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.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, et al. Classification and pharmacology of progestins. Maturitas. 2003;46:7–16.
United States Pharmacopeial Convention. USP36 NF31, U. S. pharmacopoeia national formulary. 1st edition. 2013.
Santos M, Hendry D, Sangi-Haghpeykar H, Dietrich J. Retrospective review of norethindrone use in adolescents. J Pediatr Adolesc Gynecol. 2014;27(1):41–4. https://doi.org/10.1016/j.jpag.2013.09.002.
Kumar KP, Bhowmik D, Srivastava S, Paswan S, Dutta AS. Sustained release drug delivery system potential. Pharma Innov. 2012;1(2):48–60.
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.
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.
Emami J, Varshosaz J, Ahmadi F. Preparation and evaluation of a liquid sustained-release drug delivery system for theophylline using spray drying technique. Res Pharm Sci. 2007;2:1–11 Available online at www.thepharmajournal.com.
Jong W, Borm P. Drug delivery and nanoparticles: applications and hazards. Int J Nanomedicine. 2008;3(2):133–49.
Bamrungsap S, Zhao Z, Chen T, Wang L, Li C, Fu T, et al. Nanotechnology in therapeutics: a focus on nanoparticles as a drug delivery system. Nanomedicine. 2012;7(8):1253–71. https://doi.org/10.2217/nnm.12.87.
Cho K, Wang X, Nie S, Shin DM. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res. 2008;14(5):1310–6. https://doi.org/10.1158/1078-0432.CCR-07-1441.
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.
Felt O, Buri P, Gurny R. Chitosan: a unique polysaccharide for drug delivery. Drug Dev Ind Pharm. 1998;24(11):979–93. https://doi.org/10.3109/03639049809089942.
Ilium L. Chitosan and its use as a pharmaceutical excipient. Pharm Res. 1998;15(9):1326–31.
Kumar M, Muzzarelli R, Muzzarelli C, Sashiwa H, Domb A. Chitosan chemistry and pharmaceutical perspectives. Chem Rev. 2004;104(12):6017–84. https://doi.org/10.1021/cr030441b.
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.
Kittur F, Kumar A, Tharanathan R. Low molecular weight chitosans—preparation by depolymerization with Aspergillus niger pectinase, and characterization. Carbohydr Res. 2003;338(12):1283–90. https://doi.org/10.1016/S0008-6215(03)00175-7.
Tiwari G, Tiwari R, Rai A. Cyclodextrins in delivery systems: applications. J Pharm Bioallied Sci. 2010;2(2):72–9. https://doi.org/10.4103/0975-7406.67003.
Borghetti G, Lula I, Sinisterra R, Bassani V. Quercetin/β-Cyclodextrin solid complexes prepared in aqueous solution followed by spray-drying or by physical mixture. AAPS J. 2009;10(1):235–42. https://doi.org/10.1208/s12249-009-9196-3.
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.
Brewster M, Hora M, Simpkins J, Bodor N. Use of 2-hydroxypropyl-β-cyclodextrin as a solubilizing and stabilizing excipient for protein drugs. J Pharm Res. 1991;8(6):792–5.
Prakash RT, Thiagarajan P. Nanoemulsions for drug delivery through different routes. Res Biotechnol. 2011;2(3):01–13.
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.
Obaidat R, Al-Jbour N, Al-Sou’d K, Sweidan K, Al-Remawi M, Badwan A. Some physico-chemical properties of low molecular weight chitosans and their relationship to conformation in aqueous solution. J Solut Chem. 2010;39(4):575–88. https://doi.org/10.1007/s10953-010-9517-x.
Kasaai M. Calculation of Mark–Houwink–Sakurada (MHS) equation viscometric constants for chitosan in any solvent–temperature system using experimental reported viscometric constants data. Carbohydr Polym. 2007;68(3):477–88. https://doi.org/10.1016/j.carbpol.2006.11.006.
Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, et al. DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J. 2010;12(3):263–71. https://doi.org/10.1208/s12248-010-9185-1.
Goehl TJ, Sundaresan GM, Prasad VK. Analytical methodology applicable in dissolution testing of norethindrone-mestranol tablets. Int J Pharm. 1982;11(3):181–6. https://doi.org/10.1016/0378-5173(82)90036-9.
Kaklamanos G, Theodoridis G, Papadoyannis IN, Dabalis T. Determination of anabolic steroids in muscle tissue by liquid chromatography–tandem mass spectrometry. J Agric Food Chem. 2007;55(21):8325–30. https://doi.org/10.1021/jf0713455.
Vijaya Kumar S, Mishra D. Preparation, characterization and in vitro dissolution studies of solid systems of valdecoxib with chitosan. Chem Pharm Bull. 2006;54(8):1102–6. https://doi.org/10.1248/cpb.54.1102.
Djordjevic L, Primorac M, Stupar M, Krajisnik D. Characterization of caprylocaproyl macrogolglycerides based microemulsion drug delivery vehicles for an amphiphilic drug. Int J Pharm. 2004;271(1):11–9. https://doi.org/10.1016/j.ijpharm.2003.10.037.
Paulino A, Simionato J, Garcia J, Nozaki J. Characterization of chitosan and chitin produced from silkworm crysalides. Carbohydr Polym. 2006;64(1):98–103. https://doi.org/10.1016/j.carbpol.2005.10.032.
George S, Vasudevan D. Studies on the preparation, characterization, and solubility of 2-HP-β-cyclodextrin-meclizine HCI inclusion complexes. J Young Pharm. 2012;4(4):220–7. https://doi.org/10.4103/0975-1483.104365.
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.
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.
Silverstein R, Rodin J. Spectrometric identification of organic compounds on a milligram scale: The use of complementary information. Microchem J. 1965;9(3):301–8. https://doi.org/10.1016/0026-265X(65)90049-4.
Bursi R, Groen M. Application of (quantitative) structure–activity relationships to progestagens: from serendipity to structure-based design. Eur J Med Chem. 2000;35(9):787–96. https://doi.org/10.1016/S0223-5234(00)00168-9.
Neville DM. Molecular weight determination of protein-dodecyl sulfate complexes by gel electrophoresis in a discontinuous buffer system. J Biol Chem. 1971;246(20):6328–34.
Jang M, Nah J. Characterization and modification of low molecular water-soluble chitosan for pharmaceutical application. Bull Kor Chem Soc. 2003;24(9):1303–7. https://doi.org/10.5012/bkcs.2003.24.9.1303.
Kim D, Jeong Y, Choi C, Roh S, Kang S, Jang M, et al. Retinol-encapsulated low molecular water-soluble chitosan nanoparticles. Int J Pharm. 2006;319(1):130–8. https://doi.org/10.1016/j.ijpharm.2006.03.040.
Xie H, Jia Z, Huang J, Zhang C. Preparation of low molecular weight chitosan by complex enzymes hydrolysis. Int J Chem. 2011;3(2):180. https://doi.org/10.5539/ijc.v3n2p180.
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.
Koester L, Xavier C, Mayorga P, Bassani V. Influence of β-cyclodextrin complexation on carbamazepine release from hydroxypropyl methylcellulose matrix tablets. Euro J Pharm Biopharm. 2003;55(1):85–91. https://doi.org/10.1016/S0939-6411(02)00127-3.
Hu L, Gu D, Hu Q, Shi Y, Gao N. Investigation of solid dispersion of atorvastatin calcium in polyethylene glycol 6000 and polyvinylpyrrolidone. Trop J Pharm Res. 2014;13(6):835–42. https://doi.org/10.4314/tjpr.v13i6.2.
Trapani A, Garcia-Fuentes M, Alonso M. Novel drug nanocarriers combining hydrophilic cyclodextrins and chitosan. Nanotechnology. 2008;19(18):185101. https://doi.org/10.1088/0957-4484/19/18/185101.
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.
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.
Schulz P, Rodriguez M, Del Blanco L, Pistonesi M, Agullo E. Emulsification properties of chitosan. Colloid Polym Sci. 1998;276(12):1159–65.
Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems-a review (part 2). Trop J Pharm Res. 2013;12(2):265–73. https://doi.org/10.4314/tjpr.v12i2.20.
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.
Gan Q, Wang T, Cochrane C, McCarron P. Modulation of surface charge, particle size and morphological properties of chitosan–TPP nanoparticles intended for gene delivery. Colloids Surf B Biointerfaces. 2005;44(2):65–73. https://doi.org/10.1016/j.colsurfb.2005.06.001.
Zhang H, Wu S, Tao Y, Zang L, Su ZP. Characterization of water-soluble chitosan nanoparticles as protein delivery system. J Nanomater. 2010;2010:1–5. https://doi.org/10.1155/2010/898910.
Janes K, Fresneau M, Marazuela A, Fabra A, Alonso MA. Chitosan nanoparticles as delivery systems for doxorubicin. J Control Release. 2001;73(2):255–67. https://doi.org/10.1016/S0168-3659(01)00294-2.
Yang H, Hon M. The effect of the molecular weight of chitosan nanoparticles and its application on drug delivery. Microchem J. 2009;92(1):87–91. https://doi.org/10.1016/j.microc.2009.02.001.
Ko J, Park H, Hwang S, Park J, Lee J. Preparation and characterization of chitosan microparticles intended for controlled drug delivery. Int J Pharm. 2002;249(1):165–74. https://doi.org/10.1016/S0378-5173(02)00487-8.
Chakraborty S, Shukla D, Jain A, Mishra B, Singh S. Assessment of solubilization characteristics of different surfactants for carvedilol phosphate as a function of pH. J Colloid Interface Sci. 2009;335(2):242–9. https://doi.org/10.1016/j.jcis.2009.03.047.
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.
Schiller C, Fröhlich CP, Giessmann T, Siegmund W, Mönnikes H, Hosten N, et al. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2005;22:971–9.
Koziolek M, Grimm M, Schneider F, Jedamzik P, Sager M, Kühn J-P, et al. Navigating the human gastrointestinal tract for oral drug delivery: uncharted waters and new frontiers. Adv Drug Deliv Rev. 2016;101:75–88.
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.
Setya S, Talegaonkar S, Razdan BK. Nanoemulsions: formulation methods and stability aspects. World J Pharm Pharm Sci. 2014;3(2):2214–28.
Yen CC, Chen YC, Wu MT, Wang CC, Wu YT. Nanoemulsion as a strategy for improving the oral bioavailability and anti-inflammatory activity of andrographolide. Int J Nanomedicine. 2018;13:669–80.
The authors received financial support (347/2015) from Jordan University of Science and Technology.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic Supplementary Material
About this article
Cite this article
Altaani, B.M., Al-Nimry, S.S., Haddad, R.H. et al. Preparation and Characterization of an Oral Norethindrone Sustained Release/Controlled Release Nanoparticles Formulation Based on Chitosan. AAPS PharmSciTech 20, 54 (2019). https://doi.org/10.1208/s12249-018-1261-3
- low molecular weight chitosan
- sustained/controlled release