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EP-4376808-B1 - CLEMIZOLE FORMULATION

EP4376808B1EP 4376808 B1EP4376808 B1EP 4376808B1EP-4376808-B1

Inventors

  • LEE, HAHN-JUN

Dates

Publication Date
20260506
Application Date
20220613

Claims (16)

  1. A liquid pharmaceutical composition comprising clemizole HCl; a solvent; a preservative; and glycerol, wherein the preservative comprises potassium sorbate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, methyl parahydroxybenzoate, or ethyl parahydroxybenzoate, wherein the solvent comprises a citrate buffer, and wherein the pH of the liquid pharmaceutical composition ranges from 4 to 5.
  2. The liquid pharmaceutical composition of claim 1, wherein the glycerol is at a concentration of 10 - 30% (wt/wt) and the citrate buffer is at a concentration of 90 - 70% (wt/wt).
  3. The liquid pharmaceutical composition of claim 1, wherein the glycerol concentration is 20% (wt/wt), and the citrate buffer concentration is 80% (wt/wt).
  4. The liquid pharmaceutical composition of any one of the preceding claims, wherein the preservative comprises methyl parahydroxybenzoate, potassium sorbate, or ethyl parahydroxybenzoate.
  5. The liquid pharmaceutical composition of any one of the preceding claims, further comprising a solubilizer, optionally wherein the solubilizer is tocopherol polyethylene glycol succinate (TPGS) or super-refined PEG400.
  6. The liquid pharmaceutical composition of any of the preceding claims, further comprising a sweetener and a taste modifier.
  7. The liquid pharmaceutical composition of any of the preceding claims, further comprising an anti-oxidant or a component with anti-oxidant properties.
  8. The liquid pharmaceutical composition of any of the preceding claims , wherein the clemizole HCl is at a concentration of 1 mg/mL - 30 mg/mL, preferably 5 mg/mL, in the pharmaceutical composition.
  9. The liquid pharmaceutical composition of any one of the preceding claims, wherein following up to 36 months of storage at least any one or more of the following occurs: - there is no substantial increase in clemizole HCl metabolites or related degradation products, - an amount of the preservative is maintained at substantially 97% or greater of the original amount of the preservative, - there is no substantial change in pH of the pharmaceutical composition, or - there is no substantial change in color of the pharmaceutical composition, wherein the storage occurs at a temperature of 2 - 8 °C, 25°C, or 40°C.
  10. The liquid pharmaceutical composition of any of the preceding claims, further comprising an anti-epileptic drug.
  11. A method of preparing a liquid pharmaceutical composition for treating an epilepsy disorder, comprising: dissolving at least one of a preservative, clemizole HCl, a plurality of excipients, and glycerol in a solution comprising at least one of a solvent or a solubilizer to form the liquid pharmaceutical composition, wherein the solvent is a citrate buffer, the clemizole HCl is at a concentration from 1 mg/mL to 30 mg/mL in the liquid pharmaceutical composition, and the at least one preservative comprises at least one of potassium sorbate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, methyl parahydroxybenzoate, or ethyl parahydroxybenzoate, wherein the method further comprises adding the solvent when the dissolving is in the solubilizer or adding the solubilizer when the dissolving occurs in the solvent, and adjusting the pH of the liquid pharmaceutical composition to pH 4.5 (+/- 0.5).
  12. The liquid pharmaceutical composition of any one of the preceding claims for use in the treatment of a subject having an epilepsy disorder, wherein the administering comprises one or more routes selected from oral, sublingual, sublabial, buccal, and transmucosal.
  13. The liquid pharmaceutical composition for use of claim 12, wherein the dose of clemizole HCl administered to 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.
  14. The liquid pharmaceutical composition for use of claim 12 or 13, wherein the liquid pharmaceutical composition is administered at least every 24 hours.
  15. The liquid pharmaceutical composition for use of any of claims 12-14, further comprising administering an anti-epilepsy drug, wherein the administering with the anti-epilepsy drug preferably comprises any one of: administering the liquid pharmaceutical composition separately from the anti-epilepsy drug, co-administering the liquid pharmaceutical composition with the anti-epilepsy drug, or administering the liquid pharmaceutical composition sequentially with the anti-epilepsy drug.
  16. The liquid pharmaceutical composition for use of any one of claims 12-15, 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.

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. Any references in the description to methods of treatment refer to the compounds, pharmaceutical compositions and medicaments of the present disclosure for use in a method for treatment of the human (or animal) body by therapy (or for diagnosis). 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 myocl