Elektroeğirme Yöntemi ile Antitüberkülostatik İlaç Yüklü Nanofiber Üretimi ve Karakterizasyonu

Yıl 2022, Cilt: 22 Sayı: 3, 654 - 661, 30.06.2022

Hilal İrem Onurlu Dilek Bilgiç Alkaya , Serap Ayaz Seyhan , Sümeyye Cesur , Oğuzhan Gündüz

https://doi.org/10.35414/akufemubid.1027082

Öz

Bu çalışma, Tüberküloz hastalarında antitüberküloz ilaçların etkili kombine formulasyonlarının üretilmesindeki zorluklar nedeniyle yeni kombinasyon formulasyonlarının değerlendirilmesi amacıyla tasarlanmıştır. Bunun için tedavide etkin antitüberkülostatikler olan pirazinamid, izoniazid, rifampisin ve etambutol biyolojik olarak parçalanabilen polikaprolakton (PCL), nanofiberlere yüklenmiş, böylelikle mevcut yan etkilerinin azaltılması da hedeflenmiştir. Mycobacterium Tuberculosis basiline karşı etkin bir tedavi için çalışmada etken maddelerin elektroeğirme yöntemiyle polimerik nanofiber formasyonları içine yüklenmesi gerçekleştirilmiştir. Bunun için öncelikle farklı konsantrasyonlarda hazırlanan PCL polimeri DMF:THF (1:1 w/w) karışımı içinde çözülmüş ve homojen bir çözelti verecek şekilde Tween 80 (%1) eklenmiştir. Elde edilen çözeltiden elektroeğirme yöntemi ile lifler elde edilmiştir. Sistem, farklı konsantrasyon ve voltajlar (17 kV, 20 kV, 23 kV, 26 kV ve 29 kV) uygulanarak optimize edilmiştir. Optimizasyon çalışmasında, %12 konsantrasyonda hazırlanan çözeltiden en uygun PCL fiber yapısı elde edilmiştir. Sistem optimizasyonu sonunda 4 farklı etken maddenin 20 kV, 1.0 ml/h akış hızı, 18 cm plaka mesafesi koşullarında metanol içerisinde çözeltilerinde tek tek ve kombinasyonları halinde fiber ile kaplanması sağlanmıştır. Çözeltilerinin elektriksel iletkenliği, yüzey gerilimi, yoğunluk ve viskozite özellikleri belirlenmiştir. Daha sonra, elektroeğirme yöntemiyle elde edilen nanofiberlerin karakterizasyon amacıyla SEM görüntüleri alınmış ve ilaç salınımı in vitro olarak incelenmiştir. İlaç salımı pH: 7.4 fosfat tamponu ile gerçekleştirilmiş ve salım UV spektrofotometresi ile analiz edilmiştir. İlaç kaplı liflerden ilaç salımı, uzun süreli ve kontrollü bir şekilde sağlanmıştır.

Anahtar Kelimeler

Antitüberküloz, Elektroeğirme, Polikaprolakton, İlaç Salım

Destekleyen Kurum

Marmara Üniversitesi Bilimsel Araştırma Projeleri Komisyonu Başkanlığı

Proje Numarası

SAG-C-YLP-120917-0517

Production and Characterization of Antituberculostatic Drug-Loaded Nanofibers by Electrospinning Method

Öz

This study was designed to evaluate new combination formulations because of the difficulties in producing effectively combined formulations of antituberculosis drugs in tuberculosis patients. For this, pyrazinamide, isoniazid, rifampicin, and ethambutol, which are effective antituberculostatics in treatment, are loaded on biodegradable polycaprolactone nanofibers, thus reducing the existing side effects. Loading of active ingredients into polymeric nanofiber formulations by electrospinning method in the study for an effective treatment against Mycobacterium Tuberculosis bacillus. For this, polycaprolactone (PCL) polymer prepared at different concentrations was dissolved in DMF: THF (1:1 w/w) mixture, and Tween 80 (1%) was added to give a homogeneous solution. Nanofibers were obtained from the solution obtained by the electrospinning method. The system was optimized by applying different concentration voltages (17 kV, 20 kV, 23 kV, 26 kV, and 29 kV). In the system optimization study, the most suitable PCL nanofiber structure was obtained from the solution prepared at 12% concentration. At the end of the system optimization, 4 different active substances were coated with fiber individually or in combinations in their solutions in methanol at 20 kV, 1.0 ml/h flow rate, 18 cm plate distance conditions. The electrical conductivity, surface tension, density, and viscosity properties of the solutions were determined. Then, SEM images were taken for characterization of nanofibers obtained by electrospinning method, and drug release was investigated in vitro. Drug release was performed with pH: 7.4 phosphate buffer and release were analyzed by UV spectrophotometer. Drug release from drug-coated nanofibers was achieved in a long-term and controlled manner.

Anahtar Kelimeler

Antituberculosis, Electrospinning, Polycaprolactone, Drug Release

Proje Numarası

SAG-C-YLP-120917-0517

Kaynakça

• Anwar, İ.H., Shehata N.A., Kimsawatde, G.C., Hudson, A.G., Sriranganathan, N., Joseph, G.E. and Mahajan, R.L., 2014. Studying the activity of antitubercluosis drugs inside electrospun polyvinyl alcohol, polyethylene oxide, and polycaprolacton nanofibers. Journal Of Bıomedical Materials Research A 102A, 11, 4009-4015.
• Baker, S.R., Banerjee, S., Bonin, K. and Guthold, M., 2016. Determining the mechanical properties of electrospun poly-ε-caprolactone (PCL) nanofibers using AFM and a novel fiberanchoring technique, Materials Science and Engineering C, 59,203-212.
• Booysen, L.L.I.J., Kalombo, L., Brooks, E., Hansen, R., Gıllıland, J., Gruppa, V., Lungenhofer, P., Makokotlela, B.S., Swai, H.S., Fkotze, A. and Lenaerts, A.H, 2013. In vitro / in vivo pharmacokinetic and pharmadynamic study of spray-dried-poly - ( DL-lactic-co-glycolic ) acid nanoparticles encapsulating rifampicin and isoniazid, International Journal of Pharmaceutical, 444,10-17.
• Carneiro, S.P., Carvalho, K.V., de Oliveira Aguiar Soares, R.D., Carneiro, C.M., de Andrade, M.H.G., Duarte, R.S. and dos Santos, O.D.H., 2019. Functionalized rifampicin- loaded nanostructured lipid carriers enhance macrophages uptake and antimycobacterial activity, Colloids and Surfaces B: Biointerfaces, 175: 306-313. Cavenaghi, R., 1989. Rifampicin raw material characteristics and their effect on bioavailability, Bulletin of the International Union Against Tuberculosis and Lung Disease, 64, 36-37.
• Dinh-Duy P., Fathal E., Tsapis N.,2015. Pyrazinamide- loaded poly(lactide - co - glycolide ) nanoparticles: optimization by experimental desing, Journal of drug delivery and technology, 30:384-390
• Dinler, B, 2019. Rifampisin Ve Vankomisin İçeren İmplante Nanofiberlerden Etkin Madde Çıkışını Etkileyen Parametrelerin İncelenmesi. Farmasötik Teknoloji Anabilim Dalı Yüksek Lisans Tezi, 140 sayfa.
• Espinosa, M.A., Valenzuela, M.I. Acedo, Peña A. Muñoz de la Peña, Salinas, F. and Cañada F., 2001. Comparative study of partial least squares and a modification of hybrid linear analysis calibration in the simultaneous spectrophotometric determination of rifampicin, pyrazinamide and isoniazid, Analytica Chimica Acta, 427, 129-136.
• Fang, P., Caı, H., Lı, H., Zhu, R., Tan, Q., Wei, G., Xu, P., Lıu, Y., ZhangWen-Y., Chen Y. and Zhang F.,2010. Simultaneous determination of isoniazid,rifampicin,lexofloxacin in Mouse tissue and plasma by high performance liquid chromatography-tandem mass spectrometry, Journal of Chromatography B, 878:2286-2291.
• Gajendirana, M., Heejung, J., Kyobum K. and Sengottuvelan B, 2019. In vitro controlled release of tuberculosis drugs by amphiphilic branched copolymer nanoparticles, Journal of Industrial and Engineering Chemistry, 4513:8.
• Hassounah, .A., Shehata, N.A., Hudson, G.A, Sriranganathan, N., Eugene, G., Joseph, R. and Mahajan L. ,2016. Designing and testing single tablet for tuberculosis treatment through electrospinning. Fabrication and Self-Assembly of Nanobiomaterials Applications of Nanobiomaterials 1, 335-365.
• Hivechi, A., Bahrami, S.H.and Siegel R. A., 2019. Drug release and biodegradability of electrospun cellulose nanocrystal ,reinforced polycaprolactone, Materials Science & Engineering C , 94:929-937.
• Hollinger, V.V.and Ranade, M.A. 2004. Drug Delivery Systems: Second Edition.CRC Press LLC., 72-390 Hu, J., Prabhakaran, M.P., Tıan, L., Dıng, X. and Ramakrish N., 2015. Drug loaded emulsion electrospun nanofibers: charecterization , drug release and in vitro biocompatibility , The royal Society of Chemistry, 5, 100256-100267. Janin, Y.L. 2007.Antituberculosis drugs: ten years of research. Bioorg. Med. Chem. 15, 2479-2513.
• Liu, Y. ;Li, C. ;Chen, J.,;Han, Y., Wei, M., Liu, J., Yu, X. Li, F., Hu, P., Fu, L. and Liu, Y., 2021. Electrospun high bioavailable rifampicin-isoniazid-polyvinylpyrrolidone fiber membranes, Applied Nanoscience, 11(8), 2271-2280.
• Pitt C.G., 1990. Polycaprolactone and its copolymers. In: Chasin M,Langer R, editors. biodegradable polymers as drug delivery systems. New York: Marcel Dekker, 71-120.
• Prasad, B. and Singh, S., 2010. LC-MS/TOF and UHPLC-MS/MS study of in vivo fate of rifamycin isonicotinyl hydrazone formed on oral co-administration of rifampicin and isoniazid, Journal of Pharmaceutical and Biomedical Analysis, 52:377-383.
• Rajaram, S., Vemuri, V. and Deepthi, N. R.,2014. Ascorbic acid improves stability and pharmacokinetics of rifampicin in the presence of isoniazid, Journal of Pharmaceutical and Biomedical Analysis, 100:103- 108.
• Rajasekhar, C., Suvardhan, K. and Inamuddin, 2020. Simultaneous detection of ethambutol and pyrazinamide with IL@CoFe2O4NPs@MWCNTs fabricated glassy carbon electrode. Scientific Reports ,10, 13563.
• Repanas, A. and Glasmacher, B., 2015. Dipyridamole embedded in Polycaprolactone fibers prepared by coaxial electrospinnig as a novel drug delivery system, Journal of Dug Delivery Science and Technology, 29: 132-142.
• Schlesınger, E., Cıaccıo N. and Desaı, T.A., 2015. Polycaprolactone thin-film drug delivery system: Empirical and predictive model for device desing, Materials Science and Engineering C, 57,232-239.
• Soppimath, K.S., Aminabhavi, T.M., Kulkarni, A.R. and Rudzinski, W.E., 2001. Biodegradable polymeric nanoparticles as drug delivery devices. Journal of Control. Release, 70:1-20.
• Srivastava A., Waterhouse D., Ardrey A., Ward S. A., 2012. Quantification of rifampicin in human plasma and cerebrospinal fluid by a highly sensitive and rapid liquid chromatography- tandem mass spectrometric method, Journal of pharmaceutical and biomedical analysis, 70,523-528. Schlesınger, E., Cıaccıo ,N. and Desaı T.A., 2015. Polycaprolactone thin-film drug delivery system: Empirical and predictive model for device desing, Materials Science and Engineering C, 57,232-239
• Smith, P.J., van Dyk, J and Fredericks A., 1999.Determination of rifampicin, isoniazid and pyrazinamide by high performance liquid chromatography after their simultaneous extraction from plasma. International Journal of Tuberculosis and Lung Disease, 3(11),325-328.
• Soppimath, K.S., Aminabhavi, T.M., Kulkarni, A.R. and Rudzinski, W.E.,2001. Biodegradable polymeric nanoparticles as drug delivery devices. Journal of Control. Release, 70:1-20.
• Srivastava, A., Waterhouse, D., Ardrey, A. and Ward, S. A., 2012. Quantification of rifampicin in human plasma and cerebrospinal fluid by a highly sensitive and rapid liquid chromatography- tandem mass spectrometric method, Journal of pharmaceutical and biomedical analysis, 70, 523-528.
• Tafazoli, S., Mashregi, M. and O'Brien, P. J., 2008. Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte infammation model. Toxicology. Applied Pharmacoogyl. 229, 94-101.
• Vasava, M. S., Nair, S.G., Rathwa, S.K. and Patel, D.B., 2019. Development of new drug-regimens against multidrug-resistant tuberculosis, Indian Journal of Tuberculosis 66(1), 12-19.