Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments

Samiei, Nasim; Mangas‐Sanjuán, Víctor; González‐Álvarez, Isabel; Foroutan, Mohsen; Shafaati, Alireza; Zarghi, Afshin; Bermejo, Marival

doi:10.1016/j.ejps.2013.04.025

Cited by 29 publications

(23 citation statements)

References 16 publications

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“…The SPIP technique was applied as previously reported (Luo et al, 2013;Samiei et al, 2013). The male SpragueDawley rats were fasted for 24 h but allowed free access to water.…”

Section: In Situ Intestinal Absorption Studiesmentioning

confidence: 99%

Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems:in vitro, in vivoandin situintestinal permeability studies

Lei

Cui

et al. 2014

Drug Delivery

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(2015) Enhanced oral bioavailability of piperine by selfemulsifying drug delivery systems: invitro,invivo and insitu intestinal permeability studies, Drug Delivery, 22:6, 740-747, DOI: 10.3109/10717544.2014 AbstractThe main purpose of this work was to develop and evaluate a self-emulsifying drug delivery system (SEDDS) of piperine to enhance its solubility and bioavailability. The formulation was optimized by solubility test and ternary phase diagrams. Then physiochemical properties and in vitro release of SEDDS were characterized. In vivo pharmacokinetics study and in situ singlepass intestinal perfusion were performed to investigate the effects of SEDDS on the bioavailability and intestinal absorption of piperine. The optimized formulation was composed of ethyl oleate, Tween 80 and Transcutol P (3:5.5:1.5, w/w), with the level of the piperine reached 2.5% (w/w). The in vitro dissolution rates of piperine SEDDS were significantly higher than the self-prepared capsules. In vivo pharmacokinetic study showed C max1 , C max2 and area under the curve of piperine after oral administration of SEDDS in rats were 3.8-, 7.2-and 5.2-fold higher than the self-prepared capsules, respectively, and the relative bioavailability of SEDDS was 625.74%. The in situ intestinal absorption study revealed that the effective permeability and the effective absorption rate values of piperine for SEDDS were significantly improved comparing to solutions (p50.01). So SEDDS formulation could improve the oral bioavailability and intestinal absorption of piperine effectively.

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“…The SPIP technique was applied as previously reported (Luo et al, 2013;Samiei et al, 2013). The male SpragueDawley rats were fasted for 24 h but allowed free access to water.…”

Section: In Situ Intestinal Absorption Studiesmentioning

confidence: 99%

Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems:in vitro, in vivoandin situintestinal permeability studies

Lei

Cui

et al. 2014

Drug Delivery

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“…This increases passive transcellular diffusion and enhances protein permeability, and is the principle behind the use of ion pairs to enhance drug permeation. An ion pair is formed when a pair of oppositely charged (counter) ions are held together without the formation of a covalent bond; forming a neutral molecule with higher lipophilicity, that can partition into the cell membrane easier than the parent compound4. Most ion pairing agents such as inorganic surfactants and co-solvents require high volumes, resulting in high toxicity/allergenicity and have limited applications in pharmaceutical preparations456.…”

mentioning

confidence: 99%

“…An ion pair is formed when a pair of oppositely charged (counter) ions are held together without the formation of a covalent bond; forming a neutral molecule with higher lipophilicity, that can partition into the cell membrane easier than the parent compound4. Most ion pairing agents such as inorganic surfactants and co-solvents require high volumes, resulting in high toxicity/allergenicity and have limited applications in pharmaceutical preparations456. Recently, the use of amino acids as ion pairs to enhance solubility/permeability of small molecules has been investigated as a biodegradable, low toxicity/irritant and high stability alternative6.…”

mentioning

confidence: 99%

Pre-formulation and systematic evaluation of amino acid assisted permeability of insulin across in vitro buccal cell layers

Iyire

Alaayedi

Mohammed

2016

Sci Rep

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The aim of this work was to investigate alternative safe and effective permeation enhancers for buccal peptide delivery. Basic amino acids improved insulin solubility in water while 200 and 400 μg/mL lysine significantly increased insulin solubility in HBSS. Permeability data showed a significant improvement in insulin permeation especially for 10 μg/mL of lysine (p < 0.05) and 10 μg/mL histidine (p < 0.001), 100 μg/mL of glutamic acid (p < 0.05) and 200 μg/mL of glutamic acid and aspartic acid (p < 0.001) without affecting cell integrity; in contrast to sodium deoxycholate which enhanced insulin permeability but was toxic to the cells. It was hypothesized that both amino acids and insulin were ionised at buccal cavity pH and able to form stable ion pairs which penetrated the cells as one entity; while possibly triggering amino acid nutrient transporters on cell surfaces. Evidence of these transport mechanisms was seen with reduction of insulin transport at suboptimal temperatures as well as with basal-to-apical vectoral transport, and confocal imaging of transcellular insulin transport. These results obtained for insulin are the first indication of a possible amino acid mediated transport of insulin via formation of insulin-amino acid neutral complexes by the ion pairing mechanism.

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“…Various dosage forms of oral route administration, including nanoparticle delivery systems, have been proven to be inactive due to the poor lipophilicity of amifostine and the electric charges at physiological pH (Kuna et al, 1983). Although chemical modifications, such as esterification with succinic acid, may improve amifostine bioavailability somehow (Samiei et al, 2013), the drug itself is orally inactive. A phase I clinical trial conducted by Bonner & Shaw (2002) showed that subcutaneous and other nonoral routes were effective for administrating this drug (Bonner & Shaw, 2002).…”

Section: Extended Protection Efficacymentioning

confidence: 99%

Sustained-release microspheres of amifostine for improved radio-protection, patient compliance, and reduced side effects

Jin

2016

Drug Delivery

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A biweekly administration of sustained-release microsphere dosage form of amifostine, a radioprotective drug used in radiotherapy, was performed to examine the feasibility to minimize injection frequency and blood concentration-associated side effects. Model animal trials indicated that this subcutaneously injecting microspheres, 50-100 mm in diameter, achieved bi-weekly prolonged radio-protective efficacy and, at the same time, significantly reduced skin irritation than the solution form of amifostine given by the same administration route. In addition, the hypertension associated with blood concentration of amifostine was not observed in the drug-treated rats. The animals given the amifostine microspheres and amifostine showed significantly differences in white blood cell, red blood cell, hematocrit, hemoglobin and spleen tissue histopathology after exposed under a cobalt-60 g-radiation at a dose rate of 1.0 Gy/min for 6 min. The in vitro release profile of amifostine from the micropsheres showed a minor initial burst (less than 20% of total drug loading in the first day of administration), consisting with the side effects observations. The results suggest that amifostine encapsulated in sustained-release microspheres may be an ideal dosage form for prolonged radio-protective efficacy and improved patient compliance.

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Ion-pair strategy for enabling amifostine oral absorption: Rat in situ and in vivo experiments

Cited by 29 publications

References 16 publications

Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems:in vitro, in vivoandin situintestinal permeability studies

Enhanced oral bioavailability of piperine by self-emulsifying drug delivery systems:in vitro, in vivoandin situintestinal permeability studies

Pre-formulation and systematic evaluation of amino acid assisted permeability of insulin across in vitro buccal cell layers

Sustained-release microspheres of amifostine for improved radio-protection, patient compliance, and reduced side effects

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