Enhancement of intestinal absorption of poorly absorbed hydrophilic compounds by simultaneous use of mucolytic agent and non-ionic surfactant

Takatsuka, Shinya; Kitazawa, Takeo; Morita, Takahiro; Horikiri, Yuji; Yoshino, Hiroyuki

doi:10.1016/j.ejpb.2005.07.008

Cited by 51 publications

(26 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Removal of the jejunal mucus layer should, in theory, permit the direct contact between the promoter/cargo and the intestinal epithelium. Pretreatment with the mucolytic, N-acetyl cysteine (NAC) with C 10 led to more rapid absorption of sCT in a rat jejunal instillation as measured by serum calcium reduction (Wang and Brayden, unpublished data), although this was not the case when both agents were co-administered [127]. A rectal formulation of 5-fluorouracil with C 10 and Witepsol H-15 had a rectal F of 25.5%, however when Witepsol H-15 was replaced with PEG 2000 F increased to 64.4% [128].…”

Section: [12] Intestinal Absorption Promotersmentioning

confidence: 99%

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

200

176

View full text Add to dashboard Cite

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 ...

show abstract

Section: [12] Intestinal Absorption Promotersmentioning

confidence: 99%

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

200

176

View full text Add to dashboard Cite

show abstract

“…The concentration build up in the intestine probably helps its transport across the brush border. There are reports of increased bioavailability of poorly absorbed drug if supplemented with a mucolytic agent such as NAC (Takatsuka et al, 2006). It thus appears that E supplies antioxidant activity, pH stabilization and mucolytic effects for the transport of EGCG across the brush border.…”

Section: Effect Of the Nutrient Combination As Present In E In Rat Anmentioning

confidence: 94%

Studies on the effects of oral administration of nutrient mixture, quercetin and red onions on the bioavailability of epigallocatechin gallate from green tea extract

Kale¹,

Gawande²,

Kotwal³

et al. 2010

Phytotherapy Research

View full text Add to dashboard Cite

Epigallocatechin gallate (EGCG), a main anticancer component in green tea, has a poor bioavailability in rats and humans due to oxidation, metabolism and its efflux. It was hypothesized that nutrients that address these problems might result in increased bioavailability. Plasma concentrations of EGCG at various time intervals were determined to calculate and compare the pharmacokinetic parameters after oral administration of green tea extract (GTE) or GTE as a nutrient mixture (E) or E + quercetin (Q)/red onions. In rat studies, supplementation of GTE with other nutrients (E) or E + Q raised the plasma C(max) from 55.29 +/- 1.70 to 61.94 +/- 1.70 ng/mL and 94.44 +/- 1.59 ng/mL, respectively. The corresponding t((1/2)) elimination was 2.04 +/- 0.2 h, 3.63 +/- 0.66 h and 2.28 +/- 0.049 h. The AUC(0-24h) were 510.16 +/- 9.88 for GTE, 601.72 +/- 19.10 ng.h/mL for E and 794.08 +/- 15.27 ng x h/mL (p < or = 0.05) for E + Q. In human studies when GTE was fed as GTE or E or E + red onions, the C(max) values were 348.4 +/- 76.6, 384.0 +/- 78.5 ng/mL and 468.4 +/- 131.4. AUC(0-8h) was 1784.1 +/- 56.06 (GTE), 1971.5 +/- 566.5 ng x h/mL (E) and 2490 +/- 878.1 (E + Q), but the change in t((1/2)) elimination was not significant.In conclusion, it is possible to increase the bioavailability of EGCG by supplementing it with nutrients and quercetin.

show abstract

“…It is possible that targeting can be further improved by facilitating penetration through low viscosity pores within mucus using materials such as chitosan, 18,19 polyethylene glycol, 12,26 surfactants, 27,28 or mucolytic agents. 6,9,29 These strategies have been shown to allow significant penetration of polystyrene and poly(lacticco-glycolic acid) particles up to 500 nm in size. 26 ICAM-1 targeting and uptake in GI tissue is also in accord with our recent study showing efficient binding and endocytosis of anti-ICAM NCs in Caco-2 cells, which derive from human intestinal tissue.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25] Strategies to facilitate mucus penetration can be additionally used, such as incorporation of chitosan, 18,19 polyethylene glycol, 12,26 surfactants, 27,28 or mucolytic agents. 6,9,29 These strategies have also been explored in conjunction with nanocarriers (NCs). NCs offer advantages for drug delivery since their properties can be controlled by engineering and/or chemical means, allowing versatility in material, size, architecture, stability, bioavailability, drug transport, release, etc.…”

Section: Introductionmentioning

confidence: 99%

Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice

Mane¹,

Muro²

2012

IJN

View full text Add to dashboard Cite

Drug delivery to the gastrointestinal (GI) tract is key for improving treatment of GI maladies, developing oral vaccines, and facilitating drug transport into circulation. However, delivery of formulations to the GI tract is hindered by pH changes, degradative enzymes, mucus, and peristalsis, leading to poor GI retention. Targeting may prolong residence of therapeutics in the GI tract and enhance their interaction with this tissue, improving such aspects. We evaluated nanocarrier (NC) and ligand-mediated targeting in the GI tract following gastric gavage in mice. We compared GI biodistribution, degradation, and endocytosis between control antibodies and antibodies targeting the cell surface determinant intercellular adhesion molecule 1 (ICAM-1), expressed on GI epithelium and other cell types. These antibodies were administered either as free entities or coated onto polymer NCs. Fluorescence and radioisotope tracing showed proximal accumulation, with preferential retention in the stomach, jejunum, and ileum; and minimal presence in the duodenum, cecum, and colon by 1 hour after administration. Upstream (gastric) retention was enhanced in NC formulations, with decreased downstream (jejunal) accumulation. Of the total dose delivered to the GI tract, ∼60% was susceptible to enzymatic (but not pHmediated) degradation, verified both in vitro and in vivo. Attenuation of peristalsis by sedation increased upstream retention (stomach, duodenum, and jejunum). Conversely, alkaline NaHCO 3 , which enhances GI transit by decreasing mucosal viscosity, favored downstream (ileal) passage. This suggests passive transit through the GI tract, governed by mucoadhesion and peristalsis. In contrast, both free anti-ICAM and anti-ICAM NCs demonstrated significantly enhanced upstream (stomach and duodenum) retention when compared to control IgG counterparts, suggesting GI targeting. This was validated by transmission electron microscopy and energy dispersive X-ray spectroscopy, which revealed anti-ICAM NCs in vesicular compartments within duodenal epithelial cells. These results will guide future work aimed at improving intraoral delivery of targeted therapeutics for the treatment of GI pathologies.

show abstract

Enhancement of intestinal absorption of poorly absorbed hydrophilic compounds by simultaneous use of mucolytic agent and non-ionic surfactant

Cited by 51 publications

References 23 publications

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

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

Studies on the effects of oral administration of nutrient mixture, quercetin and red onions on the bioavailability of epigallocatechin gallate from green tea extract

Biodistribution and endocytosis of ICAM-1-targeting antibodies versus nanocarriers in the gastrointestinal tract in mice

Contact Info

Product

Resources

About