Investigation on Formulation, Manufacturing Process, and Drug Release of a Bupivacaine Multivesicular Liposomal Formulation (Exparel)

Abstract

Liposomes such as unilamellar vesicles (ULVs) and multilamellar vesicles (MLVs) have been studied extensively as drug carriers for sustained drug release. A novel liposome, named multivesicular liposomes (MVLs), recently draws interest in pharmaceutical world for its unique structure and release characteristics. MVL has a pomegranate-like structure attributed to the non-concentrically assembly of numerous vesicles within the particle. This unique structure of MVLs provides them with a high drug encapsulation and a sustained drug release profile. Exparel® (Pacira Pharmaceuticals, Inc.) is a Food and Drug Administration (FDA)-approved MVL drug product indicated for regional pain relief across and/or post surgeries. With bupivacaine encapsulated as the active ingredient, Exparel is a non-opioid analgesia allowing for therapeutic effectiveness to several days, and helps minimize not only the opioid consumption but also the repetitive drug administration in patients. However, with a complex structure and manufacturing process of bupivacaine MVLs, its generic development faces great challenges. The lack of knowledge in MVL also requires investigation on MVL-based formulations. The thesis project focuses on bridging the current gaps in the generic development of bupivacaine MVLs via an extensive investigation on the formulation, manufacturing, and release of Exparel®. This dissertation is composed of three sections addressing the reverse-engineering, release profiles, and critical manufacturing parameters of bupivacaine MVLs, respectively. The first section, described in Chapter 2, focuses on the reverse-engineering of the Exparel formulation, with a comprehensive characterization on its morphology and structure, size distribution, formulation pH, drug and lipids contents, residual solvents, and in vitro release (IVR). Specifically, an accelerated IVR testing (IVRT) method was developed based on a vertical rotator for a fast product quality check. The developed IVRT allowed for an over 70% drug release from bupivacaine MVLs within 24 hours, validated with great reproducibility and discriminability. The second section, described in Chapter 3, focuses on the pharmacokinetics (PK) of bupivacaine MVLs and its release kinetics in vivo. Specifically, an implantable cage model was constructed with silicone and nylon sieve to capture the local drug release from bupivacaine MVLs in a subcutaneous environment. PK studies were conducted in rats with varied experimental parameters including different doses, administration routes, and sample dilution factors, to understand their impacts on the PK of bupivacaine MVLs. PK studies were further conducted with bupivacaine MVLs of different product qualities, along with in vivo characterization, to investigate potential in vitro in vivo association. Moreover, the local drug release of bupivacaine MVLs was captured via the developed cage model, with quantified cumulative release and morphology transformation along the time. However, a delayed Tmax was found with the cage implantation, calling for future optimization on the cage dimensions. The third section, described in Chapter 4, focuses on the production process of bupivacaine MVLs. Specifically, several critical process parameters (CPPs), including the lipids concentration, organic solvents, organic to aqueous ratio, emulsification methods, lysine concentration, and amino acids, were identified with bupivacaine MVL formulation in a double-emulsification based lab-scale production process. Critical quality attributes (CQAs), including morphology, size distribution, encapsulation efficiency, drug and lipids contents, and IVR, were characterized accordingly via the methodologies applied in the first section. This thesis provides insights into the generic development of bupivacaine MVLs, as well as deepens the understanding of MVLs and related drug products.