Treatment of protein aggregation myopathic and neurodegenerative diseases by parenteral administration of trehalose
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Publication Number
US-10493023-B2
Publication Date
2019-12-03
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
The invention provides a parenteral trehalose therapy for diseases associated with abnormal protein aggregation/inclusion bodies, including polyalanine, polyglutamine, and tauopathies. It describes an injectable aqueous pharmaceutical formulation where trehalose is the sole active ingredient, optionally with additives, intended to ameliorate a symptom in a subject having Friedreich’s ataxia. The approach is framed around increasing trehalose exposure in vivo using parenteral administration rather than oral delivery.
The described formulation is an injectable aqueous trehalose pharmaceutical formulation having trehalose concentration between about 0.1% (w/v) and about 50% (w/v), with an about 4.5–7.0 pH range and about 280–330 mOsm/kg osmolality. The formulation is described with low endotoxin thresholds of less than 0.74 EU/mL, and administration is described such that infusion is completed within less than 120 minutes.
The document states that oral trehalose has low bioavailability due to trehalase, and that intravenous administration increases plasma and muscle trehalose exposure. Preclinical support is provided by comparing IV versus oral pharmacokinetics in rats, showing higher plasma and muscle exposure after IV and low oral bioavailability, and it includes safety context together with an ongoing randomized clinical study protocol in OPMD patients using weekly IV trehalose.
Claims Coverage
The partial content includes one independent claim, focused on a method for ameliorating a symptom in a subject with Friedreich’s ataxia using a parenteral trehalose formulation. The inventive features in the dependent claims refine route, formulation characteristics, endotoxin limits, and dosing/timing constraints.
Parenteral trehalose as the sole active ingredient for Friedreich’s ataxia
A method for ameliorating a symptom in a subject wherein the subject has Friedreich's ataxia comprising parenterally administering a pharmaceutical formulation comprising trehalose as the sole active ingredient.
Trehalose concentration between 0.1% and 50% (w/v)
The pharmaceutical formulation has a trehalose concentration 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 method is characterized by using a pharmaceutical formulation that is an injectable solution for parenteral administration.
Allowed parenteral routes: intravenous, intramuscular, or intraperitoneal
The composition is administered by any one of intravenous, intramuscular, or intraperitoneal routes.
Formulation pH of about 4.5 to 7.0
The pharmaceutical formulation has a pH in the range of about 4.5 to 7.0.
Endotoxin content less than 0.75 endotoxin units per mL
The pharmaceutical formulation contains less than 0.75 endotoxin units per mL.
Per-administration dose of about 10 to about 1000 mg/kg
The formulation is administered at a per-administration dose of about 10 to about 1000 mg/kg body weight.
Across the independent and dependent claims, the core inventive theme is parenteral administration of a trehalose formulation where trehalose is the sole active ingredient for ameliorating symptoms in Friedreich’s ataxia, with specified trehalose concentration, completion of administration in under 120 minutes, and refinements specifying injectable solution form, permitted parenteral routes, formulation pH and endotoxin thresholds, and a per-administration dose range.
Stated Advantages
Improved trehalose exposure in vivo after intravenous administration versus oral administration, as described by higher plasma and muscle trehalose exposure and low oral bioavailability.
Use of a low-endotoxin pharmaceutical formulation, stated as containing less than 0.75 endotoxin units per mL.
Administration is completed within less than 120 minutes.
Documented Applications
Ameliorating a symptom in a subject having Friedreich's ataxia using parenteral administration of a trehalose formulation.
Ongoing randomized clinical study protocol in OPMD patients using weekly IV trehalose.
Therapeutic context for diseases associated with abnormal protein aggregation/inclusion bodies, including polyalanine, polyglutamine, and tauopathies.
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