(Meth)akrylátové kopolymery typu Eudragit® v technologii perorálních tablet

Stáhnout PDF English version

Autoři: Martina Naiserová ¹; Kateřina Kubová ¹; Jakub Vysloužil ¹; Jurga Bernatoniene ²; Iosif Brokalakis ¹; David Vetchý ¹
Působiště autorů: Department of Pharmaceutics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno ¹; Department of Drug Technology and Social Pharmacy, Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania ²
Vyšlo v časopise: Čes. slov. Farm., 2019; 68, 183-197
Kategorie: Review article

Souhrn

Přehledový článek se zaměřuje na charakterizaci (meth)akrylátových kopolymerů – Eudragitů^®, popis jejich chování při tepelném ošetření, možné interakce mezi kationtovými a aniontovými polymery, inkompatibility související s Eudragity^® a na jejich využití v oblasti farmaceutické technologie perorálních tablet. V přehledu jsou rozděleny na rozpustné, nerozpustné a kombinaci těchto dvou typů. Právě kombinací rozpustného a nerozpustného poly(meth)akrylátu byl získán nový typ polymeru, Eudragit^® FL. V technologii perorálních tablet se Eudragity^® hojně využívají v matricových tabletách, a to samostatně nebo i v kombinacích, kde zajišťují zejména prodloužené uvolňování léčiva. V menší míře se využívají v gastroretentivních systémech. Naopak velký význam mají Eudragity^® v technologii potahovaných tablet, kde tyto enterosolventní polymery zajišťují specifické směřování léčiva do určitých částí trávicího traktu, zejména do tenkého střeva nebo kolonu. Jsou zde zmíněny důležité systémy jako CODES^TM a MMX^® technologie. V neposlední řadě je uvedena přehledová tabulka zahrnující aktuálně dostupné perorální léčivé přípravky na českém trhu, u kterých byl jako filmotvorná látka využit některý z Eudragitů^®.

Klíčová slova:

Eudragit® – matricové tablety – flotující tablety – potahované tablety – acidorezistentní tablety – burst efekt – prodloužené uvolňování léčiva – přívod léčiva do kolonu

Zdroje

1. Evonik, Healthcare. Healthcare Evonik. Eudragit. [Online] 7. 1. 2019 [Cited: 7. 1. 2019.] https://healthcare.evonik.com/product/health-care/en/products/pharmaceutical-excipients/EUDRAGIT/

2. Skalsky B., Petereit H. Chemistry and application properties of polymethacrylate systems. In: Felton J. W., McGinity L. A. Aqueous polymeric coatings for pharmaceutical dosage forms 3. New York: Informa Healthcare USA 2008.

3. Tu J., Shen Y., Mahalingam R., Jasti B., Li X. Polymers in oral modified release systems. In: Park H., Wen K. Oral controlled release formulation design and dru delivery: Theory to practice l. New Jersey: John Wiley & Sons 2011; 71–88.

4. Nollenberger K., Alberts J. Poly(meth)acrylate-based coatings. Int. J. Pharm. 2013; 457(2), 461–469.

5. Malá R., Jirásková J., Rabišková M. Vodné disperze polymerů v obalech řídících uvolňování léčiv. Chem Listy 2014; 108(11), 1046–1052.

6. Thakral S., Thakral N. K., Majumdar D. K. Eudragit^®: a technology evaluation. Expert Opin. Drug Eval. 2013; 10(1), 131–149.

7. Ceballos A., Cirri M., Maestrlli F., Corti G., Mura P. Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets. Farmaco 2005; 11–12, 913–918.

8. Vasileiou K., Vysloužil J., Pavelková M., Vysloužil J., Kubová K. Velikostně redukované mikročástice na bázi Eudragitu^® RS připravené metodou odpaření rozpouštědla – sledování vlivu vybraných proměnných na testované parametry. Čes. slov. Farm. 2017; 6, 274–280.

9. Vysloužil J., Bavolarová J., Kejdušová M., Vetchý D., Dvořáčková K. Cationic Eudragit^® Polymers as Excipients for Microparticles Prepared by Solvent Evaporation Method. Čes. slov. Farm. 2013; 6, 249–254.

10. Gallardo D., Skalsky B., Kleinebudde P. Controlled release solid dosage forms using combinations of (meth)acrylate copolymers. Pharm. Dev. Technol. 2008; 13(5), 413–423.

11. Patra C. N., Priya R., Swain S., Jena G. K., Panigrahi K. C., Ghose D. Pharmaceutical significance of Eudragit: A review. Futur. J. Pharm. Sci. 2017; 3(1), 33–45.

12. Qi, S., Gryczke, A., Belton, P., Craig, D. Q. Characterisation of solid dispersions of paracetamol and Eudragit^® E prepared by hot-melt extrusion using thermal, microthermal and spectroscopic analysis. Int. J. Pham. 2008; 1–2(354), 158–167.

13. Liu J., Cao F., Zhang C., Ping Q. Use of polymer combinations in the preparation of solid dispersions of a thermally unstable drug by hot-melt extrusion. Acta Pharm. Sin. B 2013; 3(4), 263–272.

14. Yang Z., Nollenberger K., Alberts J., Craig D. Qi S. Microstructure of an immiscible polymer blend and its stabilization effect on amorphous solid dispersions. Mol. Pharm. 2013; 10(1), 2767–2780.

15. Li J., Lee I. W., Shin G. H., Chen X., Park H. J. Curcumin-Eudragit E PO solid dispersion: A simple and potent method to solve the problems of curcumin. Eur. J. Pharm. Biopharm. 2015; 94, 322–332.

16. Hrubý M., Filippov S. K., Felklová V., Štěpánek P. Přírodou inspirované polymery citlivé na vnější podněty pro dopravu léčiv. Chem Listy 2015; 109(7), 482–487.

17. Kadian S. S., Harikumar S. L. Eudragit and its Pharmaceutical Significance. Pharmainfo. [Online] 2016 [Cited: 1. 30. 2019] KADIAN, Satish Singh; Harikumar S. L. http://www. pharmainfo. net/satishsinghkadian/publications/eudragit-and-its-pharmaceutical-significance

18. Huyghebaert N., Vermeire A., Remon J. P. In vitro evaluation of coating polymers for enteric coating and human ileal targeting. Int. J. Pharm. 2005; 298(1), 26–37.

19. Joshi M. Role of Eudragit in targeted drug delivery. Int. J. Curr. Pharm. Res. 2013; 5(2), 58–62.

20. Brady J., Durig T., Lee P. I., Li J. X. Polymer Properties and Characterization. In: Zhang Y., Mantri G. G. Z., Chen R. V., Yu Y., Qui L. Developing Solid Oral Dosage Forms. 2. Cambridge: Academic Pres 2017; 181–223.

21. Apu A. S., Pathan A. H., Kibria G., Jalil R. U. In vitro release kinetic study of theophylline from eudragit RS PO and eudragit RL PO matrix tablets. J. Pharm. Sci. 2009; 8(1), 1–6.

22. Apu A. S., Pathan A. H., Shrestha D., Kibria G., Jalil R. U. Investigation of in vitro release kinetics of carbamazepine from Eudragit^® RS PO and RL PO matrix tablets. Trop. J. Pharm. Res. 2009; 8(2), 145–152.

23. Aleksiev A., Kostova B., Rachev D. Development of Eudragit Based Sustained Release Systems of Galantamine Hydrobromide. Int. J. Pharm. Sci. Rev. Res. 2014; 27(1), 135–140.

24. Müller-Albers J., Guha A., Assmus M. Use of an advanced new enteric combination polymer with multiple unit pellet systems and other multiparticulates. Am. Pharm. Rev. 2018; 7.

25. Moustafine R. I., Margulius E. B., Sibgatullina L. F. Kemenova V. A., van den Mooter G. Comparative evaluation of interpolyelectrolyte complexes of chitosan with Eudragit^® L100 and Eudragit^® L100-55 as potential carriers for oral controlled drug delivery. Eur. J. Pharm. Biopharm. 2008; 70(1), 215–225.

26. Mustafin R. I., Kabanova T. V., Semina I. I., Bukhovets A. V., Garipova V. R., Shilovskaya E. V. Biopharmaceutical assessment of a polycomplex matrix system based on carbomer 940 and Eudragit E PO for colon-specific drug deliery. Pharm. Chem. J. 2011; 45(8), 491–494.

27. Moustafine R. I., Kemenova V. A., van den Mooter G. Characteristics of interpolyelectrolyte complexes of Eudragit E. Int. J. Pharm. 2005; 294.

28. Li L., Wang L., Jiang S, Wang Y., Zhang X. Insights into the mechanisms of chitosan - anionic polymers-based matrix for extended drug release. Int. J. Pharm. 2014; 476, 253–265.

29. Mašková E., Kubová K., Vetchý D. Využití (meth)akrylátových kopolymerů v technologii matricových tablet s řízeným uvolňováním léčiva. Chem Listy 2015; 109, 14–20.

30. Ofokansi K. C., Kenechukwu F. C. Formulation development and evaluation of drug release kinetics from colon-targeted ibuprofen tablets based on Eudragit RL 100-chitosan interpolyelectrolyte complexes. ISRN Pharm. 2013; 1–8.

31. Azarmi S., Ghaffari F., Löbenberg R., Nokhodchi A. Mechanistic evaluation of the effect of thermal-treating on Eudragit RS matrices. Farmaco 2005; 60(11–12), 925–930.

32. Hoag S., Nyamweya N. N. Influence of coloring agents on the properties of polymeric coating systems. In: Felton L. A., McGinity J. W. Aqueous polymeric coatings for pharmaceutical dosage forms. New York: CRC Press 2008; 7, 191–222.

33. Azarmi S., Farid J., Nokhodchi A., Bahari-Savari S. M., Valizadeh H. Thermal treating as a tool for sustained release of indomethacin from Eudragit RS and RL matrices. Int. J. Pharm. 2002; 246(1–2), 171–177.

34. Dave V. S., Fahmy R. M., Bensley D., Hoag S. W. Eudragit^® RS PO/RL PO as rate-controlling matrix-formers via roller compaction: Influence of formulation and process variables on functional attributes of granules and tablets. Drug Dev. Ind. Pharm. 2012; 38(10), 1240–1253.

35. Kubová K., Peček D., Hasserová K., Doležel P., Pavelková M., Vysloužil J., Muselík J., Vetchý D. The influence of thermal treatment and type of insoluble poly(meth)acrylates on dissolution behavior of very soluble drug from hypromellose matrix tablets evaluated by multivariate data analysis. Pharm. Dev. Technol. 2017; 22(2), 206–217.

36. Sarisuta N., Lawanprasert P., Puttipipatkhachorn S., Srikummoon K. The influence of drug-excipient and drug-polymer interactions on adhesive strenght of Ranitidine Hydrochloride film-coated tablets. Drug Dev. Ind. Pharm. 2006; 32, 463–471.

37. Stroyer A., McGinity J. W., Leopold C. S. Solid state interactions between the proton pump inhibitor omeprazole and various enteric coating polymers. J. Pharm. Sci. 2006; 95(6), 1342–1353.

38. Pignatello R., Ferro M., Puglisi G. Preparation of solid dispersions of nonsteroidal anti-inflammatory drugs with acrylic polymers and studies on mechanisms of drug-polymer interactions. AAPS Pharm. Sci. Tech. 2002; 3(2), 35–45.

39. Pignatello R., Spadaro D., Vandelli M. A., Forni F., Puglisi G. Characterization of the Mechanism of Interaction in Ibuprofen-EudragitRL100 Coevaporates. Drug Dev. Ind. Pharm. 2004; 30(3), 277–288.

40. Bose A., Wong T. W., Singh N. Formulation development and optimization of sustained release matrix tablet of Itopride HCl by response surface methodology and its evaluation of release kinetics. SPJ 2013; 21(2), 201–213.

41. Quinten T., Gonnissen Y., Adraens E. Development of injection moulded matrix tablets based on mixtures of ethylcellulose and low-substituted hydroxypropylcellulose. Eur. J. Pharm. Sci. 2009; 37(3–4), 207–216.

42. Fu S., Buckner I. S., Block L. H. Inter-grade and inter-batch variability of sodium alginate used in alginate-based matrix tablets. AAPS Pharm. Sci. Tech. 2014; 15(5), 1228–1237.

43. Phaechamud T., Ritthidej G. C. Sustained-release from layered matrix system comprising chitosan and xanthan gum. Drug Dev. Ind. Pharm. 2007; 33(6), 595–605.

44. Dvořáčková K. Principy uvolňování léčiv z perorálních matricových tablet obsahujících hypromelosu. Chem Listy 2009; 103(1), 66–72.

45. Ozyacizi M., Gokce H. E., Ertan G. Release and diffusional modeling of metronidazole lipid matrices. Eur. J. Pharm. Biopharm. 2006; 63(3), 331–339.

46. Deepika B., Sameen S., Nazneen N., Madhavi A., Raju K. N., Rao K. N., Dutt K. R. Matrix drug delivery system: A review. Eur. J. Pharm. Med. Res. 2018; 5(1), 150–154.

47. Dvořáčková K., Kalėdaitė R., Gajdziok J., Rabišková M., Bajerová M., Muselík J., Lažauskas R., Pečiura R., Bernatonienė J. The development of Eudragit^® NM-based controlled-release matrix tablets. Medicina 2012; 48(4), 192–202.

48. Tolia G., Li S. K. Study of drug release and tablet characteristics of silicone adhesive matrix tablets. Eur. J. Pharm. Biopharm. 2012; 82(3), 518–525.

49. Sánchez-Lafuente C., Faucci M. T., Férnandez-Arévalo M., Álvarez-Fuentes J., Rabasco A. M., Mura P. Development of sustained release matrix tablets of didanosine containing methacrylic and ethylcellulose polymers. Int. J. Pharm. 2002; 234, 213–221.

50. Tabandeh H., Mortazavi S. A., Guilani T. B. Preparation of sustained-release matrix tablets of aspirin with ethylcellulose, Eudragit RS100 and Eudragit S100 and studying the release profiles and their sensitivity to tablet hardness. Iran J. Pharm. Res. 2010; 2(4), 201–206.

51. Chithaluru K., Tadikonda R. R., Gollapudi R., Kandula K. K. Formulation and invitro evaluation of sustained release matrix tablets of losartan potassium. Asian J. Pharm. Clin. Res. 2011; 4(3), 18–22.

52. Naiserová M., Kubová K., Vysloužil J., Pavloková S., Vetchý D., Urbanová M., Brus J., Vysloužil J., Kulich P. Investigation of dissolution behaviour HPMC/Eudragit^®/magnesium aluminometasilicate oral matrices based on NMR solid-state spectroscopy and dynamic characteristics of gel layer. AAPS Pharm. Sci. Tech. 2018; 19(2), 681–692.

53. Reddy K. R., Mutalik S., Reddy S. Once-daily sustained-release matrix tablets of nicorandil: formulation and in vitro evaluation. AAPS Pharm. Sci. Tech. 2003; 4(4), 480–488.

54. Tomuta I., Alecu C., Dudas D., Leucuta S. E. Optimization of metoprolol tartrate modified-release matrix tablet formulation using Eudragit NE as binder for metoprolol fluid bed granulation. Asian J. Pharm. 2014; 6(2), 101–106.

55. Roy H., Brahma C. K., Nandi S., Parida K. R. Formulation and design of sustained release matrix tablets of metformin hydrochloride: Influence of hypromellose and polyacrylate polymers. Int. J. App. Basic Med. Res. 2013; 3(1), 55–63.

56. Wadher K. J., Kakde R. B., Umekr M. J. Formulation and evaluation of a sustained-release tablets of metformin hydrochloride using hydrophilic synthetic and hydrophobic natural polymers. Indian J. Pharm. Sci. 2011; 73(2), 208–215.

57. Nokhodchi A., Norouzi-Sani S., Siahi-Shadbad M. R., Lotfipoor F., Saeedi M. The effect of various surfactants on the release rate of propranolol hydrochloride from hydroxypropylmethylcellulose (HPMC)-Eudragit matrices. Eur. J. Pharm. Biopharm. 2002; 54(3), 349–356.

58. Moodley K., Pillay V., Choonara Y. E., du Toit L. C., Ndesendo V. M., Kumar P., Cooppan S., Bawa P. Oral drug delivery systems comprising altered geometric configurations for controlled drug delivery. Int. J. Mol. Sci. 2012; 13(1), 18–43.

59. Oren P. L., Seidler W. M. K. Sustained release matrix. 4968508 USA, November 6, 1990.

60. Ashgar L. F. A., Chandran S. Design and evaluation of matrix base with sigmoidal release profile for colon-specific delivery using a combination of Eudragit and non-ionic cellulose ether polymers. Drug Deliv. Transl. Re. 2011; 1(2), 132–146.

61. Asghar L. F. A., Chure C. B., Chandran S. Colon specific delivery of indomethacin: effect of incorporating pH sensitive polymers in xanthan gum matrix bases. AAPS Pharm. Sci. Tech. 2009; 10(2), 418–429.

62. Tatavarti A. S., Muller F. X., Hoag S. W. Evaluation of the deformation behavior of binary systems of methacrylic acid copolymers and hydroxypropyl methylcellulose using a compaction simulator. Int. J. Pharm. 2008; 348(1–2), 46–53.

63. Corti G., Cirri M., Maestrelli F., Mennini N., Mura P. Sustained-release matrix tablets of metformin hydrochloride in combination with triacetyl-β-cyclodextrin. Eur. J. Pharm. Biopharm. 2008; 68, 303–309.

64. Huang H. P., Mehta S. C., Radebaugh G. W., Fawzi M. B. Mechanism of drug release from an acrylic polymer-wax matrix tablet. J. Pharm. Sci. 1994; 83(6), 795–797.

65. Tatavarti A. S., Hoag S. W. M2icroenvironmental pH modulation based release enhancement of a weakly basic drug from hydrophilic matrices. J. Pharm. Sci. 2006; 95(7), 1459–1468.

66. Cha K. H., Park J., Cho W., Gu D. G., Jeong K., Hwang S. J. Design of pH-independent extended release matrix tablets of minocycline hydrochloride for the treatment of dementia. Arch. Pharm. Res. 2009; 32(11), 1593–1598.

67. Rao, V. M., Engh, K., Qiu, Y. Design of pH-independent controlled release matrix tablets for acidic drugs. Int. J. Pharm. 2003; 252(1–2), 81–86.

68. Çetin M., Süleyman H., Çadirci E., Demir E. T., Polat B., Hacimüftüoglu A. Preparation and in vivo evaluation of Eudragit^® L100/Eudragit^® NM 30D enteric granules containing diclofanac sodium: anti-inflammatory and ulcerogenic activity. Turk. J. Pharm. Sci. 2010; 7(3), 237–248.

69. Arora S., Ali J., Ahuja A. Khar R. K., Baboota S. Floating Drug Delivery Systems: A Review. AAPS Pharm. Sci. Tech. 2005; 6(3), 372–390.

70. Fukuda M., Peppas N. A., McGinity J. W. Floating hot-melt extruded tablets for gastroretentive controlled drug release system. J. Control. Release 2006; 115(2), 121–129.

71. Jagdale S. C., Agavekar A. J., Pandya S. V., Kuchekar B. S., Chabukswar A. R. Formulation and evaluation of gastroretentive drug delivery system of propranolol hydrochloride. AAPS Pharm. Sci. Tech. 2009; 10(3), 1071–1079.

72. Oth M., Franz M. Timmermans J., Möes A. The bilayer floating capsule: a stomach-directed drug delivery system for misoprostol. Pharm. Res. 1992; 9(3), 298–302.

73. Kaushik A. Y., Tiwari A. K., Gaur A. Role of excipients and polymeric advancements in preparation of floating drug delivery systems. Int. J. Pharm. Investig. 2015; 5(1), 1–12.

74. Bani-Jaber A. K., Alkawareek M., Al-Gousous J., Abuhelwa A. Y. Floating and sustained-release characteristics of effervescent tablets prepared with a mixed matrix of Eudragit L-100-55 and Eudragit E PO. Chem. Pharm. Bull. 2011; 59(2), 155–160.

75. Bani-Jaber A., Al-Alani L., Alkhatib H., Al-khalidi B. Prolonged intragastric drug delivery mediated by Eudragit^® E-carrageenan polyelectrolyte matrix tablets. AAPS Pharm. Sci. Tech. 2011; 12(1), 354–361.

76. Elder D. Design, formulation and manufacture of film-coated drug products. Eur. Pharm. Rev. 2017; 22(5), 37–40.

77. Khatri P., Desai D., Shelke N., Minko T. Role of plasticizer in membrane coated extended release oral drug delivery. J. Drug. Deliv. Sci. Technol. 2018; 44, 231–243.

78. SÚKL – Státní ústav pro kontrolu léčiv. [Online] 21. 4 2019 [Cited: 21. 4. 2019] http://www.sukl.cz/modules/medication/search.php

79. Liu F., Lizio R., Mier C., Petereit H. U., Blakey P., Basit A. W. A novel concept in enteric coating: A double-coating system providing rapid drug. J. Control. Release 2009; 133(2), 119–124.

80. Wikberg M., Ulmius J., Ragnarsson G. Targeted drug delivery in treatment of intestinal diseases. Aliment. Pharm. Ther. 1997; 11, 109–115.

81. Sauer D., Zheng W., Coots L. B., McGinity J. W. Influence of processing parameters and formulation factors on the drug release from tablets powder-coated with Eudragit L 100-55. Eur. J. Pharm. Biopharm. 2007; 67(2), 464–475.

82. Szente V., Zelkó R. Site-specific drug delivery systems. I. Colon targeted delivery. Acta Pharm. Hung. 2007; 77(3), 185–189.

83. Park H. J., Jung H. J., Ho M. J., Lee D. R., Cho H. R., Choi Y. S., Jun J., Son M., Kang M. Colon-targeted delivery of solubilized bisacodyl by doubly enteric-coated multiple-unit tablet. Eur. J. Pharm. Sci. 2017; 102, 172–179.

84. Hadi M. A., Rao N. R., Rao A. S. Formulation and evaluation of ileo-colonic targeted matrix-mini-tablets of Naproxen for chronotherapeutic treatment of rhumatoid arthritis. Saudi Pharm. J. 2016; 24(1), 64–73.

85. Ren Y., Jiang L., Yang S., Gao S., Yu H., Hu J., Mao D., Peng H., Zhou Y. Design and preparation of a novel colon-targeted tablet of hydrocortisone. Braz. J. Pharm. Sci. 2016; 52(2), 239–250.

86. Amidon S., Brown J. E., Dave V. S. Colon-targeted oral drug delivery systems: Design trends and approaches. AAPS Pharm. Sci. Tech. 2015; 16(4), 731–741.

87. Mehta R., Chawla A., Sharma P., Pawar P. Formulation and in vitro evaluation of Eudragit S100 coated naproxen matrix tablets for colontargeted drug delivery system. J. Adv. Pharm. Tech. Res. 2013; 4(1), 31–41.

88. Philip A. K., Philip B. Colon targeted drug delivery systems: A review on primary and novel approaches. Oman Med. J. 2010; 25(2), 79–87.

89. Katsuma M., Watanabe S., Takemura S., Sako K., Sawada T., Masuda Y., Wilding I. R. Scintigraphic evaluation of a novel colon-targeted delivery system (CODES) in healthy volunteers. J. Pharm. Sci. 2004; 93(5), 1287–1299.

90. Kshirsagar S. J., Bhalekar M. R., Umap R. R. Design, development and in vitro-in vivo study of a colon-specific fast disintegrating tablet. Pharm. Dev. Tech. 2011; 16(5), 449–456.

91. Ibekwe V. C., Liu F., Fadda H. M., Khela M. K., Evans D. F., Parsons G. E., Basit A. W. An investigation into the in vivo performance variability of pH responsive polymers for ileo‐colonic drug delivery using gamma scintigraphy in humans. J. Pharm. Sci. 2006; 95(12), 2760–2766.

92. Mustafin R. I., Bodrov A. V., Kemenova V. A., Rombaut P., van den Mooter G. Interpolymer interaction between countercharged types of Eudragit^® RL30D and FS30D in binary films as a method of drug release modification in oral delivery systems. Pharm. Chem. J. 2012; 46(1), 45–49.

93. Moustafine R. I., Bodrov A. V., Kemenova V. A., Rombaut P., van der Mooter G. Drug release modification by interpolymer interaction between countercharged. Int. J. Pharm. 2012; 439, 17–21.

94. Ibekwe V. C., Khela M. K., Evans D. F., Basit A. W. A new concept in colonic drug targeting: a combined pH-responsive and bacterially-triggered drug delivery technology. Aliment Pharm. Ther. 2008; 28(7), 911–916.

95. Liu F., Moreno P., Basit A. W. A novel double-coating approach for improved pH-triggered delivery to the ileo-colonic region of the gastrointestinal tract. Eur. J. Pharm. Biopharm. 2010; 74(2), 311–315.

96. Sinha V. R., Kumar R. V., Bhinge J. R. Influence of polymeric blend of carbomer-gum on the targeted delivery of 5-FU. Polymer Plast. Tech. Eng. 2009; 48(12), 1287–1294.

97. Nardelli S., Pisani L. F., Tontini G. E., Vecchi M., Pastorelli L. MMX^® technology and its applications in gastrointstinal diseases. Ther. Adv. Gastroenterol. 2017; 10(7), 545–552.

98. Prantera C., Viscido A., Biancone L., Francavilla A., Giglio L., Campieri M. A new oral delivery system for 5-ASA: preliminary clinical findings for MMX. Inflamm. Bowel. Dis. 2005; 11(5), 421–427.