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AAPS PharmSciTech

, 20:54 | Cite as

Preparation and Characterization of an Oral Norethindrone Sustained Release/Controlled Release Nanoparticles Formulation Based on Chitosan

  • Bashar M. Altaani
  • Suhair S. Al-NimryEmail author
  • Razan H. Haddad
  • Rana Abu-Dahab
Research Article
  • 47 Downloads

Abstract

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 WORDS

low molecular weight chitosan hydroxyPropyl-beta-cyclodexrin norethindrone sustained/controlled release nanoemulsion 

Notes

Funding Information

The authors received financial support (347/2015) from Jordan University of Science and Technology.

Supplementary material

12249_2018_1261_MOESM1_ESM.docx (20 kb)
ESM 1 (DOCX 19 kb)

References

  1. 1.
    Schindler AE, Campagnoli C, Druckmann R, Huber J, Pasqualini JR, Schweppe KW, et al. Classification and pharmacology of progestins. Maturitas. 2003;46:7–16.CrossRefGoogle Scholar
  2. 2.
    United States Pharmacopeial Convention. USP36 NF31, U. S. pharmacopoeia national formulary. 1st edition. 2013.Google Scholar
  3. 3.
    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.CrossRefPubMedGoogle Scholar
  4. 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. 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. 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
  7. 7.
    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.Google Scholar
  8. 8.
    Jong W, Borm P. Drug delivery and nanoparticles: applications and hazards. Int J Nanomedicine. 2008;3(2):133–49.CrossRefGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    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.CrossRefPubMedGoogle Scholar
  11. 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
  12. 12.
    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.CrossRefPubMedGoogle Scholar
  13. 13.
    Ilium L. Chitosan and its use as a pharmaceutical excipient. Pharm Res. 1998;15(9):1326–31.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefPubMedGoogle Scholar
  15. 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
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 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.
  20. 20.
    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.CrossRefGoogle Scholar
  21. 21.
    Prakash RT, Thiagarajan P. Nanoemulsions for drug delivery through different routes. Res Biotechnol. 2011;2(3):01–13.Google Scholar
  22. 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.
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    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.CrossRefGoogle Scholar
  25. 25.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    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.CrossRefGoogle Scholar
  27. 27.
    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.CrossRefPubMedGoogle Scholar
  28. 28.
    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.CrossRefPubMedGoogle Scholar
  29. 29.
    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.CrossRefPubMedGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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. 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.
  34. 34.
    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.CrossRefGoogle Scholar
  35. 35.
    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.CrossRefPubMedGoogle Scholar
  36. 36.
    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.PubMedGoogle Scholar
  37. 37.
    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. CrossRefGoogle Scholar
  38. 38.
    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.CrossRefPubMedGoogle Scholar
  39. 39.
    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.CrossRefGoogle Scholar
  40. 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.
  41. 41.
    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.CrossRefGoogle Scholar
  42. 42.
    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.CrossRefGoogle Scholar
  43. 43.
    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.CrossRefPubMedGoogle Scholar
  44. 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. 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
  46. 46.
    Schulz P, Rodriguez M, Del Blanco L, Pistonesi M, Agullo E. Emulsification properties of chitosan. Colloid Polym Sci. 1998;276(12):1159–65.CrossRefGoogle Scholar
  47. 47.
    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.CrossRefGoogle Scholar
  48. 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
  49. 49.
    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.CrossRefPubMedGoogle Scholar
  50. 50.
    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.CrossRefGoogle Scholar
  51. 51.
    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.CrossRefPubMedGoogle Scholar
  52. 52.
    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.CrossRefGoogle Scholar
  53. 53.
    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.CrossRefPubMedGoogle Scholar
  54. 54.
    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.CrossRefPubMedGoogle Scholar
  55. 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
  56. 56.
    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.CrossRefGoogle Scholar
  57. 57.
    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.CrossRefGoogle Scholar
  58. 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. 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
  60. 60.
    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.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Bashar M. Altaani
    • 1
  • Suhair S. Al-Nimry
    • 1
    Email author
  • Razan H. Haddad
    • 1
  • Rana Abu-Dahab
    • 2
  1. 1.Department of Pharmaceutical TechnologyJordan University of Science and TechnologyIrbidJordan
  2. 2.Department of Biopharmacy and Clinical PharmacyThe University of JordanAmmanJordan

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