# In Vivo Efficacy of Contact Lens Drug-Delivery Systems in Glaucoma Management. A Systematic Review
###### Abstract  
Adherence is crucial in medical glaucoma therapy, although half of the patients skip eyedrops. In recent years alternative drug-delivery systems have been developed. One of the most promising seems the contact lens (CL). This systematic review aims to present the in vivo efficacy of different CL drug-delivery systems. A total of 126 studies were identified following a literature search adhering to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. After full-text evaluation, 19 studies about CL drug-delivery systems were included. To date, the following drug-delivery systems have been investigated in vivo: drug-soaked CL, CL with physical barriers (vitamin E), molecularly imprinted CL, CL with implants, and nanoparticle-loaded CL. Nanoparticle-loaded CL and CL with implants seem the most promising drug-delivery systems, although initial burst drug release and patient acceptance may limit their widespread use in current practice. Clinical trials are warranted to understand the role of CL as a drug-delivery system in improving glaucomatous patient care. Keywords:contact lens; drug-delivery system; glaucoma; nanoparticles; adherence +
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Furthermore, multiple fixed-combination eyedrops are available on the market, allowing patients to take two hypotensive drugs with a single eye drop. All fixed combinations include a beta-blocker, except one which contains brimonidine and brinzolamide [5]. Another step to improve patient cooperation has been the introduction of preservative-free eyedrops [14]. In particular, preservatives induce toxic effects such as the detergent effect on tear film (altering the external lipid layer), the direct toxic effect on corneal and conjunctival epithelia, and the immune-allergic effect [15; 16]. Nevertheless, recent studies showed that preservative-free multidose droppers required an increased squeezing force compared to multidose standard droppers, being less user-friendly for older patients or those with comorbidities [17]. Even if single vial droppers are not related to handling difficulties, it remains an expensive technology that also causes an environmental burden [14; 15]. Despite the improvements mentioned above, low adherence is one of the principal causes of medical treatment failure in glaucoma [6; 7; 8]. Moreover, eyedrops medications are characterised by a pulsatile drug-delivery, with a concentration peak followed by a tough until the next drop instillation [18]. Consequently, drug effect may not be constant over time, and IOP may change during the day [18]. Furthermore, eyedrops have low bioavailability because only 1-7% of the drug is absorbed by the eye [18]. In particular, the lacimal drainage consequent to blinking removes about 80% of the instilled drop [19]. The remaining dose penetrates through the cornea with a diffusion mechanism, primarily driven by the dose concentration [20]. Therefore, to improve penetration, it is necessary to increase the retention time or the corneal permeability [19]. A sustained drug-delivery system could overcome all the issues mentioned--adherence, pulsatile therapeutic effect, and low retention time. Therefore, over the last decade, the pharmaceutical industry has developed alternative drug-delivery systems [19; 21]. These solutions can be classified as intraocular (e.g., implants, nanoparticles, and inserts) or topical (e.g., conjunctival inserts, contact lens (CL), gels, nanoparticles, mucoadhesive polymers, ointments, solutions, and suspensions) [19]. The ideal sustained drug-delivery system releases the drug regularly without requiring invasive surgery or injection to be placed [18]. There are already 140 million people worldwide wearing a CL, with a forecasted increase in the next future [22]. Therefore, the CL as a drug-delivery system does not affect the routine lifestyle of these patients. Moreover, the CL could allow an excellent sustained drug delivery because once placed, they could release the drug for several days.