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Research Article

Desirability Based Optimization of New Mesalazine Modified Release Formulations: Compression Coated Tablets and Mini Tablets in Capsules

Author(s): Marilena Vlachou*, Angeliki Siamidi and Yannis Dotsikas

Volume 17, Issue 2, 2020

Page: [114 - 123] Pages: 10

DOI: 10.2174/1570180816666190110125812

Price: $65

Abstract

Background: Mesalazine (5-aminosalicylic acid, 5-ASA) is a drug substance with an antiinflammatory activity, which is mainly used in the symptomatic treatment of diseases, such as Ulcerative Colitis, the Crohn's disease and the idiopathic inflammatory bowel disease. Mesalazine exerts its effect locally in the inflamed area of the intestine and not through systematic absorption, therefore the investigation of its release characteristics from solid pharmaceutical formulations is of great importance.

Objective: The development of novel mesalazine modified release formulations with improved properties, regarding drug release in the gastrointestinal tract, by utilisation of the Design of Experiments (DoE) approach.

Methods: D-optimal experimental design was applied. A Simplex Lattice mixture design was used for the development of suitable capsules containing 4 mini tablets and a D-optimal mixture design was used for compression-coated tablets, with the following characteristics: ≤10% release in 2 h, to minimize its degradation in the upper gastrointestinal tract, 20-40% release in 5 h for mesalazine administration in the small intestine, and quantitative release in 12 h for colonic delivery. The dissolution experiments were conducted in gastrointestinal-like fluids and pectinases to simulate the pectinolytic enzymes present in the colon.

Results: The optimal compositions were reached via the desirability function, as a compromise to the different responses. The optimal solutions for both formulations led to colon-specific delivery of the active substance with minimal 5-ASA release in the upper gastrointestinal tract and appeared to conform with the pre-determined characteristics. Hard gelatin capsules, when filled with mini-tablets led to the aimed modified release profile, having sigmoidal characteristics and compression coated tablets led to colonic delivery.

Conclusion: Two novel mesalazine formulations were developed with the desirable colonic release, by conducting a minimal number of experiments, as suggested by DoE experimental design.

Keywords: Mesalazine, modified release, experimental design, tablets-in-capsule, compression coated tablets, desirability function.

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[1]
Lautenschläger, C.; Schmidt, C.; Fischer, D.; Stallmach, A. Drug delivery strategies in the therapy of inflammatory bowel disease. Adv. Drug Deliv. Rev., 2014, 71, 58-76.
[http://dx.doi.org/10.1016/j.addr.2013.10.001] [PMID: 24157534]
[2]
Baburajan, B.; Parkes, M. The genetics of inflammatory bowel disease. Hosp. Med., 2003, 64(10), 599-602.
[http://dx.doi.org/10.12968/hosp.2003.64.10.2326] [PMID: 14584240]
[3]
Danese, S.; Sans, M.; Fiocchi, C. Inflammatory bowel disease: the role of environmental factors. Autoimmun. Rev., 2004, 3(5), 394-400.
[http://dx.doi.org/10.1016/j.autrev.2004.03.002] [PMID: 15288007]
[4]
Karlinger, K.; Györke, T.; Makö, E.; Mester, A.; Tarján, Z. The epidemiology and the pathogenesis of inflammatory bowel disease. Eur. J. Radiol., 2000, 35(3), 154-167.
[http://dx.doi.org/10.1016/S0720-048X(00)00238-2] [PMID: 11000558]
[5]
Schmidt, C.; Stallmach, A. Etiology and pathogenesis of inflammatory bowel disease. Minerva Gastroenterol. Dietol., 2005, 51(2), 127-145.
[PMID: 15990703]
[6]
Taylor, K.M.; Irving, P.M. Optimization of conventional therapy in patients with IBD. Nat. Rev. Gastroenterol. Hepatol., 2011, 8(11), 646-656.
[http://dx.doi.org/10.1038/nrgastro.2011.172] [PMID: 21970871]
[7]
Campregher, C.; Gasche, C. Aminosalicylates. Best Pract. Res. Clin. Gastroenterol., 2011, 25(4-5), 535-546.
[http://dx.doi.org/10.1016/j.bpg.2011.10.013] [PMID: 22122769]
[8]
Efentakis, M.; Koutlis, A.; Vlachou, M. Development and evaluation of oral multiple-unit and single-unit hydrophilic controlled-release systems. AAPS PharmSciTech, 2000, 1(4) E34
[http://dx.doi.org/10.1208/pt010434] [PMID: 14727899]
[9]
Efentakis, M.; Siamidi, A. Design and Evaluation of a Multi Layer Tablet System Based on Dextran. J. Pharm. Drug Deliv. Res., 2014, 2.
[10]
Lin, S.Y.; Lin, K.H.; Li, M.J. Influence of excipients, drugs, and osmotic agent in the inner core on the time-controlled disintegration of compression-coated ethylcellulose tablets. J. Pharm. Sci., 2002, 91(9), 2040-2046.
[http://dx.doi.org/10.1002/jps.10197] [PMID: 12210050]
[11]
Lopes, C.M.; Lobo, J.M.S.; Pinto, J.F.; Costa, P. Compressed mini-tablets as a biphasic delivery system. Int. J. Pharm., 2006, 323(1-2), 93-100.
[http://dx.doi.org/10.1016/j.ijpharm.2006.05.063] [PMID: 16828999]
[12]
Pawar, R.; Jaimini, M.; Chauhan, B.S.; Sharma, S.K. Compression coated tablets as drug delivery system (tablet in tablet): A review I.J.P.R.D 2014, 1, 21-33.
[13]
Sandborn, W.J.; Hanauer, S.B. Systematic review: The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in the management of ulcerative colitis. Aliment. Pharmacol. Ther., 2003, 17(1), 29-42.
[http://dx.doi.org/10.1046/j.1365-2036.2003.01408.x] [PMID: 12492730]
[14]
Vlachou, M.; Stavrou, G.; Siamidi, A.; Flitouri, S.; Ioannidou, V.; Mavrokordopoulos, S. N-Acetylserotonin vs Melatonin. in vitro controlled release from hydrophilic matrix tablets. Lett. Drug Des. Discov., 2019, 16(3), 347-352.
[http://dx.doi.org/10.2174/1570180815666180404125519]
[15]
Vlachou, M.; Kikionis, S.; Siamidi, A.; Tragou, K.; Kapoti, S.; Ioannou, E.; Roussis, V.; Tsotinis, A. Fabrication and characterization of electrospun nanofibers for the modified release of the chronobiotic hormone melatonin. Curr. Drug Deliv., 2019, 16(1), 79-85.
[http://dx.doi.org/10.2174/1567201815666180914095701] [PMID: 30215335]
[16]
Vlachou, M.; Kikionis, S.; Siamidi, A.; Tragou, K.; Ioannou, E.; Roussis, V.; Tsotinis, A. Modified in vitro release of melatonin loaded in nanofibrous electrospun mats incorporated into mono-layered and three-layered tablets. J. Pharm. Sci., 2019, 108(2), 970-976.
[http://dx.doi.org/10.1016/j.xphs.2018.09.035] [PMID: 30312723]
[17]
Vlachou, M.; Naseef, H.; Efentakis, M. Utilization of hydrophilic swellable polymers as carriers for sustained drug delivery from matrices and three layer tablet systems. Curr. Drug Deliv., 2010, 7(4), 334-342.
[http://dx.doi.org/10.2174/156720110793360568] [PMID: 20695845]
[18]
Vlachou, M.; Ioannidou, V.; Vertzoni, M.; Tsotinis, A.; Afroudakis, P. Sugden. D. controlled release from solid pharmaceutical formulations of two N-alkanoyl-4-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ethanamines with Melatoninergic activity. Lett. Drug Des. Discov., 2015, 12, 259-262.
[http://dx.doi.org/10.2174/1570180811666141024005226]
[19]
Zampakola, A.; Siamidi, A.; Pippa, N.; Demetzos, C.; Vlachou, M. Chronobiotic hormone melatonin: Comparative in vitro release studies from matrix tablets and liposomal formulations. Lett. Drug Des. Discov., 2017, 4, 476-480.
[http://dx.doi.org/10.2174/1570180813666161006162246]
[20]
Vlachou, M.; Siamidi, A.; Pareli, I.; Zampakola, A.; Konstantinidou, S. An account of modified release of melatonin from compression-coated, uncoated and bilayer tablets. J. Pharm. Pharm. Sci., 2016, 4, 10-14.
[http://dx.doi.org/10.24218/vjpps.2016.19]
[21]
Elbary, A.A.; Aboelwafa, A.A.; Al Sharabi, I.M. Once daily, high-dose mesalazine controlled-release tablet for colonic delivery: optimization of formulation variables using Box-Behnken design. AAPS PharmSciTech, 2011, 12(4), 1454-1464.
[http://dx.doi.org/10.1208/s12249-011-9708-9] [PMID: 22038474]
[22]
Schellekens, R.C.A.; Baltink, J.H.; Woesthuis, E.M.; Stellaard, F.; Kosterink, J.G.; Woerdenbag, H.J.; Frijlink, H.W. Film coated tablets (ColoPulse technology) for targeted delivery in the lower intestinal tract: influence of the core composition on release characteristics. Pharm. Dev. Technol., 2012, 17(1), 40-47.
[http://dx.doi.org/10.3109/10837450.2010.513986] [PMID: 20923321]
[23]
Jenita, J.J.L.; Vijaya, K.; Suma, R.; Raj, B.; Siddiqca, A. Formulation and evaluation of compression coated tablets of mesalazine for colon delivery I.J.P.R.I.F 2010, 1(1), 535-541.
[24]
Patel, M.M.; Amin, A.F. Development of a novel tablet-in-capsule formulation of mesalamine for inflammatory bowel disease. Pharm. Dev. Technol., 2013, 18(2), 390-400.
[http://dx.doi.org/10.3109/10837450.2011.653819] [PMID: 22304735]
[25]
Ilhan, E.; Ugurlu, T.; Kerimoglu, O. Mini tablets: A short review-revision. Peertechz J. Med. Chem. Res, 2017, 1, 012-022.
[26]
Pandey, S.; Mehta, P.; Patel, H.; Shah, R.; Gupta, A.; Mishra, A. Novel time and site specific ‘tablets in capsule’ system for nocturnal asthma treatment. J. Pharm. Inv, 2014, 5, 381-390.
[http://dx.doi.org/10.1007/s40005-014-0133-4]
[27]
Candioti, L.V.; De Zan, M.M.; Cámara, M.S.; Goicoechea, H.C. Experimental design and multiple response optimization. Using the desirability function in analytical methods development. Talanta, 2014, 124, 123-138.
[http://dx.doi.org/10.1016/j.talanta.2014.01.034] [PMID: 24767454]
[28]
Iliou, K.; Malenović, A.; Loukas, Y.L.; Dotsikas, Y. Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development. J. Pharm. Biomed. Anal., 2018, 149, 410-418.
[http://dx.doi.org/10.1016/j.jpba.2017.11.037] [PMID: 29154196]
[29]
Hegde, A.R.; Managuli, R.S.; Naha, A.; Koteshwara, K.B.; Reddy, M.S.; Mutalik, S. Full factorial experimental design for development and validation of a RP-HPLC method for estimation of letrozole in nanoformulations. Curr. Pharm. Anal., 2018, 14, 320-330.
[http://dx.doi.org/10.2174/1573412913666171006152604]
[30]
Elkhoudary, M.M.; Abdel Salam, R.A.; Hadad, G.M. Robustness Testing in HPLC Analysis of Clarithromycin, Norfloxacin, Doxycycline, Tinidazole and Omeprazole in Pharmaceutical Dosage forms Using Experimental Design. Curr. Pharm. Anal., 2014, 10, 58-70.
[http://dx.doi.org/10.2174/157341291001140102111733]
[31]
Aşçı, B.; Koç, M. Optimum HPLC conditions for determination of dibucaine HCL, fluocortolone pivalate and fluocortolone caproate by using experimental design. Curr. Pharm. Anal., 2019, 15, 32-38.
[http://dx.doi.org/10.2174/1573412913666170707113025]
[32]
Shah, K.A.; Parmar, V. Quality by design based method development for simultaneous estimation of montelukast sodium and theophylline in tablet dosage form. Curr. Pharm. Anal., in press
[http://dx.doi.org/10.2174/1573412914666180827143700]
[33]
Kostić, N.; Dotsikas, Y.; Malenović, A.; Jančić Stojanović, B.; Rakić, T.; Ivanović, D.; Medenica, M. Stepwise optimization approach for improving LC-MS/MS analysis of zwitterionic antiepileptic drugs with implementation of experimental design. J. Mass Spectrom., 2013, 48(7), 875-884.
[http://dx.doi.org/10.1002/jms.3236] [PMID: 23832944]
[34]
Vlachou, M.; Siamidi, A.; Konstantinidou, S.; Dotsikas, Y. Optimization of controlled release matrix formulations of the chronobiotic hormone melatonin via experimental design. J. Pharm. Drug Deliv. Res., 2016, 6, 1-5.
[http://dx.doi.org/10.4172/2325-9604.1000159]
[35]
Vatsaraj, N.; Zia, H.; Needham, T. Formulation and optimization of a sustained-release tablet of ketorolac tromethamine. Drug Deliv., 2002, 9(3), 153-159.
[http://dx.doi.org/10.1080/10426500290095656] [PMID: 12396732]
[36]
Choi, H.; Shin, S.; Khoa Viet Truong, N.; Jeong, S.H. A new experimental design method to optimize formulations focusing on a lubricant for hydrophilic matrix tablets. Drug Dev. Ind. Pharm., 2012, 38(9), 1117-1127.
[http://dx.doi.org/10.3109/03639045.2011.641563] [PMID: 22348254]
[37]
Furlanetto, S.; Cirri, M.; Maestrelli, F.; Corti, G.; Mura, P. Study of formulation variables influencing the drug release rate from matrix tablets by experimental design. Eur. J. Pharm. Biopharm., 2006, 62(1), 77-84.
[http://dx.doi.org/10.1016/j.ejpb.2005.07.001] [PMID: 16154333]
[38]
Martinello, T.; Kaneko, T.M.; Velasco, M.V.; Taqueda, M.E.; Consiglieri, V.O. Optimization of poorly compactable drug tablets manufactured by direct compression using the mixture experimental design. Int. J. Pharm., 2006, 322(1-2), 87-95.
[http://dx.doi.org/10.1016/j.ijpharm.2006.05.034] [PMID: 16806756]
[39]
Dey, S.; Mahanti, B.; Khila, S.; Mazumder, B.; Gupta, S.D. Formulation development and optimization of bilayer tablets of aceclofenac. Expert Opin. Drug Deliv., 2012, 9(9), 1041-1050.
[http://dx.doi.org/10.1517/17425247.2012.707187] [PMID: 22788786]
[40]
Piepel, G.F.; Cornell, J.A. Mixture experiment approaches: examples, discussion, and recommendations. J. Qual. Technol., 1994, 26, 177-196.
[http://dx.doi.org/10.1080/00224065.1994.11979525]
[41]
Macleod, G.S.; Fell, J.T.; Collett, J.H. An in vitro investigation into the potential for bimodal drug release from pectin/chitosan/HPMC-coated tablets. Int. J. Pharm., 1999, 188(1), 11-18.
[http://dx.doi.org/10.1016/S0378-5173(99)00197-0] [PMID: 10528078]
[42]
Macleod, G.S.; Fell, J.T.; Collett, J.H.; Sharma, H.L.; Smith, A.M. Selective drug delivery to the colon using pectin:chitosan:hydroxypropyl methylcellulose film coated tablets. Int. J. Pharm., 1999, 187(2), 251-257.
[http://dx.doi.org/10.1016/S0378-5173(99)00196-9] [PMID: 10502631]
[43]
Fernandez-Hervas, M.J.; Fell, J.T. Pectin/chitosan mixtures as coatings for colon-specific drug delivery: an in vitro evaluation. Int. J. Pharm., 1998, 169(1), 115-119.
[http://dx.doi.org/10.1016/S0378-5173(98)00114-8]
[44]
Wakerly, Z.; Fell, J.T.; Attwood, D.; Parkins, D.A. in vitro evaluation of pectin-based colonic drug delivery systems. Int. J. Pharm., 1996, 1-2, 73-77.
[http://dx.doi.org/10.1016/0378-5173(95)04251-2]
[45]
Malenović, A.; Dotsikas, Y.; Mašković, M.; Jančić–Stojanović, B.; Ivanović, D.; Medenica, M. Desirability-based optimization and its sensitivity analysis for the perindopril and its impurities analysis in a microemulsion LC system. Microchem. J., 2011, 99, 454-460.
[http://dx.doi.org/10.1016/j.microc.2011.06.022]
[46]
Khlibsuwan, R.; Pongjanyakul, T. Chitosan-clay matrix tablets for sustained-release drug delivery: Effect of chitosan molecular weight and lubricant. J. Drug Deliv. Sci. Technol., 2016, 35, 303-313.
[http://dx.doi.org/10.1016/j.jddst.2016.08.003]
[47]
Korsmeyer, R.W.; Gurny, R.; Doelker, E.; Buri, P.; Peppas, N.A. Mechanisms of potassium chloride release from compressed, hydrophilic, polymeric matrices: effect of entrapped air. J. Pharm. Sci., 1983, 72(10), 1189-1191.
[http://dx.doi.org/10.1002/jps.2600721021] [PMID: 6644570]
[48]
Zen, N.I. The Use of D-Optimal Mixture Design in Optimizing Development of Okara Tablet Formulation as a Dietary Supplement Scientific World Journal., 2015, 1-7. Article ID 684319>
[49]
French, D.L.; Mauger, J.W. Evaluation of the physicochemical properties and dissolution characteristics of mesalamine: relevance to controlled intestinal drug delivery. Pharm. Res., 1993, 10(9), 1285-1290.
[http://dx.doi.org/10.1023/A:1018909527659] [PMID: 8234164]
[50]
Asthana, A.K.; Sparrow, M.P.; Peyrin-Biroulet, L. Optimizing conventional medical therapies in inflammatory bowel disease in 2014. Curr. Drug Targets, 2014, 15(11), 1002-1010.
[http://dx.doi.org/10.2174/1389450115666140915113503] [PMID: 25219568]
[51]
Siepmann, J.; Podual, K.; Sriwongjanya, M.; Peppas, N.A.; Bodmeier, R. A new model describing the swelling and drug release kinetics from hydroxypropyl methylcellulose tablets. J. Pharm. Sci., 1999, 88(1), 65-72.
[http://dx.doi.org/10.1021/js9802291] [PMID: 9874704]
[52]
Korsmeyer, R.W.; Lustig, S.R.; Peppas, N.A. Solute and penetrant diffusion in swellable polymers. I. Mathematical modeling. J. Polym. Sci. B, 1986, 24, 395-408.
[http://dx.doi.org/10.1002/polb.1986.090240214]
[53]
Korsmeyer, R.W.; Meerwall, E.V.; Peppas, N.A. Solute and penetrant diffusion in swellable polymers. II. Verification of theoretical models. J. Polym. Sci. B, 1986, 24, 409-434.
[http://dx.doi.org/10.1002/polb.1986.090240215]
[54]
Rathnam, G.; Bhadane, R. Formulation and evaluation of colon targeted compression coated tablet of mesalamine and prednisolone for ulcerative colitis. Asian J. Pharm., 2017, 3, 230-238.
[55]
Casettari, L.; Bonacucina, G.; Morris, G.A.; Perinelli, D.R.; Lucaioli, P.; Cespi, M.; Palmieri, G.F. Dextran and its potential use as tablet excipient. Powder Technol., 2015, 273, 125-132.
[http://dx.doi.org/10.1016/j.powtec.2014.12.030]
[56]
Vlachou, M.; Siamidi, A.; Efentakis, M. Investigation of a novel “tablets in capsule” theophylline formulation system for modified release. Pharm. Pharmacol. Int. J., 2017, 5, 1-7.
[http://dx.doi.org/10.15406/ppij.2017.05.00115]
[57]
Mughal, M.A.; Iqbal, Z.; Neau, S.H. Guar gum, xanthan gum, and HPMC can define release mechanisms and sustain release of propranolol hydrochloride. AAPS PharmSciTech, 2011, 12(1), 77-87.
[http://dx.doi.org/10.1208/s12249-010-9570-1] [PMID: 21174179]
[58]
Shangraw, R.F. Compressed tablets by direct compression. Pharmaceutical dosage forms: tablets; Lieberman, H.A.; Lachman, L; Schwartz, J.B., Ed.; Marcel Dekker: New York, 1989, pp. 195-246.
[59]
Sinha, V.R.; Agrawal, M.K.; Kumria, R. Influence of formulation and excipient variables on the pellet properties prepared by extrusion spheronization. Curr. Drug Deliv., 2005, 2(1), 1-8.
[http://dx.doi.org/10.2174/1567201052772898] [PMID: 16305403]
[60]
Vlachou, M.; Tsiakoulia, A.; Eikosipentaki, A. Controlled release of the pineal hormone melatonin from hydroxypropylmethylcellulose/sodium alginate matrices in aqueous media containing dioctyl sulfosuccinate. Curr. Drug Discov. Technol., 2007, 4(1), 31-38.
[http://dx.doi.org/10.2174/157016307781115449] [PMID: 17630926]
[61]
Shah, N.; Shah, T.; Amin, A. in vitro evaluation of pectin as a compression coating material for colon targeted drug delivery. Int. J. Pharma Bio Sci., 2011, 2, 410-418.

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