Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery

Su, Fang; Lin, Kun-Ju; Sonaje, Kiran; Wey, Shiaw-Pyng; Yen, Tzu Chen; Ho, Yi Cheng; Panda, Nilendu; Chuang, Er-Tuan; Maiti, B. R.; Sung, Hsing‐Wen

doi:10.1016/j.biomaterials.2011.12.038

Cited by 187 publications

(88 citation statements)

References 33 publications

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“…Several approaches have been used to improve the oral absorption of insulin from the GI tract, including encapsulation of insulin in nanoparticles (7,8), coating of insulin-loaded nanoparticles with protease inhibitors (9), enteric coating of insulin-loaded nanoparticles (10), and hydrogels (11). Although some permeation enhancers can facilitate the poor permeation of these drugs through the epithelial membrane, advances in these reagents for clinical use are limited by biological efficiency at tolerable levels of safety (2).…”

Section: Introductionmentioning

confidence: 99%

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Khafagy

Iwamae

Kamei

et al. 2015

AAPS J

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Abstract. We have reported that the cell-penetrating peptide (CPP) penetratin acts as a potential absorption enhancer in oral insulin delivery systems and that this action occurs through noncovalent intermolecular interactions. However, the region-dependent role of CPPs in intestinal insulin absorption has not been clarified. To identify the intestinal region where CPPs have the most effect in increasing insulin absorption, the region-dependent action of penetratin was investigated using in situ closed intestinal loops in rats. The order of the insulin area under the insulin concentration-time curve (AUC) increase effect by L-penetratin was ileum>jejunum>duodenum>colon. By contrast, the AUC order after coadministration of insulin with D-penetratin was colon>duodenum≥jejunum and ileum. We also compared the effects of the L-and D-forms of penetratin, R8, and PenetraMax on ileal insulin absorption. Along with the CPPs used in this study, L-and D-PenetraMax produced the largest insulin AUCs. An absorption study using ilea pretreated with CPPs showed that PenetraMax had no irreversible effect on the intestinal epithelial membrane. The degradation of insulin in the presence of CPPs was assessed in rat intestinal enzymatic fluid. The half-life (t 1/2 ) of insulin increased from 14.5 to 23.7 and 184.7 min in the presence of L-and D-PenetraMax, respectively. These enzymatic degradation-resistant effects might contribute partly to the increased ileal absorption of insulin induced by D-PenetraMax. In conclusion, this study demonstrated that the ability of the L-and D-forms of penetratin to increase intestinal insulin absorption was maximal in the ileum and the colon, respectively, and that D-PenetraMax is a powerful but transient enhancer of oral insulin absorption.

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Section: Introductionmentioning

confidence: 99%

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Khafagy

Iwamae

Kamei

et al. 2015

AAPS J

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“…For the further enhancement of bioavailability, two approaches were investigated: in the first, chitosan--PGA nanoparticles were freeze-dried and placed in an enteric-coated capsule, while in the second, a penetration enhancer -diethylene triamine pentaacetic acid (DTPA) -was added. In both cases the bioavailability was approximately 20% [70,71].…”

Section: Natural Polymersmentioning

confidence: 88%

Oral Delivery of Insulin: Novel Approaches

Elsayed¹

2012

Recent Advances in Novel Drug Carrier Systems

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“…Drugs are generally excluded from this pathway without the use of permeation enhancer (Chuang et al, 2013). As the decreasing of calcium ion concentration leads to the opening of the tight junctions, Ca 2+ chelating agents, such as ethylene glycol tetraacetic acid (EGTA) (Chuang et al, 2013), diethylene triamine pentaacetic acid (DTPA) (Su et al, 2012), could enhance the paracellular permeability by reversible opening of the tight junctions. Caco-2 cell monolayers treated with EGTA or g PGA-EGTA nanoparticles produced a significantly larger reduction in TEER compared to the control cells (Chuang et al, 2013).…”

Section: Paracellular Routementioning

confidence: 99%

“…About 51% blood glucose level reductions were achieved in severely diabetic rats (Kebede et al, 2013). This approach is (Su et al, 2012;Chuang et al, 2013) Bile salts Open the tight junctions and improve deformability and permeation (Degim et al, 2004;Niu et al, 2011Niu et al, , 2012Hu et al, 2013) Enteric coatings HPMCP, Eudragit Õ pH-sensitive Rapid release in intestinal Maroni et al, 2009;Wang & Zhang, 2012;Wu et al 2012a,b,c;Marais et al, 2013;Viehof et al, 2013;Zhao et al, 2013) …”

Section: Natural Polymersmentioning

confidence: 99%

“…With a smaller size and a higher loading efficiency compared with purely CS nanoparticles (Lin et al, 2007), the pH-sensitive CS/g-PGA nanoparticles could resist gastric acid while released rapidly in certain area of the small intestine (Sonaje et al, 2010a,b,c). g-PGA conjugated covalently by diethylene triamine pentaacetic acid (DTPA) could further prevent enzymolysis and prolong the residence time of the CS/g-PGA-DTPA system for oral insulin delivery (Su et al, 2012).…”

Section: G-pga-based Materialsmentioning

confidence: 99%

See 1 more Smart Citation

A review of biodegradable polymeric systems for oral insulin delivery

Luo

Xiong

Tian³

et al. 2015

Drug Delivery

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Currently, repeated routine subcutaneous injections of insulin are the standard treatment for insulin-dependent diabetic patients. However, patients' poor compliance for injections often fails to achieve the stable concentration of blood glucose. As a protein drug, the oral bioavailability of insulin is low due to many physiological reasons. Several carriers, such as macromolecules and liposomes have been used to deliver drugs in vivo. In this review article, the gastrointestinal barriers of oral insulin administration are described. Strategies for increasing the bioavailability of oral insulin, such absorption enhancers, enzyme inhibitors, enteric coatings are also introduced. The potential absorption mechanisms of insulin-loaded nanoparticles across the intestinal epithelium, including intestinal lymphatic route, transcellular route and paracellular route are discussed in this review. Natural polymers, such as chitosan and its derivates, alginate derivatives, g-PGA-based materials and starch-based nanoparticles have been exploited for oral insulin delivery; synthetic polymers, such as PLGA, PLA, PCL and PEA have also been developed for oral administration of insulin. This review focuses on recent advances in using biodegradable natural and synthetic polymers for oral insulin delivery along with their future prospects.

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Protease inhibition and absorption enhancement by functional nanoparticles for effective oral insulin delivery

Cited by 187 publications

References 33 publications

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Region-Dependent Role of Cell-Penetrating Peptides in Insulin Absorption Across the Rat Small Intestinal Membrane

Oral Delivery of Insulin: Novel Approaches

A review of biodegradable polymeric systems for oral insulin delivery

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