and with different amounts of propylene glycol. Percentage composition (in % w/w) C D Ingredients CE5 (35% PG) (45% PG) Torasemide 0.20 0.20 0.20 Tromethamine 1.50 1.50 1.50 Xanthan gum 0.30 0.30 0.30 Propylene glycol 0.00 35.00 45.00 Purified water 98.00 63.00 53.00 q.s. w/w Total (% w/w) 100.00 100.00 100.00 Efficacy of NC C C antimicrobial storage (Ph Eur) S. aureus NC C C E. coli C C C Ps. aeruginosa NC C C C. albicans NC C C A. brasiliensis NC C C Efficacy of NC C C antimicrobial storage (USP) S. aureus C C C E. coli C C C Ps. aeruginosa NC C C C. albicans C C C A. brasiliensis C C C NC = not compliant, C = compliant.

(29) TABLE-US-00006 TABLE 6 Evaluation of the antimicrobial efficacy of propylene glycol as a function of its content with 0.15% of Carbopol 971P. They differ from one another in the content of propylene glycol: 0, 30, 45 and 60% w/w. Percentage composition (in % w/w) Ingredients CE6 E F G Torasemide 0.20 0.20 0.20 0.20 Tromethamine 1.50 1.50 1.50 1.50 Propylene / 30.00 45.00 60.00 glycol Carbopol 971P 0.15 0.15 0.15 0.15 Purified water q.s. 100.00 q.s. 100.00 q.s. 100.00 q.s. 100.00 q.s. w/w Efficacy of NC C C C antimicrobial storage (PhEur) S. aureus C C C C E. coli C C C C Ps. aeruginosa C C C C C. albicans C C C C A. brasiliensis NC C C C NC = not compliant, C = compliant.

(30) TABLE-US-00007 TABLE 7 Evaluation of the antimicrobial efficacy of propylene glycol as a function of its content with 0.15% of xanthan gum. They differ from one another in the content of propylene glycol: 0, 45 and 60% w/w. Percentage composition (in % w/w) Ingredients CE7 H I Torasemide 0.20 0.20 0.20 Tromethamine 1.50 1.50 1.50 Propylene glycol / 45.00 60.00 Xanthan gum 0.20 0.20 0.20 Purified water q.s. 100.00 q.s. 100.00 q.s. 100.00 q.s. w/w Efficacy of NC C C antimicrobial storage (Ph Eur) S. aureus NC C C E. coli C C C Ps. aeruginosa NC C C C. albicans NC C C A. brasiliensis NC C C NC = not compliant, C = compliant.

(31) The compositions including a content grey ha or equal to 30% of propylene glycol gave an antimicrobial preservation efficacy meeting the European Pharmacopeia, the pharmacopeia having the strictest criteria (narrower ranges of tolerance) terms of antimicrobial preservation efficacy, in contrast to the compositions including less than 30% of organic solvent (i.e. propylene glycol).

Example 4

Comparison of Stability of Compositions Including Furosemide or Torasemide

(32) Compositions CE-A to CE-F are prepared according to the following procedure: 1) add ethanol to propylene glycol and homogenize; 2) add citrate buffer to the mixture obtained in step 1; 3) add the active ingredient (furosemide or torasemide) to the mixture obtained in step 2; 4) add HPC (hydroxypropylcellulose) to the mixture obtained in step 3.

(33) Compositions CE-A to CE-F all have a pH between 6.0 and 6.6.

(34) TABLE-US-00008 TABLE 7 Composition and appearance of compositions CE-A to CE-F. CE-A CE-B CE-C CE-D CE-E CE-F Formula (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) (% w/w) Furosemide 0.125 Torasemide 0.200 0.200 1.000 3.000 3.000 Propylene 48.438 48.363 60.000 48.363 24.313 48.363 glycol Absolute 38.750 20.000 20.000 38.750 60.000 38.750 ethanol HPC 3.000 3.000 3.000 3.000 3.000 3.000 Citrate 9.688 28.438 16.800 8.888 9.688 6.888 buffer TOTAL 100.001 100.000 100.000 100.001 100.001 100.001 Appearance L S P S S S L = clear solution, S = suspension, P = particles.

(35) These results show that furosemide and torasemide are not simply interchangeable.