AAPS PharmSciTech

, Volume 18, Issue 8, pp 2957–2964 | Cite as

Oral fast-dissolving films containing lutein nanocrystals for improved bioavailability: formulation development, in vitro and in vivo evaluation

  • Chen Liu
  • Daoxiao Chang
  • Xinhui Zhang
  • Hong Sui
  • Yindi Kong
  • Rongyue Zhu
  • Wenping WangEmail author
Research Article


Lutein is widely used as diet supplement for prevention of age-related macular degeneration. However, the application and efficacy of lutein in food and nutritional products has been hampered due to its poor solubility and low oral bioavailability. This study aimed to develop and evaluate the formulation of oral fast-dissolving film (OFDF) containing lutein nanocrystals for enhanced bioavailability and compliance. Lutein nanocrystals were prepared by anti-solvent precipitation method and then encapsulated into the films by solvent casting method. The formulation of OFDF was optimized by Box-Behnken Design (BBD) as follows: HPMC 2.05% (w/v), PEG 400 1.03% (w/v), Cremophor EL 0.43% (w/v). The obtained films exhibited uniform thickness of 35.64 ± 1.64 μm and drug content of 0.230 ± 0.003 mg/cm2 and disintegrated rapidly in 29 ± 8 s. The nanocrystal-loaded films with reconstituted particle size of 377.9 nm showed better folding endurance and faster release rate in vitro than the conventional OFDFs with raw lutein. The microscope images, thermograms, and diffractograms indicated that lutein nanocrystals were highly dispersed into the films. After administrated to SD rats, t max was decreased from 3 h for oral solution formulation to less than 0.8 h for OFDF formulations, and C max increased from 150 ng/mL for solution to 350 ng/mL for conventional OFDF or 830 ng/mL for nanocrystal OFDF. The AUC 0-24h of conventional or nanocrystal OFDF was 1.37 or 2.08-fold higher than that of the oral solution, respectively. These results suggested that drug nanocrystal-loaded OFDF can be applied as a promising approach for enhanced bioavailability of poor soluble drugs like lutein.

Key words

bioavailability Box-Behnken Design lutein nanocrystals oral fast-dissolving films 



This work was financially supported from the National Natural Science Foundation of China (81660665).

Compliance with Ethical Standards

Ethics Statement

All procedures were approved by the Animal Research Ethics Committee, General Hospital of Ningxia Medical University.

Conflict of Interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Apte RS. Targeting tissue lipids in age-related macular degeneration. EBioMedicine. 2016;5:26–7. doi: 10.1016/j.ebiom.2016.02.003.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Querques G, Merle BM, Pumariega NM, Benlian P, Delcourt C, Zourdani A, et al. Dynamic Drusen remodelling in participants of the nutritional AMD treatment-2 (NAT-2) randomized trial. PLoS One. 2016;11(2):e0149219. doi: 10.1371/journal.pone.0149219.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Schmidl D, Garhofer G, Schmetterer L. Nutritional supplements in age-related macular degeneration. Acta Ophthalmol. 2015;93(2):105–21. doi: 10.1111/aos.12650.CrossRefPubMedGoogle Scholar
  4. 4.
    Gleize B, Tourniaire F, Depezay L, Bott R, Nowicki M, Albino L, et al. Effect of type of TAG fatty acids on lutein and zeaxanthin bioavailability. Br J Nutr. 2013;110(01):1–10. doi: 10.1017/S0007114512004813.CrossRefPubMedGoogle Scholar
  5. 5.
    Álvarez MV, Hincapié S, Saavedra N, Alzate LM, Muñoz AM, Cartagena CJ, et al. Exploring feasible sources for lutein production: food by-products and supercritical fluid extraction, a reasonable combination. Phytochem Rev. 2015;14(6):891–7. doi: 10.1007/s11101-015-9434-0.CrossRefGoogle Scholar
  6. 6.
    Tian Y, Kijlstra A, Webers CA, Berendschot TT. Lutein and factor D: two intriguing players in the field of age-related macular degeneration. Arch Biochem Biophys. 2015;572:49–53. doi: 10.1016/ Scholar
  7. 7.
    Davidov-Pardo G, Gumus CE, McClements DJ. Lutein-enriched emulsion-based delivery systems: influence of pH and temperature on physical and chemical stability. Food Chem. 2016;196:821–7. doi: 10.1016/j.foodchem.2015.10.018.CrossRefPubMedGoogle Scholar
  8. 8.
    Yoo J, Baskaran R, Yoo B-K. Self-nanoemulsifying drug delivery system of lutein: physicochemical properties and effect on bioavailability of warfarin. Biomol Ther. 2013;21(2):173–9. doi: 10.4062/biomolther.2013.011.CrossRefGoogle Scholar
  9. 9.
    Read AM. Influence of digestion model, product type, and enrichment level on in vitro bioavailability of lutein from high lutein functional bakery products. University of Guelph. 2011.Google Scholar
  10. 10.
    Stancanelli R, Lojkner LD, Larsen KL, Guardo M, Cannava C, Tommasini S, et al. Structural and spectroscopic features of lutein/butanoyl-beta-cyclodextrin nanoassemblies. J Pharm Biomed Anal. 2012;71:214–8. doi: 10.1016/j.jpba.2012.07.034.CrossRefPubMedGoogle Scholar
  11. 11.
    Khan S, Boateng JS, Mitchell J, Trivedi V. Formulation, characterisation and stabilisation of buccal films for paediatric drug delivery of omeprazole. AAPS PharmSciTech. 2015;16(4):800–10. doi: 10.1208/s12249-014-0268-7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Shen BD, Shen CY, Yuan XD, Bai JX, Lv QY, Xu H, et al. Development and characterization of an orodispersible film containing drug nanoparticles. Eur J Pharm Biopharm. 2013;85(3):1348–56. doi: 10.1016/j.ejpb.2013.09.019.CrossRefPubMedGoogle Scholar
  13. 13.
    Montenegro-Nicolini M, Morales JO. Overview and future potential of buccal mucoadhesive films as drug delivery systems for biologics. AAPS PharmSciTech. 2016; doi: 10.1208/s12249-016-0525-z.PubMedGoogle Scholar
  14. 14.
    Abdelbary A, Bendas ER, Ramadan AA, Mostafa DA. Pharmaceutical and pharmacokinetic evaluation of a novel fast dissolving film formulation of flupentixol dihydrochloride. AAPS PharmSciTech. 2014;15(6):1603–10. doi: 10.1208/s12249-014-0186-8.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Preis M. Orally disintegrating films and mini-tablets-innovative dosage forms of choice for pediatric use. AAPS PharmSciTech. 2015;16(2):234–41. doi: 10.1208/s12249-015-0313-1.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Ye X, Patil H, Feng X, Tiwari RV, Lu J, Gryczke A, et al. Conjugation of hot-melt extrusion with high-pressure homogenization: a novel method of continuously preparing Nanocrystal solid dispersions. AAPS PharmSciTech. 2016;17(1):78–88. doi: 10.1208/s12249-015-0389-7.CrossRefPubMedGoogle Scholar
  17. 17.
    Shen CY, Shen BD, Xu H, Bai JX, Dai L, Lv QY, et al. Formulation and optimization of a novel oral fast dissolving film containing drug nanoparticles by box-Behnken design-response surface methodology. Drug Dev Ind Pharm. 2014;40(5):649–56. doi: 10.3109/03639045.2014.884116.CrossRefPubMedGoogle Scholar
  18. 18.
    Kapoor R, Pathak S, Najmi AK, Aeri V, Panda BP. Processing of soy functional food using high pressure homogenization for improved nutritional and therapeutic benefits. Innov Food Sci Emerg. 2014;26:490–7. doi: 10.1016/j.ifset.2014.05.015.CrossRefGoogle Scholar
  19. 19.
    Aslam M, Aqil M, Ahad A, Najmi AK, Sultana Y, Ali A. Application of Box–Behnken design for preparation of glibenclamide loaded lipid based nanoparticles: optimization, in vitro skin permeation, drug release and in vivo pharmacokinetic study. J Mol Liq. 2016;219:897–908. doi: 10.1016/j.molliq.2016.03.069.CrossRefGoogle Scholar
  20. 20.
    Lei YY, Kong YD, Sui H, Feng J, Zhu RY, Wang WP. Enhanced oral bioavailability of glycyrrhetinic acid via nanocrystal formulation. Drug Deliv Transl Res. 2016;6(5):519–25. doi: 10.1007/s13346-016-0300-4.CrossRefPubMedGoogle Scholar
  21. 21.
    Lai F, Franceschini I, Corrias F, Sala MC, Cilurzo F, Sinico C, et al. Maltodextrin fast dissolving films for quercetin nanocrystal delivery. A feasibility study. Carbohydr Polym. 2015;121:217–23. doi: 10.1016/j.carbpol.2014.11.070.CrossRefPubMedGoogle Scholar
  22. 22.
    Alshetaili AS, Almutairy BK, Alshahrani SM, Ashour EA, Tiwari RV, Alshehri SM, et al. Optimization of hot melt extrusion parameters for sphericity and hardness of polymeric face-cut pellets. Drug Dev Ind Pharm. 2016;42(11):1833–41. doi: 10.1080/03639045.2016.1178769.CrossRefPubMedGoogle Scholar
  23. 23.
    Garsuch V, Breitkreutz J. Comparative investigations on different polymers for the preparation of fast-dissolving oral films. J Pharm Pharmacol. 2010;62(4):539–45. doi: 10.1211/jpp/62.04.0018.CrossRefPubMedGoogle Scholar
  24. 24.
    Sushma M, Raju YP, Sundaresan CR, Vandana KR, Kumar NV, Chowdary VH. Transmucosal delivery of metformin—a comprehensive study. Curr Drug Deliv. 2014;11(2):172–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Liew KB, Tan YT, Peh KK. Characterization of oral disintegrating film containing donepezil for Alzheimer disease. AAPS PharmSciTech. 2012;13(1):134–42. doi: 10.1208/s12249-011-9729-4.CrossRefPubMedGoogle Scholar
  26. 26.
    Xia YR, Chen F, Zhang HP, Luo CL. A new method for evaluating the dissolution of orodispersible films. Pharm Dev Technol. 2015;20(3):375–9. doi: 10.3109/10837450.2014.882936.CrossRefPubMedGoogle Scholar
  27. 27.
    Yanagi M, Hisajima T, Ishibashi H, Amemiya A, Abe S, Watanabe M. Oral candidiasis deteriorated by local application of a glucocorticoid-containing film in a mouse model. Biol Pharm Bull. 2008;31(2):278–83.CrossRefPubMedGoogle Scholar
  28. 28.
    Croy SR, Kwon GS. Polysorbate 80 and Cremophor EL micelles deaggregate and solubilize nystatin at the core-corona interface. J Pharm Sci. 2005;94(11):2345–54. doi: 10.1002/jps.20301.CrossRefPubMedGoogle Scholar
  29. 29.
    Shanmugam S, Baskaran R, Balakrishnan P, Thapa P, Yong CS, Yoo BK. Solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing phosphatidylcholine for enhanced bioavailability of highly lipophilic bioactive carotenoid lutein. Eur J Pharm Biopharm. 2011;79(2):250–7. doi: 10.1016/j.ejpb.2011.04.012.CrossRefPubMedGoogle Scholar
  30. 30.
    Pandey GS, Kumar R, Sharma R, Singh Y, Teotia UVS. Effects of Maltodextrin and glycerin on mechanical properties of oral fast dissolving film of salbutamol sulphate. IJAPBC. 2014;3(1):199–209.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Chen Liu
    • 1
  • Daoxiao Chang
    • 2
  • Xinhui Zhang
    • 2
  • Hong Sui
    • 2
  • Yindi Kong
    • 2
  • Rongyue Zhu
    • 2
  • Wenping Wang
    • 2
    • 3
    Email author
  1. 1.Pharmaceutical Preparation CenterGeneral Hospital of Ningxia Medical UniversityYinchuanChina
  2. 2.Department of Pharmaceutics, School of PharmacyNingxia Medical UniversityYinchuanChina
  3. 3.Ningxia Engineering and Technology Research Center for Modernization of Hui Medicine & Key Lab of Hui Ethnic Medicine ModernizationMinistry of EducationYinchuanChina

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