Abstract
Purpose :
Active Pharmaceutical ingredient Nanoparticle Technology (APNT™) is an innovative approach to aid drugs facing challenges in solubility and bioavailability. APNT utilizes salts and sugars as milling media to reduce the particle size of active pharmaceutical ingredients (API) routinely<200 nm without use of organic solvents or chemical dispersants. In vivo studies assessed investigational ophthalmic agents utilizing APNT in a potent corticosteroid, APP13007 (API-1) clobetasol propionate, and a known macrolide antibiotic (API-2).
Methods :
Two small molecule APIs were milled using APNT and assessed in vivo in rabbits evaluating the effect of particle size, absorption, pharmacokinetics (PK), and ocular tissue distribution. For API-1, PK of unprocessed and milled API were evaluated via instillation in the conjunctival sac (50 μl, n=5). An endotoxin-induced uveoretinitis model examined the inflammatory prostaglandin E2 (PGE2) levels (1x and 2x/day, 6 days) compared to control and a commercially available corticosteroid. For API-2, a single and repeat dosing (7 days, 24h) study evaluated the PK and ocular tissue distribution (n=4). For the single dose APNT API-2 was compared to the unprocessed API observed over 6h.
Results :
For API-1 drug absorption (Cmax) significantly improved through particle size reduction via APNT. In the aqueous humor (AH), Cmax was 39 ng/ml and 2 ng/ml at 1h for the nanomilled and unprocessed API, respectively. Corneal exposure (AUC0-8h) improved ≥6 times with APNT. API-1 reduced PGE2 levels in a dose-dependent manner 5-7 times compared to the control and 2-3 times compared to the corticosteroid. No significant systemic exposure was observed in 7 days. API-2 had minimal systemic absorption and retained similar concentration in ocular tissues of the cornea, conjunctiva, and meibomian glands for 24h. API-2 was absorbed more in the AH utilizing APNT (456 ng/mL) compared to unprocessed material (132 ng/mL) at 2h.
Conclusions :
APNT nanoparticle technology affords improved delivery of poorly soluble medications and limited bioavailability. Drug penetration and residence time were enhanced by APNT in these in vivo studies with the potential to improve dissolution and distribution within ocular tissues. In the case of API-1, phase 3 trials have been conducted (presented at ASCRS 2023) for the treatment of pain and inflammation post-ocular surgery and showed promising results using APNT in humans.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.