Overcoming ocular drug delivery barriers through the use of physical forces

Huang, Di; Chen, Ying-Shan; Rupenthal, Ilva D.

doi:10.1016/j.addr.2017.09.008

Cited by 157 publications

(97 citation statements)

References 169 publications

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“…28 The corneal epithelium, more precisely, the apical surface of the epithelium, has a major contribution to the overall barrier properties of the cornea and typically is the limiting factor relating to the permeability of ophthalmic formulations. 13,69 As reported herein, the barrier of the 3D corneal tissue model is well formed (Fig. 4) and closely parallels the structure of the human corneal epithelium (Fig.…”

Section: Discussionmentioning

confidence: 78%

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New Human Organotypic Corneal Tissue Model for Ophthalmic Drug Delivery Studies

Kaluzhny

Kinuthia

Truong

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of the current work was to develop a physiologically relevant, in vitro human three-dimensional (3D) corneal epithelial tissue model for use in ophthalmic drug development.METHODS. Normal human corneal epithelial cells were cultured at the air-liquid interface to produce the 3D corneal tissue model. Corneal barrier was determined by measuring transepithelial electrical resistance (TEER). Quantitative PCR arrays were utilized to investigate expression of 84 phase I/II metabolizing enzymes and 84 drug transporter genes. Permeability was evaluated using model compounds with a wide range of hydrophobicity, molecular weight, and excipients. Finally, different formulations of latanoprost and bimatoprost were administered and drug absorption and tissue viability and integrity were investigated.RESULTS. Histologic assessment and TEER of the corneal tissue model revealed tissue structure, thickness, and barrier formation (1000 6 146 XÁcm 2 ) comparable to native human corneal epithelium. The 3D corneal tissue expressed tight junctions, mucins, and key corneal epithelial detoxification enzymes. Drug-metabolizing enzyme and transporter gene expression in 3D corneal tissue and excised human corneal epithelium were highly correlated (r 2 ¼ 0.87). Coefficients of permeation for model drugs in the tissue model and excised rabbit corneas also showed a high correlation (r 2 ¼ 0.94). As expected, latanoprost and bimatoprost free acids had much lower permeability (Papp ¼ 1.2 3 10 À6 and 1.9 3 10 À6 ) than the corresponding prodrugs (Papp ¼ 2.5 3 10 À5 and 5.6 3 10 À5 ), respectively. The presence of 0.02% benzalkonium chloride in ophthalmic formulations significantly affected tissue barrier and viability.CONCLUSIONS. The newly developed 3D corneal tissue model appears to be very useful for evaluation of corneal drug permeability and safety during ophthalmic drug development.

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Section: Discussionmentioning

confidence: 78%

“…3, 5, 6), and as a result, developing an in vivo-like diffusion barrier for drug absorption. 13 When the 3D corneal tissues are cultured in COR-100-MM (MatTek Corporation) at SCC for up to 15 days, the barrier properties are maintained (1311 6 215 XÁcm 2 , Fig. 4).…”

Section: D Corneal Tissue Transepithelial Electrical Resistancementioning

confidence: 99%

New Human Organotypic Corneal Tissue Model for Ophthalmic Drug Delivery Studies

Kaluzhny

Kinuthia

Truong

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Thus, hydrophilic compounds follow the paracellular route through tight junctions while lipophilic molecules can cross the epithelium by the transcellular route. It has been demonstrated that only small lipophilic molecules can easily diffuse from bloodstream to the vitreous and vice versa [2,3,12].…”

Section: Blood-retinal Barrier (Brb)mentioning

confidence: 99%

“…Drug permeability through the sclera depends on molecular weight, molecular radius, charge and lipophilicity, although it is usually more permeable than the cornea and conjunctiva [2,12]. Large molecules, up to 150 kDa, find harder to get through the sclera and their clearance is lower than smaller molecules.…”

Section: Scleramentioning

confidence: 99%

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Drug Delivery to the Posterior Segment of the Eye: Biopharmaceutic and Pharmacokinetic Considerations

et al. 2020

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The treatment of the posterior-segment ocular diseases, such as age-related eye diseases (AMD) or diabetic retinopathy (DR), present a challenge for ophthalmologists due to the complex anatomy and physiology of the eye. This specialized organ is composed of various static and dynamic barriers that restrict drug delivery into the target site of action. Despite numerous efforts, effective intraocular drug delivery remains unresolved and, therefore, it is highly desirable to improve the current treatments of diseases affecting the posterior cavity. This review article gives an overview of pharmacokinetic and biopharmaceutics aspects for the most commonly-used ocular administration routes (intravitreal, topical, systemic, and periocular), including information of the absorption, distribution, and elimination, as well as the benefits and limitations of each one. This article also encompasses different conventional and novel drug delivery systems designed and developed to improve drug pharmacokinetics intended for the posterior ocular segment treatment.

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