title: Design of Controlled Release PLGA Microspheres for Hydrophobic Fenretinide.
abstract: Fenretinide, a chemotherapeutic agent for cancer, is water-insoluble and has a very low oral bioavailability. Hence, the objective was to deliver it as an injectable depot and improve the drug solubility and release behavior from poly(lactide-co-glycolide) (PLGA) microspheres by incorporating nonionic surfactants with fenretinide. Enhancement of drug solubilization was observed with Brij 35 or 98, Tween 20, and Pluronic F127, but not Pluronic F68. Co-incorporation of Brij 98 with fenretinide significantly changed the microsphere morphology and improved the fenretinide release profile. The most optimal microsphere formulation, with 20% Brij 98 as excipient, showed an initial in vitro burst around 20% and a sustained release over 28 days in a solubilizing release medium at 37 °C. The effect of addition of MgCO3, drug loading, and polymer blending on the release of fenretinide from PLGA microspheres was also investigated and observed to enhance the drug release. Two sustained release formulations, one incorporating 20% Brij 98 and the other incorporating 3% MgCO3 in the oil phase, were selected for dosing in Sprague-Dawley rats and compared to a single injection of an equivalent dose of fenretinide drug suspension. These two formulations were chosen due to their high encapsulation efficiency, high cumulative release, and desirable in vitro release profile. The drug suspension resulted in a higher initial release in rats compared to the polymeric formulations, however, sustained release was also observed beyond 2 weeks, which may be attributed to the physiological disposition of the drug in vivo. The two PLGA based test formulations provided the desired low initial burst of fenretinide followed by 4 weeks of in vivo sustained release.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Wischke
authors.affiliation: Pharmaceutical Sciences and Clinical Supply, Merck Research Laboratories (MRL), Merck & Co. , Kenilworth, New Jersey 07033, United States.
authors.forename: Sachin
authors.initials: S
authors.lastname: Mittal
authors.affiliation: Pharmaceutical Sciences and Clinical Supply, Merck Research Laboratories (MRL), Merck & Co. , West Point, Pennsylvania 19486, United States.
authors.forename: Amitava
authors.initials: A
authors.lastname: Mitra
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109, United States.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Schwendeman
mesh_terms: D000818:Animals; D005079:Excipients / Q000737:chemistry; D005260:Female; D017313:Fenretinide / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D019344:Lactic Acid / Q000737:chemistry*; D008274:Magnesium / Q000737:chemistry; D008863:Microspheres; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D005079:Excipients; D011108:Polymers; D013501:Surface-Active Agents; C005479:magnesium carbonate; D017313:Fenretinide; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D008274:Magnesium
keywords: PLGA; bioavailability; excipient; microspheres; sustained release