Hyaluronan as a promising excipient for ocular drug delivery

Guter, Michaela; Breunig, Miriam

doi:10.1016/j.ejpb.2016.11.035

Cited by 59 publications

(42 citation statements)

References 146 publications

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“…To overcome an impaired fluid layer, Na-HA is ideally suited because it displays a long-lasting, intensive ocular lubricant [ 5 ]. Additionally, the chemical structure of hyaluronate allows it to retain water up to many times of its own weight.…”

Section: Discussionmentioning

confidence: 99%

“…The symptomatic therapy of choice is supplementation with artificial tears to lubricate the eye, replace missing tear fluid and normalize tear film osmolarity [ 4 ]. The naturally occurring endogenous factor hyaluronate induces long-lasting, intensive ocular lubrication [ 5 ], and this explains why several artificial tear solutions contain sodium hyaluronate (Na-HA) as a moisturizing and lubricating substance. However, commercial eye drops contain different amounts of hyaluronate and different types of buffers ( i.e.…”

Section: Introductionmentioning

confidence: 99%

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Development of In Vitro Methodologies to Investigate Binding by Sodium Hyaluronate in Eye Drops to Corneal Surfaces

Bock¹,

D²,

M³

et al. 2018

TOOPHTJ

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Purpose:To develop in vitro methods to assess binding by sodium hyaluronate in eye drops to corneal surfaces.Methods:Two different, complementary corneal binding set-ups were developed. In a dynamic in vitro model, confluent corneal epithelial cells (HCE-T) were assembled in chamber slides and a declining channel. A static model was constructed with ex vivo porcine corneas clamped in Franz cells. To test the predictive capacity of models, four different eye drops containing sodium hyaluronate were spiked with tritium-labeled sodium hyaluronate to standardize quantification. In both settings, eye drops were applied for 5 min and physiological conditions were mimicked by flushing with artificial tear fluid. Spreading experiments on HCE-T next to synthetic membranes were used for further characterization.Results:Binding was more pronounced in dynamic HCE-T model. Three of the four eye drops demonstrated sigmoidal elution of sodium hyaluronate, suggesting pronounced binding. One solution eluted distinctly faster, likewise the buffer control. The static method produced a similar ranking but at lower levels. When eye drops in which phosphate buffer was replaced by citrate buffer (i.e., to prevent calcification) were used, binding was not influenced. All eye drops spread immediately when placed on HCE-T and at the same order of magnitude on glass and polyethylene terephthalate surfaces.Conclusion:Dynamic and static models performed on different corneal sources were used to determine sodium hyaluronate binding kinetics in solutions under physiological conditions. These methodologies resulted in a ranking of the capacity of sodium hyaluronate to bind in vitro to corneal surfaces.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of In Vitro Methodologies to Investigate Binding by Sodium Hyaluronate in Eye Drops to Corneal Surfaces

Bock¹,

D²,

M³

et al. 2018

TOOPHTJ

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“…Hyaluronidase has been reported to be present at 20 turbidity reducing units (TRU) per mL in human vitreous (Schwartz et al, 1996;Wells, Furukawa and Sheardown, 2011). Hyaluronidase promotes HA turnover and is responsible for the maintenance of the vitreous structure (Guter and Breunig, 2017). Vitreal HA has an estimated half-life of 10-70 days depending on the species.…”

Section: In Vitro Enzymatic Degradationmentioning

confidence: 99%

In situ antibody-loaded hydrogel for intravitreal delivery

Awwad

Abubakre²,

Angkawinitwong³

et al. 2019

European Journal of Pharmaceutical Sciences

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Therapeutic protein medicines have transformed the treatment of blinding diseases (e.g. age-related macular degeneration, AMD) during the last 1-2 decades. Many blinding conditions such as AMD are chronic; and require multiple intravitreal injections over a long period to achieve a high and reproducible dose needed for clinical benefit. Prolonging the duration of action of ophthalmic drugs is critical to reduce the frequency of injections. Thermoresponsive hydrogels (e.g. N-isopropylacrylamide, NIPAAM) that collapse in physiological conditions can entrap and sustain the release of a therapeutic protein. However, most NIPAAM hydrogels are not biodegradable and often requires invasive surgery to remove the depot. Here, we report the preparation of a hydrogel derived from NIPAAM and acrylated hyaluronic acid (Ac-HA) as a biodegradable, macromolecular crosslinker. Ac-HA was prepared by the acrylation of hyaluronic acid (HA). Antibody (infliximab (INF), 5.0 mg/mL) or bevacizumab (BEVA), 12.5 mg/mL), NIPAAM (0.35 mmol) and Ac-HA (2.0-10.0 mg/mL, 40.0-200.0 nmol) were first mixed prior to redox polymerisation to ensure maximal protein mixing and to shorten the burst release. Hydrogels with lower amounts of Ac-HA (2.0-4.0 mg/mL, 40.0-80.0 nmol) showed favourable lower critical solution temperature (LCST) values and injectability (27-29G) than higher amounts of Ac-HA (>4.0 mg/mL, >80.0 nmol). These hydrogels were further characterised (swelling ratio (SR), water retention (WR) and rheology). All hydrogels degraded in presence of bovine testes hyaluronidase (0-50 U/mL, 37°C, 100 rpm). Release studies of BEVA-loaded hydrogels were investigated in vitro using the PK-Eye™ model, which estimates the human clearance times of proteins from the back of the eye. Phosphate buffered saline (PBS, pH 7.4, 37°C) was used rather than simulated vitreous to more effectively map trends between the formulations. A zeroorder release profile was observed between days 5 to 50 with 43.3 ± 9.5% protein released at day 50. Determining protein binding and functionality from a formulation is crucial to determine the optimal formulation prior to more detailed studies that might be necessary. BEVA showed binding to human vascular growth endothelial factor (VEGF 165) throughout the study (two months) while still maintaining a therapeutic dose (123.5 ± 45.6 ng) in the posterior cavity of the PK-Eye™ model. These encouraging results suggest that extended release of proteins in the vitreous can be achieved using injectable hydrogels derived from NIPAAM and HA.

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“…Its potential for enhancing ocular delivery is still being evaluated, although it has shown promise with drugs such as pilocarpine (Pahuja et al, ). HA stabilizes and organizes the extracellular matrix (ECM), regulates cell adhesion and motility and mediates cell proliferation and differentiation (Shu et al, ; Guter and Breunig, ). The commercially available form, sodium hyaluronate, is widely used in biomedical applications such as a scaffold material for wound healing and tissue engineering due to its biocompatible and biodegradable properties (Ha et al, ; Baino, ).…”

Section: Introductionmentioning

confidence: 99%

Principles of pharmacology in the eye

Awwad

Mohamed-Ahmed

Sharma

et al. 2017

British J Pharmacology

162

138

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*These authors contributed equally to this work.The eye is a highly specialized organ that is subject to a huge range of pathology. Both local and systemic disease may affect different anatomical regions of the eye. The least invasive routes for ocular drug administration are topical (e.g. eye drops) and systemic (e.g. tablets) formulations. Barriers that subserve as protection against pathogen entry also restrict drug permeation. Topically administered drugs often display limited bioavailability due to many physical and biochemical barriers including the precorneal tear film, the structure and biophysiological properties of the cornea, the limited volume that can be accommodated by the cul-de-sac, the lacrimal drainage system and reflex tearing. The tissue layers of the cornea and conjunctiva are further key factors that act to restrict drug delivery. Using carriers that enhance viscosity or bind to the ocular surface increases bioavailability. Matching the pH and polarity of drug molecules to the tissue layers allows greater penetration. Drug delivery to the posterior segment is a greater challenge and, currently, the standard route is via intravitreal injection, notwithstanding the risks of endophthalmitis and retinal detachment with frequent injections. Intraocular implants that allow sustained drug release are at different stages of development. Novel exciting therapeutic approaches include methods for promoting transscleral delivery, sustained release devices, nanotechnology and gene therapy.

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Hyaluronan as a promising excipient for ocular drug delivery

Cited by 59 publications

References 146 publications

Development of In Vitro Methodologies to Investigate Binding by Sodium Hyaluronate in Eye Drops to Corneal Surfaces

Development of In Vitro Methodologies to Investigate Binding by Sodium Hyaluronate in Eye Drops to Corneal Surfaces

In situ antibody-loaded hydrogel for intravitreal delivery

Principles of pharmacology in the eye

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