Safety Assessment of Formulation Vehicles Following Intravitreal Administration in Rabbits
- 182 Downloads
Evaluate 21 formulation vehicles administered to rabbits after intravitreal injection for tolerability and safety.
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.
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.
Of the 21 formulation vehicles evaluated, 10 formulation vehicles were well-tolerated in rabbits and feasible candidates for future investigations.
Key wordsexcipients formulations intravitreal rabbit safety
Blood retinal barrier
- Captisol® or SBE-β-CD
Ganglion cell layer
Inner nuclear layer
Inner plexiform layer
Inner segment of photoreceptor layer
- Medisorb® or PLGA
Myelinated nerve fiber
Outer nuclear layer
Outer plexiform layer
Outer segment of photoreceptor layer
- Pluronic® F108 or Poloxamer 338
Retinal pigment epithelium
- Solutol® HS 15
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.
- 10.OECD.org. OECD Guideline For The Testing Of Chemicals. Proposal for an unpdated TG 405. Acute Eye Irritiation/Corrosion. OECD; 1987. p. 1–15.Google Scholar
- 12.Lorget F, Parenteau A, Carrier M, Lambert D, Gueorguieva A, Schuetz C, et al. Characterization of the pH and Temperature in the Rabbit, Pig, and Monkey Eye: Key Parameters for the Development of Long-Acting Delivery Ocular Strategies. Mol Pharm. 2015;23:23.Google Scholar
- 15.Hosoya K, Makihara A, Tsujikawa Y, Yoneyama D, Mori S, Terasaki T, et al. Roles of inner blood-retinal barrier organic anion transporter 3 in the vitreous/retina-to-blood efflux transport of p-aminohippuric acid, benzylpenicillin, and 6-mercaptopurine. J Pharmacol Exp Ther. 2009;329(1):87–93.CrossRefPubMedGoogle Scholar
- 16.Yanoff M, Sassini JW. Ocular Pathology. In: Gabbedy R, editor. Ocular pathology. 6th ed: Mosby Elesevier; 2009. p. 485.Google Scholar
- 18.Dow. Technical Data Sheet CarboxwaxTM Polyethylene Glycol (PEG) 400. In: Dow, editor. 2011.Google Scholar