Journal of Pharmacy And Pharmacology

Topical delivery of ocular therapeutics: carrier systems and physical methods Joel G. Souza, Karina Dias, Tatiana Aparecida Pereira, Daniela Spuri Bernardi and Renata F. V. Lopez School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil

Keywords contact lens; dendrimers; iontophoresis; nanoparticle; topical ocular delivery Correspondence Renata F. V. Lopez, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, 14040-903, Ribeirão Preto, São Paulo, Brazil. E-mail: [email protected] Received February 27, 2013 Accepted July 23, 2013 doi: 10.1111/jphp.12132

Abstract Objective The basic concepts, major mechanisms, technological developments and advantages of the topical application of lipid-based systems (microemulsions, nanoemulsions, liposomes and solid lipid nanoparticles), polymeric systems (hydrogels, contact lenses, polymeric nanoparticles and dendrimers) and physical methods (iontophoresis and sonophoresis) will be reviewed. Key findings Although very convenient for patients, topical administration of conventional drug formulations for the treatment of eye diseases requires high drug doses, frequent administration and rarely provides high drug bioavailability. Thus, strategies to improve the efficacy of topical treatments have been extensively investigated. In general, the majority of the successful delivery systems are present on the ocular surface over an extended period of time, and these systems typically improve drug bioavailability in the anterior chamber whereas the physical methods facilitate drug penetration over a very short period of time through ocular barriers, such as the cornea and sclera. Summary Although in the early stages, the combination of these delivery systems with physical methods would appear to be a promising tool to decrease the dose and frequency of administration; thereby, patient compliance and treatment efficacy will be improved.

Introduction The topical administration of drugs remains the preferred route for the treatment of ocular diseases; this preference is primarily because of the ease of application and patient compliance. However, the absorption of topically applied drugs to the eyes is very poor because of the inherent anatomical and physiological barriers.[1] When the focus of treatment is the anterior segment of the eye, such as the inner cornea or the aqueous humour, the layers of the cornea, in particular the outermost, called the epithelium, hinder drug penetration; thereby, local bioavailability of the drug decreases. More specifically, the epithelium, which represents 90% of the total corneal cells, limits the permeation of hydrophilic molecules because of its hydrophobic properties. In contrast, the stroma, which is the corneal layer located between the epithelium and the endothelium, is composed of a highly hydrated extracellular matrix that limits the permeation of lipophilic substances.[2] Moreover, the simple application of standard eye drops on the eye surface activates the defence mechanisms of the eyes, such as lacrimation, and with tear turnover, these mechanisms

cause dilution of the drug and drainage. These mechanisms and the anatomical barriers of the eye result in less than 5% of the drug reaching the intraocular tissues, that is, low drug bioavailability and in the requirement for repeated, high-dose administrations.[3,4] The topical treatment of infections that affect the posterior segment of the eye is even more complex. The eye membranes, such as the cornea, the conjunctiva and the sclera, limit the penetration of drugs to the posterior segment; this limited penetration further limits the use of topical administration as a route for the treatment of pathologies that affect the retina, choroid or the vitreous humour.[4,5] Therefore, systemic administration plays an important role in the treatment of diseases that affect the posterior segment of the eye. However, a major disadvantage associated with systemic administration is that only 1–2% of the administered drug reaches the vitreous cavity. Thus, it is necessary to administer high concentrations of the drug; thereby, many systemic side effects are generated.[6] To improve drug bioavailability in this eye segment,

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••


Topical delivery of ocular therapeutics

Joel G. Souza et al.

Drug Delivery Systems


Physical Methods



Micro and Nanoemulsions



Contac lens

Solid lipid nanoparticles




Figure 1

Strategies used to improve ocular bioavailability of topically applied drugs.

intravitreous injections represent an effective strategy.[7] However, this route of administration is associated with many complications, such as retinal detachment, endophthalmitis and intravitreous haemorrhage.[8] Moreover, patients undergoing this type of treatment require constant monitoring after application of the drug.[9] The topical administration of drugs could overcome these disadvantages if the therapeutic window could be obtained and maintained over an extended period of time. However, the development of an efficient topical dosage form that is capable of delivering the drug at the correct dose without the need for frequent instillation represents a major challenge for pharmaceutical sciences and technology. To treat pathologies affecting the anterior segment of the eye, the development of drug delivery systems that negate high doses and repeated administrations represents an important strategy. Although there are some recent reviews that have highlighted the various delivery systems, especially nanoparticle systems, designed to improve the delivery of drugs applied to both the anterior and posterior segments of the eye, these reviews do not focus on the topical route of administration.[2,4,10–15] Usually, the reviews provide an overview of the anatomical and physiological ocular barriers, strategies to overcome these barriers, the pathological conditions and the unmet needs for treatment of these conditions.[4,13] 2

In this review, some successful delivery systems specifically designed for topical ocular administration will be highlighted. For clarity, the delivery systems will be divided into lipid-based and polymeric systems (Figure 1). The basic concepts and the major mechanisms involved in improving topical drug delivery will be described, and relevant up-to-date results obtained with topical applications will be discussed on a case-by-case basis. Moreover, the physical iontophoresis and sonophoresis methods will be presented and discussed. Although these methods are very well explored for topical drug delivery through the skin, the fundamentals of these methods for ocular administration is still underexplored. Therefore, the potential of these methods to increase the permeability of the cornea and sclera and assist in the topical administration of a drug to reach the posterior segment of the eye will be addressed in this review (see Figure 1).

Delivery systems Lipid-based Microemulsions Microemulsions are thermodynamically stable and isotropic dispersions of water, oil and surfactants. Usually, high concentrations of surfactants and cosurfactants, such as

© 2013 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology, ••, pp. ••–••

Joel G. Souza et al.

alcohols, are used to decrease the interfacial tension to near zero at the oil/water interface, and very small droplets (

Topical delivery of ocular therapeutics: carrier systems and physical methods.

The basic concepts, major mechanisms, technological developments and advantages of the topical application of lipid-based systems (microemulsions, nan...
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