title: Solution formulation development of a VEGF inhibitor for intravitreal injection.
abstract: PF-00337210 is a potent, selective small molecule inhibitor of VEGFRs and has been under consideration for the treatment of age-related macular degeneration. An ophthalmic solution formulation intended for intravitreal injection was developed. This formulation was designed to maximize drug properties such that the formulation would precipitate upon injection into the vitreous for sustained delivery. As a parenteral formulation with additional constraints dictated by this specialized delivery route, multiple features were balanced in order to develop a successful formulation. Some of these considerations included low dosing volumes (≤0.1 mL), a limited repertoire of safe excipients for intravitreal injection, and the unique physical chemical properties of the drug. The aqueous solubility as a function of pH was characterized, buffer stressing studies to select the minimal amount of buffer were conducted, and both chemical and physical stability studies were executed. The selected formulation consisted of an isotonic solution comprised of PF-00337210 free base in a citrate-buffered vehicle containing NaCl for tonicity. The highest strength for regulatory toxicology studies was 60 mg/mL. The selected formulation exhibited sufficient chemical stability upon storage with no precipitation, and acceptable potency and recovery through an intravitreal dosing syringe. Formulation performance was simulated by precipitation experiments using extracted vitreous humor. In simulated injection experiments, PF-00337210 solutions reproducibly precipitated upon introduction to the vitreous so that a depot was formed. To our knowledge, this is the first time that a nonpolymeric in situ-forming depot formulation has been developed for intravitreal delivery, with the active ingredient as the precipitating agent.
authors.affiliation: Research Enabling Group, Pfizer Inc, 10777 Science Center Drive, San Diego, California 92121, USA. michelle.marra@pfizer.com
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Marra
authors.forename: Penney
authors.initials: P
authors.lastname: Khamphavong
authors.forename: Peter
authors.initials: P
authors.lastname: Wisniecki
authors.forename: Hovhannes J
authors.initials: HJ
authors.lastname: Gukasyan
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Sueda
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000494:pharmacology; D002021:Buffers; D004285:Dogs; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004355:Drug Stability; D005079:Excipients; D006801:Humans; D006863:Hydrogen-Ion Concentration; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000188:drug therapy*; D009883:Ophthalmic Solutions; D019999:Pharmaceutical Solutions; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D011817:Rabbits; D012995:Solubility; D013535:Suspensions; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors*; D014822:Vitreous Body / Q000187:drug effects*
chemical_list: D001572:Benzofurans; D002021:Buffers; D005079:Excipients; D009883:Ophthalmic Solutions; C562231:PF 00337210; D019999:Pharmaceutical Solutions; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D013535:Suspensions; D042442:Vascular Endothelial Growth Factors