Computational modeling of drug distribution in the posterior segment of the eye: Effects of device variables and positions

Jooybar, Elaheh; Abdekhodaie, Mohammad J.; Farhadi, Fatolla; Cheng, Yu-Ling

doi:10.1016/j.mbs.2014.06.008

Cited by 39 publications

(25 citation statements)

References 30 publications

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“…Computational modeling of the eye has also been used to evaluate drug distribution within the vitreous of animals and humans after injection or release by implants, and to develop vitreous diffusion IVIVCs . The need to understand how a drug is distributed within the vitreous to access the retina has been a key driver for many of the studies focused on drug distribution within the posterior segment.…”

Section: Resultsmentioning

confidence: 99%

The PK-Eye: A Novel In Vitro Ocular Flow Model for Use in Preclinical Drug Development

Awwad

Lockwood

Brocchini

et al. 2015

Journal of Pharmaceutical Sciences

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A 2-compartment in vitro eye flow model has been developed to estimate ocular drug clearance by the anterior aqueous outflow pathway. The model is designed to accelerate the development of longer-acting ophthalmic therapeutics. Dye studies show aqueous flow is necessary for a molecule injected into the vitreous cavity to clear from the model. The clearance times of proteins can be estimated by collecting the aqueous outflow, which was first conducted with bevacizumab using phosphate-buffered saline in the vitreous cavity. A simulated vitreous solution was then used and ranibizumab (0.5 mg) displayed a clearance time of 8.1 ± 3.1 days, which is comparable to that observed in humans. The model can estimate drug release from implants or the dissolution of suspensions as a first step in their clearance mechanism, which will be the rate-limiting step for the overall resident time of a candidate dosage form in the vitreous. A suspension of triamcinolone acetonide (Kenalog®) (4.0 mg) displayed clearance times spanning 26-28 days. These results indicate that the model can be used to determine in vitro-in vivo correlations in preclinical studies to develop long-lasting therapeutics to treat blinding diseases at the back of the eye.

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Section: Resultsmentioning

confidence: 99%

The PK-Eye: A Novel In Vitro Ocular Flow Model for Use in Preclinical Drug Development

Awwad

Lockwood

Brocchini

et al. 2015

Journal of Pharmaceutical Sciences

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show abstract

“…Drugs for IVT undergo preclinical and clinical development before marketing approval. While some guidelines exist, the exact details of needle depth, size, and angle, injection time (injection speed with outlet velocities) and other variables can significantly differ [16,17]. For example, the location of an intravitreal injection has a direct influence on drug distribution and elimination in the vitreous [18,19].…”

Section: Introductionmentioning

confidence: 99%

Hydrodynamics of Intravitreal Injections into Liquid Vitreous Substitutes

et al. 2019

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Intravitreal injections have become the cornerstone of retinal care and one of the most commonly performed procedures across all medical specialties. The impact of hydrodynamic forces of intravitreal solutions when injected into vitreous or vitreous substitutes has not been well described. While computational models do exist, they tend to underestimate the starting surface area of an injected bolus of a drug. Here, we report the dispersion profile of a dye bolus (50 µL) injected into different vitreous substitutes of varying viscosities, surface tensions, and volumetric densities. A novel 3D printed in vitro model of the vitreous cavity of the eye was designed to visualize the dispersion profile of solutions when injected into the following vitreous substitutes—balanced salt solution (BSS), sodium hyaluronate (HA), and silicone oils (SO)—using a 30G needle with a Reynolds number (Re) for injection ranging from approximately 189 to 677. Larger bolus surface areas were associated with faster injection speeds, lower viscosity of vitreous substitutes, and smaller difference in interfacial surface tensions. Boluses exhibited buoyancy when injected into standard S1000. The hydrodynamic properties of liquid vitreous substitutes influence the initial injected bolus dispersion profile and should be taken into account when simulating drug dispersion following intravitreal injection at a preclinical stage of development, to better inform formulations and performance.

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“…Computational modeling can also provide information about drug distribution within the vitreous of animals and humans after injection or release by implants [122,123,124]. However, these mathematical models are limited, as they neither consider nor discuss the stability and interactions of proteins/excipients with the vitreous humor components.…”

Section: In Vitro and In Silico Models To Test Intraocular Ddsmentioning

confidence: 99%

Ocular Drug Delivery: A Special Focus on the Thermosensitive Approach

et al. 2019

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The bioavailability of ophthalmic therapeutics is reduced because of the presence of physiological barriers whose primary function is to hinder the entry of exogenous agents, therefore also decreasing the bioavailability of locally administered drugs. Consequently, repeated ocular administrations are required. Hence, the development of drug delivery systems that ensure suitable drug concentration for prolonged times in different ocular tissues is certainly of great importance. This objective can be partially achieved using thermosensitive drug delivery systems that, owing to their ability of changing their state in response to temperature variations, from room to body temperature, may increase drug bioavailability. In the case of topical instillation, in situ forming gels increase pre-corneal drug residence time as a consequence of their enhanced adhesion to the corneal surface. Otherwise, in the case of intraocular and periocular, i.e., subconjunctival, retrobulbar, peribulbar administration, among others, they have the undoubted advantage of being easily injectable and, owing to their sudden thickening at body temperature, have the ability to form an in situ drug reservoir. As a result, the frequency of administration can be reduced, also favoring the patient’s adhesion to therapy. In the main section of this review, we discuss some of the most common treatment options for ocular diseases, with a special focus on posterior segment treatments, and summarize the most recent improvement deriving from thermosensitive drug delivery strategies. Aside from this, an additional section describes the most widespread in vitro models employed to evaluate the functionality of novel ophthalmic drug delivery systems.

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Computational modeling of drug distribution in the posterior segment of the eye: Effects of device variables and positions

Cited by 39 publications

References 30 publications

The PK-Eye: A Novel In Vitro Ocular Flow Model for Use in Preclinical Drug Development

The PK-Eye: A Novel In Vitro Ocular Flow Model for Use in Preclinical Drug Development

Hydrodynamics of Intravitreal Injections into Liquid Vitreous Substitutes

Ocular Drug Delivery: A Special Focus on the Thermosensitive Approach

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