Assessment of In-Situ Gelling Microemulsion Systems upon Temperature and Dilution Condition for Corneal Delivery of Bevacizumab

Abstract

Bevacizumab (BVZ), a recombinant humanized monoclonal antibody, has recently been proposed as a topical application in the treatment of anterior segment neovascularization; however, as there are some disadvantages in the administration of common eye-drops, ophthalmic topical drug delivery systems are under study to improve the precorneal residence time, reducing the frequency of administration. In this work, oil-in-water and water-in-oil BVZ-loaded microemulsions are developed, able to increase their viscosity, either by the formation of a liquid-crystalline structure upon aqueous dilution, thanks to the presence of Epikuron® 200 and polysorbate 80, or by body-temperature-induced jellification for the presence of Pluronic® F127 aqueous solution as an external phase. In oil-in-water microemulsion, hydrophobic ion pairs of BVZ were also prepared, and their incorporation was determined by release studies. Microemulsions were characterized for rheological behavior, corneal opacity, in vitro corneal permeation, and adhesion properties. The studied microemulsions were able to incorporate BVZ (from 1.25 to 1.6 mg/mL), which maintained dose-dependent activity on retinal pigment epithelial ARPE-19 cell lines. BVZ loaded in microemulsions permeated the excised cornea easier (0.76–1.56% BVZ diffused, 4–20% BVZ accumulated) than BVZ commercial solution (0.4% BVZ diffused, 5% accumulated) and only a mild irritation effect on the excised cornea was observed. The good adhesion properties as well the increased viscosity after application, under conditions that mimic the corneal environment (from 1 × 103 to more than 100·× 103 mPa·s), might prolong precorneal residence time, proving these systems could be excellent topical BVZ release systems.

Mucus-penetrating and permeation enhancer albumin-based nanoparticles for oral delivery of macromolecules: application to bevacizumab

“…The in vitro release study was performed in simulated gastrointestinal uid and established a role for hydrophobic complexation, as bevacizumab release was slower when encapsulated as HIP complex with either DOCU or DS. Similar behaviour has been previously reported by Peira and coworkers [39], who demonstrated that the amount of bevacizumab released from lipid nanoparticles decreased when formulated as HIP complex with sodium docusate. PEG coating had no effect in the release, although its role could be more important in the presence of enzymes as its protection of proteins against enzymatic degradation has been previously described [44].…”

“…In addition, the formation of the complex was affected by the pH of the medium (particularly for DS-based complex); however, in both cases, the e ciency of the formation process was higher than 90% (molar ratio of 1:200 and pH 6.2). These experimental conditions are in line with previous results in which hydrophobic ion-pairing complexes of bevacizumab with sodium docusate have been prepared (bevacizumab-to-counterion ratio of 1:150 in water) [38,39]. The dissociation of the two HIP complexes (BEVA-DS and BEVA-DOCU) was evaluated in different media (Supplementary information, Fig.…”

Biofunctionalization of 3D printed collagen with bevacizumab-loaded microparticles targeting pathological angiogenesis

“…The aim of the formulation screening 2 was to study the effect of the PLGA/BVZ ratio and the Tween® 80/BVZ ratio on the EE and release kinetics when the surfactant is dissolved in the primary water phase (w1) (Table 2). In this screening, Tween has been preferred over Pluronic because, according to the literature, it has been previously mixed in aqueous phases for BVZ micro-and nanoencapsulation, with a beneficial effect on the EE and stability [48,49]. Span has been excluded due to its insolubility in water.…”

Fabrication of poloxamer based besifloxacin thermosensitive in situ gelling nanoemulsions for ophthalmic delivery

“…10 In situ gel nanoemulsions (in situ gel-NEs) have been fabricated successfully in numerous studies for delivering various drugs such as dorzolamide, loteprednol, sparfloxacin, brinzolamide, and bevacizumab to the eye. [11][12][13][14][15] Ophthalmic infections are mostly contributed by bacteria. There are various pathogens, including Staphylococcus aureus and Pseudomonas aeruginosa, which are two of the most common gram-positive and gram-negative pathogens involved in eye infections such as conjunctivitis and keratitis.…”

“…10 In situ gel nanoemulsions (in situ gel-NEs) have been fabricated successfully in numerous studies for delivering various drugs such as dorzolamide, loteprednol, sparfloxacin, brinzolamide, and bevacizumab to the eye. 11–15…”