Preparation of peptide loaded PLGA microspheres with controlled release characteristics
Inventors
Karavas, Evangelos • KOUTRIS, EFTHYMIOS • Minioti, Katerina • CHAITIDOU, SOTIRIA • Papanikolaou, Georgia • MANTOURLIAS, THEOFANIS
Assignees
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Publication Number
US-9943483-B2
Publication Date
2018-04-17
Expiration Date
Abstract
A novel process for the preparation of a long acting injectable composition based on biodegradable poly(D,L-lactide-co-glycolide) microspheres comprising peptide active pharmaceutical ingredients.
Core Innovation
The invention relates to a sustained-release depot formulation using biodegradable poly(D,L lactide-co-glycolide) polymer microspheres loaded with a peptide, including a pharmaceutically-acceptable salt form. The microspheres are prepared by dissolving the peptide or salt thereof to form a water phase and forming an oil-in-water or water-in-oil-water emulsion using an organic solution of the poly(D,L lactide-co-glycolide) polymer in a suitable oil phase that is non-miscible with the water phase.
The organic solution of the poly(D,L lactide-co-glycolide) polymer is cooled down to 5°C or below before forming the emulsion. During solvent evaporation, the organic solvent used in the emulsion is evaporated to form the microspheres while controlling temperature by increasing the temperature during the evaporation step.
The invention centers on controlling the temperature during evaporation by using a temperature profile that rises from an initial temperature about 15–25°C, preferably about 20°C, to a maximum up to about 35–38°C over a time window ranging from 20 minutes to 3 hours, with optional staged increases. This increasing temperature rate is used to control in-vivo and in-vitro release characteristics of the peptide, including burst, lag time, and the primary release phase.
The documented approach also addresses in vitro dissolution profile and in vivo pharmacokinetics, including an in vitro–in vivo correlation goal. The content describes dissolution and release characterization in relation to primary release phase behavior and compares pharmacokinetic outcomes after intramuscular injection in rats.
Claims Coverage
The partial content provides one independent claim defining the process, plus dependent claims that specify particular peptides and solvent choices and that add quantitative temperature and drying constraints. The independent claim includes three main inventive aspects: forming specific peptide/PLGA emulsions with cooling, evaporating solvent while increasing temperature, and tuning in-vivo and in-vitro release characteristics by controlling the increasing temperature rate during evaporation.
Cooling a PLGA organic solution to 5°C or below before emulsification
Forming an oil-in-water or water-in-oil-water emulsion in which the organic solution of the poly(D,L lactide-co-glycolide) polymer is cooled down to 5°C or below prior to evaporation to form microspheres.
Increasing temperature during solvent evaporation to form microspheres
Evaporating the organic solvent used in the emulsion to form the microspheres by controlling the temperature during the evaporation step and increasing the temperature during the evaporation step.
Tuning in-vivo and in-vitro release characteristics by increasing temperature rate
Controlling in-vivo and in-vitro release characteristics of the peptide by the increasing temperature rate during the evaporation step.
Using octreotide acetate as the peptide active substance
The process wherein the peptide active substance is octreotide acetate.
Using methanol with optional added water as the organic solvent phase
The process wherein methanol is used as the organic solvent and water is optionally present to form the water phase.
Initiating evaporation above 15°C and raising emulsion temperature above 35°C
The process wherein evaporation starts above 15°C and the emulsion temperature is increased to greater than 35°C during the evaporation.
Raising temperature over 20 minutes to 3 hours
The process wherein the temperature is increased over a duration ranging from 20 minutes to 3 hours.
Continuing drying for an extended period after temperature elevation
The process wherein drying continues for an extended period after the temperature has been elevated.
Across the independent claim and its dependencies, the core claim coverage is centered on preparing PLGA peptide-loaded microspheres by emulsion formation with a PLGA organic solution cooled to 5°C or below, then forming microspheres by evaporating solvent while increasing temperature, with release characteristics tuned by the increasing temperature rate during evaporation. Dependent claims further specify peptide and solvent selections and add quantitative temperature initiation and rise limits, a defined temperature-rise time window, and optional extended drying after temperature elevation.
Stated Advantages
Controls in-vivo and in-vitro release characteristics of the peptide by the increasing temperature rate during the evaporation step.
Produces control of release characteristics including burst, lag time, and primary release phase behavior.
Documented Applications
Sustained-release depot formulation of peptide drugs using biodegradable PLGA microspheres, including octreotide acetate, with characterization using in vitro dissolution profiles and in vivo pharmacokinetics after intramuscular injection in rats.
In vitro–in vivo correlation (IVIVC) aimed at relating dissolution/release profiles to rat plasma pharmacokinetics after IM injection.
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