Preclinical Evaluation of a Triamcinolone Acetonide Preservative Free (TAC–PF) Formulation for Intravitreal Injection

Abstract

Abstract: : Purpose: Benzyl alcohol, a preservative in Kenalog–40 (Triamcinolone Acetonide, Bristol Myers–Squibb), has been linked to a 1–2% incidence of sterile endophthalmitis in humans following intravitreal injection. We prepared a preservative free formulation of Triamcinolone Acetonide (TAC–PF) as an alternative to Kenalog–40 and compared the pharmacokinetics of both formulations following a single intravitreal injection. Methods: The USP 26 grade of triamcinolone acetonide (TA) powder available in the USA is micronized (i.e.< 10 microns). TAC–PF was prepared at the NIH pharmacy in sterile vials using a median particle size of 4 microns. The median particle size of Kenalog–40 lot 2J57505 is 17.3 microns. A standard 4 mg dose of Kenalog–40 and TAC–PF was injected into the vitreous of NZW rabbits and the animals were sacrificed over time. TA levels in the aqueous and vitreous humor were measured using HPLC. A 4 mg dose of TAC–PF was also evaluated in Dutch–Belted (DB) rabbits and a 16 mg dose of TAC–PF evaluated in NZW rabbits. Serial ERG’s and histopathology was performed in another group of rabbits, 1 receiving a 4 mg dose of TAC–PF, another receiving a 16 mg dose of TAC–PF. Results: (See Table) There were no detectable levels of TA in the aqueous humor of any of the rabbits. Clinical examinations of all test groups were normal over time. The serial ERGs remained normal over time in rabbits receiving TAC–PF 4 mg (over 4 months) and 16 mg (over 5 months) dose. Histopathology on the rabbit eyes receiving a 4 mg dose of TAC–PF was normal. Conclusions: Despite the significant differences in the median particle sizes of TA in the TAC–PF and Kenalog–40 formulations, the half–life of the drug in the vitreous was essentially the same following a 4 mg injection. A 16 mg dose of TAC–PF gives a substantially longer vitreous half–life without changes in the ERGs. With TAC–PF, the estimated length of time drug would be seen in the vitreous following a 4 mg and 16 mg intravitreal injection would be 96 and 200 days, respectively. TA vitreous half–life 

Keywords: corticosteroids • pharmacology • drug toxicity/drug effects