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Recent Patents on Biotechnology


ISSN (Print): 1872-2083
ISSN (Online): 2212-4012

Research Article

Development Insights of Surface Modified Lipid Nanoemulsions of Dihydroartemisinin for Malaria Chemotherapy: Characterization, and in vivo Antimalarial Evaluation

Author(s): Chukwuebuka E. Umeyor*, Onyedikachi Obachie, Rozeeta Chukwuka and Anthony Attama

Volume 13 , Issue 2 , 2019

Page: [149 - 165] Pages: 17

DOI: 10.2174/1872208313666181204095314

Price: $65


Background: The use of dihydroartemisinin (DHA) for effective malaria treatment is challenged by its poor aqueous solubility and inadequate bioavailability leading to treatment failures and emergence of resistant strains. A review of some novel drug delivery systems developed to address these challenges and their patents revealed that no study has reported the application of surface modified lipid nanoemulsions for improved antimalarial activity of DHA.

Objective: The main thrust of this study is to develop oral dihydroartemisinin formulations solubilized in surface modified lipid nanoemulsions, characterize, and evaluate their activity against murine malaria.

Method: Lipid nanoemulsions containing dihydroartemisinin were formulated by high pressure homogenization using soybean oil, and polyethylene glycol 4000 was employed for surface modification. The formulations were characterized for droplet size, surface charge, pH, fouriertransform infrared spectroscopy, and surface morphology, viscosity and drug content efficiency. In vitro haemolytic study as a function of cytotoxicity using red blood cells as well as in vivo anti-malarial study using murine malaria model was also investigated.

Results: Nanoemulsions recorded droplet sizes ranging from 26 – 56 nm, and zeta potential in the range of -28 to -35 mV. The formulations were slightly acidic (pH 4.4 – 5.8) with the drug molecularly dispersed as seen using infrared spectroscopy. The formulations showed non- Newtonian flow with significant drug content efficiency in the range of 77-96%. The formulations did not induce haemolysis of cells and showed good clearance of parasitaemia.

Conclusion: Surface-modified lipid nanoemulsion is a perfect carrier system for improving the anti-malarial activity of dihydroartemisinin.

Keywords: Lipid nanoemulsion, dihydroartemisinin, PEG 4000, malaria, parasitaemia, surface modification.

Graphical Abstract
World Health Organization Malaria: fact sheet (Accessed on: May 2,2018)
Nnamani PO, Hansen S, Windbergs M, Lehr C-M. Development of artemether-loaded nanostructured lipid carrier (NLC) formulation for topical application. Int J Pharm 2014; 477: 208-17.
Peyrottes S, Caldarelli S, Wein S, Perigand C, Pellet A, Vial H. Choline analogues in malaria chemotherapy. Curr Pharm Des 2012; 18: 3454-66.
van Eijk A. Coverage of malaria protection in pregnant women in sub-saharan Africa: a synthesis and analysis of national survey data. Lancet Infect Dis 2011; 11: 190-207.
Fernandez-Busquets X. Heparin-functionalized nanocapsules: enabling targeted delivery of antimalarial drugs. Future Med Chem 2013; 5(7): 737-9.
Wang D, Li H, Gu J, et al. Ternary system of dihydroartemisinin with hydroxypropyl-cyclodextrin and lecithin: simultaneous enhancement of drug solubility and stability in aqueous solutions. J Pharm Biomed Anal 2013; 83: 141-8.
Cumming JN, Ploypradith P, Posner GH. Antimalarial activity of artemisinin (qinghaosu) and related trioxanes: mechanism(s) of action. Adv Pharmacol 1997; 37: 253-97.
Ansari MT, Iqbal I, Sunderland VB. Dihydroartemisinin-cyclodextrin complexation: solubility and stability. Arch Pharm Res 2009; 32(1): 155-65.
Liu K, Dai L, Li C, Liu J, Wang L, Lei J. Self-assembled targeted nanoparticles based on transferrin-modified eight-arm-polyethylene glycol–dihydroarte-misinin conjugate. Sci Rep 2016; 6: 29461.
Denis MB, Davis TME, Hewitt S, et al. Efficacy and safety of dihydroartemisinin-piperaquine (Artekin®) in Cambodian children and adults with uncomplicated Falciparum malaria. Clin Infect Dis 2002; 35(12): 1469-76.
Dai L, Wang L, Deng L, et al. Novel multiarm polyethylene glycol-dihydroartemisinin conjugates enhancing therapeutic efficacy in non-small-cell lung cancer. Sci Rep 2014; 4: 5871.
Lu WF, Chen SF, Wen ZY, Li Q, Chen JH. In vitro evaluation of efficacy of dihydroartemisinin-loaded methoxypoly(ethylene glycol)/poly(lactic acid) amphiphilic block copolymeric micelles. J Appl Polym Sci 2013; 128: 3084-92.
Righeschi C, Coronnello M, Mastrantoni A, et al. Strategy to provide a useful solution to effective delivery of dihydroartemisinin: development, characterization and in vitro studies of liposomal formulations. Colloids Surf B Biointerfaces 2014; 116: 121-7.
Zhang X, Qiao H, Liu J, et al. Dihydroartemisinin loaded nanostructured lipid carriers (DHA-NLC): evaluation of pharmacokinetics and tissue distribution after intravenous administration to rats. Pharmazie 2010; 65: 670-8.
Wang S, Wang H, Liang W, Huang Y. An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs. Nano Res Lett 2012; 7: 219.
Sun Q, Teong B, Chen IF, Chang SJ, Gao J, Kuo SM. Enhanced apoptotic effects of dihydroartemisinin-aggregated gelatin and hyaluronan nanoparticles on human lung cancer cells. J Biomed Mater Res Part B Appl Biomater 2014; 102: 455-62.
Ma W, Xu A, Ying J, Li B, Jin Y. Biodegradable core-shell copolymer-phospholipid nanoparticles for combination chemotherapy: an in vitro study. J Biomed Nanotechnol 2015; 11: 1193-200.
Kumar S, Singh RK, Murthy RS, Bhardwai TR. Synthesis and evaluation of substituted poly(organo-phosphazenes) as a novel nanocarrier system for combined antimalarial therapy of primaquine and dihydroartemisinin. Pharm Res 2015; 32(8): 2736-52.
Plaizier-Vercammen J, Gabriels M. . Inclusion complex of artemisinin or derivates thereof with cyclodextrins.WO2004075921A1, 2004.
Ross CJ. Sublingual spray formulation comprising dihydroartemesinin. WO2010122356A1, 2010.
Guogiao L, Song J. Composition containing artemisinin for treatment of malaria. US7851512B2 2010.
Ramreddy S, Kandadi P, Veerabrahma K. Formulation and pharmacokinetics of diclofenac lipid nanoemulsions for parenteral application. PDA J Pharm Sci Technol 2012; 66: 28-37.
Araujo FA, Kelmann RG, Araujo BV, Finatto RB, Teixeira HF, Koester LS. Development and characterization of parenteral nanoemulsions containing thalidomide. Eur J Pharm Sci 2011; 42: 238-45.
Dordevic SM, Cekic ND, Savic MM, et al. Parenteral nanoemulsions as promising carriers for brain delivery of risperidone: design, characterization and in vivo pharmacokinetic evaluation. Int J Pharm 2015; 493: 40-54.
Zainol S, Basri M, Basri HB, et al. Formulation optimization of a palm-based nanoemulsion system containing levodopa. Int J Mol Sci 2012; 13: 13049-64.
Ðordevic SM, Radulovic TS, Cekic ND, et al. Experimental design in formulation of diazepam nanoemulsions: physicochemical and pharmacokinetic performances. J Pharm Sci 2013; 102: 4159-72.
Umeyor C, Attama A, Uronnachi E, et al. Formulation design and in vitro physicochemical characterization of surface modified self-nanoemulsifying formulations (SNEFs) of gentamicin. Int J Pharm 2016; 497: 161-98.
Shu G, Khalid N, Tan TB, et al. Comparison of ergocalciferol nanodispersions prepared using modified lecithin and sodium caseinate: insights of formulation, stability, and bioaccessibility. J Funct Foods 2017; 38: 28-35.
Babalola CP, Oluwalana I, Kotila OA, Adegoke OA, Kolade YT, Ameh SJ. A novel derivatization ultraviolet spectrophotometric method for the determination of dihydroartemisinin using p-nitroaniline. Trop J Pharm Res 2014; 13(1): 127-33.
nternational Conference on harmonization of technical requirements for registration of pharmaceuticals for human use. Stability testing of new drug substances and products, Q1A (R2), Geneva, Switzerland 2003.
Rhee Y-S, Park C-W, Nam T-Y, Shin Y-S, Chi S-C, Park E-S. Formulation of parenteral microemulsion containing itraconazole. Arch Pharm Res 2007; 30(1): 114-23.
Agbo C, Umeyor C, Kenechukwu F, et al. Formulation design, in vitro characterizations and anti-malarial investigations of artemether and lumefantrine-entrapped solid lipid microparticles. Drug Dev Ind Pharm 2016; 42(10): 1708-21.
Baka E, Comer JEA, Takacs-Novak K. Study of equilibrium solubility measurement by saturation shake-flask method using hydrochlorothiazide as model compound. J Pharm Biomed Anal 2008; 46: 335-41.
Doh H-J, Jung Y, Balakrishnan P, Cho H-J, Kim D-D. A novel lipid nanoemulsion system for improved permeation of granisetron. Colloids Surf B Biointerfaces 2013; 101: 475-80.
Khurana S, Bedi PMS, Jain NK. Development of nanostructured lipid carriers for controlled delivery of mefenamic acid. Int J Biomed Nanosci Nanotechnol 2012; 2(3/4): 232-50.
Mbah C, Builders P, Nzekwe I, Kunle O, Adikwu M, Attama A. Formulation and in vitro evaluation of pH-responsive ethosomes for vaginal delivery of metronidazole. J Drug Deliv Sci Technol 2014; 24(6): 565-71.
Pal N, Saxena N, Mandal A. Phase behaviour, solubilization, and phase transition of a microemulsion system stabilized by a novel surfactant synthesized from castor oil. J Chem Eng Data 2017; 62(4): 1278-91.
Najlah M, Kadan A, Wan K-W, Ahmed W, Taylor KMG, Elhissi AMA. Novel paclitaxel formulations solubilized by parenteral nutrition nanoemulsions for application against glioma cell lines. Int J Pharm 2016; 506: 102-9.
Ali HH, Hussein AA. Oral nanoemulsions of candesartan cilexetil: formulation, characterization and in vitro drug release studies. AAPS Open 2017; 3: 4.
Teixeira MC, Severino P, Andreani T, et al. D-α-tocopherol nanoemulsions: size properties, rheological behaviour, surface tension, osmolarity and cytotoxicity. Saudi Pharm J 2017; 25(2): 231-5.
Kenechukwu FC, Attama AA, Ibezim EC, et al. Novel intravaginal drug delivery system based on molecularly PEGylated lipid matrices for improved antifungal activity of miconazole nitrate. BioMed Res Int 2018; 1-18.
Awofisayo SO, Igwe CN, Jonathan NA, Francis AI, Ojobor PD. In vitro studies of food interaction with dihydroartemisinin-piperaquine antimalarial tablet. J Pharm Res Int 2017; 18(1): 1-13.
McClements DJ, Rao J. Food-grade nanoemulsions: formulation, fabrication, properties, performance, biological fate, and potential toxicity. Crit Rev Food Sci Nutr 2011; 51(4): 285-330.
Jay AW, Rowlands S. The stages of osmotic haemolysis. J Physiol 1975; 252(3): 817-32.
Borhade VB, Nair HA, Hegde DD. Design and evaluation of self-microemulsifying drug delivery system (SMEDDS) of tacrolimus. AAPS PharmSciTech 2008; 9: 13-21.
Borhade V, Pathak S, Sharma S, Patravale V. Clotrimazole nanoemulsion for malaria chemotherapy. Part II: stability assessment, in vivo pharmacodynamic evaluations and toxicological studies. Int J Pharm 2012; 431: 149-60.
Basalious EB, Shawky N, Badr-Eldin SM. SNEDDs containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I: development and optimization. Int J Pharm 2010; 391: 203-11.
Porter CJ, Charman WN. Intestinal lymphatic drug transport: an update. Adv Drug Deliv Rev 2001; 50: 61-80.
Pouton CW, Porter CJH. Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Adv Drug Deliv Rev 2008; 60: 625-37.

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