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Pharmaceutical Research

, 35:173 | Cite as

Safety Assessment of Formulation Vehicles Following Intravitreal Administration in Rabbits

  • Shirley A. Aguirre
  • Hovhannes J. Gukasyan
  • Husam S. Younis
  • Wenhu Huang
Research Paper
  • 217 Downloads
Part of the following topical collections:
  1. Ophthalmic Drug Discovery and Development

Abstract

Purpose

Evaluate 21 formulation vehicles administered to rabbits after intravitreal injection for tolerability and safety.

Methods

Forty-two Dutch Belted rabbits were anesthetized, and the eyes received a single intravitreal injection of the excipient formulation. Clinical signs and ocular irritation responses were recorded twice daily for 7 days and microscopic evaluation of the eyes, optic nerve, and eyelids was completed at 1-week post treatment.

Results

Saline (≥ 300 mOsm and ≤ 592 mOsm at pH 7.0 or 300 mOsm at pH 8.0) and 10 formulation excipients; (10% w/v PEG 3350 at pH 7.4, 1% polysorbate 21 at pH 7.4, PVA at pH 7.0, 0.2% polysorbate 80 at pH 7.2, 0.2% Pluronic F108® at pH 7.3, 2%, 100 mM sodium sulfate at pH 3.2, 2 mM sodium glycocholate at pH 7.4, and 275 mM D-mannitol pH 7.0 in sterile water, and 100 mM sodium phosphate in combination with 0.9% NaCl 300 mOsm and 0.01% or 0.05% polysorbate 80 at pH 7.4) considered as formulation vehicles for intravitreal injectables, were well-tolerated in rabbits. Clinical signs were transient and microscopic changes were not observed.

Conclusions

Of the 21 formulation vehicles evaluated, 10 formulation vehicles were well-tolerated in rabbits and feasible candidates for future investigations.

Key words

excipients formulations intravitreal rabbit safety 

Abbreviations

BRB

Blood retinal barrier

C26H42NNaO6

Sodium glycocholate

Captisol® or SBE-β-CD

Sulfobutylether-β-cyclodextrin

Da

Dalton

Ethocel™

Ethyl cellulose

GCL

Ganglion cell layer

INL

Inner nuclear layer

IPL

Inner plexiform layer

IS

Inner segment of photoreceptor layer

kDa

KiloDalton

Medisorb® or PLGA

Polylactic-co-glycolic acid

MNF

Myelinated nerve fiber

mOsm

Milliosmolarity

Na2SO4

Sodium sulfate

Na3PO4

Sodium phosphate

NaC6H7O7

Sodium citrate

NaCl

Sodium chloride

ONL

Outer nuclear layer

OPL

Outer plexiform layer

OS

Outer segment of photoreceptor layer

PEG

Polyethylene glycol

Pluronic® F108 or Poloxamer 338

Polyethylene-polypropylene glycol

PVA

Polyvinyl alcohol

RPE

Retinal pigment epithelium

Solutol® HS 15

Polyoxyl-15-hydrostearate

Notes

Acknowledgments and Disclosures

The authors would like to thank Winston Evering for review of the manuscript and helpful discussions, Carlos Esparza, Jessica Frey and Anthony Wong for histology assistance, Walter Collette III for in vivo support and Cristiana Janssen for graphic arts assistance.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Pfizer Inc., Drug Safety Research and DevelopmentLa Jolla LaboratoriesSan DiegoUSA
  2. 2.Virchow Toxpath LLCPrescottUSA
  3. 3.AllerganIrvineUSA
  4. 4.NGM Biopharmaceuticals, Inc.South San FranciscoUSA

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