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In silico–assisted development of supersaturable preconcentrated isotropic mixture of atazanavir for augmenting biopharmaceutical performance in the presence of H2-receptor antagonist

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Abstract

The therapeutic potential of atazanavir (BCS Class II drug), a highly selective inhibitor of human immunodeficiency virus (HIV-1), has been largely limited due to its low intrinsic solubility at elevated pH resulting in low oral bioavailability. Thus, the current work describes the systematic development, optimization, and evaluation of hydroxypropyl methylcellulose acetate succinate (HPMC-AS)-based supersaturable preconcentrate isotropic mixture (SP-IM) containing long-chain triglyceride to improve intestinal lymphatic transport and augment oral bioavailability of atazanavir (ATZ). A D-optimal mixture design was employed for optimization of plain IM containing corn oil, oleic acid, Tween 80, and propylene glycol, evaluating various critical quality attributes (CQAs) like particle size, polydispersity index, self-emulsification time, % transmittance, and drug content. In silico analysis and in vitro supersaturation test facilitated the selection of HPMC-AS as a best suited polymeric precipitation inhibitor (PPI) for formulating ATZ loaded SP-IM (ATZ-SP-IM). In vitro dissolution data indicated that ATZ-SP-IM exhibits superior performance in 0.025 N HCl and pH 6.8 over pure drug. Ex vivo permeation and in vivo pharmacokinetic study of ATZ-SP-IM corroborated enhanced permeation (2.03 fold) and improved drug absorption via lymphatic transport in Wistar rats. Further, the pharmacokinetic performance of ATZ-SP-IM was not affected in presence of H2 receptor antagonist. Therefore, the results showed that ATZ-SP-IM can significantly improve the biopharmaceutical attributes of ATZ so as to lay a foundation of further research on the new dosage form of ATZ.

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Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to acknowledge the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for providing Direct-SRF, sanction no 09/140(0176)/2019-EMR-I. The generous supply of atazanavir sulfate from Sun Pharmaceutical Industries Ltd., Gurugram, India, is also appreciated. The authors are also thankful to Gattefosse, BASF, and Croda Chemicals, India, for their kind donation of the surfactants and the oil used in this study.

Funding

This research work was supported by Council of Scientific and Industrial Research (CSIR), New Delhi, India (Grant No. 09/140(0176)/2019-EMR-I).

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  1. Pharmaceutics Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, 147002, India

    Sheshank Sethi & Vikas Rana

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  1. Sheshank Sethi
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  2. Vikas Rana
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All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by all authors. All authors read and approved the final manuscript.

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Correspondence to Vikas Rana.

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This article was preprinted on Research Square preprint server (https://doi.org/10.21203/rs.3.rs-1149372/v1).

Ethical approval

The research work involving ex vivo permeation and in vivo pharmacokinetics adheres to the guidelines for care and use of the laboratory animals. Thus, all the animal investigations were performed as per the requisite protocol approved by the Institutional Animal Ethics Committee (IAEC), Punjabi University, Patiala, India (Approval No. 107/99/CPCSEA/2018–05).

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No human volunteers or data related to human volunteers were involved in this research work, as the proposed study was performed on rodents. Therefore, no consent was taken from human volunteers to publish manuscript.

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Sethi, S., Rana, V. In silico–assisted development of supersaturable preconcentrated isotropic mixture of atazanavir for augmenting biopharmaceutical performance in the presence of H2-receptor antagonist. Drug Deliv. and Transl. Res. 13, 339–355 (2023). https://doi.org/10.1007/s13346-022-01210-w

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