title: Improved small molecule drug release from in situ forming poly(lactic-co-glycolic acid) scaffolds incorporating poly(β-amino ester) and hydroxyapatite microparticles.
abstract: In situ forming implants are an attractive choice for controlled drug release into a fixed location. Currently, rapidly solidifying solvent exchange systems suffer from a high initial burst, and sustained release behavior is tied to polymer precipitation and degradation rate. The present studies investigated addition of hydroxyapatite (HA) and drug-loaded poly(β-amino ester) (PBAE) microparticles to in situ forming poly(lactic-co-glycolic acid) (PLGA)-based systems to prolong release and reduce burst. PBAEs were synthesized, imbibed with simvastatin (osteogenic) or clodronate (anti-resorptive), and then ground into microparticles. Microparticles were mixed with or without HA into a PLGA solution, and the mixture was injected into buffer, leading to precipitation and creating solid scaffolds with embedded HA and PBAE microparticles. Simvastatin release was prolonged through 30 days, and burst release was reduced from 81 to 39% when loaded into PBAE microparticles. Clodronate burst was reduced from 49 to 32% after addition of HA filler, but release kinetics were unaffected after loading into PBAE microparticles. Scaffold dry mass remained unchanged through day 15, with a pronounced increase in degradation rate after day 30, while wet scaffolds experienced a mass increase through day 25 due to swelling. Porosity and pore size changed throughout degradation, likely due to a combination of swelling and degradation. The system offers improved release kinetics, multiple release profiles, and rapid solidification compared to traditional in situ forming implants.
authors.affiliation: a Department of Biomedical Engineering , University of Kentucky , Lexington , KY 40506 , USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Fisher
authors.forename: Pablo
authors.initials: P
authors.lastname: Palomino
authors.forename: Todd A
authors.initials: TA
authors.lastname: Milbrandt
authors.forename: J Zach
authors.initials: JZ
authors.lastname: Hilt
authors.forename: David A
authors.initials: DA
authors.lastname: Puleo
mesh_terms: D004002:Clodronic Acid / Q000737:chemistry; D004343:Drug Implants / Q000737:chemistry*; D065546:Drug Liberation; D017886:Durapatite / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry*; D007700:Kinetics; D019344:Lactic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry*; D016062:Porosity; D019821:Simvastatin / Q000737:chemistry
chemical_list: D004343:Drug Implants; D020100:Hydrogels; D011108:Polymers; C507253:poly(beta-amino ester); D004002:Clodronic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017886:Durapatite; D019821:Simvastatin
keywords: In situ precipitation; PLGA; clodronate; injectable; poly(β-amino ester); simvastatin