Poloxamer 407/TPGS Mixed Micelles as Promising Carriers for Cyclosporine Ocular Delivery

Abstract

Cyclosporine is an immunosuppressant agent approved for the treatment of dry eye disease and used off-label for other ocular pathologies. Its formulation and ocular bioavailability present a real challenge due to the large molecular weight (1.2 kDa), high lipophilicity, and low water solubility. The aim of the work was to develop an aqueous micellar formulation for an efficient cyclosporine delivery to the ocular tissues, using a water-soluble derivative of vitamin E (TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate) and poloxamer 407 (Pluronic ®F127) as excipients. The mixed micelles were characterized in terms of particle size, zeta potential, rheology, and stability upon dilution and freeze-drying. Additionally, the enzymatic-triggered release of vitamin E and vitamin E succinate from TPGS was investigated in vitro in the presence of esterase. Compared to the commercially available ophthalmic formulation, the poloxamer 407:TPGS 1:1 molar ratio micellar formulation significantly improved cyclosporine solubility, which increased proportionally to surfactant concentration reaching 0.4% (w/v) for 20 mM surfactant total concentration. Cyclosporine-loaded mixed micelles efficiently retained the drug once diluted in simulated lachrymal fluid and, in the presence of a 20 mM surfactant concentration, were stable upon freeze-drying. The drug-loaded mixed micelles were applied ex vivo on porcine cornea and compared to Ikervis®. Drug accumulation in the cornea resulted proportional to drug concentration (6.4 ± 1.9, 17.6 ± 5.4, and 26.9 ± 7.4 μg/g, after 3 h for 1, 2.5, and 4 mg/mL cyclosporine concentration respectively). The formulation containing cyclosporine 4 mg/mL (20 mM surfactant) was also evaluated on the sclera, with a view to targeting the posterior segment. The results demonstrated the capability of mixed micelles to diffuse into the sclera and sustain cyclosporine delivery (28 ± 7, 38 ± 10, 57 ± 9, 145 ± 27 μg/cm cyclosporine accumulated after 3, 6, 24, and 48 h respectively). Reservoir effect experiments demonstrated that the drug accumulated in the sclera can be slowly released into the underlying tissues. Finally, all the formulations developed in this work successfully passed the HET-CAM assay for the evaluation of ocular irritability.

Assembling Surfactants-Mucoadhesive Polymer Nanomicelles (ASMP-Nano) for Ocular Delivery of Cyclosporine-A

“…The nanomicelles favour solubilisation processes by sequestering the drug in the lipophilic core, formed by the non-polar tails of the surfactant, and interacting with the hydrophilic environment through an outer shell consisting of polar or charged heads. Several reports support the use of surfactant micelles for improved penetration of topically applied drugs through the cornea and enhanced ocular bioavailability [26][27][28][29][30]. Recently (2018), the FDA approved the first commercial product containing 0.09% CyA based on micellization technology (Cequa from Sun Pharmaceutical Ind., Cranbury, NJ, USA) [31].…”

<p>A Review of Topical Cyclosporine A Formulations—A Disease-Modifying Agent for Keratoconjunctivitis Sicca</p>

“…38 In addition, studies are under way to test a different aqueous micellar formulation containing poloxamer 407 and a water-soluble derivative of vitamin E as excipients to enhance CsA solubility and intraocular penetration. 39 These components may provide the advantage of enhanced drug solubility and permeability in addition to beneficial antioxidant effect from vitamin E. 39 On examination, these CsA loaded micelles demonstrated stability upon dilution and increased CsA solubility and delivery to ocular tissues. 39 Another approach to increase bioavailability and residence time of drug is by using contact lenses with hydrogel-loaded drug particles.…”

“…39 These components may provide the advantage of enhanced drug solubility and permeability in addition to beneficial antioxidant effect from vitamin E. 39 On examination, these CsA loaded micelles demonstrated stability upon dilution and increased CsA solubility and delivery to ocular tissues. 39 Another approach to increase bioavailability and residence time of drug is by using contact lenses with hydrogel-loaded drug particles. A recent study has explored monomeric gels loaded with high concentrations of CsA for in situ formation of drug particles, to bypass tolerability issues associated with excipients.…”

Fundamentals, challenges, and nanomedicine‐based solutions for ocular diseases

“…Since polymeric micelles contain a hydrophobic core and a hydrophilic shell, they are better suited for delivery of hydrophobic drugs across various ocular barriers. Polymeric micelle formulations have been shown to improve bioavailability at anterior eye tissues, offer better intrascleral diffusion and to sustain delivery of therapeutic agents for ophthalmic dug delivery applications (Grimaudo et al, ). A study reported by X. Li et al () demonstrated enhanced corneal permeation (17‐fold higher) and higher bioavailability (twofold higher) of topically administered diclofenac using a methoxy poly(ethylene glycol)–poly(3‐caprolactone) (MPEG–PCL)‐based micelle delivery system when compared to diclofenac solution in rabbit eyes.…”