Hydrophilic Prodrug Approach for Reduced Pigment Binding and Enhanced Transscleral Retinal Delivery of Celecoxib

Abstract

Purpose Transscleral retinal delivery of celecoxib, an anti-inflammatory and anti-VEGF agent is restricted by its poor solubility and binding to the melanin pigment in choroid-RPE. The purpose of this study was to develop soluble prodrugs of celecoxib with reduced pigment binding and enhanced retinal delivery. Methods Three hydrophilic amide prodrugs of celecoxib were synthesized and characterized for solubility and lipophilicity. In vitro melanin binding to natural melanin (Sepia Officinalis) was estimated for all three prodrugs. In vitro transport studies across isolated bovine sclera and sclera-choroid-RPE (SCRPE) were performed. Prodrug with the highest permeability across SCRPE was characterized for metabolism and cytotoxicity and its in vivo transscleral delivery in pigmented rats. Results Celecoxib succinamidic acid (CSA), celecoxib maleamidic acid (CMA), and celecoxib acetamide (CAA) were synthesized and characterized. Aqueous solubilities of CSA, CMA, and CAA were 300-, 182-, and 76-fold higher, respectively, than celecoxib. Melanin binding affinity and capacity was significantly lower than celecoxib for all three prodrugs. Rank order for the % in vitro transport across bovine sclera and SCRPE was CSA > CMA ~ CAA ~ celecoxib, with the transport being 8-fold higher for CSA than celecoxib. CSA was further assessed for its metabolic stability and in vivo delivery. CSA showed optimum metabolic stability in all eye tissues with only 10–20 % conversion to parent celecoxib in 30 minutes. Metabolic enzymes responsible for bioconversion included amidases, esterase, and cytochrome P-450. In vivo delivery in pigmented BN rats showed that CSA had 4.7-, 1.4-, 3.3-, 6.0-, and 4.5- fold higher delivery to sclera, choroid-RPE, retina, vitreous, and lens than celecoxib. CSA has no cytotoxicity in ARPE-19 cells in the concentration range of 0.1 to 1000 μM. Conclusions Celecoxib succinamidic acid is a soluble prodrug of celecoxib with reduced melanin binding which enhances transscleral retinal delivery of celecoxib.

Transporter Targeted Gatifloxacin Prodrugs: Synthesis, Permeability, and Topical Ocular Delivery

“…In our previous report on celecoxib amide prodrugs, we showed that amide prodrugs are metabolized by esterases, amidases, and CYP450 enzymes that are present in both ocular tissues and plasma. 41 Interestingly, we did not observe any significant conversion of the prodrug during in vitro transport study. However, we observed significant conversion during in vivo studies.…”

“…Although we have not identified the metabolic enzymes involved in bioconversion of prodrug to drug, based on prodrug chemistry we speculate that amidases, CYP450, and esterases are involved in bioconversion of prodrug to drug. In our previous report on celecoxib amide prodrugs, we showed that amide prodrugs are metabolized by esterases, amidases, and CYP450 enzymes that are present in both ocular tissues and plasma …”

“…42 Second, there is a difference in the availability of cosubstrates for enzymatic conversion between in vitro and in vivo studies. We recently reported that eye tissues metabolize amide prodrugs via multiple pathways including CYP450 enzymes, 41 which require cosubstrates such as NADPH for metabolism. Assay buffer (pH 7.4) used in this study for permeability experiments did not have a NADPH or NADPH regenerating system.…”

Overcoming ocular drug delivery barriers through the use of physical forces

“…Formulation-based approaches utilize chemical penetration enhancers [4], prodrugs [5], penetrating peptides [6], and drug delivery carriers such as liposomes [7] and nano-or microparticles [8] to increase drug penetration across these barriers. Physical force-based methods, on the other hand, generally require a physical device, driven by a power generator, to deliver energy to the barriers resulting in transient drug transport enhancement or to physically breach these barriers.…”

Controlled release of corticosteroid with biodegradable nanoparticles for treating experimental autoimmune uveitis

“…Drugs administered by SCT injection are thought to penetrate into the eye by trans-scleral diffusion [29][30][31], a process that is limited for drugs that are poorly water-soluble [32][33][34].…”