HGF preparation suitable for treatment of neurological disorders
Inventors
Fukuta, Kazuhiro • Inoue, Hayao
Assignees
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Publication Number
US-10702582-B2
Publication Date
2020-07-07
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 discloses an injection composition comprising a hepatocyte growth factor (HGF) protein as an active ingredient for treating a central nervous system disease by promoting neuronal cell survival and/or neurite outgrowth. The composition is formulated as an aqueous solution and a re-dissolution liquid prepared by dissolving a freeze-dried HGF preparation obtained from an aqueous solution comprising HGF protein, lactose, glycine, sodium chloride, a pH buffering agent, and a surfactant.
To address HGF protein-based polymer formation, the formulation further includes a surfactant, such as polysorbate. The document describes measures to improve physicochemical stability and provides stability rationale, including measured polymer content after forced deterioration storage.
The described compositions are intended for safe administration for central nervous system use, including intrathecal/intracerebroventricular administration routes and administration into spinal parenchyma or cerebral parenchyma. The central nervous system disease scope explicitly includes ALS, Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, spinal cord injury, cerebral infarction, cerebral ischemia, and multiple sclerosis.
Claims Coverage
The document includes one independent claim directed to treating central nervous system diseases using an injection composition containing an HGF protein, with defined formulations that limit HGF polymer formation and support neuronal cell survival and/or neurite outgrowth. The independent claim includes four inventive features covering therapeutic objective, formulation composition, choice between an aqueous solution and a re-dissolution liquid, and defined disease scope with daily dose range.
HGF promotes neuronal cell survival and/or neurite outgrowth
A method of treating a central nervous system disease by administering to a patient an injection composition comprising a hepatocyte growth factor (HGF) protein as an active ingredient to treat the central nervous system disease wherein neuronal cell survival and/or neurite outgrowth is promoted.
Aqueous solution formulation with lactose, glycine, sodium chloride, pH buffering agent, and surfactant
The injected composition is an aqueous solution containing the HGF protein and lactose, glycine, sodium chloride, a pH buffering agent and a surfactant, wherein lactose is present in a range of 1 to 5 parts by weight relative to 1 part by weight of the HGF protein, and wherein glycine concentration is in the range of 0.1 to 10 mg/mL.
Re-dissolution liquid from freeze-dried HGF preparation
The injected composition is a re-dissolution liquid prepared by dissolving the HGF preparation obtained by freeze-drying of an aqueous solution comprising an HGF protein and lactose, glycine, sodium chloride, a pH buffering agent and a surfactant, wherein lactose is present in a range of 1 to 5 parts by weight relative to 1 part by weight of HGF protein, and wherein glycine concentration is in the range of 0.1 to 10 mg/mL in a pharmaceutically acceptable solvent.
Defined central nervous system disease scope and daily dose range
The central nervous system disease is amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, spinal cord injury, cerebral infarction, cerebral ischemia or multiple sclerosis, wherein the daily dose of the HGF protein is 0.01 to 50 mg.
Overall, the claim coverage is centered on using an HGF protein injection composition to promote neuronal cell survival and/or neurite outgrowth for specified central nervous system diseases, with the injection composition limited to either an aqueous solution or a re-dissolution liquid prepared from a freeze-dried formulation containing lactose, glycine, sodium chloride, a pH buffering agent, and a surfactant.
Stated Advantages
Improve physicochemical stability of the HGF protein formulation.
Prevent HGF protein-based polymer formation.
Enable safe central nervous system administration via intrathecal/intracerebroventricular routes or into spinal/cerebral parenchyma.
Documented Applications
Treatment of central nervous system diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, spinal cord injury, cerebral infarction, cerebral ischemia, and multiple sclerosis.
Central nervous system safety testing in rats.
Therapeutic efficacy evaluation in a rat spinal cord injury model using the described HGF formulation.
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