Advances in ocular drug delivery: emphasis on the posterior segment

Kang-Mieler, Jennifer J.; Osswald, Christian R.; Mieler, William F.

doi:10.1517/17425247.2014.935338

Cited by 126 publications

(82 citation statements)

References 66 publications

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“…20 It is important to note, though, that the occurrence of these complications is low and with practiced techniques, rate of incidence is minimal. 14,20 Nevertheless, there is a need to reduce the number and frequency of injections to improve upon the socioeconomic impact associated with recurrent injections and to lower the risk for associated potential complications.…”

Section: Introductionmentioning

confidence: 99%

“…Sustained release of drugs with tailored characteristics can be achieved by encapsulating drugs within PLGA microspheres. 1,2,[12][13][14]19,21 PLGA is a biodegradable and biocompatible copolymer used in many FDAapproved therapeutic devices. By increasing the ratio of lactic:glycolic acid, release can be significantly extended due to the slower overall degradation of PLGA.…”

Section: Introductionmentioning

confidence: 99%

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Controlled and Extended Release of a Model Protein from a Microsphere-Hydrogel Drug Delivery System

Osswald

Kang-Mieler

2015

Ann Biomed Eng

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In extended ocular drug delivery applications, it is necessary to exert control over the release characteristics of the drug. Design considerations must be made to limit the initial burst (IB) and ensure complete release of drug from the drug delivery system (DDS). In this study, ovalbumin was used as a model protein to explore the effects on release of polymer formulation and fabrication technique in poly(lactic-co-glycolic acid) (PLGA) microspheres. Furthermore, the effect on release of suspending these microspheres in an injectable, thermo-responsive poly(N-isopropylacrylamide)-based hydrogel was determined. To characterize release, ovalbumin was radiolabeled with iodine-125. Regardless of polymer formulation or fabrication technique, pulsatile release was achieved with a second burst occurring after ~70 days for microspheres alone. Suspending PLGA 75:25 microspheres within hydrogel reduced the IB by ~75%, delayed the second burst by 28 days, and extended release out to ~200 days with steadier, consistent release throughout compared to microspheres alone. The combined microsphere-hydrogel DDS remains injectable through small-gauge needles and may have many applications, namely ocular drug delivery to the posterior segment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Controlled and Extended Release of a Model Protein from a Microsphere-Hydrogel Drug Delivery System

Osswald

Kang-Mieler

2015

Ann Biomed Eng

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“…Retinal diseases, such as AMD, are difficult to treat, partly because the anatomy of the eye makes drug delivery to its posterior segment challenging (Kang-Mieler et al, 2014). Intravitreal delivery is the most direct drug delivery method to treat retinal diseases.…”

Section: Introductionmentioning

confidence: 99%

A Mechanistic Pharmacokinetic/Pharmacodynamic Model of Factor D Inhibition in Cynomolgus Monkeys by Lampalizumab for the Treatment of Geographic Atrophy

Le¹,

Gibiansky²,

Good³

et al. 2015

J Pharmacol Exp Ther

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Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody against complement factor D (CFD), a ratelimiting enzyme in the activation and amplification of the alternative complement pathway (ACP), which is in phase III clinical trials for the treatment of geographic atrophy. Understanding of the pharmacokinetics, pharmacodynamics, and biodistribution of lampalizumab following intravitreal administration in the ocular compartments and systemic circulation is limited but crucial for selecting doses that provide optimal efficacy and safety. Here, we sought to construct a semimechanistic and integrated ocularsystemic pharmacokinetic-pharmacodynamic model of lampalizumab in the cynomolgus monkey to provide a quantitative understanding of the ocular and systemic disposition of lampalizumab and CFD inhibition. The model takes into account targetmediated drug disposition, target turnover, and drug distribution across ocular tissues and systemic circulation. Following intravitreal administration, lampalizumab achieves rapid equilibration across ocular tissues. Lampalizumab ocular elimination is relatively slow, with a t 1/2 of approximately 3 days, whereas systemic elimination is rapid, with a t 1/2 of 0.8 hours. Target-independent linear clearance is predominant in the eye, whereas targetmediated clearance is predominant in the systemic circulation. Systemic CFD synthesis was estimated to be high (7.8 mg/day); however, the amount of CFD entering the eye due to influx from the systemic circulation was small (,10%) compared with the lampalizumab dose and is thus expected to have an insignificant impact on the clinical dose-regimen decision. Our findings support the clinical use of intravitreal lampalizumab to achieve significant ocular ACP inhibition while maintaining low systemic exposure and minimal systemic ACP inhibition.

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“…Overall, novel techniques of intraocular steroid delivery aim to decrease the total dose of the steroid injected in the eye, thereby having the potential to provide beneficial steroid effects while minimizing the adverse events [27].…”

Section: Steroids In Diabetic Macular Edemamentioning

confidence: 99%

Novel Therapies in Development for Diabetic Macular Edema

et al. 2015

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Diabetic macular edema (DME) secondary to diabetic retinopathy (DR) is a major cause for functional visual loss in the developed world. Laser photocoagulation has been used for decades in the treatment of DME. However, the advent of anti-vascular endothelial growth factor (anti-VEGF) has revolutionized the treatment of DME. Three important anti-VEGF agents whose efficacy has been well established via phase III clinical trials include ranibizumab, bevacizumab, and aflibercept. However, even in the era of anti-VEGF therapies, there are some challenges that retina specialists have to confront in managing patients with DME. These include the need for frequent treatment and an unpredictable response to therapy. There is evidence to suggest that pathways other than the VEGF pathway may be playing a role in the development of DME. Thus, extensive research is focused on development of novel agents that target these pathways. This review focuses on novel therapeutic agents in development, which may be used as a monotherapy or in combination with anti-VEGF agents, for the management of DME in the future.

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Advances in ocular drug delivery: emphasis on the posterior segment

Cited by 126 publications

References 66 publications

Controlled and Extended Release of a Model Protein from a Microsphere-Hydrogel Drug Delivery System

Controlled and Extended Release of a Model Protein from a Microsphere-Hydrogel Drug Delivery System

A Mechanistic Pharmacokinetic/Pharmacodynamic Model of Factor D Inhibition in Cynomolgus Monkeys by Lampalizumab for the Treatment of Geographic Atrophy

Novel Therapies in Development for Diabetic Macular Edema

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