AAPS PharmSciTech

, Volume 19, Issue 3, pp 1392–1400 | Cite as

Formulation and Characterization of Fast-Dissolving Sublingual Film of Iloperidone Using Box–Behnken Design for Enhancement of Oral Bioavailability

  • Vaishali Londhe
  • Rucha Shirsat
Research Article


Iloperidone is a second-generation antipsychotic drug which is used for the treatment of schizophrenia and has very low aqueous solubility and bioavailability. This drug also undergoes first-pass metabolism. The aim of this work is to formulate fast-dissolving sublingual films of iloperidone to improve its bioavailability. Sublingual films were prepared by solvent casting method. Hydroxypropyl methyl cellulose E5, propylene glycol 400, and transcutol HP were optimized using Box–Behnken three-level statistical design on the basis of disintegration time and folding endurance of films. Iloperidone:hydroxypropyl-β–cyclodextrin kneaded complex was used in films instead of plain drug due to its low solubility. Optimized film was further evaluated for drug content, pH, dissolution studies, ex vivo permeation studies, and pharmacokinetic studies in rats. The optimized film disintegrated within 30 s. The in vitro dissolution of the film showed 80.3 ± 3.4% drug dissolved within first 5 min. In ex vivo permeation studies using sublingual tissue, flux achieved within first 15 min by film was around 117.1 ± 0.35 (mcg/cm2/h) which was ten times more than that of plain drug. This formulation showed excellent uniformity. AUC and Cmax of film were significantly higher (p < 0.001) as compared to plain drug and relative bioavailability of the films was 148% when compared to the plain drug. Thus, this study showed optimized fast-dissolving sublingual film to improve permeation and bioavailability of iloperidone. Fast-dissolving films will be customer-friendly approach for geadiatric schizophrenic patients.


iloperidone sublingual film Box–Behnken statistical design ex vivo permeation study pharmacokinetic studies 



Authors would like to thank Lupin Ltd. for providing iloperidone gift sample and Gattefosse for providing transcutol HP gift sample. We would like to also thank Mr. Ankit Laddha, research scholar, SPPSPTM for helping in pharmacokinetic studies.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12249_2018_954_MOESM1_ESM.pdf (609 kb)
ESM 1 (DOCX 608 kb)


  1. 1.
    Jhanjee A, Bhatia MS, Rathi A. Iloperidone–a Novel Drug for treatment of schizophrenia. Delhi Psychiatry J. 2012;5(1):204–7.Google Scholar
  2. 2.
    Breier A, Berg PH. The psychosis of schizophrenia: prevalence, response to atypical antipsychotics, and prediction of outcome. Biol Psychiatry. 1999;46(3):361–4. Scholar
  3. 3.
    Cheng YH, Ilum L, Davis S. Schizophrenia and drug delivery systems. J Drug Target. 2000;8(2):107–17. Scholar
  4. 4.
    Kaminsky BM, Bostwick JR, Guthrie SK. Alternate routes of administration of antidepressant and antipsychotic medications. Ann Pharmacother. 2015;49(7):808–17. Scholar
  5. 5.
    Correll CU. Mechanism of action of antipsychotic medications. J Clin Psychiatry. 2014;75:347–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Dazzan P, Morgan KD, Orr K, et al. Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study. Neuropsychopharmacology. 2005;30(4):765–74. Scholar
  7. 7.
    Ige P, Agrawal K, Patil U. Enhanced in vitro dissolution of iloperidone using Caesalpinia Pulcherrima mucoadhesive microspheres. Beni –Univ J Basic Appl Sci. 2015;4(1):26–32. Scholar
  8. 8.
    Tingting Z, Yan Y, Haitao W, et al. Using dissolution and pharmacokinetics studies of crystal form to optimize the original iloperidone. Cryst Growth Des. 2013;13(12):5261–6.CrossRefGoogle Scholar
  9. 9.
    Mandpe L, Pokharkar V. Targeted brain delivery of iloperidone nanostructured lipid carriers following intranasal administration: in vivo pharmacokinetics and brain distribution studies. J Nanopharmaceutics and Drug Delivery. 2013;1(2):212–25. Scholar
  10. 10.
    Siddiqui MN, Garg G, Sharma PK. A short review on-a novel approach in oral fast dissolving drug delivery system and their patents. Adv Biol Res. 2011;5(6):291–303.Google Scholar
  11. 11.
    Mansi M. Formulation and evaluation of fast dissolving film of lurasidone. Int J Pharm Res Bio. 2016;5(2):101–23.Google Scholar
  12. 12.
    Bhowmik D, Chiranjib B, Krishnakanth P, Chandira RM. Fast dissolving tablet: an overview. J Chem Pharm Res. 2009;1(1):163–77.Google Scholar
  13. 13.
    Puttalingaiah L, Mani T. Fast disintegrating tablets: an overview of formulation, technology and evaluation. Res J Pharm Biol Chem Sci. 2011;2(2):589–601.Google Scholar
  14. 14.
    Malviya R, Sharma PK. Trends in buccal film: formulation characteristics, recent studies and patents. Eur J Appl Sci. 2011;3(3):93–101.Google Scholar
  15. 15.
    Kannissery P, Tahir MA, Charoo NA, et al. Pharmaceutical product development: a quality by design approach. Int J Pharm Investig. 2016;6(3):129–38.CrossRefGoogle Scholar
  16. 16.
    Zidan AS, Sammour OA, Hammad MA, Megrab NA, Habib MJ, Khan MA. Quality by design: understanding the formulate on variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box-Behnken design and desirability function. Int J Pharm. 2007;332(1–2):55–63. Scholar
  17. 17.
    Elbary AA, Aboelwafa AA, Sharabi IM. Once daily, high-dose mesalazine controlled-release tablet for colonic delivery: optimization of formulation variables using Box-Behnken design. AAPS PharmSciTech. 2011;12(4):1454–64. Scholar
  18. 18.
    Basalious EB, El-Sebaie W, El-Gazayerly O. Application of pharmaceutical QbD for enhancement of the solubility and dissolution of a class II BCS drug using polymeric surfactants and crystallization inhibitors: development of controlled-release tablets. AAPS PharmSciTech. 2011;12(3):799–810.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hoffmann EM, Breitenbach A, Breitkreutz J. Advances in orodispersible films for drug delivery. Expert Opin Drug Delivery. 2011;8(3):299–316. Scholar
  20. 20.
    Patil P, Shrivastava SK. Fast dissolving oral films: an innovative drug delivery system. Int J Sci Res. 2014;3(7):2088–92.Google Scholar
  21. 21.
    Sherje A, Londhe V. Inclusion complexes of hydroxy propyl-β-cyclodextrin and paliperidone: preparation and characterization. Curr Drug Discov Technol. 2014;11(4):271–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Li L, Yi T, Lam C. Effects of spray-drying and choice of solid carriers on concentrations of Labrasol® and Transcutol® in solid self-microemulsifying drug delivery systems (SMEDDS). Molecules. 2013;18(12):545–60. Scholar
  23. 23.
    Kumar GP, Phani AR, Prasad RG, et al. Polyvinylpyrrolidone oral films of enrofloxacin: film characterization and drug release. Int J Pharm. 2014;471(1):146–52. Scholar
  24. 24.
    Londhe VY, Umalkar KB. Formulation development and evaluation of fast dissolving film of telmisartan. Indian J Pharm Sci. 2012;74(2):122–6. Scholar
  25. 25.
    Dixit AS, Kulkarni PK. Fast disintegrating films containing anastrozole as a dosage form for dysphagia patients. Arch Pharm Res. 2012;35(12):2171–82.CrossRefGoogle Scholar
  26. 26.
    Visser JC, Dohmen WM, Hinrichs WL, et al. Quality by design approach for optimizing the formulation and physical properties of extemporaneously prepared orodispersible films. Int J Pharm. 2015;485(1):70–6. Scholar
  27. 27.
    Sayed S, Howida K, Magdy Ibrahim M, Mohamed F. Fast-dissolving sublingual films of terbutaline sulfate: formulation and in vitro/in vivo evaluation. Mol Pharm. 2013;10(8):2942–7. Scholar
  28. 28.
    Rachid O, Mutasem R, Estelle R, Keith J. Rapidly-disintegrating sublingual tablets of epinephrine: role of non-medicinal ingredients in formulation development. Eur J Pharm Biopharm. 2012;82(3):598–604. Scholar
  29. 29.
    Chonkar A, Rao V, Srinivas M, et al. Development of fast dissolving oral films containing lercanidipine HCl nanoparticles in semicrystalline polymeric matrix for enhanced dissolution and ex vivo permeation. Eur J Pharm Biopharm. 2016;103:179–91.CrossRefPubMedGoogle Scholar
  30. 30.
    Tomar A, Sharma K, Chauhan NS, et al. Formulation and evaluation of fast dissolving oral film of dicyclomine as potential route of buccal delivery. Int J Drug Dev Res. 2012;4(2):408–17.Google Scholar
  31. 31.
    Mesnukul A, Yodkhum K, Phaechamud T. Solid dispersion matrix tablet comprising indomethacin-PEG-HPMC fabricated with fusion and mold technique. Indian J Pharm Sci. 2009;71(4):413–20. Scholar
  32. 32.
    Wu L, Qiao Y, Wang L, Guo J, Wang G, He W, et al. A self-microemulsifying drug delivery system (SMEDDS) for a novel medicative compound against depression: a preparation and bioavailability study in rats. AAPS PharmSciTech. 2015;16(5):1051–8. Scholar
  33. 33.
    Mihajlovic T, Kachrimanis K, Graovac A, et al. Improvement of aripiprazole solubility by complexation with (2-hydroxy) propyl-β-cyclodextrin using spray drying technique. AAPS PharmSciTech. 2012;13(2):623–31.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mura P, Faucci MT, Bramanti G, Corti P. Evaluation of transcutol as a clonazepam transdermal permeation enhancer from hydrophilic gel formulations. Eur J Pharm Biopharm. 2000;9(4):365–72.Google Scholar
  35. 35.
    Gannu R, Vishnu YV, Kishan V, Rao YM. In vitro permeation of carvedilol through porcine skin: effect of vehicles and penetration enhancers. PDA J Pharm Sci Technol. 2008;62(4):256–63.PubMedGoogle Scholar
  36. 36.
    Rathi AA, Dhamecha DL, Patel KA, et al. Effect of permeation enhancers on permeation kinetics of idebenone through the bovine buccal mucosa. Ind J Pharm Edu Res. 2011;45(4):370–4.Google Scholar
  37. 37.
    Ahmed ED, Basalious EB, Abdelmalak NS. Bioenhanced sublingual tablet of drug with limited permeability using novel surfactant binder and microencapsulated polysorbate: in vitro/in vivo evaluation. Eur J Pharm Biopharm. 2015;94:386–92.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Shobhaben Pratapbhai Patel School of Pharmacy & Technology ManagementSVKM’s NMIMSMumbaiIndia

Personalised recommendations