June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Prodrugs of carbonic anhydrase inhibitors to enable continuous delivery from a depot for up to 6 months after subconjunctival delivery
Author Affiliations & Notes
  • Bryan Hoang
    Graybug Vision Inc., Redwood City, California, United States
  • Christopher Crean
    Chatham Biopharma Consulting LLC, Pittsboro, North Carolina, United States
  • Ming Yang
    Graybug Vision Inc., Redwood City, California, United States
  • Abraham Anonuevo
    Graybug Vision Inc., Redwood City, California, United States
  • Ward Peterson
    Graybug Vision Inc., Redwood City, California, United States
  • Jeffrey Cleland
    Graybug Vision Inc., Redwood City, California, United States
  • Footnotes
    Commercial Relationships   Bryan Hoang, GrayBug Vision Inc (E), GrayBug Vision Inc (P); Christopher Crean, Chatham Biopharma Consulting LLC (E), GrayBug Vision Inc (C); Ming Yang, GrayBug Vision Inc (E), GrayBug Vision Inc (P); Abraham Anonuevo, GrayBug Vision Inc (E); Ward Peterson, GrayBug Vision Inc (E); Jeffrey Cleland, GrayBug Vision Inc (I), GrayBug Vision Inc (E), GrayBug Vision Inc (P), GrayBug Vision Inc (S)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4118. doi:
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      Bryan Hoang, Christopher Crean, Ming Yang, Abraham Anonuevo, Ward Peterson, Jeffrey Cleland; Prodrugs of carbonic anhydrase inhibitors to enable continuous delivery from a depot for up to 6 months after subconjunctival delivery. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4118.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Many compounds are not amenable to sustained delivery technologies due to their physicochemical properties. Prodrugs of carbonic anhydrase inhibitors (CAI) have been designed and incorporated in microparticles to provide a 6 month subconjunctival formulation.

Methods : A number of prodrugs containing brinzolamide and dorzolamide were designed and synthesized by conjugating a biodegradable polymer chain to the CAI. Physiochemical properties of the prodrugs were characterized in vitro, including solubility and degradation kinetics. The inhibitory potency of the prodrugs and their degradants against carbonic anhydrase was also measured in vitro using an enzymatic assay. Polymer microparticles encapsulating the prodrugs were developed and fully characterized in vitro, including particle size, drug loading and drug release. A pharmacokentic study was conducted to evaluate the clearance and the potential to degrade to native CAIs. Male rats were administered the prodrugs in a saline solution at 0.3 mg/kg IV dose, followed by blood and plasma collection at multiple time points over 72 hours. Samples were analyzed for the administered CAI prodrug, metabolites containing one monomer moiety, and the originally approved CAI by LC/MS.

Results : Prodrugs were shown to degrade in vitro at physiological pH and temperature. The polymer chain conjugated to the parent CAI molecules hydrolyzes and degrades into oligomers or monomer.The in vitro potency of the degradants against carbonic anhydrase increases as the length of the polymer chain decreases. After a single IV dose, the prodrugs were well tolerated. The in vivo degradation profile was similar to that of in vitro studies and the native CAI were not detected in either matrix at quantifiable concentrations above 4 ng/mL. Both brinzolamide and dorzolamide degradants with one monomer unit still attached to the parent molecules were detected at the earliest time point evaluated (15 minutes) and exhibited a rapid decline in concentration through 2 hours followed by a more prolonged terminal phase of elimination through 24 hours. Polymer microparticles encapsulating the prodrugs were shown to be able to release the payload in a sustained manner for up to 6 months in vitro.

Conclusions : This approach may lead to a new long-term and effective treatment forocular hypertension through only one to two periocular injections per year.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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