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    Development of lacosamide-loaded in-situ gels through experimental design for evaluation of ocular irritation in vitro and in vivo
    (Elsevier B.V., 2025) Çoban, Özlem; Pınar, Sıla Gülbağ; Polat, Heybet Kerem; Gedik, Gülşah; Karakuyu, Nasıf Fatih; Pezik, Esra; Ünal, Sedat
    Lacosamide (LCM) selectively increases the slow inactivation of voltage-gated sodium channels (VGSCs) and is a N-methyl D-aspartate acid (NMDA) receptor glycine site antagonist. Therefore, it can be used in dryness-related hyperexcitability of corneal cold receptor nerve terminals. Ocular in-situ gels remain in liquid form until they reach the target site, where they undergo a sol-gel transformation in response to specific stimuli. They can show mucoadhesive properties related to the polymer used and increase the residence time of the drug in the mucosa. In the presented study, ocular in-situ gel formulation of LCM, which has potential for use in ocular diseases and consists of hyaluronic acid and poloxamer 407 as polymers, was developed using cold method. The effect of formulation components on target product properties (pH, gelation temperature and viscosity) was evaluated by design of experiments (DoE) design. The optimized LCM-loaded in-situ gel had a pH value of 6.90 ± 0.01, showed pseudo-plastic flow with a viscosity of 562 ± 58 cP at 25 °C, gelled at 33 ± 0.47 °C, and released drugs via the Peppas-Sahlin mechanism. Ocular safety was confirmed via in vitro tests using two different cell lines (L929 and Arpe-19), along with in vivo Draize tests, histological examinations, and Hen's Egg Chario-Allontioc-Membrane (HET-CAM) analysis. In vitro studies confirmed the optimized LCM-loaded in-situ gel's suitability for ocular use, demonstrating long-acting effects through controlled release. In addition, ocular irritation and histological studies have supported that it will not show any toxic effect on the eye tissue. © 2024 American Pharmacists Association
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    Formulation development of dual drug-loaded thermosensitive ocular in situ gel using factorial design
    (Springer, 2023) Polat, Heybet Kerem; Arslan, Aslıhan; Ünal, Sedat; Haydar, Muhammet Kerim; Aytekin, Eren; Gözcü, Sefa; Mokhtare, Behzad
    Purpose: To overcome the problems of low bioavailability of the drug associated with the short pre-corneal residence time, a thermoresponsive in situ gel system containing poloxamer P407, hydroxypropyl methylcellulose, and chitosan was developed to prolong the pre-corneal residence time of the drug. Methods: The central composite design was utilized to assess the effects of the concentration of poloxamer 407 hydroxypropyl methylcellulose and chitosan, the concentration of polymer, and the polymer type on the viscosity, pH, and gelation temperature, which were considered indicators of optimum formulations. Results: After model selection for response analysis, the quadratic model was found to be the best-fitting model for the relationship between independent factors and response variables. As a result of the central composite design, the optimized formulation contained 15.17% poloxamer 407 and 2.141% chitosan. Viscosity 25 °C = 2199.4 ± 26.2, viscosity 35 °C = 15,487.2 ± 117.4, pH = 6.5 ± 0.01, and gelation temperature °C = 33.3 ± 0.47 were obtained. The ex-vivo study revealed that the BRN formulation containing flurbiprofen-cyclodextrin inclusion complex has higher corneal penetration (P < 0.01). The cytotoxicity of ARPE-19 cells and irritation studies, as measured by in situ gel, was found to be acceptable. In lipoxygenase studies, the effectiveness of the BRN formulation was found to be significantly higher than other formulations (P < 0.01). Conclusions: It is thought that the BRN formulation may be an alternative to the treatment of ocular allergic disease.
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    Formulation development of Lornoxicam loaded heat triggered ocular in-situ gel using factorial design
    (Taylor and Francis Ltd., 2023) Polat, Heybet Kerem; Ünal, Sedat; Aytekin, Eren; Karakuyu, Nasıf Fatih; Pezik, Esra; Haydar, Muhammet Kerim; Mokhtare, Behzad
    Objective: In the current research, lornoxicam-loaded in situ gels were developed, and their potential usage in ocular inflammation was evaluated. Significance: Lornoxicam cyclodextrin complex prepared with hydroxypropyl methylcellulose and poloxamer P407 because of the low viscosity of in situ gels to provide easy application. However, washing and removing it from the ocular surface becomes difficult due to the gelation formation with heat. Methods: A three-level factorial experimental design was used to evaluate the effects of poloxamer 407 concentration, polymer type, and polymer concentration on viscosity, pH, gelation capacity, gelation time, and gelation temperature, which were considered the optimal indicators of lornoxicam-containing formulations. Results: As a result of the three-level factorial experimental design, the optimized formulation contained 15 (%w/v) poloxamer 407 and 1 (%w/v) hydroxypropyl methylcellulose. The optimize formulation viscosity 25 °C = 504 ± 49cP, viscosity 35 °C = 11247 ± 214cP, pH = 6.80 ± 0.01, gelation temprature = 35 ± 0.2 °C, and gelation time= 34 ± 0.2 s was obtained. In the in vitro release studies, 68% of lornoxicam was released with a burst effect in the first three hours; then, the release continued for eight hours with controlled release. Release kinetics of the formulations were modeled mathematically, and it was found to be compatible with the Korsemeyer-Peppas and Weibull models. In cell culture studies, cell viability at 100 µg/mL was 83% and 96% for NL6 and NL6-CD, respectively. In Draize’s in vivo test, no negative conditions occurred in rats. Conclusions: Therefore, the NL6-CD formulation has the potential to be a favorable option for treating ocular inflammation.
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    Harnessing silk fibroin microparticles for metformin delivery: A novel approach to treating corneal neovascularization
    (Editions de Sante, 2024) Polat, Heybet Kerem; Aytekin, Eren; Karakuyu, Nasıf Fatih; Çaylı, Yağmur Akdağ; Çalamak, Semih; Demirci, Nazire; Mokhtare, Behzad
    Corneal neovascularization (CV) poses significant challenges in ophthalmology, often leading to impaired vision and discomfort. Silk fibroin microparticles have emerged as promising candidates for drug delivery applications, owing to their biocompatibility, biodegradability, and controlled release characteristics. In the current research, metformin-loaded silk microparticles were developed, and their potential for treating corneal neovascularization was evaluated. Silk microparticles were prepared using silk fibroin and polyvinyl alcohol (PVA) at various weight ratios, facilitating phase separation to create a porous structure conducive to drug loading. Metformin (MT), a widely used antidiabetic agent with potential anti-angiogenic properties, was incorporated into the silk microparticles at different concentrations. The formulation termed TB (0.3 % MT loaded Microparticles) emerged as the most promising candidate was identified through comprehensive in vitro evaluations. In in vitro cytotoxicity studies, it was determined that all formulations provided cell viability above 80%, however, in permeability studies and encapsulation efficiency studies, TB was determined to be more effective than other formulations. TB demonstrated a particle size of approximately 8.9 ± 3.6 ?m and an encapsulation efficiency of 96.3 ± 2.1%. In vitro release studies revealed that TB exhibited a burst release of 62% within the initial two days, followed by sustained release over a period of 14 days, consistent with Peppas-Sahlin kinetics. Mathematical modeling further corroborated the diffusion mechanism underlying drug release from TB microparticles. In vivo studies on rats and histochemical analyzes on corneas showed that TB exhibited efficacy comparable to dexamethasone, a standard treatment for CV, despite being administered once daily. Histological analyses of corneal tissues revealed reduced neovascularization and inflammation in the TB-treated group, underscoring its therapeutic potential. Overall, our findings highlight the promise of metformin-loaded silk fibroin microparticles as a novel therapeutic approach for managing CV, offering sustained drug release and enhanced efficacy in treating this challenging ocular condition. © 2024