Papain-cyclodextrin complexes as an intestinal permeation enhancer: Permeability and in vitro safety evaluation

Corazza, Fulvio Gabriel; Ernesto, Júlia Vaz; Nambu, Felipe Augusto Nery; Carvalho, Luma Ramirez de; Leite-Silva, Vânia Rodrigues; Varca, Gustavo H.C.; Calixto, Leandro Augusto; Vieira, Daniel Perez; Andréo-Filho, Newton; Lopes, Patrícia Santos

doi:10.1016/j.jddst.2019.101413

Cited by 15 publications

(7 citation statements)

References 85 publications

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“…Incubation of the cell monolayer with HBSS and the manipulation required for the permeability assays may lead to perturbation of the monolayer integrity. In fact, we (and others [29,35]) have observed a small but systematic decrease in the TEER value after the permeability assay. Hence, for the re-use of the cell monolayer in additional permeability assays, it is necessary to first ensure that the monolayer integrity is fully recovered.…”

Section: Permeability Assays and Transepithelial Electrical Resistance (Teer)supporting

confidence: 60%

Re-Use of Caco-2 Monolayers in Permeability Assays—Validation Regarding Cell Monolayer Integrity

et al. 2021

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Caco-2 monolayers are a common in vitro model used to evaluate human intestinal absorption. The reference protocol requires 21 days post-seeding to establish a stable and confluent cell monolayer, which is used in a single permeability assay during the period of monolayer stability (up to day 30). In this work, we characterize variations in the tightness of the cell monolayer over the stable time interval and evaluate the conditions required for their re-use in permeability assays. The monolayer integrity was assessed through TEER measurements and permeability of the paracellular marker Lucifer Yellow (LY), complemented with nuclei and ZO-1 staining for morphological studies and the presence of tight junctions. Over 150 permeability assays were performed, which showed that manipulation of the cell monolayer in the permeability assay may contribute significantly to the flux of LY, leading to Papp values that are dependent on the sampling duration. The assay also leads to a small decrease in the cell monolayer TEER, which is fully recovered when cell monolayers are incubated with culture media for two full days. When this procedure is followed, the cell monolayers may be used for permeability assays on days 22, 25, and 28, triplicating the throughput of this important assay.

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Section: Permeability Assays and Transepithelial Electrical Resistance (Teer)supporting

confidence: 60%

Re-Use of Caco-2 Monolayers in Permeability Assays—Validation Regarding Cell Monolayer Integrity

et al. 2021

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“…Also, care must be taken in the amount of CD used in the formulation, as an excess of CDs could hinder the absorption of the drug through the GI tract [ 68 , 69 ]. Nonetheless, the fascinating recent research devoted to oral CD-based pharmaceutical technologies will certainly maintain the increasing trend observed herein [ [70] , [71] , [72] , [73] , [74] , [75] ].…”

Section: Resultsmentioning

confidence: 82%

Technological evolution of cyclodextrins in the pharmaceutical field

Rincón-López

Almanza-Arjona

Riascos

et al. 2021

Journal of Drug Delivery Science and Technology

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We herein disclose how global cyclodextrin-based pharmaceutical technologies have evolved since the early 80s through a 1998 patents dataset retrieved from Derwent Innovation Index. We used text-mining techniques based on the patents semantic content to extract the knowledge contained therein, to analyze technologies related to the principal attributes of CDs: solubility, stability, and taste-masking enhancement. The majority of CDs pharmaceutical technologies are directed toward parenteral aqueous solutions. The development of oral and ocular formulations is rapidly growing, while technologies for nasal and pulmonary routes are emerging and seem to be promising. Formulations for topical, transdermal, vaginal, and rectal routes do not account for a high number of patents, but they may be hiding a great potential, representing opportunity research areas. Certainly, the progress in materials sciences, supramolecular chemistry, and nanotechnology, will influence the trend of that, apparently neglected, research. The bottom line, CDs pharmaceutical technologies are still increasing, and this trend is expected to continue in the coming years. Patent monitoring allows the identification of relevant technologies and trends to prioritize research, development, and investment in both, academia and industry. We expect the scope of this approach to be applied in the pharmaceutical field beyond CDs technological applications.

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“…It has been shown that the effect of papain on permeability is reversible and does not destroy the overall intestinal epithelium. 25 Papain is able to degrade tight junction components such as occludin, which can contribute to the observed elevation in epithelial permeability. 26,27 This mechanism can likely facilitate not only the absorption of other larger molecules but also that of papain itself.…”

Section: Discussionmentioning

confidence: 99%

“…Strikingly, fluorescent dyes with a molecular weight as high as 600 kDa were also absorbed. It has been shown that the effect of papain on permeability is reversible and does not destroy the overall intestinal epithelium 25 . Papain is able to degrade tight junction components such as occludin, which can contribute to the observed elevation in epithelial permeability 26,27 .…”

Section: Discussionmentioning

confidence: 99%

Region‐specific effects of the cysteine protease papain on gastric motility

Annaházi

Schröder

Schemann

2021

Neurogastroenterology Motil

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Background: Papaya is a traditional remedy for gastrointestinal complaints in the folk medicine. On this basis, papain, a cysteine protease of the fruit, is sold as a nutritional supplement, although scientific data on its effects in the gastrointestinal tract are lacking. We aimed to explore the effect of papain on gastric motility in vitro.Methods: Guinea pig antrum and corpus strips were mounted in organ bath. Key results:Papain reversibly increased the amplitude of ongoing phasic contractions in both circular and longitudinal antrum strips without having an effect on the frequency or on the muscle tone. All three tested doses of papain (end cc.: 12.5 mg L −1 , 50 mg L −1 , 100 mg L −1 ) were similarly effective. Contrarily, in the corpus circular and longitudinal muscle strips, papain caused a dose-dependent relaxation, which was preceded by a transient contraction in most tissues. The effect was resistant to tetrodotoxin (1 µM), but diminished by the cysteine protease inhibitor E64 (4.5 µM) in both regions. In the corpus, L-NAME (100 µM) and the protease-activated receptor (PAR)-1 antagonist SCH79797 (5 µM) or the PAR-2 antagonist GB 83 (3 µM) did not change the effect of papain significantly. This demonstrates that the effects of papain are not neurally mediated and nitrergic pathways are not involved in the mechanism. The effects are linked to the enzymatic activity, but not executed via PAR-1 or 2. Conclusions and inferences:Papain alters gastric motility in a region-specific manner, which could at least partly explain its claimed beneficial effects in functional gastrointestinal disorders.

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Papain-cyclodextrin complexes as an intestinal permeation enhancer: Permeability and in vitro safety evaluation

Cited by 15 publications

References 85 publications

Re-Use of Caco-2 Monolayers in Permeability Assays—Validation Regarding Cell Monolayer Integrity

Re-Use of Caco-2 Monolayers in Permeability Assays—Validation Regarding Cell Monolayer Integrity

Technological evolution of cyclodextrins in the pharmaceutical field

Region‐specific effects of the cysteine protease papain on gastric motility

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