An assessment of the ocular safety of inactive excipients following sub-tenon injection in rabbits.
OBJECTIVE
This work characterized the safety and toleration of inactive excipients following sub-Tenon (ST) administration.


METHODS
Rabbits were anesthetized and eyes received an ST injection of the following test excipients: carboxy methylcellulose (CMC; low [90 kDa], mid [250 kDa], and high [700 kDa] molecular weight [MW], 0.25%-1.0% w/v), polysorbate 80 (0.02 and 0.2% w/v), polyethylene glycol 3350 (PEG; 0.2 and 1.0% w/v), poloxamer 188 (0.01 and 0.25% w/v), poloxamer 182 (2% w/v), benzyl alcohol (BA; 4% w/v), benzalkonium chloride (BAC; 0.02%, 0.04%, and 0.05% w/v), and methylcellulose (MC; 0.25% w/v). After a 1-week observation period for clinical signs of ocular tolerability, the animals were euthanized and eyes were collected for histologic examination.


RESULTS
The ocular tolerability of the tested excipients were ranked as follows from the innocuous to most deleterious: saline approximately PEG (1% w/v) approximately polysorbate 80 (0.2% w/v) > CMC (0.25% w/v, 90 kDa) > MC (0.25% w/v) approximately poloxomer 188 (0.25% w/v) approximately sodium citrate (pH 9) BAC (0.05% w/v) > CMC (0.5% w/v, 700 kDa) > poloxomer 182 (2% w/v) > BA (4% w/v). Clinical signs of ocular irritation were limited to redness and chemosis observed with most test excipients. The BA excipient also produced corneal opacity. Microscopic findings included histiocytic infiltration (BAC, BA, CMC, MC, and poloxamer 188), heterophilic inflammation (BA, CMC, and poloxamer 182), and edema (BAC, BA, CMC, and poloxamer 182) in episcleral tissue. The severity of the clinical and hisopathologic effects increased with the concentration of the test excipients administered.


CONCLUSIONS
This research has evaluated the safety profile of inactive excipients that may be used to formulate new chemical entities for the treatment of ocular disease following a ST injection.
Younis
Husam S
HS
Drug Safety Research and Development, Pfizer Global Research and Development, La Jolla Laboratories, San Diego, CA 92121, USA. husam.younis@pfizer.com
Shawer
Mohannad
M
Palacio
Kimberly
K
Gukasyan
Hovhannes J
HJ
Stevens
Greg J
GJ
Evering
Winston
W
D000818:Animals; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005079:Excipients / Q000008:administration & dosage / Q000633:toxicity*; D005123:Eye / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D007267:Injections; D007509:Irritants / Q000633:toxicity; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011817:Rabbits; D012720:Severity of Illness Index
D005079:Excipients; D007509:Irritants; D004364:Pharmaceutical Preparations