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by: Panayiotis P. Constantinides and randall j. mrsny

constantinides_web-finalThe oral randy_mrsny_headshotroute is the most preferred noninvasive route of drug administration for the promise of higher patient compliance. However, advancing oral peptide therapeutics from bench to clinic and commercialization has been a formidable task. Despite major investments and scientific advances in this area over the last three decades, there is no oral water-soluble and poorly permeable (BCS III) peptide/protein drug product on the market.These desired drug products include parenteral to oral switch of marketed injectable peptide/protein therapeutics as well as new molecules in the pipeline. Oral drug delivery approaches that often used in combination in preclinical and clinical studies with BCS Class III peptides include:

  • chemical modifications such as prodrugs;
  • intestinal permeability/absorption enhancers that are classified as lipids, surfactants, and proprietary molecules;
  • lipidic and polymeric micro-/nanoparticles with and without targetable ligands directed towards M-cells/Peyer’s patches in the intestinal mucosa.

Conjugation of peptides to various ligands has been used as a strategy to either increase the lipophilicity of the peptide to enhance its passive permeation through the intestinal mucosa or to target the peptide conjugate towards certain receptors and membrane transporters, such as the folate and vitamin B12 transporters, GLP-1 GM1 ganglioside conjugate targeted to GM1 sorting system. These strategies can facilitate receptor-mediated uptake of the peptide. The resulting peptide conjugates are often complex molecules that are regarded as new molecular entities.

Micro/nanodispersions of the unmodified peptide incorporating lipids and/or polymers can improve protein dispersion in the gastrointestinal milieu and promote peptide permeation through the lipidic cell membranes. The physical stability challenges and vehicle toxicity with dispersed systems need to be considered and carefully controlled. Peptide conjugation and dispersion are not mutually exclusive since the latter strategy can be used to formulate both unmodified and conjugated peptide. The question arises, however, why pursue peptide conjugation if a “simple” dispersion of the peptide using micro-/nanoparticles incorporating absorption enhancers and peptide stabilizers can be used to improve the intestinal absorption and oral bioavailability of the peptide? From a broader perspective and comparison, what are some of the advantages and limitations of each of these two approaches?

Whether you are an established investigator or a newcomer in the field of oral peptide delivery and development, we encourage you to attend the upcoming 2016 AAPS Annual Meeting and Exposition dialogue and debate session Getting Oral Peptides to the Market: To Conjugate and/or Disperse the Peptide?. The learning objectives of this session is to: a) become familiar with the state-of-art in oral peptide therapeutics and path to commercialization, and b) apply acquired knowledge to the design and development of enabled formulations and dosage forms in a rational and timely manner where the speakers would be happy to address your questions and listen to your views and perspectives. We will be presenting and debating the aforementioned two strategies and lessons learned with active engagement from the audience.

Randall J. Mrsny, Ph.D is Professor at the University of Bath in UK and Chief Scientific Officer at Applied Molecular Transport, LLC, South San Francisco, California.
Panayiotis P. Constantinides, Ph.D., is the founder and president of Biopharmaceutical & Drug Delivery Consulting LLC, Gurnee, Illinois, and affiliated professor of Biopharmaceutical Sciences at Roosevelt University, College of Pharmacy, Schaumburg, Illinois.