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Development and characterization of composition-equivalent formulations to the Sandostatin LAR® by the solvent evaporation method

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Abstract

Sandostatin long-acting release® (SLAR) is a long-acting injectable somatostatin analogue formulation composed of octreotide encapsulated in glucose-initiated poly(lactic-co-glycolic acid) (PLGA) microspheres. Despite the end of patent protection, SLAR remains resistant to generic competition likely due to complexity of production process, the uniqueness of the glucose star polymer, and the instability of octreotide in the formulation. Here, we describe development of glucose-PLGA-based composition-equivalent to SLAR formulations prepared by double emulsion-solvent evaporation method and the effect of variations in encapsulation variables on release kinetics and other formulation characteristics. The following encapsulation variables were adjusted at constant theoretical loading of 7.0% peptide: PLGA concentration, pH of inner water phase, and stirring rate. After final drying, the microspheres were examined with and without annealing at 50 °C under vacuum for 3 days. The loading and encapsulation efficiency (EE) of octreotide acetate, manufacturing yield, and in vitro drug release kinetics in PBStc (10 mM phosphate-buffered saline (PBS) with 1% triethyl citrate and 0.02% sodium azide at pH 7.4) were determined by UPLC. The in vitro release and acylation kinetics of octreotide for the solvent evaporation formulations prepared were similar to SLAR although the initial burst was slightly higher. Key formulation steps identified to maximize microsphere yield and minimize residual solvent and initial burst release included (a) addition of acetic acid to the peptide before preparation and (b) annealing the microspheres under vacuum after drying. Controlled release octreotide formulations prepared and investigated in this study could provide a better understanding of the effect of production variables on release performance and supply information useful for making progress in manufacturing of SLAR generic equivalents.

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Acknowledgements

This paper reflects the views of the authors and should not be construed to represent the FDAʼs views or policies.

Funding

This research was funded by FDA grant U01 FD005847.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and the Biointerfaces Institute, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA

    Avital Beig, Linglin Feng, Jennifer Walker, Rose Ackermann, Justin K. Y. Hong, Tinghui Li & Steven P. Schwendeman

  2. Department of Biomedical Engineering, University of Michigan, 2200 Bonisteel Blvd, Ann Arbor, MI, 48109, USA

    Steven P. Schwendeman

  3. Evaluation and Research, Office of Research and Standards, Office of Generic Drugs, Center for Drug, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MA, 20993, USA

    Yan Wang

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  1. Avital Beig
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  2. Linglin Feng
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  5. Justin K. Y. Hong
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All authors discussed the results and contributed to the final manuscript.

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Correspondence to Steven P. Schwendeman.

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Beig, A., Feng, L., Walker, J. et al. Development and characterization of composition-equivalent formulations to the Sandostatin LAR® by the solvent evaporation method. Drug Deliv. and Transl. Res. 12, 695–707 (2022). https://doi.org/10.1007/s13346-021-01013-5

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