Treatment of protein aggregation myopathic and neurodegenerative diseases by parenteral administration of trehalose
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Publication Number
US-10869831-B2
Publication Date
2020-12-22
Expiration Date
Abstract
Disclosed is a method of treatment of a disease associated with abnormal protein aggregation comprising parenterally administering pharmaceutical formulations comprising trehalose. Also disclosed is an injectable aqueous pharmaceutical formulation comprising a therapeutically effective amount of trehalose.
Core Innovation
Disclosed is parenteral treatment of diseases associated with abnormal protein aggregation/inclusion bodies using trehalose as the therapeutic agent. The disorder set includes spinocerebellar ataxia (SCA) associated with a polyglutamine repeat mutation, spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and frontotemporal dementia.
A pharmaceutical formulation for parenteral administration comprises trehalose as the sole active ingredient. The concentration of trehalose in the formulation is between about 0.1% (w/v) and about 50% (w/v), and the administration is completed within less than 120 minutes. The formulation is described as an aqueous injectable formulation suitable for parenteral use.
The disclosure also describes injectable aqueous trehalose formulations with specified physicochemical parameters, including pH about 4.5 to about 7.0 and osmolality about 280 to about 330 mOsm/kg. Endotoxin limits are specified, including less than about 0.74 EU/mL with a maximum endotoxin level of less than about 5 EU/kg/hour.
Claims Coverage
The claim coverage includes one independent claim and several dependent refinements. It centers on a symptom-ameliorating method for specified neurodegenerative disorders by administering a trehalose-only parenteral pharmaceutical formulation with a defined trehalose concentration and an administration period of less than 120 minutes.
Trehalose-only parenteral symptom amelioration for specified disorders
A method for ameliorating a symptom in a subject having a disorder selected from spinocerebellar ataxia (SCA) associated with a polyglutamine repeat mutation, spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and frontotemporal dementia, comprising parenterally administering a pharmaceutical formulation comprising trehalose as the sole active ingredient.
Trehalose concentration range in trehalose-only formulation
The concentration of trehalose in the formulation is between about 0.1% (w/v) to about 50% (w/v).
Administration completed within less than 120 minutes
The administration is completed within less than 120 minutes.
Injectable solution for parenteral administration
The pharmaceutical formulation is an injectable solution for parenteral administration.
Parenteral route limited to intravenous, intramuscular, or intraperitoneal
The parenteral administration is any one of intravenous, intramuscular, or intraperitoneal administration.
Formulation pH about 4.5 to 7.0
The pharmaceutical formulation has a pH about 4.5 to 7.0.
Endotoxin threshold in trehalose-only formulation
The pharmaceutical formulation contains less than 0.75 endotoxin units per mL.
Optional trehalase inhibitor in formulation
The pharmaceutical formulation further comprises a trehalase inhibitor.
Overall, the claims cover symptom amelioration in specified disorders by parenteral administration of a trehalose-only pharmaceutical formulation, with claim features directed to trehalose concentration, administration time, formulation type, route, pH, endotoxin threshold, and an optional trehalase inhibitor.
Stated Advantages
Parenteral administration increases trehalose bioavailability and tissue accumulation versus oral dosing.
Higher plasma and muscle exposure after intravenous dosing is reported in preclinical pharmacokinetics.
Tolerability/safety is reported in the disclosure’s preclinical context.
Documented Applications
OPMD clinical study framework using weekly intravenous trehalose infusion escalation, with randomized dosing groups and efficacy/safety endpoints and pharmacokinetic sampling.
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