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AAPS PharmSciTech

, 20:33 | Cite as

Topical Delivery of Artemisone, Clofazimine and Decoquinate Encapsulated in Vesicles and Their In vitro Efficacy Against Mycobacterium tuberculosis

  • Lindi van Zyl
  • Joe M. Viljoen
  • Richard K. Haynes
  • Marique Aucamp
  • Andile H. Ngwane
  • Jeanetta du Plessis
Research Article

Abstract

Vesicles are widely investigated as carrier systems for active pharmaceutical ingredients (APIs). For topical delivery, they are especially effective since they create a “depot-effect” thereby concentrating the APIs in the skin. Artemisone, clofazimine and decoquinate were selected as a combination therapy for the topical treatment of cutaneous tuberculosis. Delivering APIs into the skin presents various challenges. However, utilising niosomes, liposomes and transferosomes as carrier systems may circumvent these challenges. Vesicles containing 1% of each of the three selected APIs were prepared using the thin-film hydration method. Isothermal calorimetry, differential scanning calorimetry and hot-stage microscopy indicated no to minimal incompatibility between the APIs and the vesicle components. Encapsulation efficiency was higher than 85% for all vesicle dispersions. Vesicle stability decreased and size increased with an increase in API concentration; and ultimately, niosomes were found the least stable of the different vesicle types. Skin diffusion studies were subsequently conducted for 12 h on black human female skin utilising vertical Franz diffusion cells. Transferosomes and niosomes delivered the highest average concentrations of clofazimine and decoquinate into the skin, whereas artemisone was not detected and no APIs were present in the receptor phase. Finally, efficacy against tuberculosis was tested against the Mycobacterium tuberculosis H37Rv laboratory strain. All the dispersions depicted some activity, surprisingly even the blank vesicles portrayed activity. However, the highest percentage inhibition (52%) against TB was obtained with niosomes containing 1% clofazimine.

KEY WORDS

vesicles artemisone clofazimine decoquinate topical delivery 

Notes

Acknowledgements

The authors would like to thank the South African Medical Research Council for the support under the Flagship Project MALTB Redox, the Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, South Africa and the National Research Foundation of South-Africa for their financial contribution to this project (grant number CPRR13091742482). Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors and therefore the NRF does not accept any liability in regard thereto.

References

  1. 1.
    Hickey AJ, editor. Delivery systems for tuberculosis prevention and treatment. UK: John Wiley & Sons; 2016.Google Scholar
  2. 2.
    Ingraham JL, Ingraham CA. Introduction to microbiology: a case history approach. 3rd ed. Brooks/Cole: Belmont, CA; 2007.Google Scholar
  3. 3.
    Kgosana R TB remains the no 1 killer in South Africa. 2018. https://citizen.co.za/news/south-africa/1870743/tb-remains-the-no-1-killer-in-south-africa/. Accessed 1 May 2018.
  4. 4.
  5. 5.
    WHO Global Tuberculosis Report 2018. 2018. http://www.who.int/tb/publications/global_report/en/. Accessed 25 April 2018.
  6. 6.
    WHO. Global tuberculosis report 2017 factsheet. 2017. http://www.who.int/tb/publicationsC2_2017GLOBAL_FACTSHEET.pdf?ua=1. Accessed 22 April 2018.
  7. 7.
    van Zyl L, du Plessis J, Viljoen J. Cutaneous tuberculosis overview and current treatment regimens. Tuberculosis. 2015;95:629–38.  https://doi.org/10.1016/j.tube.2014.12.006.CrossRefPubMedGoogle Scholar
  8. 8.
    Ghosh S, Aggarwal K, Jain VK, Chaudhuri S, Ghosh E, Arshdeep. Tuberculosis verrucosa cut is presenting as diffuse plantar keratoderma: an unusual sight. Indian J Dermatol. 2014;59(1):80–1.CrossRefGoogle Scholar
  9. 9.
    Stockamp NW, Paul S, Sharma S, Libke RD, Boswell JS, Nassar NN. Cutaneous tuberculosis of the penis in an HIV-infected adult. Int J STD AIDS. 2013;24:57–8.CrossRefGoogle Scholar
  10. 10.
    Abdelmalek R, Mebazaa A, Berriche A, Kilani B, Osman AB, Mokni M, et al. Cutaneous tuberculosis in Tunisia. Med Mal Infect. 2013;43(9):374–8.CrossRefGoogle Scholar
  11. 11.
    Baig IA, Moon JY, Kim MS, Koo BS, Yoon MY. Structural and functional significance of the highly-conserved residues in Mycobacterium tuberculosis acetohydroxyacid synthase. Enzym Microb Technol. 2014;58–59:52–9.CrossRefGoogle Scholar
  12. 12.
    Fader T, Parks J, Khan NU, Manning R, Stokes S, Nasir NA. Extrapulmonary tuberculosis in Kabul, Afghanistan: a hospital-based retrospective review. IJID. 2010;14(2):e102–10.PubMedGoogle Scholar
  13. 13.
    Solis AH, González NEH, Cazarez F, Pérez PM, Diaz HO, Escobar-Gutierrez A, et al. Skin biopsy: a pillar in the identification of cutaneous Mycobacterium tuberculosis infection. J Infect Dev Ctries. 2012;6(8):626–31.CrossRefGoogle Scholar
  14. 14.
    Gentry CA Atypical Mycobacteria. http://www.accp.com/docs/bookstore/psap/ p5b6sample02.pdf. Accessed 14 March 2018.Google Scholar
  15. 15.
    Jones-Lopez EC, Ellner JJ. Tuberculosis and atypical mycobacterial infections. In: Guerrant RL, Walker DH, Weller PF, editors. Tropical infectious diseases. 3rd ed. London: Elsevier Inc.; 2011. p. 228–47.Google Scholar
  16. 16.
    Walter N, Daley CL. Tuberculosis and nontuberculous mycobacterial infections. In: Spiro SG, Silvestri GA, Agustí A, editors. Clinical respiratory medicine. 4th ed. Philadelphia: Elsevier Ltd.; 2012. p. 383–405.CrossRefGoogle Scholar
  17. 17.
    Yates VM. Mycobacterial infections. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s textbook of dermatology, vol. 2. 8th ed. West Sussex: Blackwell Publishing Ltd; 2010. p. 31.1–31.41.Google Scholar
  18. 18.
    WHO. 2016. The end TB strategy. http://www.who.int/tb/post2015_TBstrategy.pdf?ua=1. Accessed 22 April 2018.
  19. 19.
    Blomberg B, Spinaci B, Fourie R, Laing R. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis, bulletin. 2001. http://www.ncbi.nirm.nih.gov/pubmed/11217670. Accessed 25 April 2018.
  20. 20.
    Dooley KE, Obuku EA, Durakovic N, Belitsky V, Mitnick C, Nuermberger V. World Health Organization group 5 drugs for the treatment of drug-resistant tuberculosis: unclear efficacy or untapped potential? J Infect Dis. 2013;207:1352–8.CrossRefGoogle Scholar
  21. 21.
    Beteck RM, Coertzen D, Smit FJ, Birkholtz LM, Haynes RK, N'Da DD. Straightforward conversion of decoquinate into inexpensive tractable new derivatives with significant antimalarial activities. Bioorg Med Chem Lett. 2016;26(13):3006–9.  https://doi.org/10.1016/j.bmcl.2016.05.024.CrossRefPubMedGoogle Scholar
  22. 22.
    Chan WC, Chan DHW, Lee KW, Tin WS, Wong HN, Haynes RK. Evaluation and optimization of synthetic routes from dihydroartemisinin to the alkylamino-artemisinins artemiside and artemisone: a test of n-glycosylation methodologies on a lipophilic peroxide. Tetrahedron. 2018;74:5156–71.CrossRefGoogle Scholar
  23. 23.
    Steyn JD, Wiesner L, du Plessis LH, Grobler AF, Smith PJ, Chan WC, et al. Absorption of the novel artemisinin derivatives artemisone and artemiside: potential application of Pheroid™ technology. Int J Pharm. 2011;414:260–6.CrossRefGoogle Scholar
  24. 24.
    Dunay IR, Chi Chan W, Haynes RK, Sibley LD. Artemisone and artemiside control acute and reactivated toxoplasmosis in a murine model. J Antimicrob Agents Chemother. 2009;53:4450–6.CrossRefGoogle Scholar
  25. 25.
    Nagelschmitz J, Voith B, Wensing G, Roemer A, Fugmann B, Haynes RK, et al. First assessment in humans of the safety, tolerability, pharmacokinetics, and ex vivo pharmacodynamics antimalarial activity of the new artemisinin derivative artemisone. Antimicrob Agents Chemother. 2008;52:3085–91.CrossRefGoogle Scholar
  26. 26.
    Vivas L, Rattray L, Stewart LB, Robinson BL, Fugmann B, Haynes RK, et al. Antimalarial efficacy and drug interactions of the novel semi-synthetic endoperoxide artemisone in vitro and in vivo. J Antimicrob Chemother. 2007;59:658–65.CrossRefGoogle Scholar
  27. 27.
    Haynes RK, Fugmann B, Stetter J, Rieckmann K, Heilmann H-D, Chan H-W, et al. Artemisone—a highly active antimalarial drug of the artemisinin class. Angew Chem Internat Edit. 2006;45:2082–8.CrossRefGoogle Scholar
  28. 28.
    Biamonte MA, Wanner J, le Roch KG. Recent advances in malaria drug discovery. Bioorganic Med Chem Lett. 2013;23:2829–43.CrossRefGoogle Scholar
  29. 29.
    Coertzen D, Readera J, van der Watt M, Nondaba SH, Gibhard L, Wiesner L, et al. Artemisone and artemiside—potent pan-reactive antimalarial agents that also synergize redox imbalance in P. falciparum transmissible gametocyte stages. Antimicrob Agents Chemother. 2018.  https://doi.org/10.1128/AAC.02214-17.
  30. 30.
    Golenser J, Buchholz V, Bagheri A, Nasereddin A, Dzikowski R, Guo J, et al. Controlled release of artemisone for the treatment of experimental cerebral malaria. Parasit Vectors. 2017;10:117.  https://doi.org/10.1186/s13071-017-2018-7.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    World Health Organisation (WHO) Facts on ACTs (Artemisinin-based combination therapies). 2006. http://www.who.int/malaria . Accessed 25 November 2017.
  32. 32.
    Cholo M, Steel H, Fourie P, Germishuizen WA, Anderson R. Clofazimine: current status and future prospects. J Antimicrob Chemother. 2012;2012(67):290–8.CrossRefGoogle Scholar
  33. 33.
    Jagannath C, Reddy M, Kailasam S, O’Sullivan JF, Gangadharam PR. Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis. In vitro, intracellular, and in vivo studies. Am J Respir Crit Care Med. 1995;151:1083–6.PubMedGoogle Scholar
  34. 34.
    Dey T, Helen G, Shubber C, Cooke G, Ford N. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother. 2013;68(2):284–93.CrossRefGoogle Scholar
  35. 35.
    Yano T, Kassovska-Bratinova S, Teh JS, Winkler J, Sullivan K, Isaacs A, et al. Reduction of clofazimine by mycobacterial type 2 NADH:quinone oxido-reductase; a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem. 2011;286:10276–87.CrossRefGoogle Scholar
  36. 36.
    Mikota SK, Plumb DC. Elephant formulary. 2017. http://elephantcare.org/resources/ formulary/drug-index/decoquinate/. Accessed 11 October 2017.Google Scholar
  37. 37.
    Williams RB. The mode of action of anticoccidial quinolones (6-decyloxy-4-hydroxyquinoline-3-carboxylates) in chickens. Int J Parasitol. 1997;27:101–11.CrossRefGoogle Scholar
  38. 38.
    Gillet A, Lecomte F, Hubert P, Ducat E, Evrard B, Piel G. Skin penetration behaviour of liposomes as a function of their composition. Eur J Pharm Biopharm. 2011;79:43–53.CrossRefGoogle Scholar
  39. 39.
    Tavano L, Gentile L, Rossi CO, Muzzalupo R. Novel gel-niosomes formulations as multicomponent systems for transdermal drug delivery. Colloids Surf B: Biointerfaces. 2013;110:281–8.CrossRefGoogle Scholar
  40. 40.
    USP Pharmacopoeia online. 2015. http://www.uspbpep.com/usp29/v29240/usp29nf245O_m22310.html. Accessed 8 January 2016.
  41. 41.
    Chembase. 2015. http://en.chembase.cn/molecule-157442.html. Accessed 11 May 2017.
  42. 42.
    Dragicevic-Curic N, Maibach HI. Percutaneous penetration enhancers—chemical methods in penetration enhancement: drug manipulation strategies and vehicle effects. 1st ed. New York: Springer; 2015.CrossRefGoogle Scholar
  43. 43.
    Borody TJ, Gosselin P. Fixed-dose pharmaceutical composition comprising rifabutin, Clarithromycin, and clofazimine. US patent no 20180125872A1. Washington, DC: U.S. Patent and Trademark Office. 2018.Google Scholar
  44. 44.
    Zhang Y, Feng J, McManus SA, Lu HD, Ristroph KD, Cho EJ, et al. Design and solidification of fast-releasing Clofazimine nanoparticles for treatment of cryptosporidiosis. Mol Pharm. 2017;14:3480–8.  https://doi.org/10.1021/acs.molpharmaceut.7b00521.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Mahale NB, Thakkar PD, Mali RG, Walunj DR, Chaudhari SR. Niosomes: novel sustained release nonionic stable vesicular systems—an overview. Adv Colloid Interf Sci. 2012;183-184:46–54.CrossRefGoogle Scholar
  46. 46.
    Nam T, McNamara CW, Bopp S, Dharia NV, Meister S, Bonamy GMC, et al. A chemical genomic analysis of decoquinate, a Plasmodium falciparum cytochrome b inhibitor. ACS Chem Biol. 2011;6:1214–22.  https://doi.org/10.1021/cb200105d.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Chen F-J, Patel MV, Fikstad DT, Zhang H, Gilyar C. Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs. US patent no 20180125979A1. Washington, DC: U.S. Patent and Trademark Office. 2018.Google Scholar
  48. 48.
    Jain S, Jain V, Mahajan SC. Lipid based vesicular drug delivery systems. Adv Pharm. 2014;2014:1–12.Google Scholar
  49. 49.
    Kaur IP, Singh H. Nanostructured drug delivery for better management of tuberculosis. J Control Release. 2014;18:36–50.CrossRefGoogle Scholar
  50. 50.
    Lim JA, Tan WC, Khor BT, Chand SDHG, Palanivelu T. Early onset of squamous cell carcinoma arising from tuberculosis verrucosa cutis. J Am Col Clin Wound Spec. 2018.  https://doi.org/10.1016/j.jccw.2018.06.003.
  51. 51.
    Agarwal R, Katare OP, Vyas SP. Preparation and in vitro evaluation of liposomal/niosomal delivery systems for antipsoriatic drug dithranol. Int J Pharm. 2001;288:43–52.CrossRefGoogle Scholar
  52. 52.
    Shaji J, Lal M. Preparation, optimization and evaluation of transferosomal formulation for enhanced transdermal delivery of a COX-2 inhibitor. Int J Pharm Pharm Sci. 2014;6:467–77.Google Scholar
  53. 53.
    New RRC. Liposomes: a practical approach. 1st ed. New York: Oxford university press; 1990.Google Scholar
  54. 54.
    Zhao C, Tong K, Tan J, Liu Q, Wu T, Sun D. Colloidal properties of montmorillonite suspensions modified with polyetheramine. Colloids Surf A Physicochem Eng Asp. 2014;457:8–15.CrossRefGoogle Scholar
  55. 55.
    Eid AM, El-enshasym HA, Aziz R, Elmarguzi NA. Preparation, characeterization and anti-inflammatory activity of Swientenia macrophylla nanoemulgel. J Nanomed Nanotechnol. 2014;5:1–10.CrossRefGoogle Scholar
  56. 56.
    Van Zyl L, du Preez J, Gerber M, du Plessis J, Viljoen J. Essential fatty acids as transdermal penetration enhancers. J Pharm Sci. 2016;105:188–93.CrossRefGoogle Scholar
  57. 57.
    Lechartier B, Cole ST. Mode of action of clofazimine and combination therapy with benzothiazinones against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2015;59:4457–63.CrossRefGoogle Scholar
  58. 58.
    TA Instruments: Microcalorimetry. 2012. http://www.tainstruments.com/pdf/brochure/ MicrocalorimetryBrochure.pdf. Accessed 24 Sept 2018.Google Scholar
  59. 59.
    DT: Dispersion technology Inc. Zeta potential, Short tutorial. 2013. http://www.dispersion.com/zeta-potential-short-tutorial. Accessed 17 May 2016.
  60. 60.
    Malvern instruments Ltd. Zetasizer nano series: User manual (MAN0317; issue 1.1). England: Malvern Instruments ltd; 2004.Google Scholar
  61. 61.
    Yukuyama MN, Ghisleni DDM, Pinto TJA, Bou-Chacra NA. Nanoemulsion: process selection and application in cosmetics—a review. Int J Cosmet Sci. 2015.  https://doi.org/10.1111/ics.12260 n/a–n/a.
  62. 62.
    Bouchemal K, Briançon S, Perrier E, Fessi H. Nano-emulsion formulation using spontaneous emulsification: solvent, oil and surfactant optimization. Int J Pharm. 2004;280(1–2):241–51.  https://doi.org/10.1016/j.ijpharm.2004.05.016.CrossRefPubMedGoogle Scholar
  63. 63.
    Allioda O, Valoura J-P, Urbaniaka S, Fessia H, Dupinb D, Charcosseta C. Preparation of oil-in-water nanoemulsions at large-scale using premix membrane emulsification and Shirasu Porous Glass (SPG) membranes. Colloids Surf A Physicochem Eng Asp. 2018;557:76–84.CrossRefGoogle Scholar
  64. 64.
    Paudel KS, Milewski M, Swadley CL, Brogden NK, Ghosh P, Stinchcomb A. Challenges and opportunities in dermal/transdermal delivery. Ther Deliv. 2010;1:109–31.CrossRefGoogle Scholar
  65. 65.
    Leite-Silva VR, De Almeida MM, Fradin A, Grice JE, Roberts MS. Delivery of drugs applied topically to the skin: advanced formulation. 2012. http://www.medscape.org/viewarticle/771038_3. Accessed 18 May 2016
  66. 66.
    Crittenden JC, Trussel RR, Hand DW, Howe KJ, Tchobanoglous G. MWH’s water treatment: principles and design. 3rd ed. New Jersey: John Wiley & Sons, Inc.; 2012.CrossRefGoogle Scholar
  67. 67.
    Colloidal Dynamics: Leaders in colloidal measurement. Electroaccoustics tutorials: The zeta potential 1999. http://www.colloidal-dynamics.com/docs/CDElTut1.pdf. Accessed 21 September 2018.
  68. 68.
  69. 69.
  70. 70.
    Ouellet H, Johnston JB, Ortiz de Montellano PR. Cholesterol catabolism as a therapeutic target in Mycobacterium tuberculosis. Trends Microbiol. 2011;19(11):530–9.CrossRefGoogle Scholar
  71. 71.
    Manconi M, Sinico C, Caddeo C, Vila AO, Valenti D, Fadda AM. Penetration enhancer containing vesicles as carriers for dermal delivery of tretinoin. Int J Pharm. 2011;412:37–46.CrossRefGoogle Scholar
  72. 72.
    Job CK, Yoder L, Jackobson RR, Hastings RC. Skin pigmentation from clofazimine therapy in leprosy patients: a reappraisal. J Am Acad Dermatol. 1990;23:236–41.CrossRefGoogle Scholar
  73. 73.
    Smith M, Accinelli A, Tejada FR, Kharel MK. Chapter 28—drugs used in tuberculosis and leprosy. Side Effect Drug Annual. 2016;38:283–93.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  1. 1.Centre of Excellence for Pharmaceutical SciencesNorth-West UniversityPotchefstroomSouth Africa
  2. 2.DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health SciencesStellenbosch UniversityTygerbergSouth Africa

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