Effects of Various Absorption Enhancers on the Intestinal Absorption of Water Soluble Drugs by in Vitro Ussing Chamber Method: Correlation with an in Situ Absorption Experiment.

Sugiyama, Tetsuo; Yamamoto, Akira; Kawabe, Yojiro; Uchiyama, Tomomi; Quan, Ying‐Shu; Muranishi, Shozo

doi:10.1248/bpb.20.812

Cited by 28 publications

(19 citation statements)

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“…Therefore, we found some discrepancies between the result of the in vitro transport studies and the result of in situ absorption studies. These findings were not well correlated with previous study of Sugiyama et al (1997) who reported that there was a good correlation between the cumulative amount of phenol red absorbed (in vitro modified Ussing chamber method) and the area under the curve (AUC) obtained from the in situ closed loop model. 24) From these findings, we suggest that there appears to be some correlation between in vitro and in vivo studies in certain conditions and circumstances, however, it did not apply to all drugs or solubilizing agents used.…”

Section: Discussioncontrasting

confidence: 94%

The Effect of Wellsolve, a Novel Solubilizing Agent, on the Intestinal Barrier Function and Intestinal Absorption of Griseofulvin in Rats

Hamid

Yang

Gao

et al. 2009

Biological & Pharmaceutical Bulletin

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Recently, molecular weights of many drugs and their candidates have been increasing by the progress of combinatorial chemistry and high throughput screening (HTS). Therefore, it is known that water solubility of these drug candidates tended to decrease because of their large molecular size and high lipophilicity. As drug solubility is one of the most important factors affecting the intestinal drug absorption after oral administration, the poor solubility of these drug candidates is one of the most serious problems to achieve the high bioavailability of these drug candidates.Many strategies have been examined to overcome the low water solubility of drugs and their candidates. These strategies include solid dispersion, salt formulation, emulsion and liposomes and pharmaceutical excipients (solubilizing agents).1) Of these strategies, solubilizing agents have been utilized to improve the solubility of poorly water-soluble drugs and their bioavailability (BA) after oral administration. These solubilizing agents were considered inert substances that would be mainly used as diluents, fillers, binders, lubricants, coatings, solvents, dyes, and in the manufacture of drug products. However, the solubilizing agents may sometimes alter the intestinal membrane integrity and affect the function of transporters including P-glycoprotein (P-gp) and peptide transporter (PEPT1) in the intestine. Indeed, our previous study demonstrated that sodium taurocholate (NaTC), a natural surfactant and a bile salt, could increase the intestinal absorption of phenol red, a poorly absorbable compound in rats and cause the intestinal membrane damage as evaluated by the release amount of protein and phospholipid from the intestinal membranes.2,3) In addition, the intestinal absorption of insulin, gentamicin and other hydrophilic drugs was improved in the presence of Labrasol, one of the typical solubilizing agent. [4][5][6] Furthermore, more recently, we found that NaTC and Labrasol at higher concentrations might alter the intestinal barrier functions and increase the intestinal absorption of 5(6)-carboxyfluorescein (CF) and fluorescein isothiocyanate-labeled dextran with an average molecular weight of 4000 (FD4) in rats. 7)As for the effect of solubilizing agents on the function of transporters, it has been reported that several common excipients could modulate the activity of P-gp, a typical efflux transporter.8) Furthermore, our previous study indicated that Cremophor EL, Tween 80,, polyethyleneglycol (PEGs) and Labrasol also inhibited the function of P-gp in the intestine, thereby reducing the secretory transport of rhodamine123 and other P-gp substrates.9-12) Therefore, it is important to find out a suitable solubilizing agent, which has high potency and no influence on the function of integrity and transporters in the intestine.Based on the background, Wellsolve, a novel solubilizing agent, has recently been developed by Celeste Co., Ltd., although the components of this agent were not disclosed. In the preliminary studies, Wellsolve coul...

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Section: Discussioncontrasting

confidence: 94%

The Effect of Wellsolve, a Novel Solubilizing Agent, on the Intestinal Barrier Function and Intestinal Absorption of Griseofulvin in Rats

Hamid

Yang

Gao

et al. 2009

Biological & Pharmaceutical Bulletin

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“…C 10 increased the absorption of ebiratide [135], phenol red [102], and insulin [136] across rat colonic, but not jejunal epithelial mucosae (Table II). C 10 also increased paracellular permeability of a number of solutes in the colon but not in the small intestinal mucosae of rats and rabbits [137].…”

Section: [12] Intestinal Absorption Promotersmentioning

confidence: 96%

“…Isolated intestinal mucosa mounted in Ussing chambers permit comparison between effects of permeation enhancers on different regions of the intestine, thus TEER and flux changes similar to that seen in Caco-2 were noted in jejunal, ileal and colonic mucosae from a range of species upon exposure to C 10 . In tissue mucosae, C 10 decreased TEER with a concomitant increase in flux of poorly permeable markers including phenol red [102], poly-sucrose [103] and a range of FITC-dextrans [104] (Table II). While high concentrations of C 10 (>13mM) invariably lead to greater enhancement of fluxes of paracellular markers in Caco-2 monolayers and isolated intestinal mucosae (Table I and II), conclusions on mechanisms of action and of the presence cytotoxicity become rather irrelevant.…”

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

201

176

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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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“…In situ preparations, where the artificially perfused organ remains attached to the systemic circulation, include the rat intestine, 1864,1951–1959 kidney,(1960) and liver. 1961–1969 The small intestine can be perfused in situ in humans, using stoppers to define a perfused segment.…”

Section: Disposition Of Chemicalsmentioning

confidence: 99%

Modeling Kinetics of Subcellular Disposition of Chemicals

Baláž

2009

Chem. Rev.

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Effects of Various Absorption Enhancers on the Intestinal Absorption of Water Soluble Drugs by in Vitro Ussing Chamber Method: Correlation with an in Situ Absorption Experiment.

Cited by 28 publications

References 0 publications

The Effect of Wellsolve, a Novel Solubilizing Agent, on the Intestinal Barrier Function and Intestinal Absorption of Griseofulvin in Rats

The Effect of Wellsolve, a Novel Solubilizing Agent, on the Intestinal Barrier Function and Intestinal Absorption of Griseofulvin in Rats

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

Modeling Kinetics of Subcellular Disposition of Chemicals

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