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JP-7856338-B2 - Cremizole preparations

JP7856338B2JP 7856338 B2JP7856338 B2JP 7856338B2JP-7856338-B2

Inventors

  • イ， ハンジュン

Assignees

  • エピジェニクス セラピューティクス インコーポレーテッド

Dates

Publication Date
20260511
Application Date
20220613
Priority Date
20210730

Claims (20)

  1. Clemiso hydrochloride (HCl); solvent; A liquid pharmaceutical composition comprising a preservative and glycerol, Here, the preservative comprises potassium sorbate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, methyl parahydroxybenzoate, or ethyl parahydroxybenzoate. The solvent comprises a citrate buffer, and the pH of the liquid pharmaceutical composition is in the range of 4 to 5. Liquid pharmaceutical composition.
  2. The glycerol is at a concentration of 10-30% (wt/wt), and the citrate buffer is at a concentration of 70-90% (wt/wt). The liquid pharmaceutical composition according to claim 1.
  3. The glycerol concentration is 20% (wt/wt), and the citrate buffer concentration is 80% (wt/wt). The liquid pharmaceutical composition according to claim 1 or claim 2.
  4. The aforementioned preservative comprises at least one of methyl parahydroxybenzoate, potassium sorbate, and ethyl parahydroxybenzoate. A liquid pharmaceutical composition according to any one of claims 1 to 3.
  5. The liquid pharmaceutical composition according to any one of claims 1 to 4, wherein the preservative is present in a concentration of 0.01 to 0.5% (w/v).
  6. The liquid pharmaceutical composition according to any one of claims 1 to 5, wherein the preservative is methyl parahydroxybenzoate at a concentration of 0.2% (w/v), or ethyl parahydroxybenzoate at a concentration of 0.02% (w/v).
  7. A liquid pharmaceutical composition according to any one of claims 1 to 6, further comprising a solubilizing agent.
  8. The liquid pharmaceutical composition according to claim 7, wherein the solubilizing agent is tocopherol polyethylene glycol succinate (TPGS) or ultra-purified PEG400.
  9. A liquid pharmaceutical composition according to any one of claims 1 to 8, further comprising a sweetener or a taste modifier.
  10. The liquid pharmaceutical composition according to claim 9, wherein the sweetener is sucralose or sodium saccharin.
  11. The liquid pharmaceutical composition according to claim 9, wherein the taste modifier comprises a flavoring agent, or the taste modifier comprises cherry flavor, orange flavor, strawberry flavor, or vanilla flavor.
  12. A liquid pharmaceutical composition according to any one of claims 1 to 11, further comprising an antioxidant or a component having antioxidant properties.
  13. The liquid pharmaceutical composition according to claim 12, wherein the antioxidant or component having antioxidant properties is selected from sodium ascorbate, ascorbic acid, and tocopherol polyethylene glycol succinate (TPGS).
  14. The liquid pharmaceutical composition according to any one of claims 1 to 13, wherein the concentration of cremisole hydrochloride in the pharmaceutical composition is 1 mg/mL to 30 mg/mL.
  15. The liquid pharmaceutical composition according to any one of claims 1 to 14, wherein the concentration of cremisole hydrochloride in the pharmaceutical composition is 5 mg/mL.
  16. A liquid pharmaceutical composition according to any one of claims 1 to 15, further comprising an antiepileptic drug.
  17. Essentially, the liquid pharmaceutical composition according to claim 1 comprises cremisole hydrochloride, a citrate buffer solution with a pH of 4.5, a preservative, glycerol, a taste modifier, a solubilizer, and a sweetener, wherein the preservative is potassium sorbate, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, methyl parahydroxybenzoate, or ethyl parahydroxybenzoate, or a combination thereof.
  18. A liquid pharmaceutical composition according to any one of claims 1 to 17, wherein at least one of the following occurs after storage for up to 36 months: There is no substantial increase in cremiso hydrochloride metabolites or related degradation products. The amount of the preservative is maintained at substantially 97% or more of the original amount of the preservative, there is no substantial change in the pH of the pharmaceutical composition, or there is no substantial change in the color of the pharmaceutical composition.
  19. The liquid pharmaceutical composition according to claim 18, wherein storage is carried out at the following temperatures: 2-8°C, 25°C, or 40°C.
  20. A method for preparing a liquid pharmaceutical composition according to any one of claims 1 to 19, The steps of forming the liquid pharmaceutical composition by dissolving at least one of a preservative, cremiso hydrochloride, a plurality of excipients, and glycerol in a solvent or solubilizer, and adjusting the pH of the liquid pharmaceutical composition to 4 to 5. Furthermore, if the dissolution is in a solubilizing agent, the method comprises adding the solvent to the liquid pharmaceutical composition, or if the dissolution is in a solvent, the method comprises adding the solubilizing agent to the liquid pharmaceutical composition. method.

Description

This disclosure relates to providing a soluble, time-stable oral formulation of cremisole hydrochloride, and a method for preparing such an oral formulation of cremisole hydrochloride. Cremizole hydrochloride is the hydrochloride form of cremizole, a first-generation histamine receptor (H1) antagonist, a class of drugs shown to possess anti-allergic activity. However, cremizole also acts as an antiepileptic drug, inhibiting behavioral and electroconvulsive seizure activity. This anti-seizure-like activity is thought to be partially regulated by cremizole's role in modulating serotonin (5-HT) receptor signaling. 1. A liquid pharmaceutical composition comprising cremisole hydrochloride; a solvent; and glycerol, wherein the solvent is a citrate buffer, the pH of the liquid pharmaceutical composition is in the range of 4 to 5, and the liquid pharmaceutical composition may contain a preservative, the preservative being at least one of potassium sorbate, sodium methyl p-hydroxybenzoate, sodium ethyl p-hydroxybenzoate, methyl p-hydroxybenzoate, or ethyl p-hydroxybenzoate. 2. Embodiment 2: The liquid pharmaceutical composition according to Embodiment 1, wherein the concentration of glycerol in the pharmaceutical composition is 10-30% (wt/wt), the concentration of the citrate buffer is 90-70% (wt/wt), and optionally, the concentration of glycerol in the pharmaceutical composition is 20% (wt/wt) and the concentration of the citrate buffer is 80% (wt/wt). 3. Embodiment 1: The liquid pharmaceutical composition according to Embodiment 1 or 2, wherein the preservative comprises at least one of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, or potassium sorbate. 4. Embodiment 4: The liquid pharmaceutical composition according to Embodiment 3, wherein the preservative has a concentration of 0.01 to 0.5% (w/v). 5. A liquid pharmaceutical composition according to any one of Embodiments 1 to 4, wherein the preservative comprises at least one selected from ethyl parahydroxybenzoate or methyl parahydroxybenzoate. 6. Embodiment 6: The liquid pharmaceutical composition according to Embodiment 5, wherein the preservative comprises at least one of 0.2% (w/v) methyl parahydroxybenzoate or 0.02% (w/v) ethyl parahydroxybenzoate. 7. A liquid pharmaceutical composition according to any one of Embodiments 1 to 6, wherein the liquid pharmaceutical composition further comprises a solubilizer. 8. A liquid pharmaceutical composition of Embodiment 126, wherein the solubilizer comprises one of TPGS or ultra-purified PEG400. 9. The liquid pharmaceutical composition of Embodiment 8, wherein the solubilizer is ultra-purified PEG400. 10. A liquid pharmaceutical composition according to Embodiment 8, wherein the solubilizer is TPGS. 11. A liquid pharmaceutical composition according to any one of Embodiments 1 to 10, wherein the liquid pharmaceutical composition further comprises a sweetener. 12. A liquid pharmaceutical composition according to Embodiment 11, wherein the sweetener contains sucralose or sodium saccharin. 13. A liquid pharmaceutical composition according to any one of Embodiments 1 to 12, wherein the liquid pharmaceutical composition further comprises a taste-modifying substance. 14. The liquid pharmaceutical composition of Embodiment 13, wherein the taste modifier comprises at least one of the following: a flavoring agent, a sweetener, liquid cherry flavor, liquid orange flavor, liquid strawberry flavor, liquid vanilla flavor, powdered cherry flavor, powdered orange flavor, powdered strawberry flavor, and powdered vanilla flavor. 15. A liquid pharmaceutical composition according to any one of Embodiments 1 to 14, wherein the liquid pharmaceutical composition further comprises an antioxidant or a component having antioxidant properties. 16. The liquid pharmaceutical composition of Embodiment 15, wherein the antioxidant or component having antioxidant properties is selected from at least one of sodium ascorbate, ascorbic acid, or tocopherol polyethylene glycol succinate (TPGS). 17. A liquid pharmaceutical composition according to one of Embodiments 15 or 16, comprising ascorbic acid. 18. A liquid pharmaceutical composition according to any one of Embodiments 1 to 17, wherein the concentration of cremiso hydrochloride is 1 mg/ml to 30 mg/ml, and optionally, the concentration of cremiso hydrochloride is one of 5 mg/ml, 10 mg/ml, 15 mg/ml, or 16 mg/ml. 19. A liquid pharmaceutical composition according to any one of Embodiments 1 to 18, wherein the liquid pharmaceutical composition further comprises an antiepileptic drug. 20. The epileptic disorder described above is Dravet syndrome, benign Rolandic epilepsy, frontal lobe epilepsy, infantile seizures, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy, childhood absence epilepsy (e.g., pycnorepsy), febrile seizures, Lafora's progressive myoclonic epilepsy, Lennox-Gastaut syndrome, Landau-Kleinfohr syndrome, generalized epilepsy with febrile seizures (GEFS+), severe myoclo