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. Kokare
Research Article


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.


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


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).


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

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

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