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EP-4741010-A2 - CLEMIZOLE FORMULATION

EP4741010A2EP 4741010 A2EP4741010 A2EP 4741010A2EP-4741010-A2

Abstract

A liquid pharmaceutical composition for the treatment of an epilepsy disorder comprising clemizole HCl, a solvent, a preservative, and glycerol. The preservative and the clemizole HCl are stable during storage. The preservative comprises at least one of methyl parahydroxybenzoate, or ethyl parahydroxybenzoate. The solvent is a citrate buffer and the liquid pharmaceutical composition has a pH of 4 to 5. A method of preparing the liquid pharmaceutical composition by dissolving the clemizole HCl, the preservative, and the excipients in at least one of the solvent, a solubilizer, or a combined solvent-solubilizer solution. The method further comprises adding glycerol and adjusting the pH to 4 to 5. A method of treating a subject having an epilepsy disorder comprising administering the liquid pharmaceutical composition.

Inventors

  • LEE, HAHN-JUN

Assignees

  • Epygenix Therapeutics, Inc.

Dates

Publication Date
20260513
Application Date
20220613

Claims (15)

  1. A liquid pharmaceutical composition for use in the treatment of an epilepsy disorder in a subject, wherein the liquid pharmaceutical composition comprises: clemizole hydrochloride (HCl); citrate buffer; a preservative, wherein the preservative is methyl parahydroxybenzoate and/or ethyl parahydroxybenzoate; super-refined PEG400; sucralose; and glycerol, wherein the pH of the liquid pharmaceutical composition ranges from 4 to 5.
  2. The liquid pharmaceutical composition for use of claim 1, wherein the concentration of glycerol is 10 - 30% (wt/wt) and the concentration of the citrate buffer is 90 - 70% (wt/wt).
  3. The liquid pharmaceutical composition for use of claim 1 or 2, wherein the preservative is at a concentration of 0.01 - 0.05% (w/v).
  4. The liquid pharmaceutical composition for use of any one of claims 1-3, wherein the preservative comprises 0.2% (w/v) methyl parahydroxybenzoate and 0.02% (w/v) ethyl parahydroxybenzoate.
  5. The liquid pharmaceutical composition for use of any one of claims 1-4, wherein the liquid pharmaceutical composition further comprises a taste modifier.
  6. The liquid pharmaceutical composition for use of any one of claims 1-5, wherein the clemizole HCl is at a concentration of 1 mg/mL - 30 mg/mL.
  7. The liquid pharmaceutical composition for use of any one of claims 1-6, wherein the clemizole HCl is at a concentration of 5 mg/mL, 10 mg/mL, 15 mg/mL, or 16 mg/mL.
  8. The liquid pharmaceutical composition for use of any one of claims 1-7, wherein the epilepsy disorder is a pediatric epilepsy disorder, Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasm, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pyknolepsy), febrile seizures, progressive myoclonus epilepsy of Lafora, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Generalized Epilepsy with Febrile Seizures (GEFS+), Severe Myoclonic Epilepsy of Infancy (SMEI), Benign Neonatal Familial Conversions (BNFC), West Syndrome, Ohtahara Syndrome, early myoclonic encephalopathies, migration partial epilepsy, infantile epileptic encephalopathies, Tuberous Sclerosis Complex (TSC), focal cortical dysplasia, Type I Lissencephaly, Miller-Dieker Syndrome, Angelman's syndrome, Fragile X syndrome, epilepsy in autism spectrum disorder, subcortical band heterotopia, Walker-Warburg syndrome, Alzheimer's disease, posttraumatic epilepsy, progressive myoclonus epilepsies, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus catamenial epilepsy, Jaksonian seizure disorder, Unverricht-Lundborg disease, or photosensitive epilepsy.
  9. The liquid pharmaceutical composition for use of any one of claims 1-8, wherein the epilepsy disorder is Dravet syndrome.
  10. The liquid pharmaceutical composition for use of any one of claims 1-8, wherein the epilepsy disorder is Lennox-Gastaut syndrome.
  11. The liquid pharmaceutical composition for use of any one of claims 1-10, wherein the liquid pharmaceutical composition is administered to the subject by an oral route of administration.
  12. The liquid pharmaceutical composition for use of any one of claims 1-11, wherein the dose of clemizole HCl used to treat the subject is about 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 12.5 mg/kg, or 15 mg/kg.
  13. The liquid pharmaceutical composition for use of any one of claims 1-12, wherein the liquid pharmaceutical composition is administered at least every 24 hours.
  14. The liquid pharmaceutical composition for use of any one of claims 1-13, wherein the liquid pharmaceutical composition comprises clemizole HCl (0.5 w/v%), methyl parahydroxybenzoate (0.2 w/v%), ethyl parahydroxybenzoate (0.02 w/v%), super-refined PEG400 (5 w/v%), glycerol (20 w/v%), cherry flavor powder (0.3 w/v%), sucralose (0.2 w/v%), and pH 4.5 citrate buffer (q.s.).
  15. The liquid pharmaceutical composition for use of any one of claims 1-13, wherein the liquid pharmaceutical composition comprises (a) clemizole HCl (0.474 w/v%), methyl parahydroxybenzoate (0.19 w/v%), ethyl parahydroxybenzoate (0.02 w/v%), super-refined PEG400 (4.73 w/v%), glycerol (18.94 w/v%), cherry flavor powder (0.28 w/v%), sucralose (0.19 w/v%), and pH 4.5 citrate buffer (q.s.); (b) clemizole HCl (0.948 w/v%), methyl parahydroxybenzoate (0.19 w/v%), ethyl parahydroxybenzoate (0.02 w/v%), super-refined PEG400 (4.73 w/v%), glycerol (18.94 w/v%), cherry flavor powder (0.28 w/v%), sucralose (0.19 w/v%), and pH 4.5 citrate buffer (q.s.); or (c) clemizole HCl (1.897 w/v%), methyl parahydroxybenzoate (0.19 w/v%), ethyl parahydroxybenzoate (0.02 w/v%), super-refined PEG400 (4.73 w/v%), glycerol (18.94 w/v%), cherry flavor powder (0.28 w/v%), sucralose (0.19 w/v%), and pH 4.5 citrate buffer (q.s.).

Description

FIELD OF INVENTION The disclosure herein relates to providing an oral formulation of clemizole HCl that is soluble and stable over time, and the methods for preparing such oral clemizole HCl formulations. BACKGROUND Clemizole HCl is the hydrochloride salt form of clemizole, a first-generation histamine receptor (H1) antagonist, a class of drugs that has been shown to have anti-allergic activities. But clemizole also acts as an anti-epileptic agent, inhibiting behavioral and electrographic seizure activity. This anti-seizure-like activity is thought to be regulated in part by clemizole's role in modulating serotonin (5-HT) receptor signaling. Serotonin (5-HT) receptor signaling has also been shown to play a role in anti-seizure activity, including Dravet syndrome, which is a severe childhood epilepsy syndrome with early onset seizures, severe cognitive defects, delayed language, and delayed motor development. Attenuation of seizure activity can be obtained with certain treatments, but a common widespread, effective treatment is still needed. SUMMARY In an aspect, the invention relates to a liquid pharmaceutical formulation comprising, consisting essentially of, or consisting of clemizole HCl, a solvent, a preservative, glycerol, a flavoring agent, a sweetener, and a solubilizer. In an aspect, the clemizole HCl formulation is stable and retains its solubility over at least certain prescribed time periods. The clemizole HCl has a solubility of 1 mg/ml - 30 mg/ml in solution. In an aspect, the invention relates to a liquid pharmaceutical formulation having a pH value of 4.5, comprising, consisting essentially of, or consisting of clemizole HCl, a pH 4.5 citrate buffer, glycerol, a sweetener, a flavoring agent, a solubilizer (polyethylene glycol (PEG)-400), and a preservative (methyl parahydroxybenzoate and ethyl parahydroxybenzoate). In an aspect, the clemizole HCl and the preservative are stable for up to 36 months. In an aspect, the invention relates to a method for generating a clemizole HCl liquid pharmaceutical formulation, comprising, consisting essentially of, or consisting of dissolving at least one preservative in a solution comprising at least one of a solvent, a solubilizer, or a combined solvent-solubilizer solution; dissolving clemizole HCl in a solution comprising at least one of the solvent, the solubilizer, or the combined solvent-solubilizer solution; dissolving a plurality of excipients in a solution comprising at least one of a solvent, a solubilizer, or a combined solvent-solubilizer solution; adding glycerol; and adjusting the pH, such that the final concentration of clemizole HCl in the liquid pharmaceutical composition ranges from 1 mg/ml - 30 mg/ml and the formulation is soluble and stable over time. In an aspect, the clemizole HCl and the preservative are stable for up to 36 months. In an aspect, the invention relates to a method for generating a clemizole HCl liquid pharmaceutical formulation, comprising, consisting essentially of, or consisting of dispensing PEG400 into a beaker, adding ethyl parahydroxybenzoate, adding methyl parahydroxybenzoate (ensuring that the first preservative is fully dissolved before adding the second preservative), adding pH 4.5 citrate buffer to a second beaker, adding clemizole HCl to the second beaker containing the buffer and mixing until fully dissolved, adding the solubilizer containing preservatives to the second beaker containing buffer and clemizole HCl while stirring, adding sweetener, adding a flavoring following full dissolution of the sweetener, adding glycerol and ensuring the mixture is homogeneous, measuring the pH and adjusting the pH to 4.5 +/- 0.5, and bringing to volume. In an aspect, the invention relates to a method of treating a subject having an epilepsy disorder, comprising administering a liquid pharmaceutical formulation comprising clemizole HCl. In an aspect, the formulation has a concentration range of clemizole HCl of 1 mg/ml - 30 mg/ml. In an aspect, the clemizole HCl liquid pharmaceutical formulation is prepared by a method comprising, consisting essentially of, or consisting of dissolving at least one preservative in a solution comprising at least one of a solvent, a solubilizer, or a combined solvent-solubilizer solution; dissolving clemizole HCl in a solution comprising at least one of the solvent, the solubilizer, or the combined solvent-solubilizer solution; dissolving a plurality of excipients in a solution comprising at least one of a solvent, a solubilizer, or a combined solvent-solubilizer solution; adding glycerol; and adjusting the pH. In an aspect, the epilepsy disorder may be Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasm, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pyknolepsy), febrile seizures, progressive myoclonus epilepsy of Lafora, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, Generalized Epilepsy with Febrile Seizure