, Volume 26, Issue 7, pp 4579–4587 | Cite as

Surfactant mediated clofazimine release from nanocellulose-hydrogels

  • Chiara Piotto
  • Paolo BettottiEmail author
Original Research


The widely tunable physical and chemical characteristics of hydrogels make them advantageous in biomedical and pharmaceutical applications, yet their hydrophilic nature might discourage their use as drug delivery systems for poorly water soluble molecules. In this work we demonstrate the sustained release of a large amount of a lipophilic drug (clofazimine) from nanocellulose hydrogels. Hydrogels are formed via ionotropic gelation and loaded with up to 37 % w/w) of the hydrophobic molecule. The kinetic profile avoids the initial burst release and we demonstrate that the surfactant co-loading is a successful strategy to increase by about 50 times the drug solubility in water, without the need of complex fabrication steps.


Nanocellulose Hydrophobic drug Hydrogels Drug release Isosbestic point 



The authors acknowledge SCA Östrand (Sweden) for the supply of cellulose material and Prof. M. Scarpa for fruitful discussions.

Supplementary material

10570_2019_2407_MOESM1_ESM.pdf (2.7 mb)
Supplementary material 1 (pdf 2783 KB)


  1. Angiolini L, Valetti S, Cohen B, Feiler A, Douhal A (2018) Fluorescence imaging of antibiotic clofazimine encapsulated within mesoporous silica particle carriers: relevance to drug delivery and the effect on its release kinetics. Phys Chem Chem Phys 20(17):11,899–11,911CrossRefGoogle Scholar
  2. Ashley GW, Henise J, Reid R, Santi DV (2013) Hydrogel drug delivery system with predictable and tunable drug release and degradation rates. Proc Natl Acad Sci 110(6):2318–2323CrossRefGoogle Scholar
  3. Baik J, Rosania GR (2012) Macrophages sequester clofazimine in an intracellular liquid crystal-like supramolecular organization. PLoS ONE 7(10):e47,494CrossRefGoogle Scholar
  4. Bakkour Y, Darcos V, Coumes F, Li S, Coudane J (2013) Brush-like amphiphilic copolymers based on polylactide and poly (ethylene glycol): synthesis, self-assembly and evaluation as drug carrier. Polymer 54(7):1746–1754CrossRefGoogle Scholar
  5. Bannigan P, Durack E, Madden C, Lusi M, Hudson SP (2017) Role of biorelevant dissolution media in the selection of optimal salt forms of oral drugs: maximizing the gastrointestinal solubility and in vitro activity of the antimicrobial molecule, clofazimine. ACS Omega 2(12):8969–8981CrossRefGoogle Scholar
  6. Bolla G, Nangia A (2012) Clofazimine mesylate: a high solubility stable salt. Cryst Growth Des 12(12):6250–6259CrossRefGoogle Scholar
  7. Chang C, Duan B, Cai J, Zhang L (2010) Superabsorbent hydrogels based on cellulose for smart swelling and controllable delivery. Eur Polym J 46(1):92–100CrossRefGoogle Scholar
  8. Chen MC, Tsai HW, Liu CT, Peng SF, Lai WY, Chen SJ, Chang Y, Sung HW (2009) A nanoscale drug-entrapment strategy for hydrogel-based systems for the delivery of poorly soluble drugs. Biomaterials 30(11):2102–2111CrossRefGoogle Scholar
  9. Daoud-Mahammed S, Grossiord J, Bergua T, Amiel C, Couvreur P, Gref R (2008) Self-assembling cyclodextrin based hydrogels for the sustained delivery of hydrophobic drugs. J Biomed Mater Res Part A 86(3):736–748CrossRefGoogle Scholar
  10. Darcos V, El Habnouni S, Nottelet B, El Ghzaoui A, Coudane J (2010) Well-defined pcl-graft-pdmaema prepared by ring-opening polymerisation and click chemistry. Polym Chem 1(3):280–282CrossRefGoogle Scholar
  11. Dash R, Ragauskas AJ (2012) Synthesis of a novel cellulose nanowhisker-based drug delivery system. RSC Adv 2(8):3403–3409CrossRefGoogle Scholar
  12. De France KJ, Hoare T, Cranston ED (2017) Review of hydrogels and aerogels containing nanocellulose. Chem Mater 29(11):4609–4631CrossRefGoogle Scholar
  13. Dong H, Snyder JF, Williams KS, Andzelm JW (2013) Cation-induced hydrogels of cellulose nanofibrils with tunable moduli. Biomacromolecules 14(9):3338–3345CrossRefGoogle Scholar
  14. Gunathilake TMSU, Ching YC, Chuah CH, Illias HA, Ching KY, Singh R, Nai-Shang L (2018) Influence of a nonionic surfactant on curcumin delivery of nanocellulose reinforced chitosan hydrogel. Int J Biol Macromol 118:1055–1064CrossRefGoogle Scholar
  15. He C, Kim SW, Lee DS (2008) In situ gelling stimuli-sensitive block copolymer hydrogels for drug delivery. J Controll Release 127(3):189–207CrossRefGoogle Scholar
  16. Izadifar M, Haddadi A, Chen X, Kelly ME (2014) Rate-programming of nano-particulate delivery systems for smart bioactive scaffolds in tissue engineering. Nanotechnology 26(1):012001CrossRefGoogle Scholar
  17. Jabeen S, Chat OA, Maswal M, Ashraf U, Rather GM, Dar AA (2015) Hydrogels of sodium alginate in cationic surfactants: surfactant dependent modulation of encapsulation/release toward ibuprofen. Carbohydr Polym 133:144–153CrossRefGoogle Scholar
  18. Jackson JK, Letchford K, Wasserman BZ, Ye L, Hamad WY, Burt HM (2011) The use of nanocrystalline cellulose for the binding and controlled release of drugs. Int J Nanomed 6:321Google Scholar
  19. Kalepu S, Nekkanti V (2015) Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B 5(5):442–453CrossRefGoogle Scholar
  20. Koetting MC, Peters JT, Steichen SD, Peppas NA (2015) Stimulus-responsive hydrogels: theory, modern advances, and applications. Mater Sci Eng R Rep 93:1–49CrossRefGoogle Scholar
  21. Koizumi T, Panomsuk SP (1995) Release of medicaments from spherical matrices containing drug in suspension: theoretical aspects. Int J Pharm 116(1):45–49CrossRefGoogle Scholar
  22. Kolakovic R, Laaksonen T, Peltonen L, Laukkanen A, Hirvonen J (2012) Spray-dried nanofibrillar cellulose microparticles for sustained drug release. Int J Pharm 430(1–2):47–55CrossRefGoogle Scholar
  23. Korhonen JT, Kettunen M, Ras RH, Ikkala O (2011) Hydrophobic nanocellulose aerogels as floating, sustainable, reusable, and recyclable oil absorbents. ACS Appl Mater Interfaces 3(6):1813–1816CrossRefGoogle Scholar
  24. Lagerwall JP, Schütz C, Salajkova M, Noh J, Park JH, Scalia G, Bergström L (2014) Cellulose nanocrystal-based materials: from liquid crystal self-assembly and glass formation to multifunctional thin films. NPG Asia Mater 6(1):e80CrossRefGoogle Scholar
  25. Li J, Mooney DJ (2016) Designing hydrogels for controlled drug delivery. Nat Rev Mater 1(12):16,071CrossRefGoogle Scholar
  26. Li S, Jasim A, Zhao W, Fu L, Ullah M, Shi Z, Yang G (2018) Fabrication of ph electroactive bacterial cellulose/polyaniline hydrogel for the development of a controlled drug release system. ES Mater Manuf 1:41–49Google Scholar
  27. Loftsson T, Brewster ME (2010) Pharmaceutical applications of cyclodextrins: basic science and product development. J Pharm Pharmacol 62(11):1607–1621CrossRefGoogle Scholar
  28. Maestri CA, Abrami M, Hazan S, Chistè E, Golan Y, Rohrer J, Bernkop-Schnürch A, Grassi M, Scarpa M, Bettotti P (2017a) Role of sonication pre-treatment and cation valence in the sol-gel transition of nano-cellulose suspensions. Sci Rep 7(1):11,129CrossRefGoogle Scholar
  29. Maestri CA, Bettotti P, Scarpa M (2017b) Fabrication of complex-shaped hydrogels by diffusion controlled gelation of nanocellulose crystallites. J Mater Chem B 5(40):8096–8104CrossRefGoogle Scholar
  30. Maswal M, Chat OA, Jabeen S, Ashraf U, Masrat R, Shah RA, Dar AA (2015) Solubilization and co-solubilization of carbamazepine and nifedipine in mixed micellar systems: insights from surface tension, electronic absorption, fluorescence and hplc measurements. RSC Adv 5(10):7697–7712CrossRefGoogle Scholar
  31. McKenzie M, Betts D, Suh A, Bui K, Kim LD, Cho H (2015) Hydrogel-based drug delivery systems for poorly water-soluble drugs. Molecules 20(11):20,397–20,408CrossRefGoogle Scholar
  32. Mehta RT (1996) Liposome encapsulation of clofazimine reduces toxicity in vitro and in vivo and improves therapeutic efficacy in the beige mouse model of disseminated mycobacterium avium-m. Intracellulare complex infection. Antimicrob Agents Chemother 40(8):1893–1902CrossRefGoogle Scholar
  33. Meng Y, Wu C, Zhang J, Cao Q, Liu Q, Yu Y (2015) Amphiphilic alginate as a drug release vehicle for water-insoluble drugs. Colloid J 77(6):754–760CrossRefGoogle Scholar
  34. Müller A, Ni Z, Hessler N, Wesarg F, Müller FA, Kralisch D, Fischer D (2013) The biopolymer bacterial nanocellulose as drug delivery system: investigation of drug loading and release using the model protein albumin. J Pharm Sci 102(2):579–592CrossRefGoogle Scholar
  35. Narang AS, Srivastava AK (2002) Evaluation of solid dispersions of clofazimine. Drug Dev Ind Pharm 28(8):1001–1013CrossRefGoogle Scholar
  36. Nie H, Mo H, Zhang M, Song Y, Fang K, Taylor LS, Li T, Byrn SR (2015) Investigating the interaction pattern and structural elements of a drug-polymer complex at the molecular level. Mol Pharm 12(7):2459–2468CrossRefGoogle Scholar
  37. Niño MRR, Patino JR (1998) Surface tension of bovine serum albumin and tween 20 at the air-aqueous interface. J Am Oil Chem Soc 75(10):1241CrossRefGoogle Scholar
  38. O’connor R, O’sullivan J, O’kennedy R (1995) The pharmacology, metabolism, and chemistry of clofazimine. Drug Metab Rev 27(4):591–614CrossRefGoogle Scholar
  39. O’Reilly JR, Corrigan OI, O’Driscoll CM (1994) The effect of simple micellar systems on the solubility and intestinal absorption of clofazimine (b663) in the anaesthetised rat. Int J Pharm 105(2):137–146CrossRefGoogle Scholar
  40. Patel V, Misra A (1999) Encapsulation and stability of clofazimine liposomes. J Microencapsul 16(3):357–367CrossRefGoogle Scholar
  41. Plackett DV, Letchford K, Jackson JK, Burt HM (2014) A review of nanocellulose as a novel vehicle for drug delivery. Nord Pulp Pap Res J 29(1):105–118CrossRefGoogle Scholar
  42. Rehman N, Mir MA, Jan M, Amin A, Dar AA, Rather GM (2009) Mixed micellization and interfacial properties of polyoxyethylene sorbitan esters with cetylpyridinium chloride: a tensiometric study. J Surfactants Deterg 12(4):295–304CrossRefGoogle Scholar
  43. Ritger PL, Peppas NA (1987) A simple equation for description of solute release i. fickian and non-fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs. J Controll Release 5(1):23–36CrossRefGoogle Scholar
  44. Saito T, Kimura S, Nishiyama Y, Isogai A (2007) Cellulose nanofibers prepared by tempo-mediated oxidation of native cellulose. Biomacromolecules 8(8):2485–2491CrossRefGoogle Scholar
  45. Salem II, Steffan G, Düzgünes N (2003) Efficacy of clofazimine-modified cyclodextrin against mycobacterium avium complex in human macrophages. Int J Pharm 260(1):105–114CrossRefGoogle Scholar
  46. Schott MA, Domurado M, Leclercq L, Barbaud C, Domurado D (2013) Solubilization of water-insoluble drugs due to random amphiphilic and degradable poly (dimethylmalic acid) derivatives. Biomacromolecules 14(6):1936–1944CrossRefGoogle Scholar
  47. Seki T, Kawaguchi T, Endoh H, Ishikawa K, Juni K, Nakano M (1990) Controlled release of 3’, 5’-diester prodrugs of 5’-fluoro-2’-deoxyuridine from poly-l-lactic acid microspheres. J Pharm Sci 79(11):985–987CrossRefGoogle Scholar
  48. Sharpe LA, Daily AM, Horava SD, Peppas NA (2014) Therapeutic applications of hydrogels in oral drug delivery. Expert Opin Drug Deliv 11(6):901–915CrossRefGoogle Scholar
  49. Shi Z, Gao X, Ullah MW, Li S, Wang Q, Yang G (2016) Electroconductive natural polymer-based hydrogels. Biomaterials 111:40–54CrossRefGoogle Scholar
  50. Sinclair GW, Peppas NA (1984) Analysis of non-fickian transport in polymers using simplified exponential expressions. J Membr Sci 17(3):329–331CrossRefGoogle Scholar
  51. Sri B, Ashok V, Arkendu C (2012) As a review on hydrogels as drug delivery in the pharmaceutical field. Int J Pharm Chem Sci 1(2):642–61Google Scholar
  52. Ullah MW, Ul-Islam M, Khan S, Kim Y, Park JK (2015) Innovative production of bio-cellulose using a cell-free system derived from a single cell line. Carbohydr Polym 132:286–294CrossRefGoogle Scholar
  53. Valo H, Arola S, Laaksonen P, Torkkeli M, Peltonen L, Linder MB, Serimaa R, Kuga S, Hirvonen J, Laaksonen T (2013) Drug release from nanoparticles embedded in four different nanofibrillar cellulose aerogels. Eur J Pharm Sci 50(1):69–77CrossRefGoogle Scholar
  54. Vashist A, Vashist A, Gupta Y, Ahmad S (2014) Recent advances in hydrogel based drug delivery systems for the human body. J Mater Chem B 2(2):147–166CrossRefGoogle Scholar
  55. Yano T, Kassovska-Bratinova S, Teh JS, Winkler J, Sullivan K, Isaacs A, Schechter NM, Rubin H (2011) Reduction of clofazimine by mycobacterial type 2 nadh: quinone oxidoreductase a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem 286(12):10,276–10,287CrossRefGoogle Scholar
  56. Zahedi P, Lee PI (2007) Solid molecular dispersions of poorly water-soluble drugs in poly (2-hydroxyethyl methacrylate) hydrogels. Eur J Pharm Biopharm 65(3):320–328CrossRefGoogle Scholar
  57. Zhang S, Anderson MA, Ao Y, Khakh BS, Fan J, Deming TJ, Sofroniew MV (2014) Tunable diblock copolypeptide hydrogel depots for local delivery of hydrophobic molecules in healthy and injured central nervous system. Biomaterials 35(6):1989–2000CrossRefGoogle Scholar
  58. Zhang Y, Feng J, McManus SA, Lu HD, Ristroph KD, Cho EJ, Dobrijevic EL, Chan HK, Prudhomme RK (2017a) Design and solidification of fast-releasing clofazimine nanoparticles for treatment of cryptosporidiosis. Mol Pharm 14(10):3480–3488CrossRefGoogle Scholar
  59. Zhang Y, Feng J, McManus SA, Lu HD, Ristroph KD, Cho EJ, Dobrijevic EL, Chan HK, Prud’homme RK (2017b) Design and solidification of fast-releasing clofazimine nanoparticles for treatment of cryptosporidiosis. Mol Pharm 14(10):3480–3488CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of PhysicsUniversity of TrentoPovoItaly

Personalised recommendations