Intravenous ganaxolone formulations and their use in treating status epilepticus and other seizure disorders

A technology of ganaxolone and preparations, applied in the field of intravenous ganaxolone preparations and its use in the treatment of status epilepticus and other seizure disorders, which can solve the problems of unapproved treatment of epilepsy in children

Inactive Publication Date: 2017-12-01
MARINUS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Mutations in the PCDH19 gene have been associated with low levels of pregnenolone, but treatment with pregnenolone is not ideal for the reasons given above
There are currently no approved treatments for pediatric epilepsy in women with PCDH19

Method used

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  • Intravenous ganaxolone formulations and their use in treating status epilepticus and other seizure disorders
  • Intravenous ganaxolone formulations and their use in treating status epilepticus and other seizure disorders
  • Intravenous ganaxolone formulations and their use in treating status epilepticus and other seizure disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0113] Example 1. Preparation of Injectable Ganaxolone Formulations

[0114] Firstly, the solubility of ganaxolone in CAPTISOL aqueous solution was determined by constructing a phase solubility diagram. Equilibrium was achieved by shaking excess ganaxolone in an aqueous solution of known concentration of CAPRISOL for 42 hours. The ganaxolone solution was filtered through a 0.45 μm syringe filter into an HPLC vial. The ganaxolone concentration of the filtrate was determined by HPLC. The results are summarized in Table 1. The moles of ganaxolone in solution are plotted against the moles of CAPTISOL added. The solubility of ganaxolone in water was found to increase linearly with the addition of CAPTISIOL, indicating the formation of a 1:1 complex between ganaxolone and CAPTISOL. The graph of the weight (mg) of ganaxolone in the solution relative to the weight (mg) of ganaxolone added ( figure 1 ) shows that the weight:weight ratio of CAPTISOL to ganaxolone required for ganax...

Embodiment 2

[0117] Example 2. Preparation of Injectable Ganaxolone-CAPTISOL Solution (5mg / mL)

[0118] Ganaxolone (0.50 g) was first mixed manually with a small amount (approximately 20 mL) of 30% w / v CAPTISOL solution in sterile water for injection using a spatula to form a homogeneous paste. An additional amount (about 40 mL) of 30% w / v CAPTISOL solution was then added to obtain a slurry. The suspension was stirred for 20 minutes with a magnetic stir bar. Sonicate it for 2 hours using a probe sonicator. While sonicating, an additional 30% w / v CAPTISOL solution was added until the total amount of CAPTISOL solution reached 99.58 mL. The stirred formulation was then heated at 68.5°C for about 2.5 hours to obtain a solution. The heat was removed and the solution was stirred at room temperature for about 2 hours. Replace volume lost due to evaporation with water. The clear solution was sterile filtered through a 0.2 μm nylon membrane.

Embodiment 3

[0119] Example 3. Preparation of lyophilized Ganaxolone-CAPTISOL powder

[0120] Prepare Ganaxolone by dissolving 42.6 mg of Ganaxolone in 6.6 mL of 40% w / v CAPTISOL and stirring for 1 hour (a small amount of undissolved Ganaxolone is filtered through a 0.45 μm syringe filter to obtain a clear solution) Xolone-CAPTISOL solution. The solution was frozen in a dry ice / acetone bath and lyophilized for 2 days to obtain 2.859 g of a free flowing white powder. The ganaxolone concentration of the lyophilized powder was determined by HPLC to be 1.26% by weight, which is slightly lower than the theoretical value (1.49% by weight). The lyophilized powder was reconstituted in water to obtain a clear solution.

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Abstract

The disclosure provides an injectable ganaxolone formulation comprising ganaxolone, sulfobutyl ether-beta-cyclodextrin; and water. The injectable ganaxolone formulation optionally includes a surfactant and a pH modifier. The ganaxolone and sulfobutyl ether-beta-cyclodextrin may be in an inclusion complex. The disclosure also provides a lyophilized powder of the ganaxolone/ sulfobutyl ether-beta-cyclodextrin formulation that may be reconstituted in water for injection. The disclosure provides a method of treating a patient having a seizure disorder, stroke, or traumatic brain injury, comprising administering an effective amount of the injectable ganaxolone formulation comprising ganaxolone, sulfobutyl ether-beta-cyclodextrin; and water. The disclosure also provides combination methods in which the injectable ganaxolone/ sulfobutyl ether-beta-cyclodextrin formulation is administered in combination with at least one additional active agent.

Description

Background technique [0001] Status epilepticus (SE) is a severe seizure disorder in which a person with epilepsy experiences seizures lasting more than 5 minutes or more than one seizure within a 5-minute period with no intervals between seizures. recover. In some cases, convulsive seizures can last for days or even weeks. Status epilepticus was treated in the emergency department with conventional anticonvulsants. GABA A Receptor modulators (such as benzodiazepines Class (benzodiazepine, BZ)) is the first-line treatment. Patients who do not respond to BZ alone are usually treated with narcotics or barbiturates in combination with BZ. Benzodiazepines Approximately 23-43% of patients with status epilepticus treated with antiepileptic drugs and at least one additional antiepileptic drug do not respond to treatment and are considered refractory (Rossetti, A.O. and Lowenstein, D.H., Lancet Neurol. (2011) 10(10):922-930). There are currently no good treatment options for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/08A61K31/57A61K47/69A61K45/06A61P25/08
CPCA61K9/0019A61K31/57A61K45/06A61K9/19A61K47/6951A61P25/08A61K31/05A61K47/26A61K47/10A61K47/28A61K2300/00A61K47/40A61K9/08A61K31/573
Inventor 张明宝雷蒙德·C·格洛瓦基
Owner MARINUS PHARMA
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