Preparation and Characterization of an Oral Norethindrone Sustained Release/Controlled Release Nanoparticles Formulation Based on Chitosan
- 47 Downloads
Norethindrone has short half-life and low bioavailability. The objective was to prepare an oral Sustained Release/Controlled Release (SR/CR) Liquid Medicated Formulation (LMF) to enhance bioavailability and improve patient compliance. Norethindrone was solubilized in HP-β-CD then complexed with different concentrations of Low Molecular Weight Chitosan (LMWC) (mucoadhesive). PolyElectrolyte Complexes (PECs) were homogenized with oleic acid using different concentrations of tween 80 to form LMFs (nanoemulsions). PECs and LMFs were characterized using different techniques. LMF 2 (optimum formula containing 2.5% w/v LMWC 11 kDa) was administered orally to dogs and mice for pharmacokinetic and adhesion evaluation. DSC, FTIR spectroscopy and SEM images indicated complex formation. Mean diameters of PECs were 183–425 nm, mean zeta potentials were + 18.6–+ 31 mV, and complexation efficiencies were 18.0–20.6%. Ten to fifteen percent tween was needed to prepare homogenous LMFs. Mean diameter of LMF 2 was 10.5 ± 0.57 nm, mean zeta potential was − 11.07 ± − 0.49 mV, encapsulation efficiency was 95.28 ± 1.75%, and each mL contained 145.5 μg norethindrone. SEM images showed spherical homogeneous oil droplets. All of these parameters were affected by molecular weight and concentration of chitosan. Norethindrone release from LMFs was controlled (zero order) for 96 h. It was little affected by molecular weight and concentration of chitosan but affected by concentration of tween 80. LMF 2 adhered to GIT for 48 h and enhanced the bioavailability. It showed no cytotoxicity after considering dilution in GIT and was stable for 3 months refrigerated. In conclusion an effective SR/CR LMF was prepared.
KEY WORDSlow molecular weight chitosan hydroxyPropyl-beta-cyclodexrin norethindrone sustained/controlled release nanoemulsion
The authors received financial support (347/2015) from Jordan University of Science and Technology.
- 2.United States Pharmacopeial Convention. USP36 NF31, U. S. pharmacopoeia national formulary. 1st edition. 2013.Google Scholar
- 4.Kumar KP, Bhowmik D, Srivastava S, Paswan S, Dutta AS. Sustained release drug delivery system potential. Pharma Innov. 2012;1(2):48–60.Google Scholar
- 5.Parashar T, Soniya SV, Singh G, Tyagi S, Patel C, Gupta A. Novel oral sustained release technology: a concise review. Int J Res Dev Pharm Life Sci. 2013;2(2):262–9.Google Scholar
- 6.Nidhi P, Anamika C, Twinkle S, Mehul S, Hitesh J, Umesh U. Controlled drug delivery system: a review. Indo Am J Pharm Sci. 2016;3(3):227–33.Google Scholar
- 11.Rinaudo M. Chitin and chitosan: properties and applications. Prog Polym Sci. 2006;31(7):603–32. https://doi.org/10.1016/j.progpolymsci.2006.06.001.CrossRefGoogle Scholar
- 15.Patil JS, Marapur SC, Gurav PB, Banagar AV. Ionotropic gelation and polyelectrolyte complexation technique: novel approach to drug encapsulation. In: Mishra M, editor. Handbook of encapsulation and controlled release. New York: Taylor & Francis; 2015. p. 278.Google Scholar
- 19.Häusler O, Müller-Goymann C. Properties and structure of aqueous solutions of hydroxypropyl-beta-cyclodextrin. Starch 1993;45(5):183–187. https://doi.org/10.1002/star.19930450508.
- 21.Prakash RT, Thiagarajan P. Nanoemulsions for drug delivery through different routes. Res Biotechnol. 2011;2(3):01–13.Google Scholar
- 22.Halnor VV, Pande VV, Borawake DD, Nagare HS. Nanoemulsion: A novel platform for drug delivery system. J Mat Sci Nanotechol. 2018;6(1):104 Available online at www.annexpublishers.com.
- 32.Bandi N, Wei W, Roberts CB, Kotra LP, Kompella UB. Preparation of budesonide–and indomethacin–hydroxypropyl-β-cyclodextrin (HPBCD) complexes using a single-step, organic-solvent-free supercritical fluid process. Eur J Pharm Sci. 2004;23(2):159–68. https://doi.org/10.1016/j.ejps.2004.06.007.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Sethia S, Squillante E. Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods. Int J Pharm. 2004;272(1):1–10. https://doi.org/10.1016/j.ijpharm.2003.11.025.
- 40.Yeh Mk, Cheng KM, Hu CS, Huang YC, Young JJ. Novel protein-loaded chondroitin sulfate chitosan nanoparticles: Preparation and characterization. Acta Biomater. 2011;7(10):3804–12. https://doi.org/10.1016/j.actbio.2011.06.026.
- 44.Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, et al. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10:57–73. https://doi.org/10.3390/pharmaceutics10020057.CrossRefPubMedCentralGoogle Scholar
- 45.De Alvarenga ES. Characterization and properties of chitosan. In: Elnashar M, editor. Biotechnology of biopolymers. Croatia: InTech; 2011. p. 91–108. Available from: http://www.intechopen.com/books/biotechnology-of-biopolymers/characterization-and-properties-of-chitosan.Google Scholar
- 48.Calvo P, Remunan-Lopez C, Vila-Jato J, Alonso M. Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. J App Polymer Sci. 1997;63(1):125–32. https://doi.org/10.1002/(SICI)1097-4628(19970103)63:1<125::AID-APP13>3.0.CO;2-4.CrossRefGoogle Scholar
- 55.Athamneh N, Tashtoush B, Qandil A, Al-Tanni B, Obaidat A, Al-Jbour N, et al. A new controlled-release liquid delivery system based on diclofenac potassium and low molecular weight chitosan complex solubilized in polysorbates. Drug Dev Ind Pharm. 2013;39(8):1217–29. https://doi.org/10.3109/03639045.2012.707205.CrossRefPubMedGoogle Scholar
- 58.Sevcikova P, Vltavska P, Kasparkova V, Krejci J. Formation, characterization and stability of nanoemulsions prepared by phase inversion. MACMESE'11 Proceedings of the 13th WSEAS international conference on Mathematical and computational methods in science and engineering. Pages 132–137. November 03–05, 2011. ISBN: 978–1–61804-046-6.Google Scholar
- 59.Setya S, Talegaonkar S, Razdan BK. Nanoemulsions: formulation methods and stability aspects. World J Pharm Pharm Sci. 2014;3(2):2214–28.Google Scholar