Reversible hydrophobic ion-paring complex strategy to minimize acylation of octreotide during long-term delivery from PLGA microparticles

Abstract

Acylation of peptide has been reported for a number of peptides and proteins during release from polymers comprising of lactide and glycolide. We hypothesize that reversible hydrophobic ion-pairing (HIP) complex may minimize octreotide acylation during release. Sodium dodecyl sulfate (SDS), dextran sulfate A (DSA, Mw 9–20kDa) and dextran sulfate B (DSB, Mw 36–50kDa) were selected as ion-pairing agents to prepare reversible HIP complex with octreotide. Complexation efficiency was optimized with respect to the mole ratio of ion-pairing agent to octreotide to achieve 100% complexation of octreotide. Dissociation studies suggested that DSA-octreotide and DSB-octreotide complexes dissociate completely at physiological pH in presence of counter ions unlike SDS-octreotide complex. DSA-octreotide and DSB-octreotide complex encapsulated PLGA microparticles (DSAMPs and DSBMPs) were prepared using the S/O/W emulsion method. Entrapment efficiencies for DSAMPs and DSBMPs were 74.7±8.4% and 81.7±6.3%, respectively. In vitro release of octreotide was performed by suspending MPs in gel. A large fraction of peptide was released in chemically intact form and <7% was acylated from DSAMPs and DSBMPs in gel over 55 days. Therefore, HIP complexation could be a viable strategy to minimize acylation of peptides and proteins during extended release from lactide and glycolide based polymers.

Intestinal permeation enhancers for oral peptide delivery

“…Other examples of HIP complexation include heparin with deoxycholylethylamine [348] and insulin with PC [351]. HIP was also used as a strategy to prevent acylation of octreotide during release from microparticles composed of lactide and glycolide [352]. there is considerable debate on how they alter intestinal permeability.…”

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

“…We have previously shown that acylation of octreotide from PGLA MPs-in-gel system can be minimized by using hydrophobic ion-pairing approach (Vaishya et al, 2015b). However, release rate was very high and as a result >80% octreotide was released within 3 weeks.…”

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

“…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]. Microparticles were prepared with HIP complexed with octreotide and PLGA polymer.…”

“…Octreotide was released for extended time period. A large percentage of released octreotide was in native form and only less than 7% was acylated [21]. In addition, Shirangi et al inhibited acylation by temporarily and reversibly block the amine groups in the peptide chain with a protective group.…”

“…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.…”