Development of a Novel Oral Delivery Vehicle for Probiotics

Author(s): Kevin Enck, Surya Banks, Hariom Yadav, Mark E. Welker, Emmanuel C. Opara*

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 26 , 2020

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Background: There is a significant interest in effective oral drug delivery of therapeutic substances. For probiotics, there is a particular need for a delivery platform that protects the bacteria from destruction by the acidic stomach while enabling targeted delivery to the intestine where microbiota naturally reside. The use of probiotics and how they impact the gut microbiota is a growing field and holds promise for the treatment of a variety of gastrointestinal diseases, including irritable bowel disease Crohn’s disease and C. diff and other diseases, such as obesity, diabetes, Parkinson’s, and Alzheimer’s diseases.

Objective: The aim of this research was to use our newly developed chemically-modified alginate hydrogel with the characteristic feature of stability in acidic environments but disintegration under neutral-basic pH conditions to design a novel system for effective targeted delivery of ingested probiotics.

Methods and Results: We have used the approach of encapsulation of bacterial cells in the hydrogel of the modified alginate with in vitro studies in both simulated stomach acid and intestinal fluid conditions to demonstrate the potential application of this novel platform in oral delivery of probiotics. Our data provide a proof-of-concept that enables further studies in vivo with this delivery platform.

Conclusion: We have demonstrated in the present study that our chemically modified alginate hydrogel is resistant to acidic conditions and protects bacterial cells encapsulated in it, but it is sensitive to neutral-basic pH conditions under which it disintegrates and releases its viable bacteria cell payload. Our data provide a proof-ofconcept that enables further studies in vivo with this delivery platform for the efficacy of therapeutic bacteria in various disease conditions.

Keywords: Alginate, chemical modification, hydrogel, oral, drug delivery, probiotics.

Murri M, Leiva I, Gomez-Zumaquero JM, et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med 2013; 11(1): 46.
[] [PMID: 23433344]
Wen L, Ley RE, Volchkov PY, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature 2008; 455(7216): 1109-13.
[] [PMID: 18806780]
Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes 2008; 57(10): 2555-62.
[] [PMID: 18820210]
Vrieze A, Van Nood E, Holleman F, et al. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome. Gastroenterology 2012; 143(4): 913-6. e7..
Kostic AD, Gevers D, Siljander H, et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 2015; 17(2): 260-73.
[] [PMID: 25662751]
Giongo A, Gano KA, Crabb DB, et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J 2011; 5(1): 82-91.
[] [PMID: 20613793]
Paun A, Yau C, Danska JS. The influence of the microbiome on type 1 diabetes. J Immunol 2017; 198(2): 590-5.
[] [PMID: 28069754]
Zheng P, Li Z, Zhou Z. Gut microbiome in type 1 diabetes: A comprehensive review. Diabetes Metab Res Rev 2018; 34(7)e3043
[] [PMID: 29929213]
Champagne CP, Gardner NJ, Roy D. Challenges in the addition of probiotic cultures to foods. Crit Rev Food Sci Nutr 2005; 45(1): 61-84.
[] [PMID: 15730189]
Champagne CP, Fustier P. Microencapsulation for the improved delivery of bioactive compounds into foods. Curr Opin Biotechnol 2007; 18(2): 184-90.
[] [PMID: 17368017]
Reid G. Probiotics and prebiotics - Progress and challenges. Int Dairy J 2008; 18(10): 969-75.
Borody TJ, Khoruts A. Fecal microbiota transplantation and emerging applications. Nat Rev Gastroenterol Hepatol 2011; 9(2): 88-96.
[] [PMID: 22183182]
Vrieze A, de Groot PF, Kootte RS, Knaapen M, van Nood E, Nieuwdorp M. Fecal transplant: a safe and sustainable clinical therapy for restoring intestinal microbial balance in human disease? Best Pract Res Clin Gastroenterol 2013; 27(1): 127-37.
[] [PMID: 23768558]
Bakken JS, Borody T, Brandt LJ, et al. Treating Clostridium difficile infection with fecal microbiota transplantation. Clin Gastroenterol Hepatol 2011; 9(12): 1044-9.
[] [PMID: 21871249]
Sastry SV, Nyshadham JR, Fix JA. Recent technological advances in oral drug delivery - a review. Pharm Sci Technol Today 2000; 3(4): 138-45.
[] [PMID: 10754543]
Sharpe LA, Daily AM, Horava SD, Peppas NA. Therapeutic applications of hydrogels in oral drug delivery. Expert Opin Drug Deliv 2014; 11(6): 901-15.
[] [PMID: 24848309]
Wang B, Hu L, Siahaan TJ. Drug delivery: Principles and applications. John Wiley & Sons 2016.
Graham DY, Smith JL. Aspirin and the stomach. Ann Intern Med 1986; 104(3): 390-8.
[] [PMID: 3511824]
Cook MT, Tzortzis G, Charalampopoulos D, Khutoryanskiy VV. Microencapsulation of probiotics for gastrointestinal delivery. J Control Release 2012; 162(1): 56-67.
[] [PMID: 22698940]
Nobaek S, Johansson M-L, Molin G, Ahrné S, Jeppsson B. Alteration of intestinal microflora is associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am J Gastroenterol 2000; 95(5): 1231-8.
[] [PMID: 10811333]
de Vos P, Faas MM, Spasojevic M, Sikkema J. Encapsulation for preservation of functionality and targeted delivery of bioactive food components. Int Dairy J 2010; 20(4): 292-302.
Lee BJ, Bak Y-T. Irritable bowel syndrome, gut microbiota and probiotics. J Neurogastroenterol Motil 2011; 17(3): 252-66.
[] [PMID: 21860817]
O’Toole PW, Cooney JC. Probiotic bacteria influence the composition and function of the intestinal microbiota. Interdisciplinary perspectives on infectious disease 2008; 2008175285
Sánchez B, Delgado S, Blanco-Míguez A, Lourenço A, Gueimonde M, Margolles A. Probiotics, gut microbiota, and their influence on host health and disease. Mol Nutr Food Res 2017; 61(1)1600240
[] [PMID: 27500859]
Amara AA, Shibl A. Role of Probiotics in health improvement, infection control and disease treatment and management. Saudi Pharm J 2015; 23(2): 107-14.
[] [PMID: 25972729]
Sanders ME, Guarner F, Guerrant R, et al. An update on the use and investigation of probiotics in health and disease. Gut 2013; 62(5): 787-96.
[] [PMID: 23474420]
Hemarajata P, Versalovic J. Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol 2013; 6(1): 39-51.
[] [PMID: 23320049]
McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101(4): 812-22.
[] [PMID: 16635227]
Tønnesen HH, Karlsen J. Alginate in drug delivery systems. Drug Dev Ind Pharm 2002; 28(6): 621-30.
[] [PMID: 12149954]
Tiwari G, Tiwari R, Sriwastawa B, et al. Drug delivery systems: An updated review. Int J Pharm Investig 2012; 2(1): 2-11.
[] [PMID: 23071954]
Simoes S, Figueiras A, Veiga F. Modular hydrogels for drug delivery. J Biomater Nanobiotechnol 2012; 3(2): 185.
Prestwich GD, Luo Y. Novel biomaterials for drug delivery. Expert Opin Ther Pat 2001; 11(9): 1395-410.
Lee KY, Yuk SH. Polymeric protein delivery systems. Prog Polym Sci 2007; 32(7): 669-97.
Murata Y, Sasaki N, Miyamoto E, Kawashima S. Use of floating alginate gel beads for stomach-specific drug delivery. Eur J Pharm Biopharm 2000; 50(2): 221-6.
[] [PMID: 10962231]
Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 2010; 75(1): 1-18.
[] [PMID: 19782542]
Alvarez-Lorenzo C, Blanco-Fernandez B, Puga AM, Concheiro A. Crosslinked ionic polysaccharides for stimuli-sensitive drug delivery. Adv Drug Deliv Rev 2013; 65(9): 1148-71.
[] [PMID: 23639519]
Amiji M, Tailor R, Ly M-K, Goreham J. Gelatin-poly(ethylene oxide) semi-interpenetrating polymer network with ph-sensitive swelling and enzyme-degradable properties for oral drug delivery. Drug Dev Ind Pharm 1997; 23(6): 575-82.
Augst AD, Kong HJ, Mooney DJ. Alginate hydrogels as biomaterials. Macromol Biosci 2006; 6(8): 623-33.
[] [PMID: 16881042]
Buffa R, Odstrčilová L, Šedová P, Basarabová I, Novotný J, Velebný V. Conjugates of modified hyaluronic acid with amino compounds for biomedical applications. Carbohydr Polym 2018; 189: 273-9.
[] [PMID: 29580409]
Bu H, Kjøniksen A-L, Elgsaeter A, Nyström B. Interaction of unmodified and hydrophobically modified alginate with sodium dodecyl sulfate in dilute aqueous solution: Calorimetric, rheological, and turbidity studies. Colloids Surffaces A: Physicochem Eng Aspects 2006; April 27 2006: 166.
Kang H-A, Shin MS, Yang J-W. Preparation and characterization of hydrophobically modified alginate. Polym Bull 2002; 47(5): 429-35.
Cikrikci S, Mert B, Oztop MH. Development of pH sensitive alginate/gum tragacanth based hydrogels for oral insulin delivery. J Agric Food Chem 2018; 66(44): 11784-96.
[] [PMID: 30346766]
Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov Today 2002; 7(10): 569-79.
[] [PMID: 12047857]
Gibbs BF, Kermasha S, Alli I, Mulligan CN. Encapsulation in the food industry: a review. Int J Food Sci Nutr 1999; 50(3): 213-24.
[] [PMID: 10627837]
Bixler HJ, Porse H. A decade of change in the seaweed hydrocolloids industry. J Appl Phycol 2011; 23(3): 321-35.
Calafiore R, Basta G. Alginate/poly-L-ornithine microcapsules for pancreatic islet cell immunoprotection Cell encapsulation technology and therapeutics. Springer 1999; pp. 138-50.
De Vos P, De Haan BJ, Wolters GH, Strubbe JH, Van Schilfgaarde R. Improved biocompatibility but limited graft survival after purification of alginate for microencapsulation of pancreatic islets. Diabetologia 1997; 40(3): 262-70.
[] [PMID: 9084963]
Weir GC. Islet encapsulation: advances and obstacles. Diabetologia 2013; 56(7): 1458-61.
[] [PMID: 23636639]
Opara EC, McQuilling JP, Farney AC. Microencapsulation of pancreatic islets for use in a bioartificial pancreasorgan regeneration: methods and protocols. Totowa, NJ: Humana Press 2013; pp. 261-6.
Agüero L, Zaldivar-Silva D, Peña L, Dias ML. Alginate microparticles as oral colon drug delivery device: A review. Carbohydr Polym 2017; 168: 32-43.
[] [PMID: 28457455]
Sosnik A. Alginate particles as platform for drug delivery by the oral route: state-of-the-art. Int Scolarly Res Notices 2014; p. 926157.
Yang J, Chen J, Pan D, Wan Y, Wang Z. pH-sensitive interpenetrating network hydrogels based on chitosan derivatives and alginate for oral drug delivery. Carbohydr Polym 2013; 92(1): 719-25.
[] [PMID: 23218359]
El-Sherbiny IM. Enhanced pH-responsive carrier system based on alginate and chemically modified carboxymethyl chitosan for oral delivery of protein drugs: Preparation and in-vitro assessment. Carbohydr Polym 2010; 80(4): 1125-36.
Lee KY, Mooney DJ. Alginate: properties and biomedical applications. Prog Polym Sci 2012; 37(1): 106-26.
[] [PMID: 22125349]
George M, Abraham TE. Polyionic hydrocolloids for the intestinal delivery of protein drugs: alginate and chitosan--a review. J Control Release 2006; 114(1): 1-14.
[] [PMID: 16828914]
Wee S, Gombotz WR. Protein release from alginate matrices. Adv Drug Deliv Rev 1998; 31(3): 267-85.
[] [PMID: 10837629]
Banks SR, Enck K, Wright M, Opara EC, Welker ME. Chemical modification of alginate for controlled oral drug delivery. J Agric Food Chem 2019; 67(37): 10481-8.
[] [PMID: 31433940]
Dalheim MØ, Vanacker J, Najmi MA, Aachmann FL, Strand BL, Christensen BE. Efficient functionalization of alginate biomaterials. Biomaterials 2016; 80(Suppl. C): 146-56.
[] [PMID: 26708091]
Chávez B, Ledeboer A. Drying of probiotics: Optimization of formulation and process to enhance storage survival. Dry Technol 2007; 25(7-8): 1193-201.

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Year: 2020
Published on: 11 August, 2020
Page: [3134 - 3140]
Pages: 7
DOI: 10.2174/1381612826666200210111925
Price: $65

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