Process for preparing microparticles containing glatiramer acetate
Inventors
BLEICH KIMELMAN, Nadav • Rubnov, Shai • Marom, Ehud
Assignees
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Publication Number
US-11471421-B2
Publication Date
2022-10-18
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 a process for preparing microparticles comprising glatiramer acetate. The process prepares an internal aqueous phase comprising glatiramer acetate and water, forms an organic phase comprising a biodegradable or non-biodegradable polymer and a water-immiscible volatile organic solvent, and mixes the internal aqueous phase and the organic phase to form a w/o emulsion.
The process further mixes the w/o emulsion with an external aqueous phase comprising water and a surfactant to produce a w/o/w double emulsion. The organic solvent is removed from the w/o/w double emulsion by applying a compressed air stream and a vacuum, followed by drying to obtain glatiramer acetate microparticles.
The resulting microparticles comprise less than about 1,000 ppm of residual organic solvent, and the described approach targets low residual volatile organic solvent, including residual dichloromethane (DCM), while maintaining microparticle characteristics and performance, including glatiramer acetate binding/potency and an in vitro release profile.
Claims Coverage
The independent claim covers a complete double-emulsification process in which solvent removal is performed using both a compressed air stream and a vacuum, producing glatiramer acetate microparticles with less than about 1,000 ppm residual organic solvent. The dependent claims further tighten residual solvent limits and specify quantitative solvent-removal and mixing conditions, along with related formulation constraints and sustained-release depot characteristics.
Double emulsion formation for glatiramer acetate microparticles
Preparing an internal aqueous phase comprising glatiramer acetate and water; preparing an organic phase comprising a biodegradable or non-biodegradable polymer and a water-immiscible volatile organic solvent; preparing an external aqueous phase comprising water and a surfactant; mixing the internal aqueous phase and the organic phase to form a w/o emulsion; and mixing the w/o emulsion with the external water phase to obtain a w/o/w double emulsion.
Solvent removal using compressed air stream and vacuum
Removing the organic solvent by mixing the w/o/w double emulsion and applying a compressed air stream at a pressure of about 0.1 to 1 bar, wherein the vacuum is applied for at least about 3 hours.
Low residual organic solvent in resulting microparticles
Drying to obtain microparticles of glatiramer acetate, said microparticles comprising less than about 1,000 ppm of residual organic solvent.
Tight residual solvent limit for microparticles
Microparticles that contain less than about 600 ppm of residual organic solvent.
Quantified compressed air, homogenizer mixing, and vacuum during solvent removal
Step (f) mixes the w/o/w double emulsion in a homogenizer at at least about 2,750 RPM, applies a compressed air stream at about 0.5 bar, and applies vacuum for at least about 5 hours.
Chlorinated hydrocarbon volatile solvent selection
The halogenated organic solvent is a chlorinated hydrocarbon selected from dichloromethane (DCM) and chloroform.
Quantified glatiramer acetate loading in microparticles
Microparticles comprising glatiramer acetate in an amount of about 20 mg to about 750 mg.
Sustained-release depot composition release duration
A pharmaceutical depot composition that releases a therapeutically effective amount of glatiramer acetate over a period of about 1 week to about 6 months.
Overall, the claim set centers on forming glatiramer acetate microparticles via w/o/w double emulsion processing, then removing the organic solvent while simultaneously applying a compressed air stream and a vacuum to achieve microparticles with less than about 1,000 ppm residual organic solvent. The dependent claims further specify tighter residual solvent limits, explicit ranges for mixing and solvent-removal operating conditions, selection of specific volatile solvents (DCM or chloroform), quantified glatiramer acetate loading, and a depot release-duration window.
Stated Advantages
Provides glatiramer acetate microparticles comprising less than about 1,000 ppm residual organic solvent.
Enables low residual volatile organic solvent, including residual dichloromethane (DCM), targeted at or below regulatory limits as described in the provided content.
Preserves microparticle morphology and glatiramer acetate binding/potency.
Maintains an in vitro release profile.
Documented Applications
Treatment of multiple sclerosis, including RRMS, using a depot formulation administered subcutaneously or intramuscularly, as described in the provided content.
Depot pharmaceutical composition releasing a therapeutically effective amount of glatiramer acetate over a period of about 1 week to about 6 months.
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