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Intranasal Zotepine Nanosuspension: intended for improved brain distribution in rats

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Abstract

Background

Zotepine (ZTP), an antipsychotic drug is well tolerated and particularly effective for treating negative symptoms of psychosis. But is limited by low oral bioavailability caused by substantial first pass metabolism and thereby less amount of drug reaches the brain due to blood brain barrier (BBB).

Objectives

Since ZTP displays dose dependent side effects, purpose of the contemporary study is to develop zotepine loaded nanosuspension (ZTP-NS) for increased brain targeting in rats at lower doses.

Methods

ZTP-NS is prepared by two techniques viz., sonoprecipitation (SP) and combination technique (high pressure homogenization preceded by precipitation) by employing various stabilizers. Optimized ZTP-NS was characterized for particle size, solid state, morphology and solubility. In vitro drug release of ZTP and formulations was conducted using Franz diffusion cell. Stability study was performed at different temperature conditions. Pharmacokinetic study was performed in Wistar rats to determine the bioavailability and brain distribution of ZTP after intra-nasal (IN) and intravenous (IV) administration. Histopathology of brain was done after repeated administration of IN ZTP dispersion and NS up to 14 days.

Results

The optimized ZTP-NS formulated with Pluronic F-127 (0.3%w/v), Hydroxypropyl methyl cellulose E15 (0.3%w/v) and soya lecithin (0.4%w/v) showed particle size of 519.26 ± 10.44 nm & 330.2 ± 12.90 nm and zeta potential of −21.7 ± 1.39 mV and − 18.26 ± 1.64 mV with sonoprecipitation and combination technique respectively. In vitro drug release was high (81.79 ± 3.23%) for ZTP-NS prepared by combination technique. Intranasal NS resulted in high brain concentrations of 8.6 fold (sonoprecipitation) and 10.79-fold hike in AUC0–24h in contrast to intravenous ZTP solution. Histopathology results reveal no significant changes in brain microscopic images.

Conclusion

ZTP-NS was successfully developed, characterized and found that nanosuspension is a favorable approach for intranasal delivery of zotepine.

Graphical abstract representing zotepine drawbacks, nanosuspension preparation, characterization and pharmacokinetic study in rats

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Acknowledgements

The authors are thankful to NIPER-HYD for providing the facilities and Department of Pharmaceuticals (DoP) for funding the research work.

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Authors and Affiliations

  1. Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500037, India

    Sravanthi Reddy Pailla, Sreekanth Talluri, Nagarjun Rangaraj, Ramdas Ramavath & Sunitha Sampathi

  2. Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, 500037, India

    Veerabhadra Swamy Challa & Nandkumar Doijad

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  1. Sravanthi Reddy Pailla
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  2. Sreekanth Talluri
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  3. Nagarjun Rangaraj
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  7. Sunitha Sampathi
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Contributions

SR designed the study, conducted experiments and drafted the manuscript. ST: analytical and bioanalytical method development. NR: reviewed and revised the manuscript. RR: helped in preparation of nanosuspension. VS: supported in oral, intranasal and intravenous dosing and blood collection& brain extraction of all the animals. ND: helped in acute toxicity study. SS: supervision of all the experiments.

Corresponding author

Correspondence to Sunitha Sampathi.

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On behalf of all the authors, we report no conflict of interest.

Human participants and/or animals

Humans are not involved in the study. Wistar rats were used in pharmacokinetics and toxicity study. The animal protocol (NIP/8/2016/PE/203) was approved by Institutional Animal Ethical Committee (IAEC) for Care and Use of Laboratory animals and the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA).

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Pailla, S.R., Talluri, S., Rangaraj, N. et al. Intranasal Zotepine Nanosuspension: intended for improved brain distribution in rats. DARU J Pharm Sci 27, 541–556 (2019). https://doi.org/10.1007/s40199-019-00281-4

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