Evaluation of Intracameral Pentablock Copolymer Thermosensitive Gel for Sustained Drug Delivery to the Anterior Chamber of the Eye

Schaefer, Elizabeth; Smith, Sidney; Salmon, John L.; Abbaraju, Santhi; Amin, Rasidul; Weiss, Sidney L; Grau, Ulrich; Velagaleti, Poonam; Gilger, Brian C.

doi:10.1089/jop.2016.0181

Cited by 8 publications

(7 citation statements)

References 21 publications

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“…The SCo injection of voriconazole-thermogel was easily injected in the SCo space and was well tolerated by all the horses, with no evidence of ocular pain observed for up to 23 days. Safety of the technique and behavior of the thermogel were consistent with previous reports of SCo injections in horses and the use of copolymers in ophthalmology [10,24,[38][39][40][41]. Even though there was a significant increase in conjunctival swelling following SCo injection, a score of 2 is considered to be mild [29,30].…”

Section: Discussionsupporting

confidence: 83%

Sustained-release voriconazole-thermogel for subconjunctival injection in horses: ocular toxicity and in-vivo studies

et al. 2020

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Background: Keratomycosis is a relatively common, sight threatening condition in horses, where treatment is often prolonged and costly. Subconjunctival (SCo) injections offer less resistance to drug diffusion than the topical route, resulting in better penetration to the ocular anterior segment. Voriconazole, a second generation triazole antifungal, is effective against common fungal organisms causing keratomycosis. If combined with a thermogel biomaterial, voriconazole can be easily injected in the SCo space to provide sustained drug release. The purpose of this study was to evaluate the drug concentrations in the anterior segment and clinical effects after SCo injections of voriconazole-containing thermogel: poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) in healthy equine eyes. Results: Voriconazole aqueous humor (AH) and tear concentrations were compared between 6 horses, receiving 1% voriconazole applied topically (0.2 mL, q4h) (Vori-Top) or 1.7% voriconazole-thermogel (0.3 mL) injected SCo (Vori-Gel). For the Vori-Gel group, voriconazole concentrations were measured in AH and tears at day 2 and then weekly for 23 days, and at day 2 only for the Vori-Top group. Ocular inflammation was assessed weekly (Vori-Gel) using the modified Hackett-McDonald scoring system. Ocular tissue concentrations of voriconazole following SCo 1.7% voriconazole-thermogel (0.3 mL) injections were evaluated post euthanasia in 6 additional horses at 3 different time points. Three horses received bilateral injections at 2 h (n = 3, right eye (OD)) and 48 h (n = 3, left eye (OS)) prior to euthanasia, and 3 horses were injected unilaterally (OS), 7 days prior to euthanasia. Voriconazole-thermogel was easily injected and well tolerated in all cases, with no major adverse effects. On day 2, drug concentrations in tears were higher in the Vori-Top, but not statistically different from Vori-Gel groups. For the Vori-Gel group, voriconazole was non-quantifiable in the AH at any time point. Total voriconazole concentrations in the cornea were above 0.5 μg/g (the target minimum inhibitory concentration (MIC) for Aspergillus sp.) for up to 48 h; however, concentrations were below this MIC at 7 days post treatment. Conclusions: Voriconazole-thermogel was easily and safely administered to horses, and provided 48 h of sustained release of voriconazole into the cornea. This drug delivery system warrants further clinical evaluation.

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Section: Discussionsupporting

confidence: 83%

Sustained-release voriconazole-thermogel for subconjunctival injection in horses: ocular toxicity and in-vivo studies

et al. 2020

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“…Only small remnants of PTS gel were present ex vivo in subcutaneous tissues of mice at the time of euthanasia and these gel remnants had NIR-labeled IgG visible on IVIS imaging, suggesting that the rate of IgG release and gel disappearance occurred in parallel. In a separate study, a similar phenomenon was observed for NIR-labeled IgG when injected intracamerally [ 15 ]. The 25% PTS gel (10GH) gradually dissolved/disintegrated over the course of 30 days in the anterior chamber of the eye and the PTS gel had a strong signal of NIR-IgG in small remnants of PTS gel until the gel was completely dissolved or disintegrated [ 15 ].…”

Section: Discussionsupporting

confidence: 60%

“…In a separate study, a similar phenomenon was observed for NIR-labeled IgG when injected intracamerally [ 15 ]. The 25% PTS gel (10GH) gradually dissolved/disintegrated over the course of 30 days in the anterior chamber of the eye and the PTS gel had a strong signal of NIR-IgG in small remnants of PTS gel until the gel was completely dissolved or disintegrated [ 15 ].…”

Section: Discussionsupporting

confidence: 60%

Sustained Release of Protein Therapeutics from Subcutaneous Thermosensitive Biocompatible and Biodegradable Pentablock Copolymers (PTSgels)

Schaefer

Abbaraju

Walsh

et al. 2016

Journal of Drug Delivery

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Objective. To evaluate thermosensitive, biodegradable pentablock copolymers (PTSgel) for sustained release and integrity of a therapeutic protein when injected subcutaneously. Materials and Methods. Five PTSgels with PEG-PCL-PLA-PCL-PEG block arrangements were synthesized. In vitro release of IgG from PTSgels and concentrations was evaluated at 37°C. Released IgG integrity was characterized by SDS-PAGE. In vitro disintegration for 10GH PTSgel in PBS was monitored at 37°C over 72 days using gravimetric loss and GPC analysis. Near-infrared IgG in PTSgel was injected subcutaneously and examined by in vivo imaging and histopathology for up to 42 days. Results. IgG release was modulated from approximately 7 days to more than 63 days in both in vitro and in vivo testing by varying polymer composition, concentration of PTSgel aqueous solution, and concentration of IgG. Released IgG in vitro maintained structural integrity by SDS-PAGE. Subcutaneous PTSgels were highly biocompatible and in vitro IgG release occurred in parallel with the disappearance of subcutaneous gel in vivo. Conclusions. Modulation of release of biologics to fit the therapeutic need can be achieved by varying the biocompatible and biodegradable PTSgel composition. Release of IgG parallels disappearance of the polymeric gel; hence, little or no PTSgel remains after drug release is complete.

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“…This type of polymers has also been used as materials in corneal wound healing [38] and other ocular delivery applications [16, 39]. In addition to the triblock polymers, multiblock polymers have also been developed for ocular delivery such as to improve the physical characteristics of the thermosensitive systems and prolong drug release after intravitreal and intracameral injections [40–42]. Only triblock PLGA-PEG-PLGA polymers were studied in the present project as the first attempt to improve subconjunctival delivery of the RNA nanoparticles.…”

Section: Discussionmentioning

confidence: 99%

RNA nanoparticle distribution and clearance in the eye after subconjunctival injection with and without thermosensitive hydrogels

Shi

Charoenputtakun

et al. 2018

Journal of Controlled Release

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Thermodynamically and chemically stable RNA nanoparticles derived from the three-way junction (3WJ) of the pRNA from bacteriophage phi29 DNA packaging motor were examined previously for ocular delivery. It was reported that, after subconjunctival injection, RNA nanoparticles with tri-way shape entered the corneal cells but not the retinal cells, whereas particle with four-way shape entered both corneal and retinal cells. The present study evaluated ocular delivery of RNA nanoparticles with various shapes and sizes, and assessed the effect of thermosensitive hydrogels (poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid); PLGA-PEG-PLGA) for increasing the retention of RNA nanoparticles in the eye. Fluorescence imaging of mouse eyes and fluorescence microscopy of dissected eye tissues from the conjunctiva, cornea, retina, and sclera were performed to determine the distribution and clearance of the nanoparticles in the eyes after subconjunctival injection in vivo. RNA nanoparticles entered the cells of the conjunctiva, cornea, retina, and sclera after subconjunctival delivery. The clearance of RNA pentagon was slower than both RNA square and triangle of the same designed edge length (10nm) in the eye, and the clearance of RNA squares of the longer edge lengths (10 and 20nm) was slower than RNA square of the shorter edge length (5nm), thus indicating that the size could affect ocular pharmacokinetics of the nanoparticles. At 24h after the injection, approximately 6-10% of the fluorescence signal from the larger nanoparticles in the study (RNA square of 20nm edge length and RNA pentagon of 10nm edge length) remained in the eye, and up to 70% of the retinal cells contained the nanoparticles. The results suggest that the larger nanoparticles were "gulped" in conjunctival, corneal, retinal, and scleral cells, similar to the behavior observed in macrophages. Additionally, the combination of RNA nanoparticles with the thermosensitive polymers increased the retention of the nanoparticles in the eye.

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Evaluation of Intracameral Pentablock Copolymer Thermosensitive Gel for Sustained Drug Delivery to the Anterior Chamber of the Eye

Abstract: The PTSgel released IgG for 28 days and was well tolerated. The polymer degraded in parallel with drug release. These results demonstrate the potential of intracameral PTSgel formulations for sustained delivery of biologic therapies to the ocular anterior segment.

Cited by 8 publications

References 21 publications

Sustained-release voriconazole-thermogel for subconjunctival injection in horses: ocular toxicity and in-vivo studies

Sustained-release voriconazole-thermogel for subconjunctival injection in horses: ocular toxicity and in-vivo studies

Sustained Release of Protein Therapeutics from Subcutaneous Thermosensitive Biocompatible and Biodegradable Pentablock Copolymers (PTSgels)

RNA nanoparticle distribution and clearance in the eye after subconjunctival injection with and without thermosensitive hydrogels

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