Ganaxolone–Sulfobutyl Ether-β-Cyclodextrin Injection for Seizures
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Solution Overview
Problem
Current treatments for refractory status epilepticus and PCDH19 female pediatric epilepsy are inadequate due to the short half-life and metabolism issues of allopregnanolone, and there are no effective therapies for these seizure disorders.
Innovation Solution
An injectable ganaxolone formulation comprising ganaxolone and sulfobutyl ether-β-cyclodextrin, which forms an inclusion complex, is developed to improve solubility and stability, allowing for aqueous injectable formulations and methods of treatment, including administration schedules with or without additional active agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If allopregnanolone is used as treatment for refractory status epilepticus, then it provides therapeutic effect, but it has very short half-life and is metabolized quickly making it non-ideal
Solution Approach 1:
The patent changes the chemical structure parameter of the drug from allopregnanolone to ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), which has a longer half-life and improved metabolic stability while maintaining the desired therapeutic effect for refractory status epilepticus
Solution Approach 2:
The patent creates a composite formulation by combining ganaxolone with sulfobutyl ether-β-cyclodextrin to form an inclusion complex, which improves the solubility and stability of the drug, enabling effective intravenous administration with sustained therapeutic action
2Ease of manufacture
If conventional anticonvulsants including benzodiazepines and anesthetics are used for refractory status epilepticus, then initial treatment is provided, but 23-43% of patients fail to respond and are considered refractory with high mortality
Solution Approach 1:
The patent extracts the therapeutic benefit of GABA receptor modulation while eliminating the limitations of conventional drugs by using ganaxolone, a novel steroid compound that acts as a positive allosteric modulator of GABA-A receptors with improved pharmacokinetic properties compared to benzodiazepines and anesthetics
Solution Approach 2:
The patent introduces ganaxolone as an intermediary substance that mediates between the GABA neurotransmitter system and the therapeutic effect, providing a new mechanism of action that is more effective for refractory cases than direct-acting conventional anticonvulsants
3Speed
If ganaxolone is formulated for injection, then it provides rapid therapeutic blood levels, but solubility and stability issues must be addressed
Solution Approach 1:
The patent uses sulfobutyl ether-β-cyclodextrin as an intermediary solubilizing agent that forms an inclusion complex with ganaxolone, enabling the hydrophobic steroid to be dissolved in aqueous injection vehicles while maintaining stability and preventing precipitation
Solution Approach 2:
The patent creates a stable composite formulation by combining ganaxolone with sulfobutyl ether-β-cyclodextrin in specific ratios, producing an injectable composition that maintains physical and chemical stability during storage and administration while enabling rapid drug delivery
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The ganaxolone formulation provides effective treatment for seizure disorders with reduced irritation and rapid therapeutic blood levels, addressing the limitations of existing treatments and improving patient outcomes.
Implementation Method 1
The ganaxolone and sulfobutyl ether-β-cyclodextrin may be in an inclusion complex
Data Source
AI summary
The disclosure provides an injectable ganaxolone formulation comprising ganaxolone, sulfobutyl ether-β-cyclodextrin; and water. The injectable ganaxolone formulation optionally includes a surfactant and a pH modifier. The ganaxolone and sulfobutyl ether-β-cyclodextrin may be in an inclusion complex. The disclosure also provides a lyophilized powder of the ganaxolone/sulfobutyl ether-β-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-β-cyclodextrin; and water. The disclosure also provides combination methods in which the injectable ganaxolone/sulfobutyl ether-β-cyclodextrin formulation is administered in combination with at least one additional active agent.