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AAPS PharmSciTech

, 20:22 | Cite as

Agranulocytosis-Protective Olanzapine-Loaded Nanostructured Lipid Carriers Engineered for CNS Delivery: Optimization and Hematological Toxicity Studies

  • Dnyandev G. Gadhave
  • Amol A. Tagalpallewar
  • Chandrakant R. KokareEmail author
Research Article
  • 16 Downloads

Abstract

Potential risk of agranulocytosis is one of the drug-induced adverse effects of the second-generation antipsychotic agents. The present investigation aimed to formulate and investigate olanzapine (OLZ)-loaded nanostructured lipid carriers (OLZ-NLCs) via intranasal (i.n.) route. The NLC was prepared by melt emulsification method and optimized by Box–Behnken design. Mucoadhesive NLC was prepared by using 0.4% Carbopol 974P (OLZ-MNLC (C)) and the combination of 17% poloxamer 407 and 0.3% of HPMC K4M (OLZ-MNLC (P+H)). The particle size, zeta potential, and entrapment efficiency were found to be 88.95 nm ± 1.7 nm, − 22.62 mV ± 1.9 mV, and 88.94% ± 3.9%, respectively. Ex vivo permeation of OLZ-NLC, OLZ-MNLC (P+H), and OLZ-MNLC (C) was found to be 545.12 μg/cm2 ± 12.8 μg/cm2, 940.02 μg/cm2 ± 15.5 μg/cm2, and 820.10 μg/cm2 ± 11.3 μg/cm2, respectively, whereas the OLZ-MNLC (P+H) formulation showed rapid drug permeation than the OLZ-NLC and OLZ-MNLC (C) formulations. The OLZ-MNLC (P+H) formulation was shown to have 13.57- and 27.64-fold more Jss than the OLZ-MNLC (C) and OLZ-NLC formulations. The OLZ nanoformulations showed sustained release of up to 8 h. Finally, the brain Cmax of technetium-99m (99mTc)-OLZ-MNLC (i.n.) and 99mTc-OLZ-NLC (i.v.) was found to be 936 ng and 235 ng, respectively, whereas the Cmax of i.n. administration was increased 3.98-fold more than the Cmax of i.v. administration. The in vivo hematological study of OLZ-MNLC (P+H) confirmed that the i.n. formulation did not reflect any variation in leukocyte, RBC and platelet counts. Hence, it can be concluded that the nose-to-brain delivery of OLZ-MNLC (P+H) can be considered as an effective and safe delivery for CNS disorders.

KEY WORDS

in vivo hematological toxicity ex vivo permeation nasal histopathology nanostructured lipid carriers brain distribution 

Notes

Funding Information

The authors express wholehearted gratitude and appreciation to Savitribai Phule Pune University (SPPU) for the financial support to complete this project in the form of research stipend (Ref/2829).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Animal Studies

All animals required for this study were approved by the institutional animal ethics committee of Sinhgad Institute of Pharmacy, Pune, India, regulated by the CPCSEA (Protocol No. SIOP/IAEC/2017/02/13).

References

  1. 1.
    Seju U, Kumar A, Sawant KK. Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery: in vitro and in vivo studies. Acta Biomater. 2011;7:4169–76.CrossRefGoogle Scholar
  2. 2.
    Dela CM, Danoff R. Thrombocytopenia and spontaneous intracranial hemorrhage after olanzapine therapy. J Am Osteopath Assoc. 2017;117:473–175.CrossRefGoogle Scholar
  3. 3.
    LS-C W, Tee CK, Gan LLY. Olanzapine-induced and risperidone-induced leukopenia: a case of synergistic adverse reaction? J Psychiatr Pract. 2018;24:121–4.Google Scholar
  4. 4.
    Kumar M, Misra A, Ak M, Mishra P, Pathak K. Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting. J Drug Target. 2008;16:806–14.CrossRefGoogle Scholar
  5. 5.
    Tolosa-Vilella C, Ruiz-Ripoll A, Mari-Alfonso B, Naval-Sendra E. Olanzapine-induced agranulocytosis: a case report and review of the literature. Prog Neuropsychopharmacol Biol Psychiatry. 2002;26:411–4.CrossRefGoogle Scholar
  6. 6.
    Beasley CM, Tollefson GD, Tran PV. Safety of olanzapine. J Clin Psychiatry. 1997;58:S13–7.Google Scholar
  7. 7.
    Malhotra K, Vu P, Wang DH, Lai H, Faziola LR. Olanzapine-induced neutropenia. Ment Illn. 2015;7:5871.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Mistry A, Stolnik S, Illum L. Nanoparticles for direct nose-to-brain delivery of drugs. Int J Pharm. 2009;379:146–57.CrossRefGoogle Scholar
  9. 9.
    Oyewumi LK, Al-Semaan Y. Olanzapine: safe during clozapine induced agranulocytosis. J Clin Psychopharmacol. 2000;20:279–81.CrossRefGoogle Scholar
  10. 10.
    Pardeshi CV, Belgamwar VS. Direct nose to brain drug delivery via integrated nerve pathways bypassing the blood-brain barrier: an excellent platform for brain targeting. Expert Opin Drug Deliv. 2013;10:957–72.CrossRefGoogle Scholar
  11. 11.
    Kozlovskaya L, Kaoud MA, Stepensky D. Quantitative analysis of drug delivery to the brain via nasal route. J Control Release. 2014;189:133–40.CrossRefGoogle Scholar
  12. 12.
    Banks WA. Drug delivery to the brain in Alzheimer’s disease: consideration of the blood-brain barrier. Adv Drug Deliv Rev. 2012;64:629–39.CrossRefGoogle Scholar
  13. 13.
    Hosny KM, Hassan AH. Intranasal in situ gel loaded with squinavir mesylate nanosized microemulsion: preparation, characterization, and in vivo evaluation. Int J Pharm. 2014;47:191–7.CrossRefGoogle Scholar
  14. 14.
    Illum L. Nasal drug delivery—recent developments and future prospects. J Control Release. 2012;161:254–63.CrossRefGoogle Scholar
  15. 15.
    Kumar M, Pandey RS, Patra KC, Jain SK, Soni ML, Dangi JS, et al. Evaluation of neuropeptide loaded trimethyl chitosan nanoparticles for nose to brain delivery. Int J Biol Macromol. 2013;61:189–95.CrossRefGoogle Scholar
  16. 16.
    Horvat S, Feher A, Wolburg H, Sipos P, Veszelka S, Toth A, et al. Sodium hyaluronate as a mucoadhesive component in nasal formulation enhances delivery of molecules to brain tissue. Eur J Pharm Biopharm. 2009;72:252–9.CrossRefGoogle Scholar
  17. 17.
    Pathak R, Dash RP, Misra M, Nivsarkar M. Role of mucoadhesive polymers in enhancing delivery of nimodipine microemulsion to brain via intranasal route. Acta Pharm Sin B. 2014;4:151–60.CrossRefGoogle Scholar
  18. 18.
    Karavasili C, Fatouros DG. Smart materials: in situ gel-forming systems for nasal delivery. Drug Discov Today. 2016;21:157–66.CrossRefGoogle Scholar
  19. 19.
    Shinde RL, Jindal AB, Devarajan PV. Microemulsions and nanoemulsions for targeted drug delivery to the brain. Curr Nanosci. 2011;7:119–33.CrossRefGoogle Scholar
  20. 20.
    Patel PA, Patil SC, Kalaria DR, Kalia YN, Patravale VB. Comparative in vitro and in vivo evaluation of lipid based nanocarriers of Huperzine A. Int J Pharm. 2013;446:16–23.CrossRefGoogle Scholar
  21. 21.
    Alam MI, Baboota S, Ahuja A, Ali M, Ali J, Sahni JK. Intranasal infusion of nanostructured lipid carriers (NLC) containing CNS acting drug and estimation in brain and blood. Drug Deliv. 2013;20:247–51.CrossRefGoogle Scholar
  22. 22.
    Alam T, Pandit J, Vohora D, Aqil M, Ali A, Sultana Y. Optimization of nanostructured lipid carriers of lamotrigine for brain delivery: in vitro characterization and in vivo efficacy in epilepsy. Expert Opin Drug Deliv. 2014;12:181–94.CrossRefGoogle Scholar
  23. 23.
    Tsai MJ, Wu PC, Huang YB, Chang JS, Lin CL, Tsai YH, et al. Baicalein loaded in tocol nanostructured lipid carriers (tocol NLCs) for enhanced stability and brain targeting. Int J Pharm. 2012;423:461–70.CrossRefGoogle Scholar
  24. 24.
    Devkar TB, Tekade AR, Khandelwal KR. Surface engineered nanostructured lipid carriers for efficient nose to brain delivery of ondansetron HCl using Delonix regia gum as a natural mucoadhesive polymer. Colloids Surf B Biointerfaces. 2014;122:143–50.CrossRefGoogle Scholar
  25. 25.
    Shinde RL, Bharkad GP, Devarajan PV. Intranasal microemulsion for targeted nose to brain delivery in neurocysticercosis: role of docosahexaenoic acid. Eur J Pharm Biopharm. 2015;96:363–79.CrossRefGoogle Scholar
  26. 26.
    Ferreira M, Chaves LL, Lima SA, Reis S. Optimization of nanostructured lipid carriers loaded with methotrexate: a tool for inflammatory and cancer therapy. Int J Pharm. 2015;492:65–72.CrossRefGoogle Scholar
  27. 27.
    Gannu R, Palem CR, Yamsani VV, Yamsani SK, Yamsani MR. Enhanced bioavailability of lacidipine via microemulsion based transdermal gels: formulation optimization, ex vivo and in vivo characterization. Int J Pharm. 2010;388:231–41.CrossRefGoogle Scholar
  28. 28.
    Zidan AS, Sammour OA, Hammad MA, Megrab NA, Habib MJ, Khan MA. Quality by design: understanding the formulation variables of a cyclosporine A self-nanoemulsified drug delivery systems by Box–Behnken design and desirability function. Int J Pharm. 2007;332:55–63.CrossRefGoogle Scholar
  29. 29.
    Ravanfar R, Tamaddon AM, Niakousari M, Moein MR. Preservation of anthocyanins in solid lipid nanoparticles: optimization of a microemulsion dilution method using the Placket-Burman and Box-Behnken designs. Food Chem. 2016;199:573–80.CrossRefGoogle Scholar
  30. 30.
    Pund S, Rasve G, Borade G. Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa. Eur J Pharm Sci. 2013;48:195–201.CrossRefGoogle Scholar
  31. 31.
    Pund S, Pawar S, Gangurde S, Divate D. Transcutaneous delivery of leflunomide nanoemulgel: mechanistic investigation into physicomechanical characteristics, in vitro anti-psoriatic and anti-melanoma activity. Int J Pharm. 2015;487:148–56.CrossRefGoogle Scholar
  32. 32.
    Bhavna MS, Ali M, Ali R, Bhatnagar A, Baboota S, Ali J. Donepezil nanosuspension intended for nose to brain targeting: in vitro and in vivo safety evaluation. Int J Biol Macromol. 2014;67:418–25.CrossRefGoogle Scholar
  33. 33.
    Pokharkar V, Patil-Gadhe A, Palla P. Efavirenz loaded nanostructured lipid carrier engineered for brain targeting through intranasal route: in-vivo pharmacokinetic and toxicity study. Biomed Pharmacother. 2017;94:150–64.CrossRefGoogle Scholar
  34. 34.
    Dandekar P, Dhumal R, Jain R, Tiwari D, Vanage G, Patravale V. Toxicological evaluation of pH-sensitive nanoparticles of curcumin: acute, sub-acute and genotoxicity studies. Food Chem Toxicol. 2010;48:2073–89.CrossRefGoogle Scholar
  35. 35.
    Qian S, Wong YC, Zuo Z. Development, characterization and application of in situ gel system for intranasal delivery of tacrine. Int J Pharm. 2014;468:272–82.CrossRefGoogle Scholar
  36. 36.
    Shinde RL, Devarajan PV. Docosahexaenoic acid-mediated, targeted and sustained brain delivery of curcumin microemulsion. Drug Deliv. 2017;24:152–61.CrossRefGoogle Scholar
  37. 37.
    Shinde UA, Modani SH, Singh KH. Design and development of repaglinide microemulsion gel for transdermal delivery. AAPS PharmSciTech. 2017;19:315–25.CrossRefGoogle Scholar
  38. 38.
    Tzankova V, Aluani D, Kondeva-Burdina M, Yordanov Y, Odzhakov F, Apostolov A, et al. Hepatoprotective and antioxidant activity of quercetin loaded chitosan/alginate particles in vitro and in vivo in a model of paracetamol-induced toxicity. Biomed Pharmacother. 2017;92:569–79.CrossRefGoogle Scholar
  39. 39.
    Md S, Khan RA, Mustafa G, Chuttani K, Baboota S, Sahni JK, et al. Bromocriptine loaded chitosan nanoparticles intended for direct nose to brain delivery: pharmacodynamic, pharmacokinetic and scintigraphy study in mice model. Eur J Pharm Sci. 2013;48:393–405.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Dnyandev G. Gadhave
    • 1
  • Amol A. Tagalpallewar
    • 1
  • Chandrakant R. Kokare
    • 1
    Email author
  1. 1.Department of Pharmaceutics, Sinhgad Institute of PharmacySinhgad Technical Education SocietyPuneIndia

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