Abstract
The present study was intended to enhance the permeation of artemether and lumefantrine by encapsulating in dissolvable microneedle arrays for extended action. Lumefantrine-nanoparticles were synthesized using chitosan mediated gelation and optimized by 22 factorial designs. The particle size, zeta potential and % entrapment efficiency of the optimized nanoparticles F5 were 105 ± 3.64 nm, 24.4 ± 0.54 mV and 83.94 ± 1.71%, respectively. The nanoparticles showed a controlled-release of 79.15 ± 2.45% for lumefantrine after 24 h and stability for 6 months. A combination of biocompatible polymers (PVA and PVP K − 12) was used to develop dissolvable microneedle of artemether co-loaded lumefantrine nanoparticles. The SEM and TEM analysis confirmed the needle-shaped morphology with a size of 672 ± 0.99 μm. The in-vitro release of microneedle showed biphasic release pattern for both artemether and lumefantrine, with an initial burst followed by controlled-release profile. The ex-vivo study of optimized formulation showed 70.94 ± 2.45% and 65.87 ± 1.94% permeation for artemether and lumefantrine, respectively, after 24 h. Thus, microneedle-based delivery provides an alternative to painful intravenous administration and a promising approach to increase the penetration of drugs across the skin barrier.
Fabrication of microneedle arrays of artemether co-loaded with lumefantrine nanoparticles.
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Abbreviations
- PVA:
-
Polyvinyl alcohol
- PVP K12:
-
Polyvinyl pyrrolidone
- ACT:
-
Artemisinin-based combination therapy
- MN:
-
Microneedle
- STPP:
-
Sodium tripolyphosphate
- BKC:
-
Benzalkonium chloride
- HPMC:
-
Hydroxypropyl methylcellulose
- HPC:
-
Hydroxypropyl cellulose
- MPS:
-
Mean particle size
- PDI:
-
Polydispersity index
- EE:
-
Entrapment efficiency
- HPH:
-
High-pressure homogenizer
References
C. Agbo et al., Formulation design, in vitro characterizations and anti-malarial investigations of artemether and lumefantrine-entrapped solid lipid microparticles. Drug Dev. Ind. Pharm. 42(10), 1708–1721 (2016). https://doi.org/10.3109/03639045.2016.1171331
S.W. Ali, S. Rajendran, M. Joshi, Synthesis and characterization of chitosan and silver loaded chitosan nanoparticles for bioactive polyester. Carbohydr. Polym. 83(2), 438–446 (2011). https://doi.org/10.1016/j.carbpol.2010.08.004
A.Z. Alkilani, M.T. McCrudden, R.F. Donnelly, Transdermal drug delivery: Innovative pharmaceutical developments based on disruption of the barrier properties of the stratum corneum. Pharmaceutics. 7(4), 438–470 (2015). https://doi.org/10.3390/pharmaceutics7040438
D. Bhadra, S. Bhadra, N.K. Jain, PEGylated peptide dendrimeric carriers for the delivery of antimalarial drug chloroquine phosphate. Pharm. Res. 23(3), 623–633 (2006). https://doi.org/10.1007/s11095-005-9396-9
S. Bhatnagar et al., Dissolvable microneedle patch containing doxorubicin and docetaxel is effective in 4T1 xenografted breast cancer mouse model. Int. J. Pharm. 556, 263–275 (2019). https://doi.org/10.1016/j.ijpharm.2018.12.022
M.D. Bhavsar, S.B. Tiwari, M.M. Amiji, Formulation optimization for the nanoparticles in-microsphere hybrid oral delivery system using factorial design. J. Cont. Rel. 110(2), 422–430 (2006). https://doi.org/10.1016/j.jconrel.2005.11.001
J. Choi et al., Development of a film-based immunochromatographic microfluidic device for malaria diagnosis. Biomed. Microdevices 21(4) (2019). https://doi.org/10.1007/s10544-019-0431-8
M. Cormier et al., Transdermal delivery of desmopressin using a coated microneedle array patch system. J. Cont. Rel. 97(3), 503–511 (2004). https://doi.org/10.1016/j.jconrel.2004.04.003
K. Derakhshandeh, M. Erfan, S. Dadashzadeh, Encapsulation of 9-nitrocamptothecin, a novel anticancer drug, in biodegradable nanoparticles: Factorial design, characterization and release kinetics. Eur. J. Pharm. Biopharm. 66(1), 34–41 (2007). https://doi.org/10.1016/j.ejpb.2006.09.004
R.F. Donnelly, M.T. McCrudden, A.Z. Alkilani, et al., Hydrogel-forming microneedles prepared from super swelling polymers combined with lyophilized wafers for transdermal drug delivery. PLoS One 9(10), e111547 (2014). https://doi.org/10.1371/journal.pone.0111547
O. Egunsola, K.A. Oshikoya, Comparative safety of artemether-lumefantrine and other artemisinin-based combinations in children: a systematic review. Malar. J. 12(1), 385 (2013). https://doi.org/10.1186/1475-2875-12-385
R. Fule et al., Solubility and dissolution rate enhancement of lumefantrine using hot melt extrusion technology with physicochemical characterization. J. Pharm. Investig. 43(4), 305–321 (2013). https://doi.org/10.1007/s40005-013-0078-z
A. Garg, K. Bhalala, D.S. Tomar, In-situ single pass intestinal permeability and pharmacokinetic study of developed lumefantrine loaded solid lipid nanoparticles. Int. J. Pharm. 516(1–2), 120–130 (2017). https://doi.org/10.1016/j.ijpharm.2016.10.064
M.J. Garland et al., Dissolving polymeric microneedle arrays for electrically assisted transdermal drug delivery. J. Cont. Rel. 159(1), 52–59 (2012). https://doi.org/10.1016/j.jconrel.2012.01.003
M. Gharib et al., Micro-needle drug delivery systems. California Instit. of Technol. 2016 U.S. Patent Application 20160144100A1
S. Henry et al., Microfabricated microneedles: A novel approach to transdermal drug delivery. J. Pharm. Sci. 87(8), 922–925 (1998). https://doi.org/10.1021/js980042+
P.P. Ige, S.N. Dipsingh, Preparation and in vitro–in vivo evaluation of surface-modified poly (lactide-co-glycolide) nanoparticles as controlled release carriers for flutamide delivery. J. Microencapsul. 32(3), 231–239 (2015). https://doi.org/10.3109/02652048.2014.995731
A. Jain et al., Fabrication, characterization and cytotoxicity studies of ionically cross-linked docetaxel loaded chitosan nanoparticles. Carbohydr. Polym. 137, 65–74 (2016). https://doi.org/10.1016/j.carbpol.2015.10.012
K.A. Janes et al., Chitosan nanoparticles as delivery systems for doxorubicin. J. Cont. Rel. 73, 255–267 (2001). https://doi.org/10.1016/S0168-3659(01)00294-2
F. Kesisoglou, S. Panmai, Y. Wu, Nanosizing-oral formulation development and biopharmaceutical evaluation. Adv. Drug Deliv. Rev. 59(7), 631–644 (2007). https://doi.org/10.1016/j.addr.2007.05.003
R. Kudarha et al., Box–Behnken study design for optimization of bicalutamide-loaded nanostructured lipid carrier: Stability assessment. Pharm. Dev. Technol. 20(5), 608–618 (2015). https://doi.org/10.3109/10837450.2014.908305
J.W. Lee, J.H. Park, M.R. Prausnitz, Dissolving microneedles for transdermal drug delivery. Biomaterials 29(13), 2113–2124 (2008). https://doi.org/10.1016/j.biomaterials.2007.12.048
I.C. Lee et al., Fabrication of a novel partially dissolving polymer microneedle patch for transdermal drug delivery. J. Mater. Chem. B 3(2), 276–285 (2015). https://doi.org/10.1039/C4TB01555J
Y. Luo et al., Preparation, characterization and evaluation of selenite-loaded chitosan/TPP nanoparticles with or without zein coating. Carbohydr. Polym. 82(3), 942–951 (2010). https://doi.org/10.1016/j.carbpol.2010.06.029
C.J. Martin et al., Low temperature fabrication of biodegradable sugar glass microneedles for transdermal drug delivery applications. J. Cont. Rel. 158(1), 93–101 (2012). https://doi.org/10.1016/j.jconrel.2011.10.024
N. Martinho, C. Damgé, C.P. Reis, Recent advances in drug delivery systems. J Biomater. Nanobiotechnol. 2, 510 (2011). https://doi.org/10.4236/jbnb.2011.225062
S.N. Murthy, S.M. Sammeta, C. Bowers, Magnetophoresis for enhancing transdermal drug delivery: Mechanistic studies and patch design. J. Cont. Rel. 148(2), 197–203 (2010). https://doi.org/10.1016/j.jconrel.2010.08.015
H.X. Nguyen et al., Poly (vinyl alcohol) microneedles: Fabrication, characterization, and application for transdermal drug delivery of doxorubicin. Eur. J. Pharm. Biopharm. 129, 88–103 (2018). https://doi.org/10.1016/j.ejpb.2018.05.017
D. Parashar, N.P. Aditya, R.S.R. Murthy, Development of artemether and lumefantrine co-loaded nanostructured lipid carriers: Physicochemical characterization and in-vivo antimalarial activity. Drug Deliv. 23(1), 123–129 (2016). https://doi.org/10.3109/10717544.2014.905883
C.V. Pardeshi et al., Novel surface modified solid lipid nanoparticles as intranasal carriers for ropinirole hydrochloride: Application of factorial design approach. Drug Deliv. 20(1), 47–56 (2013). https://doi.org/10.3109/10717544.2012.752421
K. Patel, V. Sarma, P. Vavia, Design and evaluation of lumefantrine–oleic acid self nanoemulsifying ionic complex for enhanced dissolution. Daru 21(1), 27 (2013). https://doi.org/10.1186/2008-2231-21-27
J.K. Patra, G. Das, L.F. Fraceto, et al., Nano based drug delivery systems: Recent developments and future prospects. J. Nanobiotechnol. 16, 71 (2018). https://doi.org/10.1186/s12951-018-0392-8
R. Pignatello et al., Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials. 23(15), 3247–3255 (2002). https://doi.org/10.1016/S0142-9612(02)00080-7
A. Ripolin, J. Quinn, E. Larraneta, et al., Successful application of large microneedle patches by human volunteers. Int. J. Pharm. 521(1–2), 92–101 (2017). https://doi.org/10.1016/j.ijpharm.2017.02.011
A.H. Sabri et al., Expanding the applications of microneedles in dermatology. Eur. J. Pharm. Biopharm. 140, 121–140 (2019). https://doi.org/10.1016/j.ejpb.2019.05.001
H.M. Shapiro et al., Cytometry in malaria-a practical replacement for microscopy? Curr. Protoc. Cytom. 65(1), 11–20 (2013). https://doi.org/10.1002/0471142956.cy1120s65
P. Shende, M. Salunke, Transepidermal microneedles for co-administration of folic acid with methotrexate in the treatment of rheumatoid arthritis. Biomed. Phys. Eng. Express. 5(2), 025023 (2019). https://doi.org/10.1088/2057-1976/aafbbb
P. Shende et al., Physicochemical investigation of engineered nanosuspensions containing model drug lansoprazole. J. Dispers. Sci. Technol. 37(4), 504–511 (2016). https://doi.org/10.1080/01932691.2015.1046553
P. Shende et al., Engineering of microcomplex of artemether and lumefantrine for effective drug treatment in malaria. Artif. Cells. Nanomed. Biotechnol. 45(8), 1597–1604 (2017). https://doi.org/10.1080/21691401.2016.1267012
S.P. Singh et al., Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats. Malar. J. 10(1), 293 (2011). https://doi.org/10.1186/1475-2875-10-293
R. Watkins, L. Wu, C. Zhang, et al., Natural product-based nanomedicine: Recent advances and issues. Int. J. Nanomedicine 10, 6055 (2015). https://doi.org/10.2147/IJN.S92162
N.J. White, M. van Vugt, F.D. Ezzet, Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clin. Pharmacokinet. 37(2), 105–125 (1999). https://doi.org/10.2165/00003088-199937020-00002
World Malaria Report 2010 https://www.who.int/malaria/world_malaria_report_2010/en/
R. Yoksan, J. Jirawutthiwongchai, K. Arpo, Encapsulation of ascorbyl palmitate in chitosan nanoparticles by oil-in-water emulsion and ionic gelation processes. Colloids Surf. B. Biointerfaces. 76(1), 292–297 (2010). https://doi.org/10.1016/j.colsurfb.2009.11.007
K. Zhao, J. Singh, In vitro percutaneous absorption enhancement of propranolol hydrochloride through porcine epidermis by terpenes/ethanol. J. Cont. Rel. 62(3), 359–366 (1999). https://doi.org/10.1016/s0168-3659(99)00171-6
L.J. Zhou et al., Risk of drug resistance in Plasmodium falciparum malaria therapy-a systematic review and meta-analysis. J. Parasitol. Res. 116(2), 781–788 (2017). https://doi.org/10.1007/s00436-016-5353-2
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Pawar, S., Shende, P. 22 factorial design-based biocompatible microneedle arrays containing artemether co-loaded with lumefantrine nanoparticles for transepidermal delivery. Biomed Microdevices 22, 19 (2020). https://doi.org/10.1007/s10544-020-0476-8
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DOI: https://doi.org/10.1007/s10544-020-0476-8