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The use of modern QbD approaches in the pharmaceutical development of technology of liposomal eye drops

Authors: Kruglov, Eu. M; Borshchevsky, G. I.;

The use of modern QbD approaches in the pharmaceutical development of technology of liposomal eye drops

Abstract

{"references": ["1.\tKishore Cholkar, Sulabh P. Patel, Aswani Dutt Vadlapudi, and Ashim K. Mitra. Novel strategies for anterior segment ocular drug delivery// Journal of Ocular Pharmacology and Therapeutics. Mar 2013. P. 106-123.http://doi.org/10.1089/jop.2012.0200", "2.\tHwang J. Y., Li Z., Loh X. J. Small molecule therapeutic-loaded liposomes as therapeutic carriers: from development to clinical applications // RSC Adv., 2016, Issue 74, 6. P. 70592\u201370615. https://doi.org/10.1039/C6RA09854A", "3.\tRanghar S., Sirohi P., Verma P., Agawal V. Nanoparticle-based drug delivery system. // Braz. arch. biol. technol. 2014, 57 (2). P. 209-222. https://doi.org/10.1590/S1516-89132013005000011", "4.\tAkbani J., Bashiz M. Nanomedicine and its role in Ophthalmology. // J. Cont. Med. 2014, 2 (3). P. 1-10. http://dx.doi.org/10.18049/jcmad/231", "5.\t Chromov A. Liposomal preparations - Realization of nanotechnology in medicine // Pharmacology and medicinal toxicology. - 2016. - No. 2. - P. 14-23.", "6.\tRai M. Nanotechnology Applied To Pharmaceutical Technology. M. Rai, C.A. Santos // Springer. 2017.386.", "7.\tRayaprolu BM. Quality by design: A brief introduction. // Journal of Pharmacovigilance. 2015;3(4):e142.", "8.\tTefas LR, Rus LM, Achim M, Vlase L, Tomuta I. Application of the quality by design concept in the development of quercetin-loaded polymeric nanoparticles. Farm\u00e1cia. 2018;66(5):798-810.", "9.\tSangshetti JN, Deshpande M, Zaheer Z, Shinde DB, Arote R. Quality by design approach: Regulatory need. // Arabian Journal of Chemistry. 2017;10: 3412-3425.", "10.\tLionberger RA, Lee SL, Lee L, Raw A, Yu LX. Quality by design: Concepts for ANDAs. // The AAPS Journal. 2008;10(2):268-276.", "11.\tYu L.X., Amidon G., Khan M.A., Hoag S.W., Polli J., Raju G.K., et al. Understanding pharmaceutical quality by design. // The AAPS Journal. 2014;16(4):771-783.", "12.\tOsborne D.W. Impact of Quality by Design on Topical Product Excipient Suppliers, Part I: A Drug Manufacturer's Perspective. // Pharm. Technol. 2016;40:38\u201343.", "13.\tFowler M. Quality by Design (QbD) Approach to Generic Transdermal or Topical Product Development. // American Pharmaceutical Review 2015", "14.\tChang R. K., Raw A., Lionberger R., Yu L. Generic Development of Topical Dermatologic Products: Formulation Development, Process Development, and Testing of Topical Dermatologic Products. // The AAPS J. 2013, 15. P. 41\u201352.", "15.\tRosas, J.G.; Blanco, M.; Gonz\u00e1lez, J.M.; Alcal\u00e1, M. Quality by design approach of a pharmaceutical gel manufacturing process, part 1: Determination of the design space. // J. Pharm. Sci. 2011, 100, 4432\u20134441.", "16.\tJain, S. Quality by design (QBD): A comprehensive understanding of implementation and challenges in pharmaceuticals development. // Int. J. Pharm. Pharm. Sci. 2014, 6, 29\u201335.", "17.\tChavda H. QbD in developing topical dosage forms. // Ely. J. Pharm. Res. 2016, 2, P. 1-2."]}

Introduction. Delivery of drugs to ocular tissues is of great interest, aimed at nanobiotechnological products, in particular liposomal drugs. The development of technology for the production of nanostructured drugs, which include liposomes, requires a large amount of experimental work focused on research and optimization of technological conditions, validation of processes, selection of auxiliary components. The aim of the work was to propose the technology of obtaining liposomal eye drops on the basis of experiment according to the QbD approach and to evaluate the influence of critical process parameters (CPP) on critical quality indicators (CQA) of the obtained intermediates. Materials and methods. Lipids were used to make liposomes. Value pH was monitored on a pH-meter Seven Compact (Mettler Toledo, USA). Method of high pressure extrusion, which was performed on the Microfluidiser M-110P (Microfluidics, USA) used for homogenization. The size of the liposomes was determined at 20 ��C on a Zetasizer Nano ZS (Malvern Instruments, UK). The level of encapsulation of the peptide complex in liposomes, the concentration of the peptide complex, the content of impurities were monitored by high performance liquid chromatography (HPLC) using Agilent 1200 chromatographs (USA). Results and discussion. Based on statistical modeling, a flexible and reliable technology of liposomal eye drop has been developed. The optimal parameters of the technological stages of the production process have been established. All stages of the process were studied empirically and the interactions between the variable parameters of the technology were analyzed. Key factors involved in manufacturing operations were examined for risks assessment. All possible factors were identified, analyzed and evaluated. Most of the factors were either non-critical or controlled in the process. Conclusions. While developing the technological process, risks of each unit of operation were considered. Experimental studies have been identified and performed with the aim of establishing additional scientific knowledge and understanding to reduce risks to an acceptable level. Following the experiments, the initial risk assessment of the technological process has been updated.

Keywords

eye drops, quality, technology, liposome

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