Extended release microparticle-in-gel formulation of octreotide: Effect of polymer type on acylation of peptide during in vitro release

Abstract

Polymeric microparticle(MPs)-in-gel formulations for extended delivery of octreotide were developed. We investigated influence of polymer composition on acylation of octreotide and kinetics of release during in vitro release from biodegradable polymeric formulations. Polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA) and polyethylene glycol (PEG) based triblock (TB≈PCL10k-PEG2k-PCL10k) and pentablock (PBA≈PLA3k-PCL7k-PEG2k-PCL7k-PLA3k and PBB≈PGA3k-PCL7k-PEG2k-PCL7k-PGA3k) polymers were investigated. Octreotide was encapsulated in MPs using methanol-oil/water emulsion solvent evaporation method. The particles were characterized for size, morphology, encapsulation efficiency, drug loading and in vitro release. Release samples were subjected to HPLC analysis for quantitation and HPLC-MS analysis for identification of native and chemically modified octreotide adducts. Entrapment efficiency of methanol-oil/water method with TB, PBA and PBB polymers were 45%, 60%, and 82%, respectively. A significant fraction of released octreotide was acylated from lactide and glycolide based PBA (53%) and PBB (92%) polymers. Substantial amount of peptide was not released from PBB polymers after 330 days of incubation. Complete release of octreotide was achieved from TB polymer over a period of 3 months with minimal acylation of peptide (13%). PCL based polymers resulted in minimal acylation of peptide and hence may be suitable for extended peptide and protein delivery. Conversely, polymers having PLA and PGA blocks may not be appropriate for peptide delivery due to acylation and incomplete release.

Ocular delivery of proteins and peptides: Challenges and novel formulation approaches

“…To overcome the challenges of protein/peptide degradation and burst release, various strategies of hydrophobic ion-pairing (HIP) complexation, utilization of biocaompatible block-copolymers and on-demand drug release including pH, thermo, enzyme, light, ultrasound and multi responsive systems have been developed for ocular delivery [143]. Our laboratory has previously demonstrated the potential of such strategies including HIP complexation and block polymers in gel based formulations in sustaining release (~3 months) and minimizing acylation (<7%) of octreotide from microparticles [142, 144]. Fig.…”

Synthesis of three-arm block copolymer poly(lactic-<em>co</em>-glycolic acid)&ndash;poly(ethylene glycol) with oxalyl chloride and its application in hydrophobic drug delivery

“…Amphiphilic block copolymers, which possess a hydrophilic head and a hydrophobic tail, selfassemble into micelles in aqueous solution, and the hydrophobic center is achieved in this process. 3,9 These could not only be used as the delivery material of hydrophobic drugs 10 but could also be used in the delivery of hydrophilic drugs 11,12 and peptides, 13 which significantly enhance the permeability of various drugs and prolong retention.…”

“…All kinds of aliphatic polyesters, such as poly(l-lactic acid) (PLA), 14,15 poly(ε-caprolactone), 13,16 and poly(lacticco-glycolic acid) (PLGA), 17 have been linked with a hydrophilic polyethylene glycol (PEG) segment to yield the amphiphilic copolymer structure. 18 In 1994, the effect on pharmacokinetics of PLGA microparticles externally coated with PEG was first described.…”

Recent perspectives on the delivery of biologics to back of the eye

“…Acylation of peptides has been identified as a major challenge for sustained release of peptides from delivery systems [20,98,99]. Reversible hydrophobic ion pairing (HIP) complex strategy was used to minimize octreotide acylation during long time delivery from PLGA microparticles by Vaishya et al Sodium dodecyl sulfate and dextran sulfate with different molecular weights were used as ion pairing agents to prepare HIP complex with octreotide [21].…”

“…delivery of biologics to the back-of-the-eye tissues (retina-choroid) [3], [19]. Biologics display numerous delivery related limitations such as absorption/permeability across biological membranes, poor bioavailability and in vivo stability [20,21]. Short in vivo half-life of biologics demands frequent intravitreal administrations which lowers patient compliance.…”