Chapter 18

Drug Suspension Development for the Back of the Eye

Jithan Aukunuru, Puneet Tyagi, Chandrasekar Durairaj,

and Uday B. Kompella

Abstract  With the FDA approval of triamcinolone acetonide suspensions for intravitreal injections, there is renewed interest in developing drug suspensions for sustained intravitreal delivery. For back of the eye drug delivery, suspensions can potentially be administered by various other routes including periocular, retrobulbar, and suprachoroidal routes. Suspension development, although new for back of the eye drug delivery, is not new, especially for topical, oral, and parenteral dosage forms. This chapter summarizes principles of suspension-based drug delivery and suspension formulation. Further, it highlights some unique issues related to the back of the eye suspension drug product development.

18.1  Need for Suspension Development for the Back of the Eye

There are several ways of treating ocular diseases of the back of the eye. Key diseases of the back of the eye include uveitis, macular degeneration, macular edema, and diabetic retinopathy (Yasukawa and Ogura 2010). It is generally thought that topical eye drops do not deliver therapeutic levels of drug molecules to the target tissues present at the back of the eye (Geroski and Edelhauser 2000). Therefore, various approaches such as intravitreal injections, periocular injections, and implantable delivery systems inside the eye have been developed. Intravitreal injections are often used successfully (Lee and Robinson 2009). Most commonly intravitreal injections of corticosteroids such as triamcinolone acetonide (TA) are used (Bitter et al. 2008). Suspensions not only provide a platform for formulating less

U.B. Kompella (*)

Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado, 12850 East Montview Blvd., C238-V20, Aurora, CO 80045, USA

Department of Ophthalmology, University of Colorado, Aurora, CO, USA e-mail: uday.kompella@ucdenver.edu

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 449 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_18,

© American Association of Pharmaceutical Scientists, 2011

soluble drugs to treat the back of the eye, but also offer pharmacokinetic advantages. Administration of a drug in the suspension dosage form prolongs the mean residence time in the vitreous when compared with injection of drug solution (Durairaj et al. 2009). For instance, due to its prolonged residence time, off-label intravitreal injection of Kenalog®40 was initiated by ophthalmologists. Each milliliter of the Kenalog®40 composition includes 40 mg of TA, sodium chloride as a tonicity agent, 10 mg of benzyl alcohol as a preservative, and 7.5 mg of carboxymethylcellulose and 0.4 mg of polysorbate 80 as resuspension aids. However, this formulation has several limitations for intravitreal use. At some concentrations, both the preservative benzyl alcohol and the surfactant polysorbate 80 might be toxic to the sensitive ocular tissues. They can potentially induce cell damage. There is also precipitation of the drug in the vitreous or other ocular tissues. In order to reduce the concentrations of these toxic components, clinicians employed saline “washing” to reduce the toxic concentrations of excipients. However, such a procedure itself might introduce contaminants such as endotoxins, which could lead to other intraocular complications. Also there are formulation problems. If the reformulated suspension is allowed to stand for 1–2 h, the drug separates as a precipitate. In the absence of agents that assist resuspension, uniform dose or particle size may not be delivered from such reformulated TA formulations. To overcome these limitations, Alcon and Allergan developed suspension formulations of triamcinolone acetonide for intravitreal injection and obtained FDA approval. Intravitreal injections can themselves cause potentially serious complications such as endophthalmitis, retinal tears and detachment, and cataract formation (Baum et al. 1982). All these factors need to be considered prior to a systematic development of suspension formulation to treat diseases of the back of the eye. Although ample literature is available regarding the clinical usefulness of suspension formulations directly injected into the vitreous, information from systematic studies regarding intravitreal suspension formulation development has not been emanated so far. However, this is slowly changing. Through recent patents and clinical trials, new information has been generated and practices are undertaken on various suspension formulations of drugs to treat diseases of the back of the eye (Quiram et al. 2006; Thompson 2006; Kabra and Sarkar 2009). Further, different routes of drug delivery to the eye are being elaborately investigated and new principles of drug delivery to the eye are emerging (Lee and Robinson 2009; Kompella et al. 2010). These aspects attracted the attention of pharmaceutical scientists and ophthalmologists alike. Drug suspensions can be injected not only by intravitreous route but also as subconjunctival injections, sub-Tenon injections, retrobulbar injections, suprachoroidal injections, subretinal injections, etc. Each route may pose unique issues related to drug/suspension toxicity. Drug release and delivery from suspensions is generally slower compared to solution dosage forms. However, the mean drug residence time or half-life of the drug administered as a suspension will depend on the route of administration, with the pharmacokinetics by various routes being different. Thus, there is a need for optimization of suspension formulations for each route and purpose of administration through the development of unique compositions. This chapter covers some of these aspects for suspension formulations.

18.2  Background

Some of the diseases resulting because of altered homeostasis in retina, choroid, vitreous and optic nerve include age-related macular degeneration, diabetic retinopathy, retinal vessel occlusion, and glaucoma. Key tissues affected in these diseases are located in the posterior segment of the eye. Drug access to this posterior segment of the eye after topical administration is very limited because of the anatomical barriers, induced tear production, rapid dilution and drainage by tears, and short precorneal residence time (Kompella et al. 2010). The anatomical barriers include tissues such as cornea, conjunctiva, sclera, and the outer blood–retinal barrier or the retinal pigment epithelium. Invariably, drug access into these tissues in normal as well as diseased conditions is very limited after topical drug administration, the safest mode of administration of drugs to the eye. However, several studies are published in the literature indicating that eye drops deliver some agents at therapeutic levels to the back of the eye (Sigurdsson et al. 2007; Ottiger et al. 2009). Recently, it was shown by Sigurdsson et al. (2007) that dexamethasone can gain access to retinal and optic nerve after topical administration of the drug encapsulated in lipophilic cyclodextrin. Particularly after encapsulating dexamethasone (0.5% w/v) in lipophilic methylated b-cyclodextrin and administering (50 ml) via topical route, 2 h later, drug levels in the retina and optic nerve were 33 ± 7 and 41 ± 12 ng/g, respectively. Similarly, Ottiger et al. (2009) demonstrated the delivery of ESBA105, a topically administered singlechain antibody (scFv) against tumor necrosis factor (TNFa), to the posterior segment of the eye, particularly the vitreous. In this topical ocular pharmacokinetic study in rabbits, the ESBA105 formulation without any penetration enhancer could achieve therapeutic levels in the vitreous with prolonged elimination half-life. The authors suggest that the drug might have reached the posterior segment of the eye (retina and vitreous) via trans-scleral penetration pathway. Similarly, several such examples of drugs reaching the tissues of the posterior segment of the eye after topical administration can be found in the literature. It is likely that these molecules gain access to the back of the eye following conjunctival and scleral transport. Administration of drugs by either oral route or IV route to achieve therapeutic concentrations in the posterior segment of the eye is usually unsatisfactory because of the presence of blood–retinal barriers, which limit the extent of absorption of the drugs into the target tissues. In order to overcome the systemic barriers and to achieve therapeutic concentration in the vitreous humor, a high dose of drug needs to be administered, which is of potential concern due to systemic toxicity.

Although topical mode of drug administration to achieve drug levels in the posterior segment of the eye is a possibility, even today the state-of-art in this area of practice and research for treating back of the eye diseases is the direct administration of drugs in the posterior segment of the eye. Drugs can be administered as intravitreal, subconjunctival, sub-Tenon, retrobulbar, suprachoroidal, subretinal injections, with intravitreal injections being most successful. All of these routes of administration are invariably invasive, with a 27or 30-gauge needle routinely used for injecting drug suspensions in humans and animals. Due to the rapid elimination of intravitreally injected soluble, small molecule drugs, repeated injections are often required to deliver