Drug Delivery to the Back of the Eye Following Topical Administration: an Update on Research and Patenting Activity
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Send Orders for Reprints to [email protected] Recent Patents on Drug Delivery & Formulation 2014, 8, 27-36 27 Drug Delivery to the Back of the Eye Following Topical Administration: An Update on Research and Patenting Activity Sai H.S. Boddu*, Himanshu Gupta and Soohi Patel Department of Pharmacy Practice, College of Pharmacy and Pharmaceutical Sciences, The University of Toledo, Ohio, USA – 43614 Received: December 31, 2013; Revised: January 26, 2014; Accepted: January 29, 2014 Abstract: Drug delivery to the back of the eye following topical administration remains an unmet need for the scientific community. Treatment of posterior segment diseases requires localized and long-term drug delivery to the retina, choroid, and Bruch’s membrane. Until the last decade, there was limited evidence from large clinical trials that demonstrated the usefulness of pharmacotherapy compared to laser therapy or other vitreoretinal surgical techniques for the treatment of retinal diseases. This paradigm has shifted in recent years, with strong evidence demonstrating superior efficacy of oph- thalmic drugs compared to previous gold standards. However, ophthalmologists are left with no options other than admin- istering the therapeutics via implants and intravitreal injections, which are highly invasive and associated with patient non-compliance. A non-invasive topical therapy would enhance patient compliance and minimize the side-effects associ- ated with intraocular implants and intravitreal injections. In an attempt to enhance patient compliance, the focus of re- search has shifted to the development of novel small molecule-based eye drop formulations. This review article discusses the relevant patents and summarizes the resurgence in the treatment of posterior segment eye diseases through topical drug administration. Keywords: Drug delivery, eye drops, posterior segment, retinal diseases. INTRODUCTION reaches the retina and choroid [6]. Common approaches to the treatment of posterior segment diseases include, but are Efficient drug delivery to the back of the eye remains a not limited to, systemic and intraocular injections and im- challenging task due to its unique anatomical and physio- plants. Systemic drug delivery results in inadequate retinal logical barriers [1]. The external and internal structures of concentrations and severe systemic adverse effects. Though the eye are protected by different barriers that prevent the intravitreal administration delivers a high concentration of penetration of drugs in required concentrations. The structure drugs to the retina, the inherent potential side effects like of the eye is divided into two segments: anterior and poste- increased intraocular pressure [7], hemorrhage [8], cataract rior. The anterior segment consists of the cornea, iris/ciliary [9], and endophthalmitis [10] lead to complications limiting body, and lens [2]. The posterior segment mainly consists of long-term therapy [11]. Moreover, the chronic nature of reti- the vitreous humor, retina, choroid, and optic nerve Fig. ( ). 1 nal diseases requires multiple injections, which are associ- Diseases affecting the posterior segment such as age-related ated with risk of vitreous hemorrhage, retinal detachment, macular degeneration [AMD], diabetic retinopathy [DR], and cataract progression. Implants have overcome many of diabetic macular edema [DME], proliferative vitreoretinopa- the disadvantages associated with intravitreal injections; thy [PVR], uveitis, and cytomegalovirus [CMV] require im- however, the surgical procedure and risk of drug precipita- mediate attention in order to prevent the loss of vision [3-5]. tion may result in undesirable effects [12]. A non-invasive Posterior segment eye diseases present unique anatomical, topical drug delivery system in the form of eye drops would physiological and biochemical barriers resulting in the fail- circumvent most of these problems and enhance patient ure of conventional dosage forms such as eye drops, oint- compliance. Administration of drugs in the form of eye ments and suspensions. The retina and choroid are the target drops for retinal diseases has several advantages; it allows sites for most of the posterior segment diseases. Following self-administration, localized therapeutic effect, a non- topical administration, static barriers (corneal layers, blood invasive and painless mode of drug administration, and high aqueous and blood-retinal barriers) and dynamic barriers patient compliance. (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution) prevent the drug from reaching the retina. New treatment modalities to facilitate the topical delivery Only about 1/100,000th of the drug observed in tear fluids of drugs are under development. There are currently no mar- keted topical formulations for posterior segment diseases, with only a few compounds that are undergoing testing in *Address correspondence to this author at the Department of Pharmacy clinical trials. Topical eye drops have the potential to reduce Practice, The University of Toledo HSC, College of Pharmacy and Pharma- ceutical Sciences, 3000 Arlington Ave. (MS1013), Toledo, OH 43614; Tel: the side-effects and improve patients’ quality of life and pa- 419-383-1959; Fax: 419-383-1950; E-mail: [email protected] tient compliance. 2212-4039/14 $100.00+.00 © 2014 Bentham Science Publishers 28 Recent Patents on Drug Delivery & Formulation, 2014, Vol. 8, No. 1 Boddu et al. Credit: National Eye Institute, National Institutes of Health Ref #: NEA09 Fig. (1). Structure of the eye. Pharmacokinetic studies have proven repeatedly that the The tear volume of a normal eye is ~7–9 μL, with a turnover transfer of a drug from an eye drop into the retina or vitreous rate of 0.5–2.2 μL/min [22]. Upon administration of drugs in humor is limited. This is mainly because of the long diffu- the form of an eye drop (~35–56 μL), the tear volume in- sional distance from the application site to the retina and the creases, resulting in a rise of blinking reflex rate. The excess above mentioned dynamic barriers [13]. volume of eye drops is drained into the systemic circulation through the nasolacrimal duct [26]. Conjunctival blood and However, during the last decade, some investigators have lymphatic vessels also result in the systemic drainage of documented the ability of small molecules to achieve thera- topically applied drugs. Though not completely true, drug peutic concentrations in the retina/vitreous humor following absorption through the conjunctiva is considered nonproduc- topical application [14-19]. Drug delivery to the back of the tive because of the systemic drainage. The nonkeratinized eye has become the topic of intense research among oph- squamous epithelium of the cornea and the conjunctiva pro- thalmologists and pharmaceutical scientists due to its ability tect the eye against pathogens and drugs [27]. The expres- to reduce unwanted complications resulting from intravitreal sion of efflux pumps such as P-glycoprotein (P-gp) on the injections and to enhance patient compliance. The previous corneal [28, 29] and conjunctival epithelia [30] also hinder notion that drugs applied topically do not penetrate to the the absorption of drugs. These factors collectively lower the back of the eye is currently being reassessed. This article absorption of topically applied drugs from the precorneal presents a thorough review of the findings, both research region [31]. publications and patents, related to the use of eye drops in retinal delivery. Primarily, the penetration of drugs into the cornea and conjunctiva is driven by the concentration gradient, lipophil- OBSTACLES TO THE RETINAL DELIVERY OF icity and molecular weight of the drug. The epithelial layers DRUGS VIA TOPICAL EYE DROPS of the cornea and conjunctiva act as rate-limiting barriers for drug absorption. Depending on the lipophilicity, the drug The treatment of back-of-the-eye diseases is relatively will enter the conjunctival or corneal epithelium through the more complex and challenging compared to anterior- paracellular and transcellular routes. The hydrophilic drugs segment diseases [12, 20]. In addition to the longer diffu- such as atenolol and inulin enter the epithelial layers via the sional distance, the path of a topically administered drug is paracellular route, while lipophilic drugs such as timolol and hindered by many components such as the corneal epithe- propranolol enter through the transcellular pathway [32, 33]. lium and endothelium, conjunctiva, sclera and the acellular The intercellular space of corneal and conjunctival epithelia nature of the vitreous [21]. Because of these barriers, the is sealed by the junctional complexes that hinder the trans- development of topical ocular formulations for retinal dis- port of hydrophilic compounds [34]. The rate of paracellular th eases has become unpredictable. Less than 1/100,000 quan- penetration decreases with an increase in molecular size. The tity of drug administered topically reach the retina, and often conjunctiva is 15-25 times more permeable to hydrophilic times this value is far below the therapeutic concentration of compounds compared to the cornea. This is mainly because the drug. These challenges are well understood and docu- of the larger paracellular pore diameter of the conjunctiva mented in several references [1, 12, 22-25]. The anatomical (3.0 nm ± 1.6), which allows the permeation of molecules and physiological barriers that prevent the topically adminis- with a size