title: Trehalose limits BSA aggregation in spray-dried formulations at high temperatures: implications in preparing polymer implants for long-term protein delivery.
abstract: Polymer implants are promising systems for sustained release applications but their utility for protein delivery has been hindered because of concerns over drug stability at elevated temperatures required for processing. Using bovine serum albumin (BSA) as a model, we have assessed whether proteins can be formulated for processing at elevated temperatures. Specifically, the effect of trehalose and histidine-HCl buffer on BSA stability in a spray-dried formulation has been investigated at temperatures ranging from 80°C to 110°C. When both the sugar and buffer are present, aggregation is suppressed even when exposed to 100°C, the extrusion temperature of poly(lactide-co-glycolide) (PLGA), a bioresorbable polymer. Estimation of aggregation rate constants (k) indicate that though both trehalose and histidine-HCl buffer contribute to BSA stability, the effect because of trehalose alone is more pronounced. BSA-loaded PLGA implants were prepared using hot-melt extrusion process and in vitro release was conducted in phosphate buffered saline at 37°C. Comparison of drug released from implants prepared using four different formulations confirmed that maximal release was achieved from the formulation in which BSA was least aggregated. These studies demonstrate that when trehalose and histidine-HCl buffer are included in spray-dried formulations, BSA stability is maintained both during processing at 100°C and long-term residence within implants.
authors.affiliation: Drug Delivery Department, Genentech Inc., 1 DNA Way South San Francisco, California 94080, USA. rajagopal.karthikan@gene.com
authors.forename: Karthikan
authors.initials: K
authors.lastname: Rajagopal
authors.forename: Joseph
authors.initials: J
authors.lastname: Wood
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tran
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Patapoff
authors.forename: Thierry
authors.initials: T
authors.lastname: Nivaggioli
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D002417:Cattle; D003692:Delayed-Action Preparations / Q000737:chemistry*; D003890:Desiccation; D006358:Hot Temperature; D019344:Lactic Acid / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D055550:Protein Stability; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000737:chemistry; D014199:Trehalose / Q000737:chemistry*
chemical_list: D003692:Delayed-Action Preparations; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D012710:Serum Albumin, Bovine; D019344:Lactic Acid; D014199:Trehalose
keywords: hot-melt extrusion; polymer implants; protein delivery; solid state; spray drying; stability; trehalose