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Nanotechnology and drug delivery systems for topical ocular therapy: a promising new chapter

Srinivasan, Sathish FRCSEd, FRCOphth, FACS

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Journal of Cataract & Refractive Surgery: July 2022 - Volume 48 - Issue 7 - p 751-752
doi: 10.1097/j.jcrs.0000000000000980
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Cataract extraction is the most prevalent surgical procedure of all medical specialties, with an estimated 3.7 million cases per year in the United States, 7 million in Europe, and 20 million worldwide.1,2 Phacoemulsification with intraocular lens implant in the capsular bag is the standard of care, resulting in excellent anatomic and functional outcomes and a relatively low complication rate.3 Like other types of surgery, cataract surgery induces a surgical inflammatory response. Uncontrolled inflammation may lead to serious side effects, such as posterior synechia, uveitis, secondary glaucoma, and cystoid macular edema.

Currently, two groups of drugs are available to control ocular inflammation: glucocorticoids (GCs) and nonsteroidal anti-inflammatory drugs. The clinical and cellular actions of GCs are mediated by a 95 kDa cytosolic α-isoform of the glucocorticoid receptor. On GC binding, the glucocorticoid receptor undergoes conformational changes that expose a nuclear import signal, and the receptor is translocated to the nucleus. The translocation is ATP dependent and heat shock protein 90 dependent.4 Corticosteroids decrease prostaglandin synthesis by inhibiting phospholipase A2 during the arachidonic acid cascade. In addition to this anti-inflammatory effect, corticosteroids also inhibit macrophage and neutrophil migration and decrease capillary permeability and vasodilation.5 Intraocular surgery initiates a cascade of inflammatory events that lead to the breakdown of the blood–aqueous and blood–retinal barriers, and topical GCs are the most commonly used anti-inflammatory agent postoperatively.

Most topical ophthalmic drugs exhibit first-order kinetics, where the absorption rate and elimination rate of the drugs vary directly with the drug concentration. Therefore, the drug half-life is constant regardless of the amount of the drug present. Ocular penetration of topically applied drugs permeates through the conjunctiva, the cornea, and thereafter the sclera. However, in practice, the majority of all topical drugs penetrate through the cornea. Nonetheless, the cornea is not equally permeable to all topically applied drugs. Pharmacokinetically, it is a “complex sandwich” consisting of a lipid-rich hydrophobic epithelial cell membrane, a hydrophilic stroma, and a hydrophobic endothelium. Effectively, the greatest barrier to drug penetration is the lipid-rich corneal epithelium, which retards the ingress of polar, hydrophilic derivatives such as prednisolone phosphate.6 However, the corneal epithelium is much less of a barrier to lipophilic derivatives such as alcohol and acetate forms of dexamethasone and prednisolone.7 For prednisolone acetate, the optimum dose–response effect in experimental keratitis occurs at a 1% concentration and is not improved by further increases in concentration.8

Developing a new ocular drug delivery system remains a fascinating and difficult issue facing formulation and development experts. The complex anatomy, physiology, and biochemistry of the human eye make it nearly inaccessible to foreign particulates, including drugs. The performance of many ophthalmic preparations is often restricted by short retention time, restricted permeability of the corneal epithelium, high precorneal clearance rate due to rapid blinking rates (6–15 times/min), high tear turnover (0.5–2.2 L/min), nasolacrimal discharge, and nonproductive conjunctival uptake.9 Furthermore, the low retention volume (∼30 L) of the conjunctival sac typically results in a decreased corneal or scleral transport of drugs.10

Nanotechnology involves the use of nanoemulsions to develop new drug delivery systems capable of facilitating actives to penetrate through various physiological barriers that exist in the ocular region.11 Nanoemulsions are colloidal carriers of drug molecules with a droplet size in the range of 500 to 1000 nm (preferably from 100 nm to 500 nm). As a drug delivery system, they not only increase the therapeutic efficacy by providing sustained release of drugs; these nanocarriers prevent a rapid loss of drugs through the nasolacrimal system and rapid tear turnover. In addition, by inhibiting the P-glycoprotein activity in corneal epithelial cells and opening up tight junctions by nonionic surface active agents, they improve the ocular bioavailability.12,13

In this issue, Valvecchia et al. (page 753) in a multicenter, double-blind, randomized clinical trial evaluate the efficacy and safety of difluprednate 0.05% nanoemulsion vs the traditional prednisolone acetate 1% suspension for treating inflammation after cataract surgery. In this nicely designed study, the authors demonstrated that twice-a-day application of difluprednate was safe and as effective as using prednisolone acetate 4 times a day. Although anterior chamber flare meter was not used to objectively quantify the degree of anterior chamber inflammation in the 2 groups, they used central corneal thickness as a surrogate marker of corneal edema and inflammation.

Given the challenges that the ocular surface poses to the pharmacodynamics and pharmacokinetics of topical therapy, the use of nanotechnology with nanomolecules certainly opens new doors to develop more efficient topical steroids, antibiotics, antivirals, and antifungals that could certainly help to improve efficacy and compliance and, in turn, the visual outcome of our patients.


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