Purpose: The 1-month Lupron Depot® (LD) is a poly(lactic-co-glycolic acid) (PLGA) microsphere product encapsulating water-soluble leuprolide acetate (LUP). Despite expiration of patent coverage, no generic product for the LD has been approved in the US, likely due to the complexity of manufacturing processes involved in the LD formulation. To help enable generic development of this important dosage form, we sought to develop composition-equivalent microsphere formulations to the LD 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 the same components as the LD including Wako PLGA (lactide:glycolide = 75:25, molecular weight = ~13 kDa) and Nitta type B gelatin with bloom number 300. The following manufacturing variables were adjusted at constant theoretical loading of 16.4% peptide: homogenization speed for the first emulsification, homogenization time for the second emulsification, volume of second water phase and stirring rate. The microspheres in the size range of 0-75 µm were collected. The loading of LUP, encapsulation efficiency (EE), yield, particle size distribution 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) were determined by UPLC.
Results: The prepared microspheres achieved close to the desired LD loading of 10% w/w LUP. During development of composition equivalent formulations, the EE of gelatin (98.95 ± 0.03%) was observed to be much higher than the EE of LUP, further complicating achievement of identical compositions. The majority of composition equivalent formulations had desirable loading of LUP except for several formulations, which fell outside a desired ± 5% specification of the 10% official loading (Figure 1). The second emulsification step resulted in the loss of LUP. Increasing 2nd homogenization time and speed decreased the EE of LUP. The in vitro release kinetics of the formulations prepared were highly similar to the LD.
Conclusion: The characterization of composition-equivalent formulations described here could be useful for further development of generic leuprolide microspheres, and for guiding decisions on the influence of manufacturing process variables on product attributes and release performance.
Acknowledgement: This research was funded by FDA contract HHSF223201510170C A0001 BAA.
Disclaimer: This abstract reflects the views of authors and should not be construed to represent FDA’s views or policies.
Jennifer Walker– University of Michigan, Ann Arbor, Michigan
Rose Ackermann– University of Michigan, Michigan
Karl Olsen– 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
Anna Schwendeman– University of Michigan
Steven Schwendeman– Professor, Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, Michigan