Process for preparing microparticles containing glatiramer acetate
Inventors
BLEICH KIMELMAN, Nadav • Rubnov, Shai • Marom, Ehud
Assignees
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Publication Number
US-12097292-B2
Publication Date
2024-09-24
Expiration Date
Abstract
The present invention provides an improved process for preparing microparticles containing glatiramer acetate having low levels of residual organic solvent(s), in particular dichloromethane. The microparticles are incorporated into long acting parenteral pharmaceutical compositions in depot form that are suitable for subcutaneous or intramuscular implantation or injection, and that may be used to treat multiple sclerosis.
Core Innovation
The invention relates to an improved double-emulsification process for making long acting parenteral pharmaceutical compositions in sustained release depot form comprising glatiramer acetate, where microparticles comprise less than about 1,000 ppm of residual organic solvent. The process prepares an internal aqueous phase comprising glatiramer acetate and water, an organic phase comprising a biodegradable or non-biodegradable polymer and a water-immiscible volatile organic solvent, and an external aqueous phase comprising water and a surfactant.
The internal aqueous phase and organic phase are mixed to form a water-in-oil emulsion, followed by mixing with the external aqueous phase to obtain a water-in-oil-in-water double emulsion. The organic solvent is removed from the double emulsion by applying a compressed air stream and vacuum while mixing, and the composition is then dried to obtain glatiramer acetate microparticles.
The invention is framed as addressing long-acting depot formulation for relapsing-remitting multiple sclerosis by administering a sustained release depot composition containing 40 mg glatiramer acetate on a dosing schedule of once every 2 weeks to once monthly. In representative uses, treating and alleviating at least one symptom of relapsing-remitting multiple sclerosis is associated with reducing frequency of relapses, and one embodiment includes poly(lactide-co-glycolide) in the depot composition.
The disclosed compositions and process are presented as enabling a low residual organic solvent depot formulation for parenteral administration, including subcutaneous or intramuscular implantation at a medically acceptable location. The document further specifies polymer and surfactant selections, including PLA, PGA, PLGA, polycaprolactone, PVA, and partially hydrolyzed PVA.
Claims Coverage
The document includes three independent claims that collectively cover long-acting parenteral sustained-release depot compositions of glatiramer acetate for relapsing-remitting multiple sclerosis, with less than about 1,000 ppm residual organic solvent, prepared by w/o/w double emulsification and solvent removal using compressed air and vacuum. Across the independent claims, there are approximately three core inventive feature groupings: depot treatment and dosing, low-residual-solvent w/o/w microparticle preparation, and formulation specificity including PLGA in one independent claim.
Alleviating RRMS symptoms with long acting depot glatiramer acetate dosing
A method of alleviating at least one symptom of relapsing-remitting multiple sclerosis in a patient suffering from RRMS, comprising administering a long acting parenteral pharmaceutical composition in sustained release depot form comprising 40 mg glatiramer acetate at a dosing schedule of once every 2 weeks to once monthly.
Preparing w/o/w double emulsion and removing organic solvent using compressed air and vacuum
The pharmaceutical composition is prepared by preparing an internal aqueous phase comprising glatiramer acetate and water, an organic phase comprising a biodegradable or non-biodegradable polymer and a water-immiscible volatile organic solvent, and an external aqueous phase comprising water and a surfactant; forming a water-in-oil emulsion; mixing with the external aqueous phase to obtain a water-in-oil-in-water double emulsion; removing the organic solvent by applying a compressed air stream at a pressure of about 0.1 to 1 bar and applying a vacuum for at least about 3 hours; and drying to obtain microparticles of glatiramer acetate.
Microparticles with less than about 1,000 ppm residual organic solvent
The drying step yields microparticles of glatiramer acetate comprising less than about 1,000 ppm of residual organic solvent.
Treating RRMS using a PLGA-comprising depot with low residual organic solvent
A method of treating a human patient suffering from relapsing-remitting multiple sclerosis, comprising administering a long acting parenteral pharmaceutical composition comprising 40 mg glatiramer acetate and poly(lactide-co-glycolide) at a dosing schedule of once every 2 weeks to once monthly, wherein the pharmaceutical composition comprises less than about 1,000 ppm of residual organic solvent and is prepared in the form of a sustained release depot comprising microparticles of glatiramer acetate.
Across the independent claims, the inventive coverage centers on providing long-acting sustained release depot formulations of 40 mg glatiramer acetate for RRMS patients on a dosing schedule of once every 2 weeks to once monthly, where the formulation is a depot of glatiramer acetate microparticles having less than about 1,000 ppm residual organic solvent. The preparation is based on w/o emulsion followed by w/o/w double emulsion processing, with organic solvent removal achieved by applying a compressed air stream and vacuum and drying to obtain microparticles, and one independent claim further specifies PLGA in the depot composition.
Stated Advantages
Microparticles of glatiramer acetate comprising less than about 1,000 ppm of residual organic solvent.
Alleviating at least one symptom of relapsing-remitting multiple sclerosis and treating RRMS using a long acting parenteral sustained release depot.
In one dependent refinement, alleviating at least one symptom of RRMS by reducing the frequency of relapses.
Documented Applications
Treating and alleviating at least one symptom of relapsing-remitting multiple sclerosis in a patient by administering a long acting parenteral sustained release depot pharmaceutical composition comprising 40 mg glatiramer acetate dosed once every 2 weeks to once monthly.
Use of a long acting parenteral sustained release depot containing 40 mg glatiramer acetate and poly(lactide-co-glycolide) for treating a human patient suffering from RRMS, where the depot comprises glatiramer acetate microparticles with less than about 1,000 ppm residual organic solvent.
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