Purpose: The Sandostatin LAR (SLAR) is a glucose-star poly(lactic-co-glycolic acid) (PLGA) microsphere product encapsulating water-soluble octreotide acetate (Oct). Despite expiration of patent coverage, no generic product for the SLAR has been approved in the US, likely due to the complexity of manufacturing processes and raw materials involved in the SLAR formulation. To help enable generic development of this important dosage form, we sought to develop composition-equivalent microsphere formulations to the SLAR as a function of manufacturing variables and understand their influence on the product attributes.
Methods: Composition equivalent formulations were developed using the double emulsion solvent evaporation method with similar components as SLAR including Evonik glucose-star PLGA (lactide:glycolide = 55:45, molecular weight = ~45 kDa measured by GPC relative to polystyrene linear standards). The following manufacturing variables were adjusted at constant theoretical loading of 7.0% peptide: homogenization speed for the first emulsification, homogenization time for the second emulsification, volume of second water phase and stirring rate. The pH of innerwater phase was adjusted to 6, 4, and 3 by small addition of acetic acid in order to decrease the peptide-polymer interactions during preparation. The microspheres in the size range of 20-90 µm were collected. After final drying of the microspheres, they were annealed under various conditions (50 or 60 C) under vacuum during 3 days and particle size distribution was determined with a Malvern Mastersizer. The loading of Oct, encapsulation efficiency (EE), yield and in vitro release kinetics in PBST (10 mM phosphate-buffered saline (PBS) with 0.02% Tween 80 and 0.02% sodium azide at pH 7.4) and PBStc (10 mM phosphate-buffered saline (PBS) with 1% triethyl citrate and 0.02% sodium azide at pH 7.4) were determined by UPLC. Tg was measured by DSC.
Results: The prepared microspheres achieved close to the desired Oct loading of 5.6% w/w Oct. The majority of composition equivalent formulations had desirable loading of Oct to within 6% of SLAR. Using methanol as a solvent for water phase decreased the yield. Increasing both the homogenization pressure to make the primary emulsion and the stir rate while in-liquid drying increased the EE of Oct. Increasing stir rate also increased the microsphere yield. Annealing of microspheres led to decreased initial burst release, reduced microsphere size, increased Tg and decreased residual solvent. The in vitro release kinetics of the formulations prepared were similar to SLAR although with a slightly higher initial burst.
Conclusion: Key formulation steps identified to maximize microsphere yield, and minimize residual solvent and initial burst release include adding acetic acid to the peptide before preparation and annealing the microspheres under vacuum after drying. The characterization of composition-equivalent formulations described here could be useful for further development of generic octreotide microspheres, and for guiding decisions on the influence of manufacturing process variables on product attributes and release performance.
Linglin Feng– University of Michigan
Jennifer Walker– University of Michigan, Ann Arbor, Michigan
Rose Ackermann– University of Michigan, Michigan
Justin Hong– University of Michigan, Michigan
Yan Wang– Staff Fellow, United States Food and Drug Administration
Xiaohui (Jeff) Jiang– U.S. Food and Drug Administration
Steven Schwendeman– Professor, Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Michigan