Gastrointestinal Region Specific Insulin Permeation Enhancement by Aloe vera Gel

Author(s): Elizca Pretorius, Clarissa Willers*, Josias H. Hamman, Johan D. Steyn

Journal Name: Drug Delivery Letters

Volume 10 , Issue 2 , 2020

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Graphical Abstract:


Background: The oral administration route is still the most preferred by patients for drug treatment, but is unfortunately not suitable for all drug compounds. For example, protein and peptide drugs (e.g. insulin) are typically administered via injection seeing as they are unstable in the gastrointestinal luminal environment and have poor membrane permeation properties. To overcome this problem, functional excipients such as drug absorption enhancers can be co-administered. Although Aloe vera gel has the ability to improve the permeation of drugs across the intestinal epithelium, its drug permeation enhancing effect has not been investigated in the different regions of the gastrointestinal tract yet.

Objective: The aim of this study was to investigate the insulin permeation enhancing effects of A. vera gel material across excised pig intestinal tissues from different regions of the gastrointestinal tract and to identify the gastrointestinal region where the highest insulin permeation enhancement was achieved.

Methods: Insulin transport across excised pig intestinal tissues from the duodenum, proximal jejunum, medial jejunum, distal jejunum, ileum and colon was measured in the absence and presence of A. vera gel (0.5% w/v) using both the Sweetana-Grass diffusion chamber and everted sac techniques.

Results: The insulin permeation results obtained from both ex vivo techniques showed varied permeation enhancing effects of A. vera gel as a function of the different regions of the gastrointestinal tract. The colon was identified as the gastrointestinal region where A. vera gel was the most effective in terms of insulin permeation enhancement in the Sweetana-Grass diffusion chamber technique with a Papp value of 5.50 x 10-7 cm.s-1, whereas the ileum was the region where the highest permeation enhancement occurred in the everted sac technique with a Papp value of 5.45 x 10-7 cm.s-1.

Conclusion: The gastrointestinal permeation enhancing effects of A. vera gel on insulin is region specific with the highest effect observed in the ileum and colon.

Keywords: Aloe vera, drug absorption enhancement, everted sac, ex vivo permeation, insulin, pig intestinal tissue, Sweetana- Grass diffusion chamber.

Yogendraji, K.A.; Priyanka, L.; Nisha, S.; Ritu, S. Newer strategies for insulin delivery. Int. J. Res. Ayurveda Pharm., 2011, 2(6), 1717-1721.
Verma, A.; Kumar, N.; Malviya, R.; Sharma, P.K. Emerging trends in noninvasive insulin delivery. J. Pharm. (Cairo), 2014, 2014378048
[] [PMID: 26556194]
Park, K.; Kwon, I.C.; Park, P. Oral protein delivery: current status and future prospect. React. Funct. Polym., 2011, 71(3), 280-287.
Morishita, M.; Peppas, N.A. Is the oral route possible for peptide and protein drug delivery? Drug Discov. Today, 2006, 11(19-20), 905-910.
[] [PMID: 16997140]
Hamman, J.H.; Enslin, G.M.; Kotzé, A.F. Oral delivery of peptide drugs: barriers and developments. BioDrugs, 2005, 19(3), 165-177.
[] [PMID: 15984901]
Chen, W.; Lu, Z.; Viljoen, A.; Hamman, J. Intestinal drug transport enhancement by Aloe vera. Planta Med., 2009, 75(6), 587-595.
[] [PMID: 19214949]
Salama, N.N.; Eddington, N.D.; Fasano, A. Tight junction modulation and its relationship to drug delivery. Adv. Drug Deliv. Rev., 2006, 58(1), 15-28.
[] [PMID: 16517003]
Muranishi, S. Absorption enhancers. Crit. Rev. Ther. Drug Carrier Syst., 1990, 7(1), 1-33.
[PMID: 2257635]
Whitehead, K.; Mitragotri, S. Mechanistic analysis of chemical permeation enhancers for oral drug delivery. Pharm. Res., 2008, 25(6), 1412-1419.
[] [PMID: 18311478]
Mahato, R.I.; Narang, A.S.; Thoma, L.; Miller, D.D. Emerging trends in oral delivery of peptide and protein drugs. Crit. Rev. Ther. Drug Carrier Syst., 2003, 20(2-3), 153-214.
[] [PMID: 14584523]
Hollander, D. The intestinal permeability barrier. A hypothesis as to its regulation and involvement in Crohn’s disease. Scand. J. Gastroenterol., 1992, 27(9), 721-726.
[] [PMID: 1411276]
Chiba, H.; Osanai, M.; Murata, M.; Kojima, T.; Sawada, N. Transmembrane proteins of tight junctions. Biochim. Biophys. Acta, 2008, 1778(3), 588-600.
[] [PMID: 17916321]
Johnson, P.H.; Frank, D.; Costantino, H.R. Discovery of tight junction modulators: significance for drug development and delivery. Drug Discov. Today, 2008, 13(5-6), 261-267.
[] [PMID: 18342803]
Beneke, C.; Viljoen, A.; Hamman, J. In vitro drug absorption enhancement effects of Aloe vera and Aloe ferox. Sci. Pharm., 2012, 80(2), 475-486.
[] [PMID: 22896832]
Kotzé, A.F.; De Leeuw, B.J.; Luessen, H.L. Chitosans for enhanced delivery of therapeutic peptides across intestinal epithelia: in vitro evaluation in Caco-2 cell monolayers. Int. J. Pharm., 1997, 159, 243-253.
Junginger, H.E.; Verhoef, J.C. Macromolecules as safe penetration enhancers for hydrophilic drugs: a fiction? Pharm. Sci. Technol. Today, 1998, 1(9), 370-376.
Newton, L.E. Aloes in habitat.Aloes: The genus Aloe; Reynolds, T., Ed.; CRC Press LLC: Boca Raton, Florida, 2004, pp. 4-13.
Hamman, J.H. Composition and applications of Aloe vera leaf gel. Molecules, 2008, 13(8), 1599-1616.
[] [PMID: 18794775]
Lebitsa, T.; Viljoen, A.; Lu, Z.; Hamman, J. In vitro drug permeation enhancement potential of aloe gel materials. Curr. Drug Deliv., 2012, 9(3), 297-304.
[] [PMID: 22452404]
Haasbroek, A.; Willers, C.; Glyn, M.; du Plessis, L.; Hamman, J. Intestinal drug absorption enhancement by Aloe vera gel and whole leaf extract: In vitro investigations into the mechanisms of action. Pharmaceutics, 2019, 11(1), 36.
[] [PMID: 30669246]
Balimane, P.V.; Chong, S.; Morrison, R.A. Current methodologies used for evaluation of intestinal permeability and absorption. J. Pharmacol. Toxicol. Methods, 2000, 44(1), 301-312.
[] [PMID: 11274897]
Swindle, M.M.; Smith, A.C. Comparative anatomy and physiology of the pig. Scand. J. Lab. Anim. Sci., 1998, 25, 11-21.
Rombeau, J. Physiologic and metabolic effects of intestinal stomas.Atlas of Intestinal Stomas; Fazio, V.W.; Church, J.M; Wu, J.S., Ed.; Springer-Verlag: New York, USA, 2012, pp. 59-67.
Le Ferrec, E.; Chesne, C.; Artusson, P.; Brayden, D.; Fabre, G.; Gires, P.; Guillou, F.; Rousset, M.; Rubas, W.; Scarino, M.L. In vitro models of the intestinal barrier. The report and recommendations of ECVAM Workshop 46. European Centre for the Validation of Alternative methods. Altern. Lab. Anim., 2001, 29(6), 649-668.
[] [PMID: 11709041]
Grass, G.M.; Sweetana, S.A. In vitro measurement of gastrointestinal tissue permeability using a new diffusion cell. Pharm. Res., 1988, 5(6), 372-376.
[] [PMID: 3244649]
Söderholm, J.D.; Hedman, L.; Artursson, P.; Franzén, L.; Larsson, J.; Pantzar, N.; Permert, J.; Olaison, G. Integrity and metabolism of human ileal mucosa in vitro in the Ussing chamber. Acta Physiol. Scand., 1998, 162(1), 47-56.
[] [PMID: 9492901]
Barthe, L.; Woodley, J.; Houin, G. Gastrointestinal absorption of drugs: methods and studies. Fundam. Clin. Pharmacol., 1999, 13(2), 154-168.
[] [PMID: 10226759]
Cieplak, T.; Wiese, M.; Nielsen, S.; Van de Wiele, T.; van den Berg, F.; Nielsen, D.S. The Smallest Intestine (TSI)-a low volume in vitro model of the small intestine with increased throughput. FEMS Microbiol. Lett., 2018, 365(21)
[] [PMID: 30247563]
Legen, I.; Salobir, M.; Kerc, J. Comparison of different intestinal epithelia as models for absorption enhancement studies. Int. J. Pharm., 2005, 291(1-2), 183-188.
[] [PMID: 15707745]
Srinivasan, B.; Kolli, A.R.; Esch, M.B.; Abaci, H.E.; Shuler, M.L.; Hickman, J.J. TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom., 2015, 20(2), 107-126.
[] [PMID: 25586998]
Dixit, P.; Jain, D.K.; Dumbwani, J. Standardization of an ex vivo method for determination of intestinal permeability of drugs using everted rat intestine apparatus. J. Pharmacol. Toxicol. Methods, 2012, 65(1), 13-17.
[] [PMID: 22107724]
USP, United States Pharmacopeia. United States Pharmacopeia and National Formulary USP 36-NF 31. United States Pharmacopoeial Convention:Rockville, MD. 2013. 1225, Validation of Compendial Procedures, pp. 983-988
FDA, Food and Drug Administration. Guidance for Industry. Bioanalytical Method Validation; Center for Drug Evaluation and Research: Rockville, MD, 2001.
Thanou, M.M.; Kotzé, A.F.; Scharringhausen, T.; Luessen, H.L.; DeBoer, A.G.; Verhoef, J.C.; Junginger, H.E. Effect of degree of quaternization of N-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal Caco-2 cell monolayers J. Control. Release, 2000, 60(a), 15-25.
Jonker, C.; Hamman, J.H.; Kotzé, A.F. Intestinal paracellular permeation enhancement with quaternised chitosan: in situ and in vitro evaluation. Int. J. Pharm., 2002, 238(1-2), 205-213.
[] [PMID: 11996824]
Fetih, G.; Lindberg, S.; Itoh, K.; Okada, N.; Fujita, T.; Habib, F.; Artersson, P.; Attia, M.; Yamamoto, A. Improvement of absorption enhancing effects of n-dodecyl-β-D-maltopyranoside by its colon-specific delivery using chitosan capsules. Int. J. Pharm., 2005, 293(1-2), 127-135.
[] [PMID: 15778050]
Shen, Q.; Li, X.; Li, W.; Zhao, X. Enhanced intestinal absorption of daidzein by borneol/menthol eutectic mixture and microemulsion. AAPS PharmSciTech, 2011, 12(4), 1044-1049.
[] [PMID: 21842308]

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Article Details

Year: 2020
Published on: 26 April, 2020
Page: [117 - 122]
Pages: 6
DOI: 10.2174/2210303109666191022153551
Price: $25

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