Trevor R. Carmichael

A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases

Intravitreal implantable device technology utilizes engineered materials or devices that could revolutionize the treatment of posterior segment eye diseases by affording localized drug delivery, responding to and interacting with target sites to induce physiological responses while minimizing side-effects. Conventional ophthalmic drug delivery systems such as topical eye-drops, systemic drug administration or direct intravitreal injections do not provide adequate therapeutic drug concentrations that are essential for efficient recovery in posterior segment eye disease, due to limitations posed by the restrictive blood-ocular barriers. This review focuses on various aspects of intravitreal drug delivery such as the impediment of the blood-ocular barriers, the potential sites or intraocular drug delivery device implantation, the various approaches employed for ophthalmic drug delivery and includes a concise critical incursion into specialized intravitreal implantable technologies for the treatment of anterior and posterior segment eye disease. In addition, pertinent future challenges and opportunities in the development of intravitreal implantable devices is discussed and explores their application in clinical ophthalmic science to develop innovative therapeutic modalities for the treatment of various posterior segment eye diseases. The inherent structural and functional properties, the potential for providing rate-modulated drug delivery to the posterior segment of the eye and specific development issues relating to various intravitreal implantable drug delivery devices are also expressed in this review.

Ocular drug delivery – a look towards nanobioadhesives

Importance of the field: A major challenge emanating in the design of topical ophthalmic preparations is their short precorneal residence time. Retention of a drug delivery system in the front of the eye is thus desirable. One solution identified to address this concern is a retentive system that can preferably be delivered in a liquid drop form and ultimately remain attached to the corneal tissue owing to incorporation of a bioadhesive component. Forward-thinking approaches are required to achieve advancements in this approach for the attainment of an effective drug concentration at the site of action. Accordingly, several investigators have identified the benefits of nanotechnology-based drug delivery systems for ophthalmic drug delivery. Areas covered in this review: A concerted effort was made to review critically all ‘nanobioadhesives’, that is, nanosystems designed for ocular drug delivery with the goal of attaining prolonged ocular retention, in a systematic, chronological manner, from their reported point of inception to the present. What the reader will gain: A perspective on possible future trends in this growing field of ocular drug delivery is formulated. Take home message: The importance of and need for new developments in the field of ocular nanobioadhesives is emphasized.

Effective and accurate screening for diabetic retinopathy using a 60° mydriatic fundus camera

Objectives. To establish whether an experienced endocrinologist could screen accurately for diabetic retinopathy using mydriatic 60° fundus photographs compared with a reference standard, viz. the combined highest scores of two experienced ophthalmologists. Design. Retrospective review of 60° colour transparency photographs taken over a 6-year period. Retinopathy was graded in a standardised way. Setting. Patients attending the diabetic clinic at Johannesburg Hospital, South Africa. Subjects. Fifteen hundred and seventeen patients (2 446 eyes) formed the basis for the study. Patients were included if there was more than 50% readability of the fundus photographs. Outcome measures. Outcome measures were prevalence of any retinopathy and presence of referable (severe) retinopathy. Inter-observer agreement was measured using the kappa statistic, and sensitivity and specificity of the screener were evaluated. Results. The prevalence of retinopathy at the clinic was approximately 30%, but only about 12% was severe enough to warrant referral to the ophthalmology outpatient department. The endocrinologist was very accurate in determining cases requiring referral; there was 97% agreement with the reference standard, viz. the combined highest score of two experienced ophthalmologists (gold standard). Correlation on the determination of any retinopathy was less accurate (80% agreement), mostly owing to the endocrinologist reporting more isolated microaneurysms than the ophthalmologists. The screening method used gave a sensitivity of 83% and specificity of 99% which are within recommended standards. Conclusions. The screening strategy using a mydriatic fundus camera at the diabetic clinic was found to be effective and accurate and greatly reduced the number of possible referrals to the ophthalmology outpatient department.

The Genetics of POAG in Black South Africans: A Candidate Gene Association Study

Multiple loci have been associated with either primary open angle glaucoma (POAG) or heritable ocular quantitative traits associated with this condition. This study examined the association of these loci with POAG, with central corneal thickness (CCT), vertical cup-to-disc ratio (VCDR) and with diabetes mellitus in a group of black South Africans (215 POAG cases and 214 controls). The population was homogeneous and distinct from other African and European populations. Single SNPs in the MYOC, COL8A2, COL1A1 and ZNF469 gene regions showed marginal associations with POAG. No association with POAG was identified with tagging SNPs in TMCO1, CAV1/CAV2, CYP1B1, COL1A2, COL5A1, CDKN2B/CDKN2BAS-1, SIX1/SIX6 or the chromosome 2p16 regions and there were no associations with CCT or VCDR. However, SNP rs12522383 in WDR36 was associated with diabetes mellitus (p = 0.00008). This first POAG genetic association study in black South Africans has therefore identified associations that require additional investigation in this and other populations to determine their significance. This highlights the need for larger studies in this population if we are to achieve the goal of facilitating early POAG detection and ultimately preventing irreversible blindness from this condition.

A review of topically administered mini-tablets for drug delivery to the anterior segment of the eye.

The human eye is a unique and intricate structure which has made drug delivery to the eye a formidable undertaking. Anterior‐segment eye diseases are ubiquitous, especially among elderly patients, and conventional eye drops, although a first‐choice dosage form, are not always an efficient treatment option. The development of novel drug delivery systems for improved treatment is therefore imperative.

The role of heredity in pterygium development

Several risk factors, which include heredity, ultra-violet (UV) light and chronic inflammation, contribute to pterygium development. However, there is no report integrating these factors in the pathogenesis of pterygium. The aim of this review is to describe the connection between heredity, UV, and inflammation in pterygium development. Existing reports indicate that sunlight exposure is the main factor in pterygium occurrence by inducing growth factor production or chronic inflammation or DNA damage. Heredity may be a factor. Our studies on factors in pterygium occurrence and recurrence identify that heredity is crucial for pterygium to develop, and that sunlight is only a trigger, and that chronic inflammation promotes pterygium enlargement. We propose that genetic factors may interfere with the control of fibrovascular proliferation while UV light or (sunlight) most likely only triggers pterygium development by inducing growth factors which promote vibrant fibrovascular proliferation in predisposed individuals. It also just triggers inflammation and collagenolysis, which may be promoters of the enlargement of the fibrovascular mass. Pterygium probably occurs in the presence of exuberant collagen production and profuse neovascularisation.

Studies on a novel doughnut-shaped minitablet for intraocular drug delivery

The objective of this study was to evaluate the effect of 2 independent formulation variables on the drug release from a novel doughnut-shaped minitablet (DSMT) in order to optimize formulations for intraocular drug delivery. Formulations were based on a 32 full-factorial design. The 2 independent variables were the concentration of Resomer (% wt/wt) and the type of Resomer grade (RG502, RG503, and RG504), respectively. The evaluated response was the drug release rate constant computed from a referenced marketed product and in vitro drug release data obtained at pH 7.4 in simulated vitreous humor. DSMT devices were prepared containing either of 2 model drugs, ganciclovir or foscarnet, using a Manesty F3 tableting press fitted with a novel central-rod, punch, and die setup. Dissolution data revealed biphasic drug release behavior with 55% to 60% drug released over 120 days. The inherent viscosity of the various Resomer grades and the concentration were significant to achieve optimum release rate constants. Using the resultant statistical relationships with the release rate constant as a response, the optimum formulation predicted for devices formulated with foscarnet was 70% wt/wt of Resomer RG504, while 92% wt/wt of Resomer RG503 was ideal for devices formulated with ganciclovir. The results of this study revealed that the full-factorial design was a suitable tool to predict an optimized formulation for prolonged intraocular drug delivery.

Design of an anti‐inflammatory composite nanosystem and evaluation of its potential for ocular drug delivery

This study compared two specific embodiments of an ocular nanosystem (NS): one portraying a purely polymeric system, referred to as the chitosan-poly(ε-caprolactone) nanosystem, and the other based on a composite lipoidal-polymeric NS architecture utilizing phospholipids-the lipoidal-chitosan-poly(ε-caprolactone) nanosystem. Investigations undertaken were implicit to warrant inclusion in an implantable system for the intelligent treatment of inflammatory disorders (specifically ocular afflictions). Results obtained highlighted the enhanced efficacy of both NS to an indomethacin suspension in terms of tissue permeation, cell uptake, and anti-inflammatory activity. Furthermore, the size (134.3 vs. 140.7 nm); surface charge (+49.4 vs. +55.7 mV); drug incorporation efficiency (75.00% vs. 67.20%); flux across the retinal pigment epithelium-choroid-sclera (0.002951 vs. 0.001255 mg cm (-2) h(-1) ); anti-inflammatory efficacy, demonstrated by a decrease in 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole complex formation (0.0031 vs. 0.0023 mmol L(-1) ) and decrease in NFκB formation (decrease in relative optical density of 0.2027 vs. 0.2420); and enhanced inflammatory cell uptake, visualized via high-speed fluorescence and confocal microscopy, all highlighted the enhanced potential of the lipoidal system compared with the purely polymeric NS for potentially targeting inflammatory disorders of the posterior segment of the eye. Mechanics energy relationships revealed the favorable hydrophilic-lipophilic balance of the composite NS compared with the purely polymeric NS.

In vivo evaluation of a biodegradable donut‐shaped minitablet for prolonged posterior segment drug delivery in the rabbit eye model

This study focused on the in vivo evaluation of a biodegradable ganciclovir-loaded donut-shaped minitablet (DSMT) for controlled drug delivery in the New Zealand white albino rabbit eye model. Specialized tablet tooling was used to manufacture a poly(lactic-co-glycolic acid) DSMT device that was implanted into 18 rabbits through the pars plana/peripheral retina of the right eyes of each rabbit. The left eyes were used as controls. Possible adverse effects on ocular tissues were assessed by histomorphology, slit-lamp biomicroscopy, intraocular pressure (IOP) measurements, and indirect ophthalmoscopy. The ex vivo microenvironmental vitreous pH was also monitored. Rabbits were euthanized at predetermined intervals and the residual devices, vitreous humor, and ocular tissue were retrieved and stored appropriately until further analysis. The DSMT was well tolerated up to 72 days and was still visible in the superotemporal quadrant of the eye. The mean IOP range (6-8 mmHg; N = 18) and changes in vitreous pH (7.25 ± 0.01; N = 3) correlated with baseline measurements. The DSMT displayed constant ganciclovir release at a rate of 2.02 μ g/h maintained within the 50% effective dose for human cytomegalovirus retinitis (N = 3). The design simplicity and application of the biodegradable DSMT device may provide a superior alternative for prolonged rate-controlled intraocular drug delivery.

Traditional eye medication and pterygium occurrence in Limpopo Province

BACKGROUND The relative importance of environmental and hereditary factors in the occurrence of pterygium in African blacks has not been reported. AIM To investigate the relative significance of factors associated with pterygium occurrence. METHODS This was a prospective case-controlled study where 150 pterygium patients and 150 controls participated. Interviews were conducted, eyes examined and multivariate analysis done. The families of 51 pterygium cases and 50 controls were examined for presence of pterygium. RESULTS Of 150 cases and 150 controls, 79 (52.6%) and 60 (40%) used traditional eye drops (odds ratio (OR) 2.03; p=0.009. Ten cases (6.6%) and 26 controls (17.3%) had unstable tear film (OR 0.30; p=0.007. Forty-six cases (30.6%) and 15 controls (10%) reported a positive family history (OR 3.93; p<0.001). Groups of 3 - 5 pterygium cases in a household occurred in 36 of 51 pterygium families (70.5%) v. 1 of 50 controls (2%). CONCLUSIONS Pterygium occurrence was associated with the use of traditional eye drops, a positive family history and having groups of diagnosed pterygium-affected relatives. However, unstable tear film seemed protective against pterygium occurrence.