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Solution Formulation Development of a VEGF Inhibitor for Intravitreal Injection

  • Research Article
  • Theme: Sterile Products: Advances and Challenges in Formulation, Manufacturing, Devices and Regulatory Aspects
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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.

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Acknowledgments

The supporting contributions of the following colleagues are gratefully acknowledged: Dr. Danhua Chen, Brian Samas, Chris Seadeek, Dr. Jaymin Shah, Chang Shu, and Dr. Anand Sistla.

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Authors and Affiliations

  1. Research Enabling Group, Pfizer Inc, 10777 Science Center Drive, San Diego, California, 92121, USA

    Michelle T. Marra, Penney Khamphavong & Hovhannes J. Gukasyan

  2. Parenteral Center of Emphasis, Pfizer Inc, Groton, Connecticut, USA

    Peter Wisniecki

  3. Pharmaceutical Development, GlaxoSmithKline, Research Triangle Park, North Carolina, USA

    Katsuhiko Sueda

Authors
  1. Michelle T. Marra
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  2. Penney Khamphavong
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  3. Peter Wisniecki
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Correspondence to Michelle T. Marra.

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Guest Editors: Lavinia Lewis, Jim Agalloco, Bill Lambert, Russell Madsen, and Mark Staples

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Marra, M.T., Khamphavong, P., Wisniecki, P. et al. Solution Formulation Development of a VEGF Inhibitor for Intravitreal Injection. AAPS PharmSciTech 12, 362–371 (2011). https://doi.org/10.1208/s12249-011-9591-4

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  • DOI: https://doi.org/10.1208/s12249-011-9591-4

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