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    Oral peptide delivery: Translational challenges due to physiological effects. Tyagi Puneet,Pechenov Sergei,Anand Subramony J Journal of controlled release : official journal of the Controlled Release Society Oral delivery of peptide therapeutics as a convenient alternate to injections has been an area of research for the pharmaceutical scientific community for the last several decades. However, systemic delivery of therapeutic peptides via the oral route has been a daunting task due to the low pH denaturation of the peptides in the stomach, enzymatic instability, and poor transport across the tight junctions resulting in very low bioavailability. The low bioavailability is accompanied by large intra- and inter-subject variability leading to translational issues, preventing the development of successful peptide therapeutics. The inter-subject variability leads to large differences in pharmacologic responses in individuals and thus the dose required to produce therapeutic effect could vary between individuals making the development of drug product a very difficult task. A substantial amount of research has been (and continues to be) performed with a focus on getting acceptable absorption and reproducible results. Nonetheless, the high variability and low bioavailability during oral administration of peptides is still a work in progress and under-explored in a systematic way. While there are several review articles and scattered publications that discuss potential technologies for oral peptide delivery, a detailed look into the physiological challenges and absorption barriers which are a hindrance to successful clinical translation, is lacking. Herein, we have analyzed the physiological barriers within the gastrointestinal (GI) tract that are the root causes for the low bioavailability and high variability of oral delivery of peptides in humans. In particular, we have taken a detailed look at the key influencing factors such as the nature of various GI tract parameters, components of the GI tract that influences the uptake, site of absorption, pH of the gastric and intestinal compartments, food effect, and role of peptidases in affecting oral peptide absorption. Lack of in vitro - in vivo correlations and variability in animal models have also been highlighted as key impediments in understanding the challenges. The unique perspective presented herein for overcoming the physiological absorption barriers, will offer better developability approaches and will positively impact clinical translation of future oral peptide therapeutics. A deep understanding of these effects are vital, given the emergence of microbiome and oral biologic drug delivery that are fast emerging as the next wave of personalized patient centric therapies. 10.1016/j.jconrel.2018.08.032
    Oral delivery of anti-diabetes therapeutics using cell penetrating and transcytosing peptide strategies. Rehmani Sahrish,Dixon James E Peptides Oral delivery of insulin and other anti-diabetic peptides is inhibited by low intestinal absorption caused by the poor permeability across cellular membranes and the susceptibility to enzymatic degradation in the gastrointestinal tract. Cell-penetrating peptides (CPPs) have been investigated for a number of years as oral absorption enhancers for hydrophilic macromolecules by electrostatic or covalent conjugation on in conjunction with nanotechnology. Endogenous cellular uptake mechanisms present in the intestine can be exploited by engineering peptide conjugates that transcytose; entering cells by endocytosis and leaving by exocytosis. Efficiently delivering hydrophilic and sensitive peptide drugs to safely transverse the digestive barrier with no effect on gut physiology using remains a key driver for formulation research. Here we review the use of CPP and transcytosis peptide approaches, their modification and use in delivering anti-diabetic peptides (with the primary example of Insulin and engineered homologues) by direct oral administration to treat diabetes and associated metabolic disorders. 10.1016/j.peptides.2017.12.014
    The Human Salivary Antimicrobial Peptide Profile according to the Oral Microbiota in Health, Periodontitis and Smoking. Grant Melissa,Kilsgård Ola,Åkerman Sigvard,Klinge Björn,Demmer Ryan T,Malmström Johan,Jönsson Daniel Journal of innate immunity Antimicrobial peptides (AMPs) are a diverse family of peptides that defend the mucosal surfaces of the oral cavity and other locations. Many AMPs have multiple functions and properties that influence aspects of innate defense and colonization by microorganisms. The human oral cavity is home to the second-most diverse microbiome, and the health of the mouth is influenced by the presence of these bacteria as well as by extrinsic factors such as periodontitis and smoking. This study hypothesized that the AMP profile is different in the presence of extrinsic factors and that this would also be reflected in the bacteria present. The AMP profile was analyzed by quantitative selected-reaction-monitoring mass spectrometry analysis and 40 bacterial species were quantified by DNA-DNA hybridization in saliva donated by 41 individuals. Periodontal status was assessed through dental examination and smoking status through medical charting. Periodontal health (in nonsmokers) was associated with a higher abundance of ribonuclease 7, protachykinin 1, β-defensin 128, lipocalin 1, bactericidal permeability-increasing protein fold-containing family B member 3, and bone-marrow proteoglycan. Nonsmoking periodontal disease was associated with an abundance of neutrophil defensin 1 and cathelicidin. However, 7 AMPs were overabundant in periodontal disease in smokers: adrenomedullin, eosinophil peroxidase, 3 different histones, myeloperoxidase, and neutrophil defensin 1. There were no differentially abundant AMPs in smokers versus nonsmokers with periodontal health. Correlation network inference of healthy nonsmokers, healthy smokers, nonsmoking periodontitis, or smoking periodontitis donors demonstrated very different networks growing in complexity with increasing numbers of stressors. The study highlights the importance of the interaction between the oral cavity and its resident microbiota and how this may be influenced by periodontal disease and smoking. 10.1159/000494146
    Enhancing Oral Bioavailability of Cyclic RGD Hexa-peptides by the Lipophilic Prodrug Charge Masking Approach: Redirection of Peptide Intestinal Permeability from a Paracellular to Transcellular Pathway. Schumacher-Klinger Adi,Fanous Joseph,Merzbach Shira,Weinmüller Michael,Reichart Florian,Räder Andreas F B,Gitlin-Domagalska Agata,Gilon Chaim,Kessler Horst,Hoffman Amnon Molecular pharmaceutics Hydrophilic peptides constitute most of the active peptides. They mostly permeate via tight junctions (paracellular pathway) in the intestine. This permeability mechanism restricts the magnitude of their oral absorption and bioavailability. We hypothesized that concealing the hydrophilic residues of the peptide using the lipophilic prodrug charge masking approach (LPCM) can improve the bioavailability of hydrophilic peptides. To test this hypothesis, a cyclic N-methylated hexapeptide containing Arg-Gly-Asp (RGD) and its prodrug derivatives, masking the Arg and Asp charged side chains, were synthesized. The library was evaluated for intestinal permeability in vitro using the Caco-2 model. Further investigation of metabolic stability ex vivo models in rat plasma, brush border membrane vesicles (BBMVs), and isolated CYP3A4 microsomes and pharmacokinetic studies was performed on a selected peptide and its prodrug (peptide 12). The parent drug analogues were found to have a low permeability rate in vitro, corresponding to atenolol, a marker for paracellular permeability. Moreover, palmitoyl carnitine increased the P of peptide 12 by 4-fold, indicating paracellular permeability. The P of the prodrug derivatives was much higher than that of their parent peptides. For instance, the P of the prodrug 12P was 20-fold higher than the P of peptide 12 in the apical to basolateral (AB) direction. Whereas the permeability in the opposite direction (BA of the Caco-2 model) was significantly faster than the P AB, indicating the involvement of an efflux system. These results were corroborated when verapamil, a P-gp inhibitor, was added to the Caco-2 model and increased the P AB of prodrug 12P by 3-fold. The prodrug 12P was stable in the BBMVs environment, yet degraded quickly (less than 5 min) in the plasma into the parent peptide 12. Pharmacokinetic studies in rats showed an increase in the bioavailability of peptide 12 > 70-fold (from 0.58 ± 0.11% to 43.8 ± 14.9%) after applying the LPCM method to peptide 12 and converting it to the prodrug 12P. To conclude, the LPCM approach converted the absorption mechanism of the polar peptides from a paracellular to transcellular pathway that tremendously affects their oral bioavailability. The LPCM method provides a solution for the poor bioavailability of RGD cyclohexapeptides and paves the way for other active hydrophilic and charged peptides with poor oral bioavailability. 10.1021/acs.molpharmaceut.8b00466