HGF preparation suitable for treatment of neurological disorders
Inventors
Fukuta, Kazuhiro • Inoue, Hayao
Assignees
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Publication Number
US-10213485-B2
Publication Date
2019-02-26
Expiration Date
Abstract
The present invention provides a hepatocyte growth factor (HGF) preparation in the form of an injection or the like that is highly safe for central nerves and highly stable and can be used for intrathecal or intracerebroventricular administration or for administration into the spinal or cerebral parenchyma for the treatment of central nervous system diseases. The HGF preparation of the present invention contains an HGF protein as an active ingredient and lactose, glycine, sodium chloride, a pH buffering agent and a surfactant as additional ingredients.
Core Innovation
The invention relates to a hepatocyte growth factor (HGF) preparation obtained by freeze-drying of an aqueous solution comprising an HGF protein as an active ingredient and specific excipients. The excipients include lactose, glycine, sodium chloride, a pH buffering agent, and a surfactant, where the surfactant is polysorbate. The formulation parameters define ranges for lactose, glycine, HGF protein, pH buffering agent, polysorbate, and sodium chloride, and the pH buffering agent keeps the pH of an HGF solution obtained by redissolving the HGF preparation within 4.5 to 8.0.
A central aspect of the disclosed preparation is that the combination of lactose, glycine, sodium chloride, a citric-acid-based pH buffer, and polysorbate is used in a freeze-dried formulation of HGF. The objective is to address HGF protein-based polymer formation in the formulation and upon reconstitution/redissolving. The preparation is also presented as reducing central nervous system toxicity associated with administering HGF in the central nervous system.
The document further describes an injectable formulation and central nervous system use of the HGF lyophilized preparation, including intrathecal/intracerebroventricular and spinal or cerebral parenchyma administration. The disclosure includes data showing reduced polymer content after accelerated storage and safety in rat intrathecal dosing. The document also reports therapeutic efficacy in a rat spinal cord injury model using BBB scale locomotor function, with improved BBB score and without observed systemic CNS abnormalities.
Claims Coverage
The partial content identifies one independent claim and dependent refinements that further define the HGF protein identity or sequence. The independent claim covers a freeze-dried HGF preparation with defined excipients and concentration/pH ranges.
Freeze-dried HGF formulation with defined excipient and concentration ranges
A hepatocyte growth factor (HGF) preparation obtained by freeze-drying of an aqueous solution comprising an HGF protein as an active ingredient and lactose, glycine, sodium chloride, a pH buffering agent, and a surfactant, wherein lactose, glycine, HGF protein, pH buffering agent, polysorbate, and sodium chloride are each defined by specified concentration ranges.
Citric-acid-based pH buffer maintaining redissolved pH
The pH buffering agent is a combination of citric acid or a hydrate thereof with a salt of citric acid, having the effect of keeping the pH of an HGF solution obtained by redissolving the HGF preparation within the range of 4.5 to 8.0.
Polysorbate surfactant at specified concentration range
The surfactant is polysorbate, wherein the concentration of the polysorbate in the aqueous solution is in the range of 0.005 to 1.0% by weight.
Human HGF protein as active ingredient
The HGF preparation uses a human HGF protein.
HGF protein sequence defined by SEQ ID NO: 5 or SEQ ID NO: 6
The HGF protein consists of an amino acid sequence represented by SEQ ID NO: 5 or SEQ ID NO: 6.
HGF protein with at least 80% sequence identity retaining HGF biological activity
The HGF protein has 80% or more sequence identity with an amino acid sequence represented by SEQ ID NO: 5 and retains HGF biological activity.
Across the independent and dependent claims, the core claim coverage centers on a freeze-dried HGF preparation formulated with lactose, glycine, sodium chloride, a citric-acid-based pH buffering system, and a polysorbate surfactant, with defined concentration ranges and a required redissolved pH of 4.5 to 8.0. Dependent claims narrow the active ingredient to a human HGF protein defined by specific SEQ ID sequences or by high sequence identity while retaining HGF biological activity.
Stated Advantages
Prevention of HGF protein-based polymer formation.
Reduction of central nervous system toxicity.
Reduced polymer content after accelerated storage.
Safety in rat intrathecal dosing with no observed systemic CNS abnormalities.
Therapeutic efficacy in a rat spinal cord injury model, including improved BBB score.
Documented Applications
Central nervous system use of an HGF injectable formulation derived from the freeze-dried HGF preparation, including intrathecal and intracerebroventricular administration and administration to spinal parenchyma or cerebral parenchyma.
Treatment/assessment in a rat spinal cord injury model using BBB scale locomotor function, reporting improved BBB score and no observed systemic CNS abnormalities.
Rat intrathecal bolus safety testing involving assessment for central nervous system safety/toxicity.
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