LIQUID ORAL FORMULATION OF BUMETANIDE

Abstract

The invention relates to a liquid oral formulation of bumetanide for the treatment of autism, more particularly for the improvement of the Autism Spectrum Disorder (ASD) core symptoms, tuberous sclerosis complex, fragile X syndrome, Rett syndrome, Down syndrome, cancer and particularly gliomas, spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts, various types of epilepsies, and also acute lung injury such as pneumonias or Severe Acute Respiratory Disease due to Coronavirus-2 (SARS-CoV-2). Said formulation is especially designed for paediatric populations. The invention relates also to a posology for the administration of said liquid oral formulation.

Claims

1. A liquid oral formulation for use in the treatment of a patient in need thereof consisting of: an amount of 0.5 mg/ml of bumetanide; an effective amount of an antimicrobial preservative or a combination of antimicrobial preservatives; a buffering agent or a combination of buffering agents; a sweetening agent; and water.

2. The formulation of claim 1 wherein the antimicrobial preservative is selected from sodium benzoate, sorbate, salt of edetate, benzaldionium chloride and paraben, salts thereof or a combination thereof.

3. The formulation of claim 1, wherein the antimicrobial preservative is selected from alkyl paraben salts, and preferably a combination of alkyl paraben salts.

4. The formulation of claim 3 wherein the combination of antimicrobial preservative compounds consists in sodium methyl paraben combined with sodium propyl paraben.

5. The formulation of claim 1, wherein the buffering agent is selected from carbonates, citrates, gluconates, lactates, phosphates or tartrates, or a combination thereof.

6. The formulation of claim 5, wherein the buffering agent is a combination of sodium dihydrogen phosphate dihydrate and disodium phosphate.

7. The formulation of claim 1, wherein the sweetening agent is selected from sucrose, fructose, dextrose, xylitol, maltitol, sorbitol, mannitol, erythritol, sucralose, aspartame, acesulfame potassium, saccharin, sodium saccharin, neotame or any derivative thereof.

8. The formulation of claim 7, wherein the sweetening agent is selected from sucralose, aspartame, acesulfame potassium, saccharin, sodium saccharin and neotame.

9. The formulation according to claim 7, wherein the sweetening agent is acesulfame potassium.

10. The formulation according to claim 1, wherein its pH is 6.5.

11. The formulation according to claim 1 for use twice a day in the treatment of a pathology or condition selected from autism, Fragile X syndrome, tuberous sclerosis complex, Rett syndrome, Down syndrome, cancer and particularly gliomas, spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts and various types of epilepsies and also acute lung injury such as pneumonia or Severe Acute Respiratory Disease due to Coronavirus-2 (SARS-CoV-2), and more preferably in the treatment of autism and particularly for the improvement of autism spectrum disorder (ASD) core symptoms.

12. The formulation of claim 11 wherein the patient is a child.

13. A method for the treatment of a paediatric population in need thereof comprising the administration of a liquid oral formulation consisting of: an amount of 0.5 mg/ml of bumetanide; an effective amount of an antimicrobial preservative or a combination of antimicrobial preservatives; a buffering agent or a combination of buffering agents; a sweetening agent; and water; twice a day.

14. The method of treatment of claim 13 wherein the paediatric population in need thereof is a population with a pathology or condition selected from autism and particularly autism spectrum disorder (ASD) core symptoms, Fragile X syndrome, tuberous sclerosis complex, Rett syndrome, Down syndrome, cancer and particularly gliomas, spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts and various types of epilepsies and also acute lung injury such as pneumonia or Severe Acute Respiratory Disease due to Coronavirus-2 (SARS-CoV-2).

15. The method of treatment of claim 13 wherein the pathology or condition is autism.

Description

EXAMPLE

Impact of Sorbitol on the Stability of the Oral Bumetanide Solution

[0063] The composition of the oral solution used at the beginning of the development is described in the table below:

TABLE-US-00002 TABLE 2 Component Centesimal formula (g/100 mL) Bumetanide 0.05 Sodium Methyl Paraben 0.18 Sodium Propyl Paraben 0.02 NaH.sub.2PO.sub.4 2H.sub.2O 0.738 Na.sub.2HPO.sub.4 0.22 Acesulfame Potassium 0.09 Sorbitol 70% 10.00 Water for injection Qs 100 mL

[0064] During stability studies, the following modifications were observed: coloring of the solution and apparition of degradation compounds

[0065] A study has been performed to explain these observations.

[0066] To assess the situation, three solutions were prepared: [0067] solution A corresponding to the solution described in the table above, [0068] solution B corresponding to solution A without acesulfame and without sorbitol, and [0069] solution C corresponding to solution A without sorbitol.

[0070] The detailed composition of he three solutions is described in he table 3 below.

TABLE-US-00003 TABLE 3 Composition of the Solution Solution Solution 3 solutions (g/100 mL) A B C Bumetanide 0.05 0.05 0.05 Sodium Methyl Paraben 0.18 0.18 0.18 Sodium Propyl Paraben 0.02 0.02 0.02 NaH.sub.2PO.sub.4 2H.sub.2O 0.738 0.738 0.738 Na.sub.2HPO.sub.4 0.22 0.22 0.22 Acesulfame Potassium 0.09 — 0.09 Sorbitol 70% 10.00 — — Water for injection Qs 100 mL Qs 100 mL Qs 100 mL

[0071] The solutions have been stored in closed bottles at 55° C.-60° C. for 1 month.

[0072] After 1 month the coloring and the degradation compounds have been checked.

[0073] The color of the solution has been checked according to the European Pharmacopoeia method (Ph.Eur 2.2.2), The degradation compounds have been quantified by HPLC.

Results

[0074] The results are described in the table 4 below:

TABLE-US-00004 TABLE 4 Solution A Solution B Solution C 1 month 1 month 1 month T0 at 55-60 T0 at 55-60 T0 at 55-60 Coloration <B9 <B3 <B9 <B9 <B9 <B9 Yellow brown solution Total Degradation — 1.01% — ND .sup.(*.sup.) — ND .sup.(*.sup.) compounds .sup.(*.sup.) ND = No degradation compound detected (limit of detection = 0.02%)

[0075] The presence of sorbitol is clearly responsible for the stability issues observed with formulation used at the beginning of the development.

[0076] As a conclusion the withdrawal of the sorbitol is mandatory for the stability of the oral liquid formulation according to the invention.