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Wang D, Jiang Q, Dong Z, Meng T, Hu F, Wang J, Yuan H. Nanocarriers transport across the gastrointestinal barriers: The contribution to oral bioavailability via blood circulation and lymphatic pathway. Adv Drug Deliv Rev 2023; 203:115130. [PMID: 37913890 DOI: 10.1016/j.addr.2023.115130] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 09/27/2023] [Accepted: 10/27/2023] [Indexed: 11/03/2023]
Abstract
Oral administration is the preferred route of drug delivery in clinical practice due to its noninvasiveness, safety, convenience, and high patient compliance. The gastrointestinal tract (GIT) plays a crucial role in facilitating the targeted delivery of oral drugs. However, the GIT presents multiple barriers that impede drug absorption, including the gastric barrier in the stomach and the mucus and epithelial barriers in the intestine. In recent decades, nanotechnology has emerged as a promising approach for overcoming these challenges by utilizing nanocarrier-based drug delivery systems such as liposomes, micelles, polymeric nanoparticles, solid lipid nanoparticles, and inorganic nanoparticles. Encapsulating drugs within nanocarriers not only protects them from degradation but also enhances their transport and absorption across the GIT, ultimately improving oral bioavailability. The aim of this review is to elucidate the mechanisms underlying nanocarrier-mediated transportation across the GIT into systemic circulation via both the blood circulation and lymphatic pathway.
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Affiliation(s)
- Ding Wang
- College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China
| | - Qi Jiang
- College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China
| | - Zhefan Dong
- College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China
| | - Tingting Meng
- College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China
| | - Fuqiang Hu
- College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China
| | - Jianwei Wang
- The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, 310009, PR China
| | - Hong Yuan
- College of Pharmaceutical Science, Zhejiang University, Hangzhou 310058, PR China; China Jinhua Institute of Zhejiang University, Jinhua 321299, PR China.
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Wang S, Gao Z, Liu L, Li M, Zuo A, Guo J. Preparation, in vitro and in vivo evaluation of chitosan-sodium alginate-ethyl cellulose polyelectrolyte film as a novel buccal mucosal delivery vehicle. Eur J Pharm Sci 2022; 168:106085. [PMID: 34856348 DOI: 10.1016/j.ejps.2021.106085] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 10/22/2021] [Accepted: 11/26/2021] [Indexed: 01/02/2023]
Abstract
This paper describes the development of a film comprising chitosan (CS), sodium alginate (SA), and ethyl cellulose (EC) for buccal mucosal administration. A film of CS-SA unidirectional release drug-containing water-repellent layer EC was produced by interfacial reaction solvent-drying technique using self-made equipment. The CS-SA-EC film had superior mechanical properties compared to CS-EC and SA-EC films. The existence of the amide bond was confirmed by FT-IR. DSC confirmed that the drug was dispersed in the carrier material in an amorphous form. The drug release studies emerged that the model drugs from CS-SA-EC films presented better release properties. The Ritger-Peppas model best describes all ratios of drugs release mechanisms. The permeability characteristics of the films were evaluated in the TR146 cells model and the rabbit buccal mucosae. The cumulative penetration amounts of the model drugs were significantly increased. The permeability mechanism of the film was studied preliminarily using immunofluorescence and Western Blot. The results showed that the film inhibited the expression of ZO-1 protein, and the expressive trend of ZO-1 protein was consistent with the results of in vitro permeation experiments. The pharmacokinetics of the drugs loaded films were evaluated and compared with oral administration in rats. The relative bioavailability of the model drugs was 246.00% (Zolmitriptan) and 142.12% (Etodolac) relative to oral administration. The results of this study demonstrate the potential of CS-SA-EC vehicle in buccal mucosa drug delivery.
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Affiliation(s)
- Shuangqing Wang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Zhonggao Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Lei Liu
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Mingxin Li
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China
| | - Along Zuo
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China; Yanbian Medical and Health Industry Pilot Base, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China; Yanbian K&D Biotechnology Co., Ltd. Yanji, 133002, Jilin Province, China.
| | - Jianpeng Guo
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China; Yanbian Medical and Health Industry Pilot Base, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.
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3
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Green one-pot synthesis of multicomponent-crosslinked carboxymethyl cellulose as a safe carrier for the gentamicin oral delivery. Int J Biol Macromol 2020; 164:2873-2880. [DOI: 10.1016/j.ijbiomac.2020.08.168] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/15/2020] [Accepted: 08/21/2020] [Indexed: 12/30/2022]
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4
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Renaud V, Faucher M, Perreault V, Serre E, Dubé P, Boutin Y, Bazinet L. Evolution of cranberry juice compounds during in vitro digestion and identification of the organic acid responsible for the disruption of in vitro intestinal cell barrier integrity. JOURNAL OF FOOD SCIENCE AND TECHNOLOGY 2020; 57:2329-2342. [PMID: 32431359 PMCID: PMC7230080 DOI: 10.1007/s13197-020-04271-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Revised: 01/14/2020] [Accepted: 01/21/2020] [Indexed: 01/02/2023]
Abstract
Cranberry juice is increasingly consumed for its richness in polyphenols having a positive impact on human health. Unfortunately, when regularly consumed, its high concentration in organic acids may cause some intestinal discomforts. In the present study, its organic acid content was reduced of 41% by electrodialysis with bipolar membrane (EDBM), and the resulted deacidified juice was divided in five different juices readjusted or not with different concentrations of citric and/or malic acid(s) corresponding to the concentration of this/these acid(s) recovered during EDBM or at the titratable acidity (TA) of the non-deacidified cranberry juice. The evolution of the cranberry juice main interesting compounds (organic acids and polyphenols), according to the concentration and nature of the organic acids present, was studied for the first time at each specific stages of the digestion. After digestion, Caco-2 cells were exposed to all digested juices to identify the organic acid(s) responsible for the loss of integrity of the epithelial barrier. It appeared that organic acid contents did not change during the different steps of the digestion while polyphenolic compounds decreased starting from the gastric phase. Whatever the organic acid concentration or nature, the concentration of PACs significantly decreased between the salivary and the gastric steps but was different according to their structure when the concentration of most of anthocyanins significantly decreased at the gastric step. Also, to the best of our knowledge, it was the first time that citric acid was demonstrated as the organic acid responsible for the loss of integrity of Caco-2 cell monolayers.
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Affiliation(s)
- Valentine Renaud
- Institute of Nutrition and Functional Foods (INAF), Department of Food Sciences, Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
- Laboratory of Food Processing and ElectroMembrane Processes (LTAPEM), Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
| | - Mélanie Faucher
- Institute of Nutrition and Functional Foods (INAF), Department of Food Sciences, Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
- Laboratory of Food Processing and ElectroMembrane Processes (LTAPEM), Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
| | - Véronique Perreault
- Institute of Nutrition and Functional Foods (INAF), Department of Food Sciences, Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
- Laboratory of Food Processing and ElectroMembrane Processes (LTAPEM), Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
| | - Elodie Serre
- Institute of Nutrition and Functional Foods (INAF), Department of Food Sciences, Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
- Laboratory of Food Processing and ElectroMembrane Processes (LTAPEM), Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
| | - Pascal Dubé
- Industrial Research Center of Quebec (CRIQ), Quebec, QC G1P 4C7 Canada
| | | | - Laurent Bazinet
- Institute of Nutrition and Functional Foods (INAF), Department of Food Sciences, Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
- Laboratory of Food Processing and ElectroMembrane Processes (LTAPEM), Paul Comtois Pavillion, Laval University, Quebec, QC G1V 0A6 Canada
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Salimi A, Sharif Makhmal Zadeh B, Kazemi M. Preparation and optimization of polymeric micelles as an oral drug delivery system for deferoxamine mesylate: in vitro and ex vivo studies. Res Pharm Sci 2019; 14:293-307. [PMID: 31516506 PMCID: PMC6714110 DOI: 10.4103/1735-5362.263554] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Deferoxamine mesylate (DFO) is administered as a slow subcutaneous or intravenous infusion due to its poor oral bioavailability and lack of dose proportionality. The aim of the present study was to prepare and optimize polymeric micelles containing DFO, as an oral drug delivery system for increasing permeability and oral bioavailability. Based on a full factorial design with three variables in two levels, eight polymeric micelle formulations were made using film hydration method. Two polymers including 0.1% of carbomer 934 and Poloxamer®P 407 and two blends of surfactant + co-surfactant including 1 and 2 fold of critical micelle concentration of Labrafil® + Labrasol® and Tween 80 + Span 20 were used to prepare polymeric micelles. The effect of variables on particle size (PS), entrapment efficiency (EE), drug release, thermal behavior, in vitro iron bonding and ex vivo rat intestinal permeability were evaluated. The PS of polymeric micelles was less than 83 nm that showed 80% EE with continuous drug release pattern. The change in type of polymer from carbomer to Ploxamer® significantly increased drug release. All polymeric micelles increased the iron-bonding ability of DFO compared to control. This could be due to surfactants that can play an important role in this ability. Polymeric micelles increased drug permeability through intestine more than 2.5 folds compared to control mainly affected by polymer type. Optimized polymeric micelle consists of Tween 80 and Span 20 with 1.35 folds of critical micelle concentration and Poloxamer® demonstrated 97.32% iron bonding and a 3-fold increase in permeation through the rat intestine compared with control.
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Affiliation(s)
- Anayatollah Salimi
- School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I.R. Iran.,Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I.R. Iran
| | - Behzad Sharif Makhmal Zadeh
- School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I.R. Iran.,Nanotechnology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I.R. Iran
| | - Moloud Kazemi
- School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, I.R. Iran
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Mazumder S, Dewangan AK, Pavurala N. Enhanced dissolution of poorly soluble antiviral drugs from nanoparticles of cellulose acetate based solid dispersion matrices. Asian J Pharm Sci 2017; 12:532-541. [PMID: 32104366 PMCID: PMC7032198 DOI: 10.1016/j.ajps.2017.07.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 06/09/2017] [Accepted: 07/03/2017] [Indexed: 11/28/2022] Open
Abstract
Polysaccharide-based polymers were used to produce nanoparticles of poorly soluble antiviral drugs using a rapid precipitation process. The structure-property relationships of four novel cellulose acetate-based polymers were studied for their solubility enhancement of poorly soluble drugs. Particles were purified by dialysis, and dried powders were recovered after freeze-drying. The particle diameters were 150–200 nm. The target drug loading in the particles was 25 wt%, and the drug loading efficiencies were 80–96%. The effects of the formulation process and nanoparticle properties on drug solubility were investigated. All nanoparticles afforded increased solubility and faster release compared to pure drugs. Drug release was a function of the relative hydrophobicity (or solubility parameters) of the polymers.
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Affiliation(s)
- Sonal Mazumder
- Department of Chemical Engineering, Birla Institute of Science and Technology, Pilani, Rajasthan 333031, India
| | - Ashish Kumar Dewangan
- Department of Chemical Engineering, Birla Institute of Science and Technology, Pilani, Rajasthan 333031, India
| | - Naresh Pavurala
- Oak Ridge Associated Universities, Food and Drug Administration, Silver Spring, MD, USA
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7
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Zhou Y, Xu X, Yu B, Yu G. Characterization of in vitro effects of microcystin-LR on intestinal epithelial cells. ENVIRONMENTAL TOXICOLOGY 2017; 32:1539-1547. [PMID: 27758031 DOI: 10.1002/tox.22375] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Revised: 09/29/2016] [Accepted: 10/05/2016] [Indexed: 06/06/2023]
Abstract
The intestinal epithelium is a single-cell layer that provides an important barrier against natural toxins. Microcystin-LR (MC-LR), a cyclic heptapeptide, is one of the best known toxins able to alter the functions of intestine. This study evaluated the toxic effects and the possible mechanisms of MC-LR on barrier function of the intestinal epithelial cells. Intestinal epithelial cells (IEC-6) were exposed to 0, 6.25, 12.5, 25 and 50 μM MC-LR. Cell viability significantly decreased, while the ratio of apoptotic cells increased after exposure to 12.5μM and higer concentration of MC-LR. As expected, the integrity of a polarized IEC-6 monolayer was affected by MC-LR exposure, as demonstrated by a decrease in the transepithelial electrical resistance (TEER) values, becoming most pronounced at 50μM, 24 h. No effects were detected on the protein expression levels of the tight junction protein claudin at 50μM. However, the expression of occludin and zonula occludens-1 (ZO-1) declined. Furthermore, MC-LR can immigrate into IEC-6 cells. The activity of protein phosphatases 2A (PP2A) decreased from the concentration of 12.5 μM, showing a dose-dependent decline. These results provide new information that strengthens the concept that the intestinal epithelium is important targets for toxic effects of water contaminants like MC-LR. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1539-1547, 2017.
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Affiliation(s)
- Yuan Zhou
- College of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Xiaoping Xu
- Zhejiang Prov Ctr Dis Prevent & Control, Hangzhou, Zhejiang, 310051, China
| | - Beibei Yu
- School of Foreign Languages, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China
| | - Guang Yu
- College of Medicine and Life Sciences, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
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8
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Stoyanova K, Vinarov Z, Tcholakova S. Improving Ibuprofen solubility by surfactant-facilitated self-assembly into mixed micelles. J Drug Deliv Sci Technol 2016. [DOI: 10.1016/j.jddst.2016.10.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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9
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Serre E, Boutin Y, Langevin ME, Lutin F, Pedneault K, Lacour S, Bazinet L. Deacidification of cranberry juice protects against disruption of in-vitro intestinal cell barrier integrity. J Funct Foods 2016. [DOI: 10.1016/j.jff.2016.06.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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10
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Chitosan in nasal delivery systems for therapeutic drugs. J Control Release 2014; 190:189-200. [DOI: 10.1016/j.jconrel.2014.05.003] [Citation(s) in RCA: 286] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 04/25/2014] [Accepted: 05/02/2014] [Indexed: 01/07/2023]
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11
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Polymeric micelles, a promising drug delivery system to enhance bioavailability of poorly water-soluble drugs. JOURNAL OF DRUG DELIVERY 2013; 2013:340315. [PMID: 23936656 PMCID: PMC3712247 DOI: 10.1155/2013/340315] [Citation(s) in RCA: 312] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Revised: 06/04/2013] [Accepted: 06/11/2013] [Indexed: 01/27/2023]
Abstract
Oral administration is the most commonly used and readily accepted form of drug delivery; however, it is find that many drugs are difficult to attain enough bioavailability when administered via this route. Polymeric micelles (PMs) can overcome some limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1) protection of the loaded drug from the harsh environment of the GI tract, (2) release of the drug in a controlled manner at target sites, (3) prolongation of the residence time in the gut by mucoadhesion, and (4) inhibition of efflux pumps to improve the drug accumulation. To explain the mechanisms for enhancement of oral bioavailability, we discussed the special stability of PMs, the controlled release properties of pH-sensitive PMs, the prolongation of residence time with mucoadhesive PMs, and the P-gp inhibitors commonly used in PMs, respectively. The primary purpose of this paper is to illustrate the potential of PMs for delivery of poorly water-soluble drugs with bioavailability being well maintained.
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Vinarov Z, Petrova L, Tcholakova S, Denkov ND, Stoyanov SD, Lips A. In vitro study of triglyceride lipolysis and phase distribution of the reaction products and cholesterol: effects of calcium and bicarbonate. Food Funct 2013; 3:1206-20. [PMID: 22899020 DOI: 10.1039/c2fo30085k] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We describe a relatively simple in vitro model for triglyceride (TG) lipolysis which mimics closely the conditions in the human stomach and small intestine. The main model advantages are: (1) as in vivo, sodium bicarbonate is used for buffering; (2) the pH-profile in the small intestine is closely matched; (3) the experimental procedure does not include complex equipment. To test its performance, the proposed in vitro model is applied to quantify the effects of Ca(2+), pH, and bicarbonate on the degree of TG lipolysis and on the solubilization of the lipolysis products and cholesterol in the aqueous phase. We found that TG lipolysis passes through a shallow minimum at 3.5 mM Ca(2+) when varying the calcium concentration between 1 and 11 mM, while the presence of bicarbonate and the increase of pH led to a higher degree of lipolysis. Centrifugation and filtration were used to separate the aqueous phase and to study the solubilisation of the lipophilic components in the aqueous phase. We found that the solubilized cholesterol increases linearly with the concentration of free fatty acids (FFA) which is evidence for co-solubilization of these two components in the bile micelles. At high Ca(2+) concentrations, aggregates larger than 300 nm were observed by cryo-microscopy and light scattering, which solubilize well cholesterol and saturated FFA. In contrast, the monoglycerides were always predominantly solubilized in the small bile micelles with diameters around 4 nm.
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Affiliation(s)
- Zahari Vinarov
- Department of Chemical Engineering, Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria
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Sundell KS, Sundh H. Intestinal fluid absorption in anadromous salmonids: importance of tight junctions and aquaporins. Front Physiol 2012; 3:388. [PMID: 23060812 PMCID: PMC3460234 DOI: 10.3389/fphys.2012.00388] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 09/11/2012] [Indexed: 01/17/2023] Open
Abstract
The anadromous salmonid life cycle includes both fresh water (FW) and seawater (SW) stages. The parr-smolt transformation (smoltification) pre-adapt the fish to SW while still in FW. The osmoregulatory organs change their mode of action from a role of preventing water inflow in FW, to absorb ions to replace water lost by osmosis in SW. During smoltification, the drinking rate increases, in the intestine the ion and fluid transport increases and is further elevated after SW entry. In SW, the intestine absorbs ions to create an inwardly directed water flow which is accomplished by increased Na+, K+-ATPase (NKA) activity in the basolateral membrane, driving ion absorption via ion channels and/or co-transporters. This review will aim at discussing the expression patterns of the ion transporting proteins involved in intestinal fluid absorption in the FW stage, during smoltification and after SW entry. Of equal importance for intestinal fluid absorption as the active absorption of ions is the permeability of the epithelium to ions and water. During the smoltification the increase in NKA activity and water uptake in SW is accompanied by decreased paracellular permeability suggesting a redirection of the fluid movement from a paracellular route in FW, to a transcellular route in SW. Increased transcellular fluid absorption could be achieved by incorporation of aquaporins (AQPs) into the enterocyte membranes and/or by a change in fatty acid profile of the enterocyte lipid bilayer. An increased incorporation of unsaturated fatty acids into the membrane phospholipids will increase water permeability by enhancing the fluidity of the membrane. A second aim of the present review is therefore to discuss the presence and regulation of expression of AQPs in the enterocyte membrane as well as to discuss the profile of fatty acids present in the membrane phospholipids during different stages of the salmonid lifecycle.
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Affiliation(s)
- Kristina S Sundell
- Fish Endocrinology Laboratory, Department of Biology and Environmental Sciences, University of Gothenburg Gothenburg, Sweden
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Cheng HG, Ding LA, Qu LL, Niu DG. Correlation between intestinal permeability and expression of E-cadherin protein in intestinal mucosa in rats with intraperitoneal infection. Shijie Huaren Xiaohua Zazhi 2012; 20:2479-2484. [DOI: 10.11569/wcjd.v20.i26.2479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the correlation between intestinal permeability and the expression levels of E-cadherin protein in the intestinal mucosa in rats with intraperitoneal infection.
METHODS: Forty healthy adult Wistar rats were randomly divided into control group (n = 8) and abdominal infection group (n = 32). The control group underwent celiotomy only, while the abdominal infection group was further equally divided into four subgroups and underwent cecal ligation and puncture to induce abdominal infection at 12, 24, 36, and 48 h after celiotomy. All the rats were sacrificed, and ileum tissue 10 cm away from the ileocecal junction was sampled for histological examination and evaluation of mucosal damage. Plasma D-lactate was measured at various time points. The expression of E-cadherin protein in the intestinal mucosa was detected using Western blot.
RESULTS: Intestinal barrier began to show significant changes 12 h after induction of infection. At 12 h, the abdominal infection group had lower villous thickness, higher mucosal damage index and plasma levels of D-lactat (all P < 0.01) than the control group. The damage reached the peak at 24 h, and lowest villus height, maximum mucosal injury score, and highest lever of D-lactate were observed at this time point (all P < 0.05). The level of D-lactate began to fall at 36 h but remained higher than that in the control group (P < 0.01). The expression level of E-cadherin protein was lowest at 24 h (P < 0.05), and began to rise at 36 and 48 h but remained lower than those in the control group (both P < 0.01). D-lactate levels had a significant correlation with the expression levels of E-cadherin protein (r = -0.605, P < 0.01).
CONCLUSION: There is a significant correlation between intestinal permeability and the expression levels of E-cadherin protein in the intestinal mucosa in rats with intraperitoneal infection.
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Vinarov Z, Tcholakova S, Damyanova B, Atanasov Y, Denkov ND, Stoyanov SD, Pelan E, Lips A. Effects of emulsifier charge and concentration on pancreatic lipolysis: 2. Interplay of emulsifiers and biles. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2012; 28:12140-12150. [PMID: 22680619 DOI: 10.1021/la301820w] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
As a direct continuation of the first part of our in vitro study (Vinarov et al., Langmuir 2012, 28, 8127), here we investigate the effects of emulsifier type and concentration on the degree of triglyceride lipolysis, in the presence of bile salts. Three types of surfactants are tested as emulsifiers: anionic, nonionic, and cationic. For all systems, we observe three regions in the dependence degree of fat lipolysis, α, versus emulsifier-to-bile ratio, f(s): α is around 0.5 in Region 1 (f(s) < 0.02); α passes through a maximum close to 1 in Region 2 (0.02 < f(s) < f(TR)); α is around zero in Region 3 (f(s) > f(TR)). The threshold ratio for complete inhibition of lipolysis, f(TR), is around 0.4 for the nonionic, 1.5 for the cationic, and 7.5 for the anionic surfactants. Measurements of interfacial tensions and optical observations revealed the following: In Region 1, the emulsifier molecules are solubilized in the bile micelles, and the adsorption layer is dominated by bile molecules. In Region 2, mixed surfactant-bile micelles are formed, with high solubilization capacity for the products of triglyceride lipolysis; rapid solubilization of these products leads to complete lipolysis. In Region 3, the emulsifier molecules prevail in the adsorption layer and completely block the lipolysis.
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Affiliation(s)
- Zahari Vinarov
- Department of Chemical Engineering, Faculty of Chemistry and Pharmacy, Sofia University, Sofia, Bulgaria
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Agüeros M, Espuelas S, Esparza I, Calleja P, Peñuelas I, Ponchel G, Irache JM. Cyclodextrin-poly(anhydride) nanoparticles as new vehicles for oral drug delivery. Expert Opin Drug Deliv 2011; 8:721-34. [DOI: 10.1517/17425247.2011.572069] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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17
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Park JW, Kim SK, Al-Hilal TA, Jeon OC, Moon HT, Byun Y. Strategies for oral delivery of macromolecule drugs. BIOTECHNOL BIOPROC E 2010. [DOI: 10.1007/s12257-009-3058-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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He W, Guo X, Xiao L, Feng M. Study on the mechanisms of chitosan and its derivatives used as transdermal penetration enhancers. Int J Pharm 2009; 382:234-43. [PMID: 19686826 DOI: 10.1016/j.ijpharm.2009.07.038] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2009] [Revised: 07/23/2009] [Accepted: 07/29/2009] [Indexed: 11/26/2022]
Abstract
The efficacy of chitosan (CS) and its derivatives used as transdermal penetration enhancers has been confirmed in our previous research. This study investigated the mechanisms of penetration enhancement by CS and its derivatives, i.e., N-trimethyl chitosan (TMC) with different degree of quaternization (DQ) and mono-N-carboxylmethyl chitosan (MCC). After treatment with CS, TMCs or MCC, the secondary structure changes of keratin in stratum corneum (SC) from mice were examined by an Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) combined with the application of the second-order derivative, deconvolution and curve-fitting. The water content in the SC was also studied by ATR-FTIR. HaCaT cell lines were employed as the cell models in the study. HaCaT cells were first treated with blank D-Hanks solution, CS or its derivatives, and were then fluorescent labeled with DiBAC(4) (3). The change of membrane potential was measured by a flow cytometer (FCM). Alternatively, the treated HaCaT cells were labeled with NBD-C(6)-HPC and the change of membrane fluidity was examined under a Confocal Laser Scanning Microscope (CLSM). It was found that CS, TMCs and MCC could significantly affect the secondary structure of keratin in SC in different ways. Although the amide II absorption peak of keratin moved to a lower wave number following treatment with CS, TMCs, or MCC, the beta-turning structure of keratin was converted to beta-sheeting and random coiling after treatment with TMCs and was converted to beta-sheeting and alpha-helix following treatment with MCC and CS. At the same time, CS and its derivatives all could increase the water content of SC, decrease HaCaT cells membrane potentials and enhance HaCaT cells membrane fluidity significantly. The effect of TMCs appeared to be independent of their DQ. The results suggest that the mechanisms of transdermal enhancement of CS, TMCs and MCC are closely related to their effects on the secondary structure of keratin and water content in SC, cell membrane potential and fluidity.
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Affiliation(s)
- Wen He
- Department of Pharmacy of Renmin Hospital, Wuhan University, Wuhan 430060, People's Republic of China.
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19
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Tang C, Yu J, Yin L, Yin C, Pei Y. Transport of Insulin in Modified Valia-Chien Chambers and Caco-2 Cell Monolayers. Drug Dev Ind Pharm 2008; 33:449-56. [PMID: 17523009 DOI: 10.1080/03639040601011231] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The transport characteristics of insulin were investigated using two different absorption models. Using the modified Valia-Chien chambers, permeability coefficients of insulin in the duodenum, jejunum, and ileum were 0.71x10(-7), 7.11x10(-7) and 9.45x10(-7) cm/s, respectively. In the Caco-2 cell monolayers, the bidirectional transepithelial fluxes of insulin across Caco-2 cell line showed symmetry. Confocal laser scanning microscopy visualized that FD-4 and FITC-insulin were mainly located in the paracellular route. It is evident that the lower intestine might be an advantageous region, and absorption enhancer that helps open tight junctions between cells should be used for oral delivery of insulin.
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Affiliation(s)
- Cui Tang
- State Key Laboratory of Genetic Engineering, Department of Pharmaceutical Sciences, School of Life Sciences, Fudan University, Shanghai, P.R. China
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20
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Mukaizawa F, Taniguchi K, Miyake M, Ogawara KI, Odomi M, Higaki K, Kimura T. Novel oral absorption system containing polyamines and bile salts enhances drug transport via both transcellular and paracellular pathways across Caco-2 cell monolayers. Int J Pharm 2008; 367:103-8. [PMID: 18929635 DOI: 10.1016/j.ijpharm.2008.09.027] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2008] [Revised: 09/10/2008] [Accepted: 09/18/2008] [Indexed: 11/19/2022]
Abstract
The combinatorial use of spermine (SPM), a typical polyamine, and sodium taurocholate (STC), a typical bile salt, was found to be a promising safe preparation for improving the oral absorption of poorly water-soluble and/or poorly absorbable drug in our previous studies utilizing rats and dogs. To clarify the mechanisms behind the synergistic enhancement effect of the polyamine and bile salt, the transport of rebamipide, which is classified into Biopharmaceutics Classification System Class IV, was investigated in Caco-2 cell monolayers. The synergistic enhancement of rebamipide transport by SPM and STC was certainly observed in Caco-2 cells as well, while the separate use of either SPM or STC did not significantly improve the transport of rebamipide. The combinatorial use of SPM and STC significantly decreased the transepithelial electrical resistance (TEER) in Caco-2 cell monolayers, suggesting that the opening of paracellular pathway. On the other hand, it was also confirmed that the decrease in TEER was transient and reversible after removal of SPM and STC and that cell viability was maintained. Voltage-clamp study clearly showed that their combinatorial use improved rebamipide transport via both paracellular and transcellular pathways, and that the contribution of transcellular route could be larger than paracellular route.
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Affiliation(s)
- Fuyuki Mukaizawa
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan
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21
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Bejugam N, Sou M, Uddin A, Gayakwad S, D'Souza M. Effect of Chitosans and Other Excipients on the Permeation of Ketotifen, FITC-Dextran, and Rhodamine 123 through Caco-2 Cells. J BIOACT COMPAT POL 2008. [DOI: 10.1177/0883911507088399] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The determination of drug permeability is an important part of formulation, development, and studying the effect of excipients on drug delivery processes. Ketotifen, FITC-labeled dextran, and Rhodamine 123 permeation was evaluated across Caco-2 cells grown on permeable inserts in the presence of chitosan, N,O-carboxymethyl chitosan (NOCC), Carbopol 934P, Polysorbate 80, and Disodium edetate. Samples with chitosan decrease in transepithelial electrical resistance in a concentration dependent manner not seen with the other excipients used. This corresponds with significant improvement of paracellular permeation of FITC-dextran and Rhodamine 123 compared to the control (p<0.005) but Ketotifen permeation with chitosan does not show statistically significant improvement as compared to the control. Although Rhodamine 123 is a known p-glycoprotein substrate, this data would indicate that the p-glycoprotein transport system is not the rate limiting factor in Rhodamine 123 permeation. Ketotifen permeation is improved slightly in the presence of NOCC, Polysorbate 80, and Disodium edetate. These excipients have been associated with improved transcellular permeation. Carbopol 934P does not improve any of the drug models' permeation. These results clearly show the effectiveness of using Caco-2 cells for screening formulations and excipients for drug development.
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Affiliation(s)
| | - M. Sou
- Novartis Corporation, Paramus, NJ, USA
| | - A.N. Uddin
- Emipshere Technologies, Tarrytown, NY, USA
| | - S.G. Gayakwad
- Department of Pharmaceutical Sciences, Mercer University Atlanta, GA 30341, USA
| | - M.J. D'Souza
- Department of Pharmaceutical Sciences, Mercer University Atlanta, GA 30341, USA,
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22
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Narkar Y, Burnette R, Bleher R, Albrecht R, Kandela A, Robinson JR. Evaluation of Mucosal Damage and Recovery in the Gastrointestinal Tract of Rats by a Penetration Enhancer. Pharm Res 2007; 25:25-38. [DOI: 10.1007/s11095-007-9509-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2007] [Accepted: 08/15/2007] [Indexed: 02/07/2023]
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23
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Balimane PV, Chong S, Patel K, Quan Y, Timoszyk J, Han YH, Wang B, Vig B, Faria TN. Peptide transporter substrate identification during permeability screening in drug discovery: comparison of transfected MDCK-hPepT1 cells to Caco-2 cells. Arch Pharm Res 2007; 30:507-18. [PMID: 17489369 DOI: 10.1007/bf02980227] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
The purpose of this study was to investigate the utility of stably transfected MDCK-hPepT1 cells for identifying peptide transporter substrates in early drug discovery and compare the characteristics of this cell line with Caco-2 cells. MDCK-hPepT1, MDCK-mock, and Caco-2 cells grown to confluence on 24-well Transwell were used for this study. Expression levels of different transporter proteins (PepT1, PepT2, P-gp) in these cell lines were assessed by qRT-PCR. Permeability studies were conducted in parallel in all the cells with a diverse set of peptide substrates using the optimized experimental condition: 100 microM, apical pH 6.0, basolateral pH 7.4, 2 hr incubation at 37 degrees C. Permeability studies were also conducted with classical P-gp substrates (tested in bi-directional mode) and paracellularly absorbed probes to investigate the differences between the cell lines. As expected, MDCK-hPepT1 cells express significantly higher level of PepT1 mRNA compared to both Caco-2 and MDCK-mock cells. Efflux transporter, P-gp, was expressed adequately in all the cell lines. Permeability studies demonstrated that classical peptide substrates had significantly higher permeability in stably transfected MDCK-hPepT1 cells compared to MDCK-mock and Caco-2 cells. The transfected MDCK-hPepT1 cells were qualitatively similar to Caco-2 cells with respect to functional P-gp efflux activity and paracellular pore activity. Stably transfected MDCK-hPepT1 cells have been demonstrated as a viable alternative to Caco-2 cells for estimating the human absorption potential of peptide transporter substrates. These cells behave similar to Caco-2 cells with regards to P-gp efflux and paracellular pore activity but demonstrate greater predictability of absorption values for classical peptide substrates (for which Caco-2 cells under-estimate oral absorption).
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Affiliation(s)
- Praveen V Balimane
- Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
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24
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Nicolazzo JA, Reed BL, Finnin BC. Buccal penetration enhancers--how do they really work? J Control Release 2005; 105:1-15. [PMID: 15894393 DOI: 10.1016/j.jconrel.2005.01.024] [Citation(s) in RCA: 144] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2004] [Accepted: 01/03/2005] [Indexed: 10/25/2022]
Abstract
Certain agents that increase drug delivery through the skin, including surfactants, bile salts, and fatty acids, have been shown to exert a similar effect on the buccal mucosa. These agents enhance skin permeability by interacting with and disrupting the ordered intercellular lipid lamellae within the keratinized stratum corneum, and it has been assumed that a similar mechanism of action occurs in the nonkeratinized buccal mucosa. However, the chemical and structural nature of the lipids present within the intercellular regions of the buccal mucosa is quite different to that found within the stratum corneum, and so extrapolation of results between these two tissues may be misleading. To assume that the mechanism of action of buccal penetration enhancers is based on the disruption of intercellular lipids may be erroneous, and may result in the inappropriate prediction that certain skin penetration enhancers will similarly enhance drug delivery through the buccal mucosa. The data available in the literature suggest that agents that enhance buccal penetration exert their effect by a mechanism other than by disruption of intercellular lipids. Rather, buccal penetration enhancement appears to result from agents being able to (a) increase the partitioning of drugs into the buccal epithelium, (b) extract (and not disrupt) intercellular lipids, (c) interact with epithelial protein domains, and/or (d) increase the retention of drugs at the buccal mucosal surface. The purpose of this review is to identify the major differences in the structural and chemical nature of the permeability barriers between the buccal mucosa and skin, to clarify the mechanisms of action of buccal penetration enhancers, and to identify the limitations of certain models that are used to assess the effect of buccal penetration enhancers.
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Affiliation(s)
- Joseph A Nicolazzo
- Department of Pharmaceutics, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
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25
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Sander GR, Cummins AG, Henshall T, Powell BC. Rapid disruption of intestinal barrier function by gliadin involves altered expression of apical junctional proteins. FEBS Lett 2005; 579:4851-5. [PMID: 16099460 DOI: 10.1016/j.febslet.2005.07.066] [Citation(s) in RCA: 134] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2005] [Accepted: 07/19/2005] [Indexed: 10/25/2022]
Abstract
Coeliac disease is a chronic enteropathy caused by the ingestion of wheat gliadin and other cereal prolamines derived from rye and barley. In the present work, we investigated the mechanisms underlying altered barrier function properties exerted by gliadin-derived peptides in human Caco-2 intestinal epithelial cells. We demonstrate that gliadin alters barrier function almost immediately by decreasing transepithelial resistance and increasing permeability to small molecules (4 kDa). Gliadin caused a reorganisation of actin filaments and altered expression of the tight junction proteins occludin, claudin-3 and claudin-4, the TJ-associated protein ZO-1 and the adherens junction protein E-cadherin.
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Affiliation(s)
- Guy R Sander
- Tissue Development and Repair, Epithelial Biology Laboratory, Child Health Research Institute, 72 King William Road, North Adelaide, SA 5006, Australia.
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26
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Abstract
The model systems that are currently used to determine the intestinal permeability characteristics of discovery compounds often represent a combination of high-throughout, but less predictive, in silico and in vitro models and low-throughput, but more predictive, in vivo models. Cell-based permeability models have been integrated into the discovery paradigm for some time and represent the "method of choice" across the industry. Here, in addition to an objective analysis of the utility of cell culture models for permeability screening, anticipated future trends in the field of cell culture models are discussed.
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Affiliation(s)
- Praveen V Balimane
- Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
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27
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Tirumalasetty PP, Eley JG. Evaluation of Dodecylmaltoside as a Permeability Enhancer for Insulin Using Human Carcinoma Cells. J Pharm Sci 2005; 94:246-55. [PMID: 15570604 DOI: 10.1002/jps.20234] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Dodecylmaltoside (DDM), an alkylglycoside showing tissue-permeability-enhancing properties, has been successful in improving nasal and ocular transport of poorly absorbed drugs. It was hypothesized that optimization of DDM concentration would improve the transport of insulin across epithelial monolayers without causing cell damage. Samples of markers and insulin were collected over a 6-h period and transepithelial electrical resistance was measured at concurrent time points to ascertain the effect of DDM on tight junctions. Samples were analyzed for lucifer yellow and insulin using reversed-phase high-performance liquid chromatography and for (3)[H]-mannitol by scintillation counting. A significant increase in the transport of markers and insulin was recorded in DDM-treated cells compared with controls. DDM enhanced the transport of markers and insulin in a concentration-dependent manner. Decreased transepithelial electrical resistance values confirmed that enhanced transport is caused by loosening of tight junctions. Cell recovery was >95% in 8 h indicating the potential of DDM as a penetration enhancer for clinical administration of insulin and other poorly absorbed drugs without causing cell damage.
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28
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Siccardi D, Turner JR, Mrsny RJ. Regulation of intestinal epithelial function: a link between opportunities for macromolecular drug delivery and inflammatory bowel disease. Adv Drug Deliv Rev 2005; 57:219-35. [PMID: 15555739 DOI: 10.1016/j.addr.2004.08.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2004] [Accepted: 08/11/2004] [Indexed: 12/11/2022]
Abstract
The intestinal epithelium performs a multitude of tasks related to digestion and homeostasis. As a consequence of ingestion, this tissue must also participate in activities associated with protecting the body from potential pathogenic agents and toxic materials. To efficiently perform tasks associated with digestion and these protective functions, the intestinal epithelium has established several anatomical, biochemical and physiological barriers to impede unregulated uptake of materials. In order to perform functions of digestion and homeostasis, the intestinal epithelium uses mechanisms that allow dynamic modulation of regulated uptake pathways that can respond rapidly to changes in diet, health and challenges from pathogenic agents and macromolecules. This review focuses on specific, recent advances made in understanding cellular pathways and mechanisms that regulate dynamic processes of these barriers and examines the feasibility of drug delivery strategies focusing on macromolecular therapeutics potentially useful in the treatment of inflammatory bowel disease (IBD).
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Affiliation(s)
- Dario Siccardi
- Welsh School of Pharmacy, University of Wales, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, Wales, UK
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29
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Daugherty AL, Mrsny RJ. Emerging technologies that overcome biological barriers for therapeutic protein delivery. Expert Opin Biol Ther 2004; 3:1071-81. [PMID: 14519072 DOI: 10.1517/14712598.3.7.1071] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
In the past decade, genomic research and the nascent field of proteomics have exponentially increased the number of potential protein therapeutic molecules for treating medical needs that were previously unmet. To realise the full clinical potential of many of the novel protein drug entities arising from these intense research efforts, emerging protein delivery technologies may be required. Advanced delivery technologies may offer the ability to overcome biochemical and anatomical barriers to protein drug transport, without incurring adverse events, to deliver the agent(s) at a certain desired rate and duration, to protect therapeutic macromolecules from in situ or systemic degradation, as well as increase their therapeutic index by targeting the drug action to a specific site. This review will cover a myriad of novel and emerging technologies that are directed at bypassing biological barriers and that have shown promise in advancing the therapeutic potential of protein drugs.
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Affiliation(s)
- Ann L Daugherty
- Department of Pharmaceutical Research and Development, Genentech, Inc., South San Francisco, CA 94080, USA
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30
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Abstract
The intestinal barrier function of GI tract is very important in the body except for the function of digestion and absorption. The functional status of gut barrier basically reflects the stress severity when body suffers from trauma and various stimulations. Many harmful factors such as drugs, illnesses, trauma and burns can damage the gut barrier, which can lead to the barrier dysfunction and bacterial/endotoxin translocation. The paper discusses and reviews the concepts, anatomy, pathophysiology of gut barrier and its clinical relations.
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Affiliation(s)
- Lian-An Ding
- Department of General Surgery, Affilitated Hospital of Medical School, Qingdao University, Qingdao 266003, Shandong Province, China.
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31
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Gonzalez-Correa CA, Brown BH, Smallwood RH, Stephenson TJ, Stoddard CJ, Bardhan KD. Low frequency electrical bioimpedance for the detection of inflammation and dysplasia in Barrett's oesophagus. Physiol Meas 2003; 24:291-6. [PMID: 12812415 DOI: 10.1088/0967-3334/24/2/305] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Biological tissues undergoing inflammation and dysplasia seem to exhibit changes in the intercellular space that can be sensed using low frequency electrical impedance methods. Basically, low frequency electric current flows through this space and its widening as well as the disruption of the tight junction decrease the resistance, facilitating current flow. The electrical changes accompanying structural changes from columnar tissue to adenocarcinoma in Barrett's metaplastic mucosa and gastric tissue are illustrated using resected tissue from 32 patients. Two hundred and fifty-eight biopsies were analysed, correlating their electrical resistivity (R) at 9.6 kHz and their histopathological interpretation. Compared to non-inflamed non-dysplastic columnar tissue (R = 4.9 ohms m), the results suggest a small but statistically significant decrease of electrical impedance in columnar tissue showing inflammation (R = 4.2 ohms m, p = 0.016) and a larger decrease when dysplasia is present (R = 3.4 ohms m, p = 0.040). If this method is validated further, this technique could be used to obtain guided biopsies from patients undergoing surveillance programmes for Barrett's oesophagus. We aim to refine this technique using a new system with lower frequencies and, possibly, in vitro (cultured cells) and in vivo (rats) models of Barrett's oesophagus.
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Affiliation(s)
- C A Gonzalez-Correa
- Department of Medical Physics and Clinical Engineering, University of Sheffield, Sheffield, UK.
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32
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Abstract
The rapid integration of new technologies by the pharmaceutical industry has resulted in numerous breakthroughs in the discovery, development and manufacturing of pharmaceutical products. In particular, the commercial-scale production of high-purity recombinant proteins has resulted in important additions to treatment options for many large therapeutic areas. In addition to proteins, other macromolecules, such as the animal-derived mucopolysaccharide heparins, have also seen dramatic growth as injectable pharmaceutical products. To date, macromolecules have been limited as therapeutics by the fact that they cannot be orally delivered. This article will address the current status and future possibilities of oral macromolecular drug delivery.
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Affiliation(s)
- Michael Goldberg
- Emisphere Technologies Inc, 765 Old Saw Mill River Road Tarrytown, New York 10591, USA.
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33
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Malkov D, Wang HZ, Dinh S, Gomez-Orellana I. Pathway of oral absorption of heparin with sodium N-[8-(2-hydroxybenzoyl)amino] caprylate. Pharm Res 2003; 19:1180-4. [PMID: 12240944 DOI: 10.1023/a:1019802310702] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
PURPOSE The oral bioavailability of heparin is negligible. Recent studies, however, have shown that sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) and other N-acylated amino acids enable oral heparin absorption. To investigate the mechanism by which heparin crosses the intestinal epithelium in the presence of SNAC, we have used fluorescence microscopy to follow the transport of heparin across Caco-2 cell monolayers. METHODS The experiments were carried out on Caco-2 monolayers and Caco-2 cells grown to confluence on culture dishes, using different concentrations of SNAC. The localization of fluorescently labeled heparin was determined using epi-fluorescence and confocal microscopy. DNA dyes were used to determine the effect of SNAC on the plasma membrane integrity. F-actin was labeled with fluorescent phalloidin to investigate the stability of perijunctional actin rings in the presence of SNAC. RESULTS Heparin was detected in the cytoplasm only after incubation of the cells with heparin and SNAC. No DNA staining was observed in cells incubated with a DNA dye in the presence of SNAC concentrations at which heparin transport occurred. In addition, no signs of actin redistribution or perijunctional ring disbandment were observed during the transport of heparin. CONCLUSIONS The results indicate that SNAC enables heparin transport across Caco-2 monolayers via the transcellular pathway. Heparin transport in the presence of SNAC is selective and does not involve permeabilization of the plasma membrane or tight junction disruption.
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Affiliation(s)
- Dmitry Malkov
- Emisphere Technologies, Inc., Tarrytown, New York 10591, USA
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Dorkoosh FA, Setyaningsih D, Borchard G, Rafiee-Tehrani M, Verhoef JC, Junginger HE. Effects of superporous hydrogels on paracellular drug permeability and cytotoxicity studies in Caco-2 cell monolayers. Int J Pharm 2002; 241:35-45. [PMID: 12086719 DOI: 10.1016/s0378-5173(02)00115-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The aim of this study was to evaluate the effect of superporous hydrogel (SPH) and SPH composite (SPHC) as permeation enhancers for peptide drug delivery on Caco-2 cell monolayers. Moreover, the cytotoxic effects of these polymers were also studied using trypan blue test, MTT assay and propidium iodide staining. Transepithelial electrical resistance (TEER) studies revealed that both SPH and SPHC polymers were able to decrease TEER values to about 40% of initial values, indicating the ability of these polymers to open tight junctions. Recovery studies of TEER showed that the effects of polymers on Caco-2 cell monolayers were reversible, indicating viability of the cells after incubation with polymers. Both polymers were able to enhance the transport of the hydrophilic marker 14C-mannitol up to 2.7 and 3.8-fold in comparison to the control group. The cumulative transport of fluorescein isothiocyanate labelled dextrans with a molecular weight of 4400 Da (FD4) and 19600 Da (FD20) was enhanced by SPH and SPHC polymers by opening of tight junctions; however, this enhancement was inversely proportional to the molecular weight of marker compounds. Cytotoxicity studies confirmed that the transport enhancing properties of SPH and SPHC polymers were not caused by damage of the Caco-2 cell monolayers. The cells were able to exclude trypan blue as well as propidium iodide after incubation with SPH and SPHC polymers. MTT assay showed that the number of viable cells was higher than 95% after incubation with SPH and SPHC polymers. This indicates that the mitochondrial metabolic activities of the cells were preserved after application of the polymers.
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Affiliation(s)
- Farid A Dorkoosh
- Department of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands
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35
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Dorkoosh FA, Borchard G, Rafiee-Tehrani M, Verhoef JC, Junginger HE. Evaluation of superporous hydrogel (SPH) and SPH composite in porcine intestine ex-vivo: assessment of drug transport, morphology effect, and mechanical fixation to intestinal wall. Eur J Pharm Biopharm 2002; 53:161-6. [PMID: 11879998 DOI: 10.1016/s0939-6411(01)00222-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The objective of this study was to investigate the potential of superporous hydrogel (SPH) and SPH composite (SPHC) polymers to enhance the transport of N-alpha-benzoyl-L-arginine ethylester (BAEE) and fluorescein isothiocyanate-dextran 4400 (FD4) across porcine intestinal epithelium ex-vivo, and to study any possible morphological damage to the epithelium by applying these polymers. In addition, the ability of these polymers to attach to the gut wall by mechanical pressure was examined by using a specifically designed centrifuge model. The transport of BAEE and FD4 across the intestinal mucosa was enhanced 2- to 3-fold by applying SPHC polymer in comparison to negative control. No significant morphological damage was observed by applying these polymers inside the intestinal lumen. Moreover, the SPH and SPHC polymers were able to attach mechanically to the intestinal wall by swelling and did not move in the intestinal lumen even when a horizontal force of 13 gms(-2) was applied. In conclusion, these polymers are appropriate vehicles for enhancing the intestinal absorption of peptide and protein drugs.
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Affiliation(s)
- Farid A Dorkoosh
- Department of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands
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36
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Thanou M, Verhoef JC, Junginger HE. Oral drug absorption enhancement by chitosan and its derivatives. Adv Drug Deliv Rev 2001; 52:117-26. [PMID: 11718935 DOI: 10.1016/s0169-409x(01)00231-9] [Citation(s) in RCA: 477] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Chitosan is a non-toxic, biocompatible polymer that has found a number of applications in drug delivery including that of absorption enhancer of hydrophilic macromolecular drugs. Chitosan, when protonated (pH<6.5), is able to increase the paracellular permeability of peptide drugs across mucosal epithelia. Chitosan derivatives have been evaluated to overcome chitosan's limited solubility and effectiveness as absorption enhancer at neutral pH values such as those found in the intestinal tract. Trimethyl chitosan chloride (TMC) has been synthesized at different degrees of quaternization. This quaternized polymer forms complexes with anionic macromolecules and gels or solutions with cationic or neutral compounds in aqueous environments and neutral pH values. TMC has been shown to considerably increase the permeation and/or absorption of neutral and cationic peptide analogs across intestinal epithelia. The mechanism by which TMC enhances intestinal permeability is similar to that of protonated chitosan. It reversibly interacts with components of the tight junctions, leading to widening of the paracellular routes. Mono-carboxymethylated chitosan (MCC) is a polyampholytic polymer, able to form visco-elastic gels in aqueous environments or with anionic macromolecules at neutral pH values. MCC appears to be less potent compared to the quaternized derivative. Nevertheless, MCC was found to increase the permeation and absorption of low molecular weight heparin (LMWH; an anionic polysaccharide) across intestinal epithelia. Neither chitosan derivative provokes damage of the cell membrane, and therefore they do not alter the viability of intestinal epithelial cells.
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Affiliation(s)
- M Thanou
- Leiden/Amsterdam Center for Drug Research, Division of Pharmaceutical Technology, Leiden University, PO Box 9502, 2300RA Leiden, The Netherlands
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Sood A, Panchagnula R. Peroral route: an opportunity for protein and peptide drug delivery. Chem Rev 2001; 101:3275-303. [PMID: 11840987 DOI: 10.1021/cr000700m] [Citation(s) in RCA: 136] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- A Sood
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160 062, India
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Thanou M, Verhoef JC, Junginger HE. Chitosan and its derivatives as intestinal absorption enhancers. Adv Drug Deliv Rev 2001; 50 Suppl 1:S91-101. [PMID: 11576697 DOI: 10.1016/s0169-409x(01)00180-6] [Citation(s) in RCA: 275] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Chitosan is a non-toxic, biocompatible polymer that has found a number of applications in drug delivery including that of absorption enhancer of hydrophilic macromolecular drugs. Chitosan, when protonated (pH<6.5), is able to increase the paracellular permeability of peptide drugs across mucosal epithelia. Chitosan derivatives have been evaluated to overcome chitosan's limited solubility and effectiveness as absorption enhancer at neutral pH values such as those found in the intestinal tract. Trimethyl chitosan chloride (TMC) has been synthesized at different degrees of quaternization. This quaternized polymer forms complexes with anionic macromolecules and gels or solutions with cationic or neutral compounds in aqueous environments and neutral pH values. TMC has been shown to considerably increase the permeation of neutral and cationic peptide analogs across Caco-2 intestinal epithelia. The mechanism by which TMC is enhancing the intestinal permeability is similar to that of protonated chitosan. It reversibly interacts with components of the tight junctions, leading to widening of the paracellular routes. This chitosan derivative does not provoke damage of the cell membrane, and does not alter the viability of intestinal epithelial cells. Co-administrations of TMC with peptide drugs were found to substantially increase the bioavailability of the peptide in both rats and juvenile pigs compared with administrations without the polymer.
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Affiliation(s)
- M Thanou
- Leiden/Amsterdam Center for Drug Research, Division of Pharmaceutical Technology, Leiden University, P.O. Box 9502, 2300RA Leiden, The Netherlands
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Dorkoosh FA, Verhoef JC, Borchard G, Rafiee-Tehrani M, Junginger HE. Development and characterization of a novel peroral peptide drug delivery system. J Control Release 2001; 71:307-18. [PMID: 11295223 DOI: 10.1016/s0168-3659(01)00232-2] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Novel drug delivery systems were developed for peroral administration of peptide and protein drugs for site specific mechanical fixation at the gut wall and with specific release patterns. These so-called shuttle systems were designed by using superporous hydrogels (SPH) and SPH composite (SPHC) as the conveyor of a core which contained the model compound N-alpha-benzoyl-L-arginine ethylester (BAEE). Two different types of shuttle systems were evaluated: (a) core inside the shuttle system, and (b) core attached to the surface of shuttle system. Each of these systems was made of two parts: (1) the conveyor system made of SPHC which is used for keeping the dosage form at specific site(s) of the GI tract by mechanical interaction of the dosage form with the intestinal membranes, and (2) the core containing the active ingredient and incorporated in the conveyor system. The effect of formulation composition of the core on the release profile of BAEE was investigated by changing the type and amount of excipients in the formulations. In addition, the effect of various enteric-coat layers on the release profile and dissolving of the dosage form was investigated. The systems were also characterized for trypsin inactivation and Ca(2+) binding. The release profile of BAEE from the core formulation consisting of PEG 6000 microparticles or small tablets showed the desired burst release. When these core formulations were incorporated into the conveyor system made of SPH and SPHC, a suitable time-controlled release profile was obtained. Changing the type, concentration and thickness of the enteric-coat layer influenced the starting time of BAEE release from the dosage form, which indicates the necessary lag time for dissolving of the dosage form at any desired specific site of drug absorption in the intestine. Both SPH and SPHC were found to partly inhibit the activity of trypsin, due to two mechanisms: Ca(2+) binding and entrapment of the enzyme in these polymers. In conclusion, the presently developed delivery systems demonstrate suitable in vitro characteristics with an appropriate time-controlled release profile, making these systems very promising for effective peroral delivery of peptide and protein drugs.
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Affiliation(s)
- F A Dorkoosh
- Department of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
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Thanou M, Verhoef JC, Marbach P, Junginger HE. Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo. J Pharm Sci 2000; 89:951-7. [PMID: 10861597 DOI: 10.1002/1520-6017(200007)89:7<951::aid-jps13>3.0.co;2-1] [Citation(s) in RCA: 93] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Octreotide acetate is a somatostatin analogue used for the control of endocrine tumors of the gastrointestinal (GI) tract and the treatment of acromegaly. The oral absorption of octreotide is limited because of the limited permeation across the intestinal epithelium. Both chitosan hydrochloride and N-trimethyl chitosan chloride (TMC), a quaternized chitosan derivative, are nonabsorbable and nontoxic polymers that have been proven to effectively increase the permeation of hydrophilic macromolecules across mucosal epithelia by opening the tight junctions. This study investigates the intestinal absorption of octreotide when it is coadministered with the polycationic absorption enhancer TMC. Caco-2 cell monolayers were used as an in vitro intestinal epithelium model, and male Wistar rats were used for in vivo studies. Octreotide with or without polymers (TMC; chitosan hydrochloride) was administered intrajejunally in rats, and serum peptide levels were measured by radioimmunoassay. All applications and administrations were performed at neutral pH values (i.e., pH = 7.4). In vitro transport studies with Caco-2 cells revealed an increased permeation of octreotide in the presence of TMC. Enhancement ratios ranged from 34 to 121 with increasing concentrations of the polymer (0.25-1.5%, w/v). In rats, 1.0% (w/v) TMC solution significantly increased the absorption of the peptide analogue, resulting in a 5-fold increase of octreotide bioavailability compared with the controls (octreotide alone). Coadministration of 1.0% (w/v) chitosan hydrochloride did not enhance octreotide bioavailability. These results in combination with the nontoxic character of TMC suggest that this polymer is a promising excipient in the development of solid dosage forms for the peroral delivery and intestinal absorption of octreotide.
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Affiliation(s)
- M Thanou
- Leiden/Amsterdam Center for Drug Research, Division of Pharmaceutical Technology, Leiden University, The Netherlands
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