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

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

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.

    Article  Google Scholar 

  2. 2.

    United States Pharmacopeial Convention. USP36 NF31, U. S. pharmacopoeia national formulary. 1st edition. 2013.

  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.

    CAS  Article  PubMed  Google 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.

    CAS  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.

    CAS  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.

    CAS  Google Scholar 

  8. 8.

    Jong W, Borm P. Drug delivery and nanoparticles: applications and hazards. Int J Nanomedicine. 2008;3(2):133–49.

    Article  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Ilium L. Chitosan and its use as a pharmaceutical excipient. Pharm Res. 1998;15(9):1326–31.

    Article  Google 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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  PubMed Central  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  PubMed Central  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google 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.

    Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  PubMed Central  Google 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.

    CAS  Article  PubMed  PubMed Central  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  PubMed  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed Central  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  PubMed  Google 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.

    CAS  Article  Google 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.

    CAS  Article  Google 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.

  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.

    CAS  Article  Google Scholar 

Download references

Funding

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

Author information

Affiliations

Authors

Corresponding author

Correspondence to Suhair S. Al-Nimry.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

ESM 1

(DOCX 19 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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

Download citation

KEY WORDS

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