PLGA encapsulated γ-cyclodextrin-meropenem inclusion complex formulation for oral delivery

Aun Raza; Jared A Miles; Fekade Bruck Sime; Benjamin P Ross; Jason A Roberts; Amirali Popat; Tushar Kumeria; James R Falconer

doi:10.1016/j.ijpharm.2021.120280

PLGA encapsulated γ-cyclodextrin-meropenem inclusion complex formulation for oral delivery

Int J Pharm. 2021 Mar 15:597:120280. doi: 10.1016/j.ijpharm.2021.120280. Epub 2021 Feb 1.

Authors

Aun Raza¹, Jared A Miles², Fekade Bruck Sime¹, Benjamin P Ross², Jason A Roberts³, Amirali Popat⁴, Tushar Kumeria⁵, James R Falconer⁶

Affiliations

¹ School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia; Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Woolloongabba 4102, QLD, Australia.
² School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia.
³ School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia; Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Woolloongabba 4102, QLD, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane 4029, QLD, Australia; Department of Pharmacy, Royal Brisbane and Women's Hospital, Brisbane 4029, QLD, Australia.
⁴ School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia; Mucosal Diseases Group, Mater Research Institute - The University of Queensland, Translational Research Institute, 37 Kent St, Woolloongabba, QLD 4102, Australia. Electronic address: a.popat@uq.edu.au.
⁵ School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia; School of Materials Science and Engineering, The University of New South Wales, Sydney NSW-2052, Australia. Electronic address: t.kumeria@unsw.edu.au.
⁶ School of Pharmacy, The University of Queensland, Woolloongabba 4102, Australia. Electronic address: j.falconer@uq.edu.au.

PMID: 33540004
DOI: 10.1016/j.ijpharm.2021.120280

Abstract

Meropenem (MER) is one of the last resort antibiotics used to treat resistant bacterial infections. However, the clinical effectiveness of MER is hindered due to chemical instability in aqueous solution and gastric pH, and short plasma half-life. Herein, a novel multi-material delivery system based on γ-cyclodextrin (γ-CD) and poly lactic-co-glycolic acid (PLGA) is demonstrated to overcome these challenges. MER showed a saturated solubility of 14 mg/100 mL in liquid CO₂ and later it was loaded into γ-CD to form the inclusion complex using the liquid CO₂ method. The γ-CD and MER inclusion complex (MER-γ-CD) was encapsulated into PLGA by the well-established double emulsion solvent evaporation method. The formation of the inclusion complex was confirmed using FTIR, XRD, DSC, SEM, and ¹H NMR and docking study. Further, MER-γ-CD loaded PLGA nanoparticles (MER-γ-CD NPs) were characterized by SEM, DLS, and FTIR. The drug loading and entrapment efficiency for MER-γ-CD were 21.9 and 92. 2% w/w, respectively. However, drug loading and entrapment efficiency of MER-γ-CD NPs was significantly lower at up to 3.6 and 42.1% w/w, respectively. In vitro release study showed that 23.6 and 27.4% of active (non-degraded drug) and total drug (both degraded and non-degraded drug) were released from MER-γ-CD NPs in 8 h, respectively. The apparent permeability coefficient (Papp) (A to B) for MER, MER-γ-CD, and MER-γ-CD NPs were 2.63 × 10^-6 cm/s, 2.81 × 10^-6 cm/s, and 2.92 × 10^-6 cm/s_, respectively. For secretory transport, the Papp (B to A) were 1.47 × 10^-6 cm/s, 1.53 × 10^-6 cm/s, and 1.58 × 10^-6 cm/s for MER, MER-γ-CD and MER-γ-CD NPs_, respectively. Finally, the MER-γ-CD inclusion complex and MER-γ-CD NPs retained MER's antibacterial activities against Staphylococcus aureus and Pseudomonas aeruginosa. Overall, this work demonstrates the significance of MER-γ-CD NPs to protect MER from gastric pH with controlled drug release, while retaining MER's antibacterial activity.

Keywords: Cyclodextrins; Liquid CO(2); Meropenem; Oral antibiotics; Oral drug delivery; PLGA nanoparticles.

MeSH terms

Drug Carriers
Drug Liberation
Glycols
Meropenem
Nanoparticles*
Particle Size
gamma-Cyclodextrins*

Substances

Drug Carriers
Glycols
gamma-Cyclodextrins
Meropenem