Methods of intravenous administration of glyburide
Inventors
Assignees
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Publication Number
US-9254259-B2
Publication Date
2016-02-09
Expiration Date
Abstract
The present disclosure is drawn to a method of administering glyburide intravenously to a subject over a period of time as a first bolus administration of glyburide; a second bolus administration of glyburide, after the first bolus; and a first continuous infusion administration of glyburide, wherein the first continuous infusion is administered at a first rate of administration for a first period of time, after the second bolus administration of glyburide.
Core Innovation
A method of administering glyburide to a subject provides intravenous dosing over a period of time using phased dosing steps. The method includes a first bolus administration of glyburide, followed by a second bolus administration after the first bolus, and a first continuous infusion administration at a first rate of administration for a first period of time.
Further phased regimens administer glyburide by continuing after the first continuous infusion with additional continuous infusion administrations at a second rate for a second period of time. The overall dosing occurs over a period of time and includes sequences such as first bolus, then continuous infusion at first rate for a first period, then second continuous infusion at a second rate for a second period, with the combined regimen defining a glyburide administration profile over time.
The document also discloses quantitative constraints to shape the administration profile, including constraints on total daily dose and administration rates for one or more continuous infusions. Examples of constraints stated in the document include daily total glyburide amounts less than about 10 mg per day and, in further embodiments, less than about 3 mg per day, and continuous infusion rate ranges and comparative relationships between a first rate and a second rate. The stated approach links the dosing sequence of boluses and sequential continuous infusions to therapeutic plasma concentration-time objectives while reducing excessive exposure.
The document further discloses formulation and container contact measures directed to avoiding polyvinyl chloride (PVC) adsorption effects on glyburide concentration. It describes using polyethylene components and PVC-free containers, and includes filtering and flushing approaches for concentrated solutions prior to use in PVC-free containers. A Phase 1 study is described, including pharmacokinetic observations that steady state is reached after the bolus and pharmacodynamic/safety observations related to blood glucose and hypoglycemia at higher dosing exposures.
Claims Coverage
The partial content identifies four independent method claims (clm-00001, clm-00017, clm-00048, and dependent quantitative refinements clm-00052 and clm-00056), each covering an intravenous glyburide administration regimen using bolus and continuous infusion phases with specified sequencing and time/rate/dose constraints. The independent claims focus on the multi-phase administration structure, while dependent claims further refine quantitative constraints and treatment targeting.
First bolus, second bolus, then first continuous infusion at a first rate
An intravenous method comprising a first bolus administration of glyburide, a second bolus administration after the first bolus, and a first continuous infusion administered at a first rate for a first period of time after the second bolus.
First bolus, then first continuous infusion followed by second continuous infusion at a second rate
A method comprising a first bolus administration, a first continuous infusion after the first bolus administered at a first rate for a first period of time, and a second continuous infusion after the first continuous infusion administered at a second rate for a second period of time, with glyburide administered over a period of time.
Sequential three-phase continuous infusion with first, second, and third rate ranges after a first bolus
A method comprising a first bolus administration, a first continuous infusion at about 125 μg/hr to about 150 μg/hr after the first bolus, a second continuous infusion at about 100 μg/hr to about 125 μg/hr after the first continuous infusion, and a third continuous infusion at about 15 μg/hr to about 300 μg/hr after the second continuous infusion, with glyburide administered over a period of time.
Each period of time is about 1 hour to about 72 hours
A method of administering glyburide wherein each period of time is about 1 hour to about 72 hours.
Total amount administered is less than about 3 mg per day
A method of administering glyburide wherein the total amount of glyburide administered is less than about 3 mg per day.
Across the identified independent claims, coverage centers on intravenous glyburide administration using bolus and sequential continuous infusion phases, including specified ordering (bolus-to-infusion, and first continuous-to-second continuous), and in one claim, a three-stage continuous infusion sequence with defined rate ranges. Additional independent quantitative refinements constrain the time range of each phase and the total daily dose.
Stated Advantages
Allows rapid attainment and maintenance of therapeutic plasma levels while avoiding excessive exposure.
Aims to reduce adverse effects related to blood glucose, including hypoglycemia at higher dosing exposures.
Avoids PVC adsorption effects that reduce glyburide concentration by using polyethylene components and PVC-free containers.
Improves glyburide concentration delivery by using filtering and flushing approaches for concentrated solutions prior to use in PVC-free containers.
Documented Applications
Administering glyburide for acute stroke, traumatic brain injury, spinal cord injury, myocardial infarction, shock, organ ischemia, and ventricular arrhythmias.
Administering glyburide for acute ischemic injury and hypoxia/ischemia.
Use in a Phase 1 study (Study 101) with described pharmacokinetic and pharmacodynamic/safety observations.
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