Development of a Sustained-Release Voriconazole-Containing Thermogel for Subconjunctival Injection in Horses

Cuming, Rosemary; Abarca, Eva; Duran, Sue H.; Wooldridge, Anne A.; Stewart, Allison J.; Ravis, William R.; Babu, R. Jayachandra; Lin, Yuh-Jing; Hathcock, Terri

doi:10.1167/iovs.16-20899

Cited by 20 publications

(14 citation statements)

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“…This study is the first to use the SCo route for voriconazole delivery from a biodegradable thermogel in live horses. The results of the injection technique were in agreement with a previous report in ex vivo model [24]. Voriconazole-thermogel was easy and safe to administer in horses with no major adverse effects.…”

Section: Discussionsupporting

confidence: 89%

“…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: 84%

“…As described by Cuming et al, voriconazolecontaining thermogel, has shown to be easily injected into the dorsal SCo space of equine eyes, forming a welldefined gel deposit [24]. Furthermore, the voriconazole-PLGA-PEG-PLGA thermogel studied achieved a sustained release of voriconazole above the target MIC of 0.5 μg/mL for more than 28 days in vitro [24]. The demonstrated voriconazole sustained-release from the thermogel, together with the ease of administration in the SCo space, makes this method of potential clinical importance.…”

Section: Introductionmentioning

confidence: 90%

“…All 12 horses tolerated the SCo injections and had normal physical examinations with no evidence of ocular pain for up to 23 days (total duration of the study). The 0.3 mL volume of the 1.7% voriconazolethermogel was easily delivered in the SCo space using a 30 gauge needle as described [24]. After injection, a well-defined gel deposit was observed in the dorsal bulbar conjunctiva ( Fig.…”

Section: Clinical Findings and Ocular Toxicitymentioning

confidence: 99%

“…The thermogel was selected and prepared based on a previous study by our group [24]. Briefly, a combination of the thermogels PEG-PLGA-PEG AK19 (MW 1500-1500-1500, 1:1 lactide:glycolide) and AK24 (MW 1100-1000-1100, 3:1 lactide:glycolide) (Akina Inc., West Lafayette, IN) in a 1:1 ratio was used in order to reach a gelation temperature between 33.3°C-35.3°C (temperature of the SCo space in horses) [24]. The thermogel was stored at 4°C thereafter, and 24 h before injection, both the AK19 and AK24 solutions were mixed in a single container.…”

Section: Preparation Of the Voriconazole-thermogelmentioning

confidence: 99%

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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: 89%

Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 90%

Section: Clinical Findings and Ocular Toxicitymentioning

confidence: 99%

Section: Preparation Of the Voriconazole-thermogelmentioning

confidence: 99%

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

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Narrow molecular weight margins for the thermogelling property of polyester–polyether block copolymers in aqueous solutions

Garner

Hadar

Skidmore

et al. 2019

J of Applied Polymer Sci

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Polyester–polyether block copolymers with thermogelling properties have been widely used in pharmaceutical and biomedical applications for their biocompatibility and degradation to nontoxic components. The biodegradable polymers, such as poly(lactide‐co‐glycolide) and poly(lactide‐co‐caprolactone) (PLCL), have been used as the polyester block. The most commonly used polyether has been poly(ethylene glycol) (PEG). The thermogelling polymers dissolve in cold water, but become a semisolid gel at higher temperatures, for example, body temperature. This thermogelling property, however, occurs only within very narrow molecular weight ranges of the polyester at given polyether blocks. Only a few hundred Dalton differences in the polyester block can turn a thermogelling polymer into a water‐insoluble polymer. This study describes the hydrophilic and hydrophobic block sizes for endowing the thermogelling property and a simple, water‐free, synthesis of new thermogelling PLCL–PEG–PLCL triblock polymers. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020, 137, 48673.

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Paper spray high-resolution accurate mass spectrometry for quantitation of voriconazole in equine tears

et al. 2019

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Development of a Sustained-Release Voriconazole-Containing Thermogel for Subconjunctival Injection in Horses

Abstract: Voriconazole-containing thermogels have potential application in treatment of keratomycosis. Further research is required to evaluate their performance in vivo.

Cited by 20 publications

References 63 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

Narrow molecular weight margins for the thermogelling property of polyester–polyether block copolymers in aqueous solutions

Paper spray high-resolution accurate mass spectrometry for quantitation of voriconazole in equine tears

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