Advertisement

Pharmaceutical Research

, Volume 34, Issue 9, pp 1934–1943 | Cite as

Increasing the Bile Acid Sequestration Performance of Cationic Hydrogels by Using an Advanced/Controlled Polymerization Technique

  • Patrícia V. Mendonça
  • André Matos
  • Andreia F. Sousa
  • Arménio C. Serra
  • Sérgio Simões
  • Jorge F. J. CoelhoEmail author
Research Paper
  • 317 Downloads

Abstract

Purpose

To investigate the influence of the polymerization technique and the content of hydroxyl groups on the performance of new bile acid sequestrants based on PAMPMTA-co-PHEA (PAMPTMA: poly((3-acrylamidopropyl)trimethylammonium chloride); PHEA: poly(2-hydroxyethyl acrylate)) hydrogels.

Methods

PAMPMTA-co-PHEA hydrogels were prepared using either free radical polymerization or supplemental activator and reducing agent atom transfer radical polymerization. The chemical structure and composition of the hydrogels was confirmed by both FTIR and ssNMR. The binding of sodium cholate as the model bile salt was evaluated in simulated intestinal fluid using HPLC. The degradation of the polymers was evaluated in vitro in solutions mimicking the gastrointestinal tract environment.

Results

The binding showed that an increase of the amount of HEA in the hydrogel lead to a decrease of the binding capacity. In addition, it was demonstrated for the first time that the hydrogels produced by SARA ATRP presented a higher binding capacity than similar ones produced by FRP. Finally, it was observed that copolymers of PAMPTMA-co-PHEA showed no sign of degradation in solutions mimicking both the stomach and the intestine environment.

Conclusions

The use of an advanced polymerization technique, such as the SARA ATRP, could be beneficial for the preparation of BAS with enhanced performance.

KEY WORDS

bile acid sequestrants (BAS) cationic hydrogel free radical polymerization (FRP) supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP) 

Abbreviations

AIBN

2,2′-Azobis(2-methylpropionitrile)

BAS

Bile acid sequestrants

BDDA

1,4-Butanediol diacrylate

EBiB

Ethyl α-bromoisobutyrate

ECP

Ethyl 2-chloropropionate

FRP

Free radical polymerization

GI

Gastrointestinal

HPLC

High performance liquid chromatography (HPLC)

Me6TREN

Tris[2-(dimethylamino)ethyl]amine

NaCA

Sodium cholate

PAMPTMA

Poly((3-acrylamidopropyl)trimethylammonium chloride)

PHEA

Poly(2-hydroxyethyl acrylate)

PMA

Poly(methyl acrylate)

SARA ATRP

Supplemental activator and reducing agent atom transfer radical polymerization

SGF

Simulated gastric fluid

SIF

Simulated intestinal fluid

Notes

Acknowledgments and Disclosures

Patrícia Mendonça acknowledges FCT-MCTES for her postdoctoral grant (Project PTDC/CTMPOL/6138/2014). AFS thanks FCT (Fundação para a Ciência e Tecnologia) and POPH/FSE for the postdoctoral grant (SFRH/BPD/73383/2010). 1H NMR data was collected at the UC-NMR facility which is supported in part by FEDER – European Regional Development Fund through the COMPETE Programme (Operational Programme for Competitiveness) and by National Funds through FCT – Fundação para a Ciência e a Tecnologia (Portuguese Foundation for Science and Technology) through grants REEQ/481/QUI/2006, RECI/QEQ-QFI/0168/2012, CENTRO-07-CT62-FEDER-002012, and Rede Nacional de Ressonância Magnética Nuclear (RNRMN). The authors would like to thank Bluepharma for the technical and scientific discussions regarding the BAS technology. Also, Doctor Luís Mafra is strongly acknowledge for the fruitful scientific discussions regarding 13C HPDEC ssNMR spectroscopy.

Supplementary material

11095_2017_2204_MOESM1_ESM.docx (264 kb)
ESM 1 (DOCX 263 kb)

References

  1. 1.
    Organization WH. Fact sheet on cardiovascular diseases (CVDs). In: World Health Organization; 2016.Google Scholar
  2. 2.
    Dhal PK, Huval CC, Holmes-Farley SR. Biologically active polymeric sequestrants: design, synthesis, and therapeutic applications. Pure Appl Chem. 2007;79(9):1521–30.CrossRefGoogle Scholar
  3. 3.
    Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European atherosclerosis society (EAS). Eur Heart J. 2011;32(14):1769–818.CrossRefPubMedGoogle Scholar
  4. 4.
    Banach M, Serban C, Ursoniu S, Rysz J, Muntner P, Toth PP, et al. Statin therapy and plasma coenzyme Q10 concentrations—a systematic review and meta-analysis of placebo-controlled trials. Pharmacol Res. 2015;99:329–36.CrossRefPubMedGoogle Scholar
  5. 5.
    Okuyama H, Langsjoen PH, Hamazaki T, Ogushi Y, Hama R, Kobayashi T, et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015;8(2):189–99.CrossRefPubMedGoogle Scholar
  6. 6.
    Insull W. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a scientific review. South Med J. 2006;99(3):257–73.CrossRefPubMedGoogle Scholar
  7. 7.
    Dhal PK, Polomoscanik SC, Avila LZ, Holmes-Farley SR, Miller RJ. Functional polymers as therapeutic agents: concept to market place. Adv Drug Deliv Rev. 2009;61(13):1121–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Hou R, Goldberg AC. Lowering low-density lipoprotein cholesterol: statins, ezetimibe, bile Acid Sequestrants, and combinations: comparative efficacy and safety. Endocrinol Metab Clin N Am. 2009;38(1):79–97.CrossRefGoogle Scholar
  9. 9.
    Huval CC, Holmes-Farley SR, Mandeville WH, Sacchiero R, Dhal PK. Syntheses of hydrophobically modified cationic hydrogels by copolymerization of alkyl substituted diallylamine monomers and their use as bile acid sequestrants. Eur Polym J. 2004;40(4):693–701.CrossRefGoogle Scholar
  10. 10.
    Mendonça PV, Serra AC, Silva CL, Simões S, Coelho JFJ. Polymeric bile acid sequestrants—synthesis using conventional methods and new approaches based on “controlled”/living radical polymerization. Prog Polym Sci. 2013;38(3–4):445–61.CrossRefGoogle Scholar
  11. 11.
    Zhou K, Xia W, Zhang C, Yu L. In vitro binding of bile acids and triglycerides by selected chitosan preparations and their physico-chemical properties. Food Sci Technol. 2006;39(10):1087–92.Google Scholar
  12. 12.
    Nichifor M, Cristea D, Mocanu G, Carpov A. Aminated polysaccharides as bile acid sorbents: in vitro study. J Biomater Sci Polym Ed. 1998;9(6):519–34.CrossRefPubMedGoogle Scholar
  13. 13.
    Baille WE, Huang WQ, Nichifor M, Zhu XX. Functionalized β-cyclodextrin polymers for the sorption of bile salts. J Macromol Sci A. 2000;37(7):677–90.CrossRefGoogle Scholar
  14. 14.
    Nichifor M, Zhu XX, Cristea D, Carpov A. Interaction of hydrophobically modified cationic dextran hydrogels with biological surfactants. J Phys Chem B. 2001;105(12):2314–21.CrossRefGoogle Scholar
  15. 15.
    Mendonca PV, Moreno MJ, Serra AC, Simoes S, Coelho JFJ. Synthesis of tailor-made bile acid sequestrants by supplemental activator and reducing agent atom transfer radical polymerization. RSC Adv. 2016;6(57):52143–53.CrossRefGoogle Scholar
  16. 16.
    Mandeville WH, Goldberg DI. The sequestration of bile acids, a non- absorbed method for cholesterol reduction. A review. In: Sliskovic DR, editor. Current pharmaceutical design. Hilversum: Bentham Science Publishers; 1997. p. 15–26.Google Scholar
  17. 17.
    L-h Z, Janout V, Renner JL, Uragami M, Regen SL. Enhancing the “stickiness” of bile acids to cross-linked polymers: a Bioconjugate approach to the Design of Bile Acid Sequestrants. Bioconjug Chem. 2000;11(3):397–400.CrossRefGoogle Scholar
  18. 18.
    Mendonca PV, Konkolewicz D, Averick SE, Serra AC, Popov AV, Guliashvili T, et al. Synthesis of cationic poly((3-acrylamidopropyl)trimethylammonium chloride) by SARA ATRP in ecofriendly solvent mixtures. Polym Chem. 2014;5(19):5829–36.CrossRefGoogle Scholar
  19. 19.
    Abreu CMR, Fu L, Carmali S, Serra AC, Matyjaszewski K, Coelho JFJ. Aqueous SARA ATRP using inorganic sulfites. Polym Chem. 2017;8(2):375–87.CrossRefPubMedGoogle Scholar
  20. 20.
    Gois JR, Konkolewic D, Popov AV, Guliashvili T, Matyjaszewski K, Serra AC, et al. Improvement of the control over SARA ATRP of 2-(diisopropylamino)ethyl methacrylate by slow and continuous addition of sodium dithionite. Polym Chem. 2014;5(16):4617–26.CrossRefGoogle Scholar
  21. 21.
    Flory PJ. Principles of polymer chemistry: Paul J. Flory: Cornell University; 1953.Google Scholar
  22. 22.
    Li W, Gao H, Matyjaszewski K. Influence of initiation efficiency and polydispersity of primary chains on gelation during atom transfer radical copolymerization of monomer and cross-linker. Macromolecules. 2009;42(4):927–32.CrossRefGoogle Scholar
  23. 23.
    Zhong M, Wang Y, Krys P, Konkolewicz D, Matyjaszewski K. Reversible-deactivation radical polymerization in the presence of metallic copper. Kinetic Simulation Macromolecules. 2013;46(10):3816–27.Google Scholar
  24. 24.
    Constantin M, Mihalcea I, Oanea I, Harabagiu V, Fundueanu G. Studies on graft copolymerization of 3-acrylamidopropyl trimethylammonium chloride on pullulan. Carbohydr Polym. 2011;84(3):926–32.CrossRefGoogle Scholar
  25. 25.
    Vargün E, Usanmaz A. Polymerization of 2-hydroxyethyl acrylate in bulk and solution by chemical initiator and by ATRP method. J Polym Sci A Polym Chem. 2005;43(17):3957–65.CrossRefGoogle Scholar
  26. 26.
    Lee JK, Kim SY, Kim SU, Kim JH. Synthesis of cationic polysaccharide derivatives and their hypocholesterolaemic capacity. Biotechnol Appl Biochem. 2002;35(3):181–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Einarsson K, Ericsson S, Ewerth S, Reihnér E, Rudling M, Ståhlberg D, et al. Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism. Eur J Clin Pharmacol. 1991;40(1):S53–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhu X, Wen Y, Wang L, Li C, Cheng D, Zhang H, et al. Binding of sodium cholate in vitro by cationic Microfibrillated cellulose. Ind Eng Chem Res. 2014;53(48):18508–13.CrossRefGoogle Scholar
  29. 29.
    Brockman H. Pancreatic lipase. In: II CMM, Tso P, Kuksis A, editors. Intestinal Lipid Metabolism: Springer US; 2001. p. 61–79.Google Scholar
  30. 30.
    Yoon JA, Gayathri C, Gil RR, Kowalewski T, Matyjaszewski K. Comparison of the Thermoresponsive Deswelling kinetics of poly(2-(2-methoxyethoxy)ethyl methacrylate) hydrogels prepared by ATRP and FRP. Macromolecules. 2010;43(10):4791–7.CrossRefGoogle Scholar
  31. 31.
    Matyjaszewski K, Spanswick J. Controlled/living radical polymerization. Mater Today. 2005;8(3):26–33.CrossRefGoogle Scholar
  32. 32.
    Lee JK, Kim SU, Kim JH. Modification of chitosan to improve its hypocholesterolemic capacity. Biosci Biotechnol Biochem. 1999;63(5):833–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang Y, Zhang J, Zhu XX, Yu A. Specific binding of cholic acid by cross-linked polymers prepared by the hybrid imprinting method. Polymer. 2007;48(19):5565–71.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Patrícia V. Mendonça
    • 1
  • André Matos
    • 1
  • Andreia F. Sousa
    • 2
  • Arménio C. Serra
    • 1
  • Sérgio Simões
    • 3
  • Jorge F. J. Coelho
    • 1
    Email author
  1. 1.CEMUC, Department of Chemical EngineeringUniversity of CoimbraCoimbraPortugal
  2. 2.CICECO - Aveiro Institute of Materials and Department of ChemistryUniversity of AveiroAveiroPortugal
  3. 3.Bluepharma, Indústria Farmacêutica, SACoimbraPortugal

Personalised recommendations