title: Extended release microparticle-in-gel formulation of octreotide: Effect of polymer type on acylation of peptide during in vitro release.
abstract: Polymeric microparticles (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.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA; Insys therapeutics Inc., 444 South Ellis St., Chandler, AZ 85224, USA. Electronic address: rvaishya@insysrx.com.
authors.forename: Ravi D
authors.initials: RD
authors.lastname: Vaishya
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA.
authors.forename: Abhirup
authors.initials: A
authors.lastname: Mandal
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA.
authors.forename: Sulabh
authors.initials: S
authors.lastname: Patel
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, MO 64108-2718, USA. Electronic address: mitraa@umkc.edu.
authors.forename: Ashim K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D000215:Acylation; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics; D005782:Gels; D019344:Lactic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D008863:Microspheres; D015282:Octreotide / Q000737:chemistry* / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000737:chemistry* / Q000493:pharmacokinetics; D011091:Polyesters / Q000737:chemistry / Q000493:pharmacokinetics; D011100:Polyglycolic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D011108:Polymers / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D003692:Delayed-Action Preparations; D005782:Gels; D010446:Peptide Fragments; D011091:Polyesters; D011108:Polymers; C016240:polycaprolactone; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide); D015282:Octreotide
keywords: Drug delivery; Hydrogel; Microparticles; Peptide; Peptide chemical stability; Polycaprolactone; Polyglycolic acid; Polylactic acid; Sustained delivery