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Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide

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Abstract

Purpose

Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF.

Methods

As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS2), and compared to the commercial acetate salt (OCT.OAc2) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS2 and OCT.OAc2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats.

Results

LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures.

Conclusion

The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

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ACKNOWLEDGMENTS AND DISCLOSURES

We kindly thank Dr. Jason Dang for acquiring all HRMS data and Dr. Kasiram Katneni for support with Caco-2 studies. This research article describes intellectual property in the use of ionic liquids/lipophilic salts in drug delivery that has been assigned to Lonza Group. Authors Peng Li, Leigh Ford, Hywel D. Williams, Vincent Jannin, Hassan Benameur were from Lonza Group.

Funding

Funding support was provided by Lonza Group.

Author information

Authors and Affiliations

  1. Oral Drug Delivery Innovation, Lonza Global R&D, Melbourne, Australia

    Peng Li, Leigh Ford & Hywel D. Williams

  2. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia

    Shadabul Haque, Christopher J. H. Porter, Hassan Benameur & Colin W. Pouton

  3. Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia

    Mitchell P. McInerney

  4. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia

    Peter J. Scammells & Philip E. Thompson

  5. Oral Drug Delivery Innovation, Lonza Global R&D, Strasbourg, France

    Vincent Jannin & Hassan Benameur

  6. ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia

    Christopher J. H. Porter

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  1. Peng Li
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Contributions

Peng Li, Hywel D. Williams, Peter J. Scammells, Philip Thompson, Vincent Jannin, Christopher J. H. Porter, Hassan Benameur, Colin Pouton substantially contributed to the conception and design of the work.

Peng Li, Leigh Ford, Shadabul Haque, Mitchell P. McInerney, Hywel D. Williams, Peter J. Scammells, Philip Thompson, Vincent Jannin, Christopher J. H. Porter, Hassan Benameur, Colin Pouton, substantially contributed to the acquisition, analysis, and interpretation of data for the work.

Peng Li, Leigh Ford, Shadabul Haque, Mitchell P. McInerney, Hywel D. Williams, Vincent Jannin, Christopher J. H. Porter, substantially contributed to the draft manuscript and critically revised the manuscript.

All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Christopher J. H. Porter, Hassan Benameur or Colin W. Pouton.

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Li, P., Ford, L., Haque, S. et al. Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide. Pharm Res 38, 1125–1137 (2021). https://doi.org/10.1007/s11095-021-03063-3

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  • DOI: https://doi.org/10.1007/s11095-021-03063-3

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