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EP-4739290-A1 - LYOPHILIZED METOLAZONE FORMULATION FOR PARENTERAL ADMINISTRATION

EP4739290A1EP 4739290 A1EP4739290 A1EP 4739290A1EP-4739290-A1

Abstract

The invention relates to a novel metolazone lyophilizate composition and a pharmaceutically acceptable diluent that can be used to reconstitute the metolazone lyophilizate to provide a clear solution suitable for parenteral administration. The invention also relates to a novel metolazone pre-lyophilizate composition as well as uses of the reconstituted metolazone lyophilizate.

Inventors

  • PATIL, ATUL

Assignees

  • Hyloris Developments SA

Dates

Publication Date
20260513
Application Date
20240724

Claims (20)

  1. 1. A metolazone lyophilizate kit, comprising: a. a first container, comprising: a metolazone lyophilizate composition in the form of a lyophilized powder, comprising: i. metolazone; and, b. a second container, comprising: a pharmaceutically acceptable diluent, wherein the diluent is suitable to reconstitute the lyophilizate composition into a drug product having a pH of about 5.0-8.0 for parenteral administration.
  2. 2. The metolazone lyophilizate kit according to Claim 1 wherein the metolazone lyophilizate composition in the form of a lyophilized powder comprises a bulking agent.
  3. 3. The metolazone lyophilizate kit according to Claim 2 wherein the bulking agent is selected from mannitol, lactose, dextrose, sucrose and hydroxypropyl-P-cyclodextrin; preferably wherein the bulking agent is mannitol.
  4. 4. The metolazone lyophilizate kit according to any of the preceding claims wherein the pharmaceutically acceptable diluent comprises water.
  5. 5. The metolazone lyophilizate kit according to any of the preceding claims wherein the pharmaceutically acceptable diluent comprises a solubilizer.
  6. 6. The metolazone lyophilizate kit according to any of the preceding claims wherein the pharmaceutically acceptable diluent comprises a buffer.
  7. 7. The metolazone lyophilizate kit according to any of the preceding claims wherein the volume of the diluent is 5-20 mL.
  8. 8. The metolazone lyophilizate kit according to any of the preceding claims, wherein the metolazone lyophilizate composition contains between 0.2-1.75 mg of tertiary butyl alcohol.
  9. 9. The metolazone lyophilizate kit according to any of the preceding claims, further comprising a connect for holding the first and second containers.
  10. 10. The metolazone lyophilizate kit according to any of the preceding claims, wherein the diluent, further comprises: 2-4% w/v macrogol- 15 -hydroxy stearate.
  11. 11. The metolazone lyophilizate kit according to any of the preceding claims, wherein the metolazone lyophilizate composition, comprises: i. 2.5-20 mg metolazone; and, ii. 2.5-1000 mg of mannitol; and, the diluent, comprises: i. 25-45% w/v polyethylene glycol 400; ii. TRIS buffer or phosphate buffer; and, iii. the remainder, water; wherein the pH of the diluent is 7-8.
  12. 12. The metolazone lyophilizate kit according to Claim 11 , wherein the metolazone lyophilizate composition, comprises: i. 2.5-10 mg metolazone; and, ii. 25-500 mg of mannitol; and, the diluent, comprises: i. 30-40% w/v polyethylene glycol 400; ii. TRIS buffer or phosphate buffer; and, iii. the remainder, water; wherein the pH of the diluent is 7.5.
  13. 13. A process for reconstituting a metolazone lyophilizate composition, the process comprising: providing a metolazone lyophilizate composition in the form of a lyophilized powder comprising metolazone, contacting the metolazone lyophilizate composition and a pharmaceutically acceptable diluent; and, mixing the resulting solution until clear; wherein the resulting clear solution is suitable for parenteral administration and wherein the diluent is suitable to reconstitute the lyophilizate composition into a drug product having a pH of about 5.0-8.0 for parenteral administration.
  14. 14. The process of Claim 13, wherein a clear solution is obtained in less than 5 minutes.
  15. 15. A clear reconstituted metolazone solution for use in a natriuretic and/or diuretic treatment of a patient in need thereof, comprising: providing a metolazone lyophilizate composition in the form of a lyophilized powder comprising metolazone, contacting the metolazone lyophilizate composition and a pharmaceutically acceptable diluent; wherein the diluent is suitable to reconstitute the lyophilizate composition into a drug product having a pH of about 5.0-8.0 for parenteral administration mixing the resulting solution until a clear, reconstituted metolazone solution is obtained; administering to the patient in need of the natriuretic and/or diuretic treatment a therapeutically effective amount of the clear, reconstituted metolazone solution.
  16. 16. A clear reconstituted metolazone solution for use in the treatment of furosemide resistance in a patient in need thereof, comprising: providing a metolazone lyophilizate composition in the form of a lyophilized powder comprising metolazone, contacting the metolazone lyophilizate composition and a pharmaceutically acceptable diluent; wherein the diluent is suitable to reconstitute the lyophilizate composition into a drug product having a pH of about 5.0-8.0 for parenteral administration mixing the resulting solution until a clear, reconstituted metolazone solution is obtained; administering to the patient in need of furosemide resistance treatment a therapeutically effective amount of the clear, reconstituted metolazone solution.
  17. 17. A liquid, metolazone pre-lyophilizate composition, comprising: a. metolazone; b. a bulking agent; c. an alcohol; and, d. water; wherein the liquid, metolazone pre-lyophilizate composition forms a lyophilized powder after being subjected to lyophilization.
  18. 18. The metolazone pre-lyophilizate composition of Claim 17, wherein the alcohol is tertiary butyl alcohol.
  19. 19. The metolazone pre-lyophilizate composition of Claim 17 or 18, wherein the bulking agent is selected from mannitol, lactose, dextrose, sucrose and hydroxypropyl-P-cyclodextrin.
  20. 20. The metolazone pre-lyophilizate composition of Claim 17, 18 or 19, comprising: a. 0.1-2 mg/ml metolazone; b. 1-50 mg/mL mannitol; c. 30-70% v/v tertiary butyl alcohol; and, d. the remainder, water.

Description

LYOPHILIZED METOLAZONE FORMULATION FOR PARENTERAL ADMINISTRATION TECHNICAL FIELD [0001] The present invention is situated in the field of pharmaceutical compositions and medical uses of pharmaceutical compositions. The present invention also relates to the manufacturing of pharmaceutical compositions. The active ingredient concerned is metolazone. The invention is advantageous as it provides a stable metolazone formulation suitable for parenteral administration where hereto only metolazone tablets are commercially available. The invention has for an effect that patients with a metolazone-responsive disease can be treated effectively even if unconscious or even if having problems swallowing. BACKGROUND OF THE INVENTION [0002] Metolazone is a well-known active ingredient and is commercially available in the form of 2,5 mg, 5 mg, and 10 mg tablets. Its chemical name is 7-chloro-l,2,3,4-tetrahydro-2-methyl-3-(2- methylphenyl)-4-oxo-6- quinazoline sulfonamide (formula I, below). It is poorly soluble in water 2,4 x 10-5 g/mL at 25 °C and in ethanol 9 x 10'3 g/mL at 25°C. [0003] Metolazone is a quinazoline diuretic used to reduce the swelling and fluid retention caused by congestive heart failure or chronic kidney disease. Metolazone is used to alleviate salt and water retention, called edema. Metolazone is used in congestive heart failure and to treat hypertension. [0004] There is no injectable form of metolazone commercially available mainly due to its extremely low solubility and instability in solution (e.g., it degrades in solution making long-term storage difficult, if not impossible). Because there is no injectable form of metolazone available, there is an unmet medical need for patients who cannot take metolazone orally or where administration or titration of the metolazone dose is critical to achieve maximum effect or where a fast onset of action is required. [0005] U.S. Patent No. 5,124,152 describes parenteral formulations of metolazone including an aqueous solution comprising 0,1-8 mg/mL metolazone, 5-15% w/v of 95% ethanol, 0-3% v/v benzyl alcohol, and a cosolvent selected from 30-65 w/v propylene glycol, 25-50% v/v polyethylene glycol 300 or 25-50% v/v polyethylene glycol 400. It has now been found that the use of any of these cosolvents leads to degradation products on storage. Thus, these formulations lack long-term stability. [0006] The liquid metolazone formulations mentioned in U.S. Patent No. 5,124,152 were proposed as an alternative to a lyophilized solid prepared from the sodium salt of metolazone and sodium hydroxide, which on reconstitution with water provided a pH of about 11. This is too high for administration to a patient. [0007] In U.S. Patent Nos. 5,633,240, 5,684,009, and 5,814,623, liquid metolazone formulations for parenteral administration were proposed using an aqueous buffer system of pH 10,5 to 12,5, which is not suitable for administration to a patient. Also, these solutions were found to lack long-term stability. [0008] In U.S. Patent No. 6,048,874, a method for making a pharmaceutical metolazone composition was described, comprising providing a solvent comprising a) propylene glycol, polyethylene glycol, polypropylene glycol, or glycerin; b) adding metolazone to the solvent, and c) heating the solvent and metolazone mixture. The method provided a metolazone concentration of 9 mg/mL, which is above the apparent equilibrium solubility. It is expected that these formulations would lack long-term stability. [0009] In U.S. Patent Nos. 7,923,447 and 9,427,398, dimethylacetamide is proposed as a solvent in parenteral metolazone formulations. This solvent is however considered to be a developmental toxicant (see OECD SIDS N,N-dimethylacetamide DMAC, 2001). [0010] In U.S. Patent Publication No. 2018/0296556, non-aqueous, homogeneous metolazone solutions comprising a solubilized lipophilic agent and an amphiphilic liquid polymeric solvent were described. The formulations were essentially free of non-polymeric organic solvents, water, and non-solubilized particles, and the solubilized lipophilic pharmaceutical agent had a concentration of at least about 0.5 mg/mL, and further wherein the solution remains stable and essentially free of non-solubilized particles for at least 40 days when stored at room temperature of 25°C. However, this system too did not provide long-term stability as required in the pharmaceutical supply chain. [0011] In view of the above, there remains a need in the art for metolazone formulations that can be used for parenteral administration and have adequate long-term storage stability for use in the pharmaceutical supply chain. [0012] The objective of the present invention is to solve at least one or more of the problems as described above. In particular, the invention aims to provide a metolazone formulation with longterm storage stability. SUMMARY OF THE INVENTION [0013] In an aspect, there are described novel metolazone lyophilizate compositions, comprising