Challenges and Complications of Poly(lactic--glycolic Acid)-Based Long-Acting Drug Product Development

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2022 Mar 26

PMID 35335988

Authors

Yi Wen Lim

Wen Siang Tan

Kok Lian Ho

Abdul Razak Mariatulqabtiah

Noor Hayaty Abu Kasim

Noorsaadah Abd Rahman

Tin Wui Wong

Chin Fei Chee

Affiliations

Soon will be listed here.

Abstract

Poly(lactic--glycolic acid) (PLGA) is one of the preferred polymeric inactive ingredients for long-acting parenteral drug products that are constituted of complex formulations. Despite over 30 years of use, there are still many challenges faced by researchers in formulation-related aspects pertaining to drug loading and release. Until now, PLGA-based complex generic drug products have not been successfully developed. The complexity in developing these generic drug products is not just due to their complex formulation, but also to the manufacturing process of the listed reference drugs that involve PLGA. The composition and product attributes of commercial PLGA formulations vary with the drugs and their intended applications. The lack of standard compendial methods for in vitro release studies hinders generic pharmaceutical companies in their efforts to develop PLGA-based complex generic drug products. In this review, we discuss the challenges faced in developing PLGA-based long-acting injectable/implantable (LAI) drug products; hurdles that are associated with drug loading and release that are dictated by the physicochemical properties of PLGA and product manufacturing processes. Approaches to overcome these challenges and hurdles are highlighted specifically with respect to drug encapsulation and release.

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References

Mohammad A, Reineke J . Quantitative detection of PLGA nanoparticle degradation in tissues following intravenous administration. Mol Pharm. 2013; 10(6):2183-9. DOI: 10.1021/mp300559v. View

Gaudana R, Khurana V, Parenky A, Mitra A . Encapsulation of Protein-Polysaccharide HIP Complex in Polymeric Nanoparticles. J Drug Deliv. 2011; 2011:458128. PMC: 3095424. DOI: 10.1155/2011/458128. View

Zolnik B, Leary P, Burgess D . Elevated temperature accelerated release testing of PLGA microspheres. J Control Release. 2006; 112(3):293-300. DOI: 10.1016/j.jconrel.2006.02.015. View

Hua Y, Wang Z, Wang D, Lin X, Liu B, Zhang H . Key Factor Study for Generic Long-Acting PLGA Microspheres Based on a Reverse Engineering of Vivitrol. Molecules. 2021; 26(5). PMC: 7975983. DOI: 10.3390/molecules26051247. View

Simoes M, Pinto R, Simoes S . Hot-melt extrusion in the pharmaceutical industry: toward filing a new drug application. Drug Discov Today. 2019; 24(9):1749-1768. DOI: 10.1016/j.drudis.2019.05.013. View

Rezvantalab S, Moraveji M . Microfluidic assisted synthesis of PLGA drug delivery systems. RSC Adv. 2022; 9(4):2055-2072. PMC: 9059828. DOI: 10.1039/c8ra08972h. View

Fredenberg S, Wahlgren M, Reslow M, Axelsson A . The mechanisms of drug release in poly(lactic-co-glycolic acid)-based drug delivery systems--a review. Int J Pharm. 2011; 415(1-2):34-52. DOI: 10.1016/j.ijpharm.2011.05.049. View

Andhariya J, Choi S, Wang Y, Zou Y, Burgess D, Shen J . Accelerated in vitro release testing method for naltrexone loaded PLGA microspheres. Int J Pharm. 2017; 520(1-2):79-85. DOI: 10.1016/j.ijpharm.2017.01.050. View

Bohr A, Kristensen J, Dyas M, Edirisinghe M, Eleanor Stride . Release profile and characteristics of electrosprayed particles for oral delivery of a practically insoluble drug. J R Soc Interface. 2012; 9(75):2437-49. PMC: 3427507. DOI: 10.1098/rsif.2012.0166. View

10.

Garner J, Skidmore S, Park H, Park K, Choi S, Wang Y . Beyond Q1/Q2: The Impact of Manufacturing Conditions and Test Methods on Drug Release From PLGA-Based Microparticle Depot Formulations. J Pharm Sci. 2017; 107(1):353-361. DOI: 10.1016/j.xphs.2017.10.027. View

11.

Patel R, Carlson A, Solorio L, Exner A . Characterization of formulation parameters affecting low molecular weight drug release from in situ forming drug delivery systems. J Biomed Mater Res A. 2010; 94(2):476-84. PMC: 2914550. DOI: 10.1002/jbm.a.32724. View

12.

Wang G, Yu B, Wu Y, Huang B, Yuan Y, Liu C . Controlled preparation and antitumor efficacy of vitamin E TPGS-functionalized PLGA nanoparticles for delivery of paclitaxel. Int J Pharm. 2013; 446(1-2):24-33. DOI: 10.1016/j.ijpharm.2013.02.004. View

13.

Duncanson W, Lin T, Abate A, Seiffert S, Shah R, Weitz D . Microfluidic synthesis of advanced microparticles for encapsulation and controlled release. Lab Chip. 2012; 12(12):2135-45. DOI: 10.1039/c2lc21164e. View

14.

Doty A, Weinstein D, Hirota K, Olsen K, Ackermann R, Wang Y . Mechanisms of in vivo release of triamcinolone acetonide from PLGA microspheres. J Control Release. 2017; 256:19-25. DOI: 10.1016/j.jconrel.2017.03.031. View

15.

Keohane K, Brennan D, Galvin P, Griffin B . Silicon microfluidic flow focusing devices for the production of size-controlled PLGA based drug loaded microparticles. Int J Pharm. 2014; 467(1-2):60-9. DOI: 10.1016/j.ijpharm.2014.03.051. View

16.

Beig A, Feng L, Walker J, Ackermann R, Hong J, Li T . Physical-Chemical Characterization of Octreotide Encapsulated in Commercial Glucose-Star PLGA Microspheres. Mol Pharm. 2020; 17(11):4141-4151. DOI: 10.1021/acs.molpharmaceut.0c00619. View

17.

Martinez M, Rathbone M, Burgess D, Huynh M . Breakout session summary from AAPS/CRS joint workshop on critical variables in the in vitro and in vivo performance of parenteral sustained release products. J Control Release. 2009; 142(1):2-7. DOI: 10.1016/j.jconrel.2009.09.028. View

18.

Swider E, Koshkina O, Tel J, Cruz L, de Vries I, Srinivas M . Customizing poly(lactic-co-glycolic acid) particles for biomedical applications. Acta Biomater. 2018; 73:38-51. DOI: 10.1016/j.actbio.2018.04.006. View

19.

Ford Versypt A, Pack D, Braatz R . Mathematical modeling of drug delivery from autocatalytically degradable PLGA microspheres--a review. J Control Release. 2012; 165(1):29-37. PMC: 3518665. DOI: 10.1016/j.jconrel.2012.10.015. View

20.

Burgess D, S Hussain A, Ingallinera T, Chen M . Assuring quality and performance of sustained and controlled release parenterals: workshop report. AAPS PharmSci. 2002; 4(2):E7. PMC: 2751292. DOI: 10.1208/ps040205. View