[en] Phage therapy is recognized to be a promising alternative to fight antibiotic-resistant infections. In the quest for oral dosage forms containing bacteriophages, the utilization of colonic-release Eudragit® derivatives has shown potential in shielding bacteriophages from the challenges encountered within the gastrointestinal tract, such as fluctuating pH levels and the presence of digestive enzymes. Consequently, this study aimed to develop targeted oral delivery systems for bacteriophages, specifically focusing on colon delivery and employing Eudragit® FS30D as the excipient. The bacteriophage model used was LUZ19. An optimized formulation was established to not only preserve the activity of LUZ19 during the manufacturing process but also ensure its protection from highly acidic conditions. Flowability assessments were conducted for both capsule filling and tableting processes. Furthermore, the viability of the bacteriophages remained unaffected by the tableting process. Additionally, the release of LUZ19 from the developed system was evaluated using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME®) model. Finally, stability studies demonstrated that the powder remained stable for at least 6 months when stored at +5 °C.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Tabare, Emilie ; Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université Libre de Bruxelles, 1050 Brussel, Belgium
Dauchot, Tiffany; Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université Libre de Bruxelles, 1050 Brussel, Belgium
Cochez, Christel; Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, 1120 Brussels, Belgium
Glonti, Tea ; Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, 1120 Brussels, Belgium
Antoine, Céline ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH)
Laforêt, Fanny ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH)
Pirnay, Jean-Paul ; Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, 1120 Brussels, Belgium
Delcenserie, Véronique ; Université de Liège - ULiège > Département de sciences des denrées alimentaires (DDA) > Gestion de la qualité dans la chaîne alimentaire
Thiry, Damien ; Université de Liège - ULiège > Département des maladies infectieuses et parasitaires (DMI) > Bactériologie vétérinaire et maladies bactériennes animales
Goole, Jonathan; Laboratory of Pharmaceutics and Biopharmaceutics, Faculty of Pharmacy, Université Libre de Bruxelles, 1050 Brussel, Belgium
Language :
English
Title :
Eudragit® FS Microparticles Containing Bacteriophages, Prepared by Spray-Drying for Oral Administration
Levy S.B. Marshall B. Antibacterial Resistance Worldwide: Causes, Challenges and Responses Nat. Med. 2004 10 S122 S129 10.1038/nm1145
Dufour N. Debarbieux L. La phagothérapie: Une arme crédible face à l’antibiorésistance Med. Sci. 2017 33 8 10.1051/medsci/20173304011 28497737
Melo L.D.R. Oliveira H. Pires D.P. Dabrowska K. Azeredo J. Phage Therapy Efficacy: A Review of the Last 10 Years of Preclinical Studies Crit. Rev. Microbiol. 2020 46 78 99 10.1080/1040841X.2020.1729695
Gutiérrez D. Fernández L. Rodríguez A. García P. Are Phage Lytic Proteins the Secret Weapon to Kill Staphylococcus aureus? mBio 2018 9 e01923-17 10.1128/mBio.01923-17
Dąbrowska K. Abedon S.T. Pharmacologically Aware Phage Therapy: Pharmacodynamic and Pharmacokinetic Obstacles to Phage Antibacterial Action in Animal and Human Bodies Microbiol. Mol. Biol. Rev. 2019 83 e00012-19 10.1128/MMBR.00012-19
Duan Y. Young R. Schnabl B. Bacteriophages and Their Potential for Treatment of Gastrointestinal Diseases Nat. Rev. Gastroenterol. Hepatol. 2021 19 135 144 10.1038/s41575-021-00536-z 34782783
Zalewska-Piątek B. Piątek R. Phage Therapy as a Novel Strategy in the Treatment of Urinary Tract Infections Caused by E. Coli Antibiotics 2020 9 304 10.3390/antibiotics9060304 32517088
Newman J.W. Floyd R.V. Fothergill J.L. The Contribution of Pseudomonas Aeruginosa Virulence Factors and Host Factors in the Establishment of Urinary Tract Infections FEMS Microbiol. Lett. 2017 364 10.1093/femsle/fnx124 28605563
Nicolle L. Complicated Urinary Tract Infection in Adults Can. J. Infect. Dis. Med. Microbiol. 2005 16 349 360 10.1155/2005/385768 18159518
Chuang C.-H. Wang Y.-H. Chang H.-J. Chen H.-L. Huang Y.-C. Lin T.-Y. Ozer E.A. Allen J.P. Hauser A.R. Chiu C.-H. Shanghai Fever: A Distinct Pseudomonas aeruginosa Enteric Disease Gut 2014 63 736 743 10.1136/gutjnl-2013-304786
Khanal D. Chang R.Y.K. Hick C. Morales S. Chan H.-K. Enteric-Coated Bacteriophage Tablets for Oral Administration against Gastrointestinal Infections Int. J. Pharm. 2021 609 121206 10.1016/j.ijpharm.2021.121206
Okuda J. Hayashi N. Okamoto M. Sawada S. Minagawa S. Yano Y. Gotoh N. Translocation of Pseudomonas aeruginosa from the Intestinal Tract Is Mediated by the Binding of ExoS to an Na,K-ATPase Regulator, FXYD3 Infect. Immun. 2010 78 4511 4522 10.1128/IAI.00428-10 20805335
Bertrand X. Thouverez M. Talon D. Boillot A. Capellier G. Floriot C. Hélias J. Endemicity, Molecular Diversity and Colonisation Routes of Pseudomonas Aeruginosa in Intensive Care Units Intensive Care Med. 2001 27 1263 1268 10.1007/s001340100979 11511937
Marshall J.C. Christou N.V. Meakins J.L. The Gastrointestinal Tract The “Undrained Abscess” of Multiple Organ Failure Ann. Surg. 1993 218 111 119 10.1097/00000658-199308000-00001 8342990
Stoutenbeek C.P. van Saene H.K. Miranda D.R. Zandstra D.F. The Effect of Selective Decontamination of the Digestive Tract on Colonisation and Infection Rate in Multiple Trauma Patients Intensive Care Med. 1984 10 185 192 10.1007/BF00259435
Blair P. Rowlands B.J. Lowry K. Webb H. Armstrong P. Smilie J. Selective Decontamination of the Digestive Tract: A Stratified, Randomized, Prospective Study in a Mixed Intensive Care Unit Surgery 1991 110 303 310 303–309; discussion 309–310
Ledingham I.M. Alcock S.R. Eastaway A.T. McDonald J.C. McKay I.C. Ramsay G. Triple Regimen of Selective Decontamination of the Digestive Tract, Systemic Cefotaxime, and Microbiological Surveillance for Prevention of Acquired Infection in Intensive Care Lancet 1988 1 785 790 10.1016/S0140-6736(88)91656-X
De Jonge E. Schultz M.J. Spanjaard L. Bossuyt P.M.M. Vroom M.B. Dankert J. Kesecioglu J. Effects of Selective Decontamination of Digestive Tract on Mortality and Acquisition of Resistant Bacteria in Intensive Care: A Randomised Controlled Trial Lancet 2003 362 1011 1016 10.1016/S0140-6736(03)14409-1
Międzybrodzki R. Kłak M. Jończyk-Matysiak E. Bubak B. Wójcik A. Kaszowska M. Weber-Dąbrowska B. Łobocka M. Górski A. Means to Facilitate the Overcoming of Gastric Juice Barrier by a Therapeutic Staphylococcal Bacteriophage A5/80 Front. Microbiol. 2017 8 467 10.3389/fmicb.2017.00467
Malik D.J. Sokolov I.J. Vinner G.K. Mancuso F. Cinquerrui S. Vladisavljevic G.T. Clokie M.R.J. Garton N.J. Stapley A.G.F. Kirpichnikova A. Formulation, Stabilisation and Encapsulation of Bacteriophage for Phage Therapy Adv. Colloid Interface Sci. 2017 249 100 133 10.1016/j.cis.2017.05.014
Ma Y. Pacan J.C. Wang Q. Xu Y. Huang X. Korenevsky A. Sabour P.M. Microencapsulation of Bacteriophage Felix O1 into Chitosan-Alginate Microspheres for Oral Delivery AEM 2008 74 4799 4805 10.1128/AEM.00246-08
Ma Y. Pacan J.C. Wang Q. Sabour P.M. Huang X. Xu Y. Enhanced Alginate Microspheres as Means of Oral Delivery of Bacteriophage for Reducing Staphylococcus Aureus Intestinal Carriage Food Hydrocoll. 2012 26 434 440 10.1016/j.foodhyd.2010.11.017
Śliwka P. Mituła P. Mituła A. Skaradziński G. Choińska-Pulit A. Niezgoda N. Weber-Dąbrowska B. Żaczek M. Skaradzińska A. Encapsulation of Bacteriophage T4 in Mannitol-Alginate Dry Macrospheres and Survival in Simulated Gastrointestinal Conditions LWT 2019 99 238 243 10.1016/j.lwt.2018.09.043
Soto M.J. Retamales J. Palza H. Bastías R. Encapsulation of Specific Salmonella Enteritidis Phage F3αSE on Alginate-Spheres as a Method for Protection and Dosification Electron. J. Biotechnol. 2018 31 57 60 10.1016/j.ejbt.2017.11.006
Kim S. Jo A. Ahn J. Application of Chitosan-Alginate Microspheres for the Sustained Release of Bacteriophage in Simulated Gastrointestinal Conditions Int. J. Food Sci. Technol. 2015 50 913 918 10.1111/ijfs.12736
Dini C. Islan G.A. de Urraza P.J. Castro G.R. Novel Biopolymer Matrices for Microencapsulation of Phages: Enhanced Protection Against Acidity and Protease Activity: Novel Biopolymer Matrices for Microencapsulation of Phages: Enhanced Protection Macromol. Biosci. 2012 12 1200 1208 10.1002/mabi.201200109 22847825
Tang Z. Huang X. Baxi S. Chambers J.R. Sabour P.M. Wang Q. Whey Protein Improves Survival and Release Characteristics of Bacteriophage Felix O1 Encapsulated in Alginate Microspheres Food Res. Int. 2013 52 460 466 10.1016/j.foodres.2012.12.037
Samtlebe M. Carrier Systems for Bacteriophages to Supplement Food Systems: Encapsulation and Controlled Release to Modulate the Human Gut Microbiota Food Sci. Technol. 2016 7 334 340 10.1016/j.lwt.2015.12.039
Gill J.J. Sabour P.M. Leslie K.E. Griffiths M.W. Bovine Whey Proteins Inhibit the Interaction of Staphylococcus Aureus and Bacteriophage K J. Appl. Microbiol. 2006 101 377 386 10.1111/j.1365-2672.2006.02918.x 16882145
Puapermpoonsiri U. Spencer J. van der Walle C.F. A Freeze-Dried Formulation of Bacteriophage Encapsulated in Biodegradable Microspheres Eur. J. Pharm. Biopharm. 2009 72 26 33 10.1016/j.ejpb.2008.12.001 19118627
González-Menéndez E. Fernández L. Gutiérrez D. Pando D. Martínez B. Rodríguez A. García P. Strategies to Encapsulate the Staphylococcus Aureus Bacteriophage PhiIPLA-RODI Viruses 2018 10 495 10.3390/v10090495 30217072
Vinner G.K. Vladisavljević G.T. Clokie M.R.J. Malik D.J. Microencapsulation of Clostridium Difficile Specific Bacteriophages Using Microfluidic Glass Capillary Devices for Colon Delivery Using PH Triggered Release PLoS ONE 2017 12 e0186239 10.1371/journal.pone.0186239 29023522
Leung S.S.Y. Morales S. Britton W. Kutter E. Chan H.K. Microfluidic-Assisted Bacteriophage Encapsulation into Liposomes Int. J. Pharm. 2018 545 176 182 10.1016/j.ijpharm.2018.04.063
Vinner G.K. Malik D.J. High Precision Microfluidic Microencapsulation of Bacteriophages for Enteric Delivery Res. Microbiol. 2018 169 522 530 10.1016/j.resmic.2018.05.011 29886256
Vinner G.K. Rezaie-Yazdi Z. Leppanen M. Stapley A.G.F. Leaper M.C. Malik D.J. Microencapsulation of Salmonella-Specific Bacteriophage Felix O1 Using Spray-Drying in a Ph-Responsive Formulation and Direct Compression Tableting of Powders into a Solid Oral Dosage Form Pharmaceuticals 2019 12 43 10.3390/ph12010043
Leung S.S.Y. Parumasivam T. Gao F.G. Carrigy N.B. Vehring R. Finlay W.H. Morales S. Britton W.J. Kutter E. Chan H.K. Production of Inhalation Phage Powders Using Spray Freeze Drying and Spray Drying Techniques for Treatment of Respiratory Infections Pharm. Res. 2016 33 1486 1496 10.1007/s11095-016-1892-6
Leung S.S.Y. Parumasivam T. Gao F.G. Carter E.A. Carrigy N.B. Vehring R. Finlay W.H. Morales S. Britton W.J. Kutter E. et al. Effects of Storage Conditions on the Stability of Spray Dried, Inhalable Bacteriophage Powders Int. J. Pharm. 2017 521 141 149 10.1016/j.ijpharm.2017.01.060
Vandenheuvel D. Singh A. Vandersteegen K. Klumpp J. Lavigne R. Van Den Mooter G. Feasibility of Spray Drying Bacteriophages into Respirable Powders to Combat Pulmonary Bacterial Infections Eur. J. Pharm. Biopharm. 2013 84 578 582 10.1016/j.ejpb.2012.12.022
Vandenheuvel D. Instability of Bacteriophages in Spray-Dried Trehalose Powders Is Caused by Crystallization of the Matrix Int. J. Pharm. 2014 4 202 205 10.1016/j.ijpharm.2014.06.026
Tabare E. Glonti T. Cochez C. Ngassam C. Pirnay J.-P. Amighi K. Goole J. A Design of Experiment Approach to Optimize Spray-Dried Powders Containing Pseudomonas AeruginosaPodoviridae and Myoviridae Bacteriophages Viruses 2021 13 1926 10.3390/v13101926
Stanford K. McALLISTER T.A. Niu Y.D. Stephens T.P. Mazzocco A. Waddell T.E. Johnson R.P. Oral Delivery Systems for Encapsulated Bacteriophages Targeted at Escherichia Coli O157:H7 in Feedlot Cattle J. Food Prot. 2010 73 1304 1312 10.4315/0362-028X-73.7.1304
Duyvejonck H. Merabishvili M. Pirnay J.-P. De Vos D. Verbeken G. Van Belleghem J. Gryp T. De Leenheer J. Van der Borght K. Van Simaey L. et al. Development of a QPCR Platform for Quantification of the Five Bacteriophages within Bacteriophage Cocktail 2 (BFC2) Sci. Rep. 2019 9 13893 10.1038/s41598-019-50461-0 31554892
Antoine C. Laforêt F. Blasdel B. Fall A. Duprez J.-N. Mainil J. Delcenserie V. Thiry D. In Vitro Characterization and In Vivo Efficacy Assessment in Galleria Mellonella Larvae of Newly Isolated Bacteriophages against Escherichia Coli K1 Viruses 2021 13 2005 10.3390/v13102005 34696434
Kutter E. Phage Host Range and Efficiency of Plating Bacteriophages Clokie M.R.J. Kropinski A.M. Methods in Molecular Biology Humana Press Totowa, NJ, USA 2009 Volume 501 141 149 978-1-58829-682-5
Lebrun P. Krier F. Mantanus J. Grohganz H. Yang M. Rozet E. Boulanger B. Evrard B. Rantanen J. Hubert P. Design Space Approach in the Optimization of the Spray-Drying Process Eur. J. Pharm. Biopharm. 2012 80 226 234 10.1016/j.ejpb.2011.09.014
Tietje C. Brouder A. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Handbook of Transnational Economic Governance Regimes Brill|Nijhoff Leiden, Belgium 2010 1041 1053 978-90-04-18156-4
Chang R.Y. Wong J. Mathai A. Morales S. Kutter E. Britton W. Li J. Chan H.K. Production of Highly Stable Spray Dried Phage Formulations for Treatment of Pseudomonas Aeruginosa Lung Infection Eur. J. Pharm. Biopharm. 2017 121 1 13 10.1016/j.ejpb.2017.09.002 28890220
Lechanteur A. Evrard B. Influence of Composition and Spray-Drying Process Parameters on Carrier-Free DPI Properties and Behaviors in the Lung: A Review Pharmaceutics 2020 12 55 10.3390/pharmaceutics12010055 31936628
Mah P.T. O’Connell P. Focaroli S. Lundy R. O’Mahony T.F. Hastedt J.E. Gitlin I. Oscarson S. Fahy J.V. Healy A.M. The Use of Hydrophobic Amino Acids in Protecting Spray Dried Trehalose Formulations against Moisture-Induced Changes Eur. J. Pharm. Biopharm. 2019 144 139 153 10.1016/j.ejpb.2019.09.014
Ali Rashidinejad S.M.J. Spray Drying Encapsulation of Bioactive Materials CRC Press Boca Raton, FL, USA 2021 978-0-429-35546-2
Malik D.J. Targeted Delivery of Bacteriophages to the Gastrointestinal Tract and Their Controlled Release Microbiome and Metabolome in Diagnosis, Therapy, and other Strategic Applications Elsevier Amsterdam, The Netherlands 2019 185 194 978-0-12-815249-2
Chablani L. Tawde S.A. D’Souza M.J. Spray-Dried Microparticles: A Potential Vehicle for Oral Delivery of Vaccines J. Microencapsul. 2012 29 388 397 10.3109/02652048.2011.651503
Kshirsagar S.J. Bhalekar M.R. Umap R.R. In Vitro In Vivo Comparison of Two PH Sensitive Eudragit Polymers for Colon Specific Drug Delivery J. Pharm. Sci. 2009 10 61
Skrdla P.J. Floyd P.D. Dell’Orco P.C. The Amorphous State: First-Principles Derivation of the Gordon–Taylor Equation for Direct Prediction of the Glass Transition Temperature of Mixtures; Estimation of the Crossover Temperature of Fragile Glass Formers; Physical Basis of the “Rule of 2/3” Phys. Chem. Chem. Phys. 2017 19 20523 20532 10.1039/C7CP04124A
Chang R.Y.K. Kwok P.C.L. Khanal D. Morales S. Kutter E. Li J. Chan H. Inhalable Bacteriophage Powders: Glass Transition Temperature and Bioactivity Stabilization Bioeng. Transl. Med. 2020 5 e10159 10.1002/btm2.10159 32440564
Pirnay J.-P. Verbeken G. Ceyssens P.-J. Huys I. De Vos D. Ameloot C. Fauconnier A. The Magistral Phage Viruses 2018 10 64 10.3390/v10020064 29415431
