Melittin as a Permeability Enhancer II: In Vitro Investigations in Human Mucus Secreting Intestinal Monolayers and Rat Colonic Mucosae

Maher, Sam; Feighery, Linda; Brayden, David J.; McClean, Siobhán

doi:10.1007/s11095-007-9246-z

Cited by 31 publications

(15 citation statements)

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“…Furthermore, the sideness of the melittin effect indicates that systemic delivery of melittin would have limited toxicity. The polarised effect of melittin on both TER and drug permeability was also observed in rat colon (30).…”

Section: Discussionmentioning

confidence: 67%

Melittin as an Epithelial Permeability Enhancer I: Investigation of Its Mechanism of Action in Caco-2 Monolayers

et al. 2007

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Section: Discussionmentioning

confidence: 67%

Melittin as an Epithelial Permeability Enhancer I: Investigation of Its Mechanism of Action in Caco-2 Monolayers

et al. 2007

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“…Detergents such as SDS (46) and polymers including chitosan (47) have bacteriocidal actions, while methacrylate-based polymers were also found to inhibit the growth and epithelial attachment of Salmonella to HT29 cells (48). In addition, the bee venom-derived anti-microbial cationic peptide defensin, mellitin, was recently shown to act as a tight junction opener at similar concentrations to those of its antibiotic effect (49). Therefore, many established and potential formulation excipients are likely to have direct anti-microbial effects, largely based on a combination of nonspecific mechanisms including cationic charge, bacterial membrane targeting, and detergent actions.…”

Section: Discussionmentioning

confidence: 99%

In vitro Interactions Between the Oral Absorption Promoter, Sodium Caprate (C10) and S. typhimurium in Rat Intestinal Ileal Mucosae

et al. 2007

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“…C 10 inhibits Ca 2+ -and cAMP-dependent electrogenic chloride secretion in rat and human colonic mucosae [104,205]. The effect of the promoter on reducing the chloride secretion induced by the adenylate cyclase activator, forskolin, and muscarinic agonists was reversed at 24 hours [156].…”

Section: [23] Preclinical Safety Data For C 10mentioning

confidence: 98%

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

Maher

Leonard²,

Jacobsen

et al. 2009

Advanced Drug Delivery Reviews

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A major challenge in oral drug delivery is the development of novel dosage forms to promote absorption of poorly permeable Class III drugs across the intestinal epithelium.To date, no absorption promoter has been approved in a formulation specifically designed for oral delivery of Class III molecules. Promoters that are designated safe for human consumption have been licensed for use in a recently approved buccal insulin spray delivery system and also for many years as part of an ampicillin rectal suppository.Unlike buccal and rectal delivery, oral formulations containing absorption promoters have the additional technical hurdle whereby the promoter and payload must be coreleased in high concentrations at the small intestinal epithelium in order to generate significant but rapidly reversible increases in permeability. The most advanced promoter in the clinic is the medium chain fatty acid (MCFA), sodium caprate (C 10 ) , a compound already approved as a direct food additive. We discuss how it has evolved to a matrix tablet format suitable for administration to humans under the headings of mechanism of action at the cellular and tissue level and in vitro and in vivo efficacy and safety studies.In specific clinical examples, we review how C 10 -based formulations are being tested for oral delivery of bisphosphonates using Gastro Intestinal Permeation Enhancement Technology, GIPET® (Merrion Pharmaceuticals, Ireland) and in a related solid dose format for anti-sense oligonucleotides (ISIS Pharmaceuticals, USA).Keywords: Oral drug delivery, Sodium caprate (C 10 ), absorption promoter, drug delivery platforms, clinical trials, oral formulation, drug delivery systems.3 TJs form a barrier to the uncontrolled absorption of noxious luminal antigens (gate function), and maintain epithelial polarity (fence function) [8,9]. In general, the TJ consists of a restrictive pathway (shunt) with a sharp molecular size cut off, and a second unrestrictive pathway (small pore) that permits paracellular permeation of molecules of radii <4.0 Å [10,11]. Depending on the intestinal region, TJ pore sizes range from 6-22Å, sufficient to permit mannitol (6.7 Å) and EDTA (10.8 Å) to permeate to an extent, whereas the passage of inulin (30-40 Å) and fluorescent-dextran 4kDa (FD-4, 26 Å) is essentially impeded [12][13][14][15][16].A number of approaches have been used to promote oral delivery of Class III drugs ( Alternatively, the use of nanoparticles comprising biocompatible polymers (e.g. chitosan,polylactide-co-glycolide, starch and glucans) can protect cargoes from GI proteases, increase GI retention and promote absorption across gut associated lymphoid tissue (GALT) and to a lesser extent, enterocytes [45][46][47]. Most data on nanoparticle absorption from rodent models suggest that M cells in the follicle-associated epithelium of Peyer's patches (PP) are the favored site of uptake for particles of diameter 500nm-1000nm [45].Given the paucity of M cells in the GI tract of adults, the relevance of PP uptake remains controversial ...

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Melittin as a Permeability Enhancer II: In Vitro Investigations in Human Mucus Secreting Intestinal Monolayers and Rat Colonic Mucosae

Abstract: The rapid and reversible nature of melittin's permeation enhancing properties and its limited cytotoxicity in polarized intestinal epithelia, suggests a potential drug delivery role for the peptide in oral formulations of poorly absorbed drugs.

Cited by 31 publications

References 54 publications

Melittin as an Epithelial Permeability Enhancer I: Investigation of Its Mechanism of Action in Caco-2 Monolayers

Melittin as an Epithelial Permeability Enhancer I: Investigation of Its Mechanism of Action in Caco-2 Monolayers

In vitro Interactions Between the Oral Absorption Promoter, Sodium Caprate (C10) and S. typhimurium in Rat Intestinal Ileal Mucosae

Safety and efficacy of sodium caprate in promoting oral drug absorption: from in vitro to the clinic

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