Flurbiprofen-encapsulated microsphere laden into heat-triggered situ gel for ocular delivery

Yıl 2024, , 108 - 121, 26.08.2024

Heybet Kerem Polat , Sedat Ünal

https://doi.org/10.26650/IstanbulJPharm.2024.1269717

Öz

Background and Aims: This investigation aimed to enhance flurbiprofen’s (FB) pre-corneal residence period and ocular availability in the postoperative management of ocular inflammation.

Methods: The microsphere (MS) material was poly (lactic-co-glycolic acid) PLGA, and FB-laden microspheres were prepared using a single emulsification/solvent evaporation process, loaded onto thermosensitive in situ gels, and then characterised.

Results: The size of the microparticles was measured as 19.3±2.1 μm. Entrapment efficiency, zeta potential, and in vitro release; it was observed that the microspheres were released for six days. The optimum gelling capacity was obtained using 15% Poloxamer 407, 8% Poloxamer 188, and 1% HEC (viscosity 80-125 cp). Poloxamer 407 concentration was reduced, resulting in increased gelation temperature and duration. It was determined that the gelling temperature of the selected formulation was 35±0.1 °C, the pH was 6.9±0.02, and the viscosity at the gelling temperature was 11042±247 cP. The addition of hydroxyethyl cellulose increased the mucoadhesive strength. - in vitro release of FB from FB-PLGA MS followed the Korsmeyer-Peppas model , –, and the in situ gel preparation was found to be compatible with the Peppas-Sahlin model. In addition, MTT analysis of the ARPE-19 cell line revealed that the in situ gel formulation was biocompatible.

Conclusion: Flurbiprofen release was sustained, ocular availability was improved, and residence time was increased when flurbiprofen-loaded microspheres were incorporated into in situ gel bases.

Anahtar Kelimeler

Flurbiprofen, Poloxamer Gel, Ocular Gel, PLGA Microsphere, Release Kinetics

Kaynakça

• Abd Elhady, S. S., Mortada, N. D., Awad, G. A., and Zaki, N. M. (2003). Development of an in situ gelling and much adhesive mebeverine hydrochloride solution for rectal administration. Saudi Pharmaceutical Journal, 11. google scholar
• Aksungur, P., Demirbilek, M., Denkbaş, E. B., Vandervoort, J., Lud-wig, A., Ünlü, N. (2011). Development and characterisation of Cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies. Journal of controlled release, 151(3), 286-294. google scholar
• Akyüz, L., Duman, F. and Murat, K. (2017). Encapsulation of flur-biprofen by chitosan using a spray drying method with in vitro drug release and molecular docking. Turkish Journal of Pharma-ceutical Sciences, 14(1), 34. google scholar
• nderson, J. M., & Shive, M. S. (1997). Biodegradation and biocompat-ibility of PLA and PLGA microspheres. Advanced drug delivery reviews, 28(1), 5-24. google scholar
• Asasutjarit, R., Thanasanchokpibull, S., Fuongfuchat, A., and Veer-anondha, S. (2011). Optimisation and evaluation of thermore-sponsive diclofenac sodium ophthalmic in situ gels. International Journal of Pharmaceutics, 411(1-2), 128-135. google scholar
• Aytekin, E., Öztürk, N., Vural, İ., Polat, H. K., Çakmak, H. B., Çalış, S., and Pehlivan, S. B. (2020). Design of ocular drug delivery platforms and in vitro-in vivo evaluation of riboflavin in the cornea using a non-interventional (epi-on) technique for keratoconus treatment. J Control Release, 324, 238-249. doi:10.1016/j.jconrel.2020.05.017 google scholar
• Cabana, A., Aıt-Kadi, A., & Juhasz, J. (1997). Study of the gelation process of polyethylene oxidea-polypropylene ox-ideb-polyethylene oxideacopolymer (poloxamer 407) aqueous so-lutions. Journal of colloid and interface science, 190(2), 307-312. google scholar
• D’Souza, S. S., and DeLuca, P. P. (2006). Methods to assess in vitro drug release from injectable polymeric particulate systems. Phar-maceutical Research, 23, 460-474. google scholar
• Ding, D., Kundukad, B., Somasundar, A., Vijayan, S., Khan, S. A., & Doyle, P. S. (2018). Design of mucoadhesive PLGA microparticles for ocular drug delivery. ACS Appl Biomater, 1(3), 561-571. google scholar
• Dumortier, G., Grossiord, J. L., Agnely, F., & Chaumeil, J. C. (2006). A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharmaceutical Research, 23, 2709-2728. google scholar
• Fathallae, Z. M., Mangala, A., Longan, M., Khaled, K. A., Hussein, A. K., El-Garhy, O. H., & Alan, R. G. (2017). Poloxamer-based ther-moresponsive ketorolac tromethamine in situ gel preparations: De-sign, characterisation, toxicity and transcorneal permeation stud-ies. European Journal of Pharmaceutics and Biopharmaceutics, 114, 119-134. google scholar
• Gilbert, J. C., J. L. Richardson, M. C. Davies, K. J., & Hadgraft, J. (1987). Effects of solutes and polymers on the gelation properties of pluronic F-127 solutions for controlled drug delivery. Journal of controlled release, 5(2), 113-118. google scholar
• Gonjari, I. D., A. H. Hosmani, A. B. Karmarkar, A. S. Godage, S. B. Kadam, and P. N. (2009). Formulation and evaluation of an in situ thermoreversible mucoadhesive gel of fluconazole. Drug Discovery and Therapeutics, 3(1). google scholar
• Gonzalez-Pizarro, R., Carvajal-Vidal, P., Halbault Bellows, L., alpena, A. C., spina, M., & (iarcıa, M. L. (2019). In-situ forming gels containing fluorometholone-loaded polymeric nanoparticles for ocular inflammatory conditions. Colloids Surf B Biointerfaces, 175, 365-374. doi:10.1016/j.colsurfb.2018.11.065 google scholar
• Hu, C., Feng, H., & Zhu, C. (2012). Preparation and characterisa-tion of rifampicin-PLGA microspheres/sodium alginate in situ gel combination delivery system. Colloids Surf B Biointerfaces, 95, 162-169. doi:10.1016/j.colsurfb.2012.02.030 google scholar
• Ishibashi, T., Yokoi, N., Bron, A. J., Tiffany, J. M., Komuro, A., and Kinoshita, S. (2003). Reversible retention of thermo-gelling tim-olol on the human ocular surface studied by video meniscometry. Current eye research, 27(2), 117-122. google scholar
• Khan, S., Parade, S., & Qinghai, D. J. (2018). Improvement in ocular bioavailability and prolonged delivery of tobramycin sulphate following topical ophthalmic administration of drug-loaded mu-coadhesive microparticles incorporated in a thermosensitive in situ gel. Journal of ocular pharmacology and therapeutics, 34(3), 287-297. google scholar
• Lorenzo-Veiga, B., Diaz-Rodriguez, P., Alvarez-Lorenzo, C., Lofts-son, T., and Sigurdsson, H. H. (2020). In Vitro and Ex Vivo Evaluation of Nepafenac-Based Cyclodextrin Microparticles for Treatment of Eye Inflammation. Nanomaterials (Basel), 10(4). doi:10.3390/nano10040709 google scholar
• Mansour, M., Mansour, S., Mortada, N. D., & Abd ElHady, S. S. (2008). Ocular poloxamer-based ciprofloxacin hydrochloride in situ forming gels. Drug development and industrial pharmacy, 34(7), 744-752. google scholar
• Momoh, M., Adedokun, M., Lawal S, Ubochi G. (2014). Formulation and in vitro evaluation of ibuprofen-loaded poly (D, L-lactide-co-glycolide) microparticles. Tropical Journal of Pharmaceutical Research, 13(10), 1571-1576. google scholar
• Morsi, N., Ghorab, D., Refai H, Teba H. (2016). Ketoroloac-tromethamine-loaded nanodispersion incorporated into ther-mosensitive in situ gel for prolonged ocular delivery. International Journal of Pharmaceutics, 506(1-2), 57-67. google scholar
• Öztürk, A. A., Yenilmez, E., Şenel, B., Kıyan, H. T., and Güven, U. M. (2020). Effect of different molecular weight PLGA on flurbiprofen nanoparticles: formulation, characterisa-tion, cytotoxicity, and in vivo anti-inflammatory effects using the HET-CAM assay. Drug Dev Ind Pharm, 46(4), 682-695. doi:10.1080/03639045.2020.1755304 google scholar
• Patel, A., Cholkar, K., Agrahari, V. and Mitra, A. K. (2013). Ocular drug delivery systems: An overview. World journal of pharmacol-ogy, 2(2), 47-49, 2018. google scholar
• Polat, H. K., (2022). Design of a Metformin-HCl and Moxifloxacin-HCl-loaded Thermosensitive In Situ Gel. Journal of Research in Pharmacy, 26(5). google scholar
• Polat, H. K., Arslan, A., Ünal, S., Haydar, M. K., Aytekin, E., Gözcü S., Mokhtare, B. (2023). Development of a Dual Drug-Loaded Ther-mosensitive Ocular In Situ Gel Using Factorial Design. Journal of Pharmaceutical Innovation, 1-21. google scholar
• Polat, H. K., Kurt, N., Aytekin, E., Akdağ Çaylı, Y., Bozdağ Pehlivan, S., & Çalış, S. (2022). Design of Besifloxacin HCl-loaded nanos-tructured lipid carriers: in vitro and ex vivo evaluation. Journal of ocular pharmacology and therapeutics, 38(6), 412-423. google scholar
• Polat, H. K., Ünal, S., Aytekin, E., Karakuyu, N. F., Pezik, E., Haydar, M. K., Mokhtare, B. (2023). Development of a Lornoxicam-loaded heat-triggered ocular in situ gel using factorial design. Drug Dev Ind Pharm, 1-15. doi:10.1080/03639045.2023.2264932 google scholar
• Puthli, S., and Vavia, P. R. (2009). Stability studies of a micropartic-ulate system using piroxicam as model drug. Aaps Pharmscitech, 10, 872-880. google scholar
• Ricci, E., Lunardi, L. O., Nanclares, D., and Marchetti, J. M. (2005). Sustained release of lidocaine from Poloxamer 407 gels. Interna-tional journal of pharmaceutics, 288(2), 235-244. google scholar
• Samatı, Y., Yüksel, N., & Tarimcı, N. (2006). Preparation and char-acterisation of poly (D, L-lactic-co-glycolic acid) microspheres containing flurbiprofen sodium. Drug Delivery, 13(2), 105-111. google scholar
• Samdancioglu, S., Calis, S., Sumnu, M. and Atilla Hincal, A. (2006). Formulation and in vitro evaluation of bisphosphonate-loaded mi-crospheres for implantation in osteolysis. Drug development and industrial pharmacy, 32(4), 473-481. google scholar
• Siepmann, J., Faisant, N., & Benoit, J.-P. (2002). A new mathematical model for quantifying drug release from bioerodible microparti-cles using Monte Carlo simulations. Pharmaceutical Research, 19, 1885-1893. google scholar
• Signatella, R., Bulolo, C., pedaliers, G., Maltese, A., & Puglisi, G. (2002). Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials, 23(15), 3247-3255. google scholar
• Supramaniam, J., Adnan, R., Mohd Kaus, N. H., & Bushra, R. (2018). Magnetic nanocellulose alginate hydrogel beads as a potential drug delivery system. Int J Biol Macromol, 118(Pt A), 640-648. doi:10.1016/j.ijbiomac.2018.06.043 google scholar
• Vasconcelos, A., Vega, E., Perez, Y., Gomara, M. J., Garda, M. L., & Haro, I. (2015). Conjugation of cell-penetrating peptides with poly(lactic-co-glycolic acid)-polyethylene glycol nanoparti-cles improves ocular drug delivery. Int J Nanomedicine, 10, 609631. doi:10.2147/ijn. S71198 google scholar
• Venkatesh, D., Kamlesh, L. and Kumar, P. (2013). Development and evaluation of chitosan-based thermosensitive in situ gels of pilo-carpine. Int J Pharm Pharmaceut Sci, 5, 164-169. google scholar
• Wanka, G., Hoffmann, H. and Ulbricht, W. (1994). Phase dia-grams and aggregation behaviours of poly (oxyethylene)-poly (oxypropylene)-poly (oxyethylene) triblock copolymers in aque-ous solutions. Macromolecules, 27(15), 4145-4159. google scholar
• Yasukawa, T., Kimura, H., Tabata, Y., & Ogura, Y. (2001). Biodegrad-able scleral plugs for vitreoretinal drug delivery. Advanced drug delivery reviews, 52(1), 25-36. google scholar