Demircioğlu, İbrahim Hakkı; Dalkılıç, Oğuzhan; Çelik, Saffet; Akman, Tugrul Cagri; Kılıç, Hamdullah; Kandemir, Levent; Atila, Alptuğ

Extractables and Leachables studies require highly reliable and sensitive analytical methods to ensure pharmaceutical product safety. Plastic additives are widely used during production to improve the physicochemical properties of polymeric products. However, these additives may constitute a potential toxicological risk by contaminating active pharmaceutical ingredients and pharmaceutical preparations. In this study, a short-term, sensitive, accurate, and reliable LC-MS/MS method was developed for the analysis of 15 plastic additives defined in the European Pharmacopoeia and validated in accordance with the ICH Q2(R2) guideline. An electrospray ionization source was used for the analyses in both negative and positive modes. Chromatographic separation was carried out using a reverse-phase phenyl C18 column and a mixture of methanol and ultrapure water containing 5 mM ammonium acetate as the mobile phase by the gradient elution method. As a result of method optimization, the flow rate and total analysis time were determined to be 0.7 mL/min and 15 min, respectively. Diphenyl phthalate was chosen as the internal standard. The LLOQ values of plastic additives were generally determined as 50 ng/mL (150 ng/mL for oleamide). The reliability of the method was verified by intraday/interday precision and accuracy analyses. Both extractable and leachable studies were performed using the developed method. It was effectively used to detect plastic additive contamination in pharmaceutical products such as bromobutyl stoppers, LDPE containers, disposable eye drop packaging, and polypropylene bags. The developed LC-MS/MS method was successfully applied to the analysis of pharmaceutical formulations containing 1.4% polyvinyl alcohol and 0.6% povidone, sodium hyaluronate, salbutamol sulfate, and 0.9% isotonic sodium chloride.

Çoban, Özlem; Pınar, Sıla Gülbağ; Polat, Heybet Kerem; Gedik, Gülşah; Karakuyu, Nasıf Fatih; Pezik, Esra; Ünal, Sedat; Mokhtare, Behzad; Akşit, Aleyna

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.