Preparation and optimization of polymeric micelles as an oral drug delivery system for deferoxamine mesylate: in vitro and ex vivo studies

Anayatollah Salimi , Behzad Sharif Makhmal Zadeh , Moloud Kazemi

Abstract


Deferoxamine mesylate (DFO) is administered as a slow subcutaneous or intravenous infusion due to its poor oral bioavailability and lack of dose proportionality. The aim of the present study was to prepare and optimize polymeric micelles containing DFO, as an oral drug delivery system for increasing permeability and oral bioavailability. Based on a full factorial design with three variables in two levels,  eight polymeric micelle formulations were made using film hydration method. Two polymers including 0.1% of carbomer 934 and Poloxamer® P 407 and two blends of surfactant + co-surfactant including1 and 2 fold of critical micelle concentration of Labrafil® + Labrasol® and Tween 80 + Span 20 were used to prepare polymeric micelles. The effect of variables on particle size (PS), entrapment efficiency (EE),  drug release, thermal behavior, in vitro iron bonding and ex vivo rat intestinal permeability were evaluated. The PS of polymeric micelles was less than 83 nm that showed 80% EE with continuous drug release pattern. The change in type of polymer from carbomer to Ploxamer® significantly increased drug release. All polymeric micelles increased the iron-bonding ability of DFO compared to control. This could be due to surfactants that can play an important role in this ability. Polymeric micelles increased drug permeability through intestine more than 2.5 folds compared to control mainly affected by polymer type.Optimized polymeric micelle consists of Tween 80 and Span 20 with 1.35 folds of critical micelle concentration and Poloxamer® demonstrated 97.32% iron bonding and a 3-fold increase in permeation through the rat intestine compared with control.

 


Keywords


Deferoxamine mesylate; Iron chelators; Oral bioavailability; Polymeric micelle; Thalassemia.

Full Text:

PDF

References


Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. 2011;434(3):365-381.

Aisen P, Enns C, Wessling-Resnick M. Chemistry and biology of eukaryotic iron metabolism. Int J Biochem Cell Biol. 2001;33(10):940-959.

Franzer DM, Anderson GJ. The regulation of iron transport. Biofactors. 2014;40(2):206-214.

Hoffbrand AV, Taher A, Capellini MD. How I treat transfusional iron overload. Blood. 2012;120(18):3657-3669.

Tygi P, Kumar Y, Gupta D, Singh H, Kumar A. Therapeutic advancements in management of iron overload-A review. Int J Pharm Sci. 2015;7(8): 35-44.

Porter JB, Garbowski M. The pathophysiology of transfutional iron overload. Hematol Oncol Clin North Am. 2014;28(4):683-701.

Brittenham GM. Iron-Chelating therapy for transfutional iron overload. N Engl J Med. 2011;364(2):146-156.

Delea TE, Edelsberg J, Sofrygin O, Thomas SK, Baladi JF, Phatak PD, et al. Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion-dependent thalessemia: a literature review. Transfusion. 2007;47(10): 1919-1929.

Schnebli HP, Hassan I, Hamilton KO, Lynch S, Jin Y, Nick HP, et al. Toward Better Chelation Therapy: Current Concepts and Research Strategy. In: Bergeron RJ, Brittenham GM, editors. The Development of Iron Chelators for Clinical Use. Boca Raton: CRC Press; 1994. pp. 131-149.

Ihnat PML, Vennerstrom JL, Robinson DH. Synthesis and solution properties of deferoxamine amides. J Pharm Sci. 2000;89(12):1525-1536.

Daugherty AL, Mrsny RJ. Regulation of the intestinal epithelial paracellular barrier. Pharm Sci Technolo Today. 1999;2(7):281-287.

Ensign LM, Cone R, Hanes J. Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers. Adv Drug Deliv Rev. 2012;64(6):557-570.

Neufeld EJ. Oral chelators defevasirox and deferiprone fpr transfusional iron overload in the thalassemia major: new data, new questions. Blood. 2006; 107(9): 3436-3441.

Hallaway PE, Eaton JW, Panter SS, Hedlund BE. Modulation of deferoxamine toxicity and clearance by covalent attachment to biocompatible polymers. Proc Natl Acad Sci U S A. 1989;86(24): 10108-10112.

Imran ul-hag M, Hamilton JL, Lai BF, Shenoi RA, Horte S, Constantinescu I, et al. Design of long circulating nontoxic dendritic polymers for the removal of iron in vivo. ACS Nano. 2013;7(12):10704-10716.

Lu Y, Park K. Polymeric micelles and alternative nanonized delivery vehicles for poorly soluble drugs. Int J Pharm. 2013;453(1):198-214.

Wu C, Ying A, Ren S. Fabrication of polymeric micelles with core-shell-corona structure for application in controlled drug release. Colloid Polym Sci. 2013;291(4);827-834.

Bagheri M, Bigdeli E, Pourmoazzen Z. Self-assembled micellar nanoparticles of a novel amphiphilic cholestryl-poly(L-lactic acid)-b-poly (poly(ethylene glycol)methacrylate) block-brush copolymer. Iran Polym J. 2013;22(4):293-302.

Vlassi E, Papagiannopoulos A, Pispas S. Amphiphilic poly(2-oxazoline) copolymers as self-assembled carriers for drug delivery applications. Eur Polym J. 2017;88:516-523.

Zhang J, Ma PX. Polymeric core-shell assemblies mediated by host-guest interactions: versatile nanocarriers for drug delivery. Angew Chem Int Ed Engl. 2009;48(5):964-968.

Smeets NMB. Amphiphilic hyperbranched polymers from the copolymerization of a vinyl and divinyl monomer: The potential of catalytic chain transfer polymerization. Eur Polym J. 2013;49(9): 2528-2544.

Kang N, Perron ME, Prud'homme RE, Zhang Y, Gaucher G, Leroux JC. Stereocomplex block copolymer micelles: core-shell nanostructures with enhanced stability. Nano Lett. 2005;5(2):315-319.

Srinivas G, Mohan RV, Kelkar AD. Polymer micelle assisted transport and delivery of model hydrophilic components inside a biological lipid vesicle: a coarse-grain simulation study. J Phys Chem B. 2013;117(40):12095-12104.

Torchilin VP. Structure and design of polymeric surfactant based drug delivery systems. J Control Release. 2001;73(2-3):137-172.

Simões SM, Figueiras AR, Veiga F, Concheiro A, Alvarez-Lorenzo C. Polymeric micelles for oral drug administration enabling locoregional and systemic treatments. Expert Opin Drug Deliv. 2015;12(2):297-318.

Moazeni E, Gilani K, Rouholamini Najafabadi A, Rouini MR, Mohajel N, Amini M, et al. Preparation and evaluation of inhalable itraconazole chitosan based polymeric micelles. Daru. 2012;20(1):85-94.

Zhang X, Jackson JK, Burt HM. Development of amphiphilic diblock copolymers as micellar carriers of taxol. Int J Pharm. 1996;132(1-2):195-206.

Cao XT, Kim YH, Park JM, Lim KT. One-pot syntheses of dual-responsive core cross-linked polymeric micelles and coavalently entrapped drug by click chemistry. Eur Polym J. 2016;78:264-273.

Shahin M, Safaei-Nikouei N, Lavasanifar A. Polymeric micelles for pH-responsive delivery of cisplatin. J Drug Target. 2014;22(7):629-637.

Davis BA, Porter JB. Results of long term iron chelation treatment with deferoxamine. Adv Exp Med Biol. 2002;509:91-125.

Burke A, Yilmaz E, Hasirci N. Evaluation of chitosan as a potential medical iron (III) ion adsorbent. Turk J Med Sci. 2000;30(4):341-348.

Bolton S. Chelatometric determination of ferrous iron with 2-pyridinealdoxime as an indicator. J Pharm Sci. 1963;52(9):858-860.

Schiller C, Frohlich CP, Giessmann T, Siegmund W, Monnikes H, Hostern N, et al. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment Pharmacol Ther. 2005;22(10):971-977.

Dabholkar RD, Sawant RM, Mongayt DA, Devarajan PV, Torchilin VP. Polyethylene glycol-phosphatidylethanolamine conjugate (PEG-PE)-based mixed micelles: some properties, loading with paclitaxel, and modulation of P-glycoprotein-mediated efflux. Int J Pharm. 2006;315(1-2): 148-157.

dos Santos S, Medronho B, dos Santos T, Antunes FE. Amphiphilic Molecules in Drug Delivery Systems. In: Coelho J, editor. Drug Delivery Systems: Advanced Technologies Potentially Applicable in Personalised Treatment. Dordrechet: Springer; 2013. pp. 35-87.

Su CY, Liu JJ, Ho YS, Huang YY, Chang VH, Liu DZ, et al. Development and characterization of docetaxel-loaded lecithin-stabilized micellar drug delivery system (LsbMDDs) for improving the therapeutic efficacy and reducing systemic toxicity. Eur J Pharm Biopharm. 2018;123:9-19.

Emami J, Rezazadeh M, Sadeghi H, Khadivar K. Development and optimization of transferrin-conjugated nanostructured lipid carriers for brain delivery of paclitaxel using Box-Behnken design. Pharm Dev Technol. 2017;22(3):370-382.

Long MA, Kaler EW, Lee SP. Structural characterization of the micelle-vesicle transition in lecithin- bile salt solutions. Biophys J. 1994;67(4):1733-1742.

Vignesh S, Annapoorna M, R J, Subramania I, Shantikumar VN, et al. Injectable deferoxamine nanoparticles loaded chitosan-hyaluronic acid coacervate hydrogel for therapeutic angiogenesis. Colloids Surf B Biointerfaces. 2018;161:129-138.

Qiu M, Wang C, Chen D, Shen C, Zhao H, He Y. Angiogenic and osteogenic coupling effects of DFO-loaded poly(lactide-c0-glycolide)-poly(lactide-co-glycolide) nanoparticles. Appl Sci. 2016;6(10):290-304.

Zweers ML, Grijpma DW, Engbers GH, Feijen J. The preparation of monodisperse biodegradable polyester nanoparticles with a controlled size. J Biomed Mater Res B Appl Biomater. 2003;66(2):559-566.

Carlos Bregni, Diego Chiappetta, Natalia Faiden, Adriana Carlucci, Roberto García And Ricardoc Pasquali. Release study of diclofenac from new carbomer gels. Pak. J. Pharm. Sci., Vo.21, No.1, January 2008, pp.12-16.

Muller RH, Radtke M, Wissing SA. Solid lipid nanoparticles and nanostructured lipid carriers in cosmetic and dermatological preparations. Adv Drug Deliv Rev. 2002;54:S131-S155.

Taş C, Ozkan Y, Savaşer A, Baykara T. In vitro and ex vivo permeation studies of chlorpheniramine maleate gels prepared by carbomer derivatives. Drug Dev Ind Pharm. 2004;30(6):637-647.

Nanki SG, Pantopoulos K, Bikiaris DN. Synthesis of biocompatible poly(ɛ-caprolactone)- block-poly(propylene adipate) copolymers appropriate for drug nanoencapsulation in the form of core-shell nanoparticles. Int J Nanomedicine. 2011;6:2981-2995.

Kazemi M, Varshosaz J, Tabbakhian M. Preparation and evaluation of lipid-based liquid crystalline formulation of fenofibrate. Adv Biomed Res. 2018;7:126.

Emami J, Mohiti H, Hamishehkar H, Varshosaz J. Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design. Res Pharm Sci. 2015;10(1):17-33.

Lai J, Lu Y, Yin Z, Hu F, Wu W. Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles. Int J Nanomedicine. 2010;2;5:13-23.

Li Y, Li J, Zhang X, Ding J, Mao S. Non-ionic surfactants as novel intranasal absorption enhancers: in vitro and in vivo characterization. Drug Deliv. 2016;23(7):2272-2279.

Fischer SM, Parmentier J, Buckley ST, Reimold I, Brandl M, Fricker G. Oral bioavailability of ketoprofen in suspension and solution formulations in rats: the influence of poloxamer 188. J Pharm Pharmacol. 2012;64(11):1631-1637.

Francis MF, Cristea M, Yang Y, Winnik FM. Engineering polysaccharide-based polymeric micelles to enhance permeability of cyclosporin A across Caco-2 cells. Pharm Res. 2005;22(2):209-219.

Hamilton JL, Kizhakkedathu JN. Polymeric nanocarriers for the treatment of systemic iron overload. Mol Cell Ther. 2015;3:3-17.

Rossi NA, Mustafa I, Jackson JK, Burt HM, Horte SA, Scott MD, et al. In vitro chelating, cytotoxicity, and blood compatibility of degradable poly(ethylene glycol)-based macromolecular iron chelators. Biomaterials. 2009;30(4):638-648.

Winston A, Varaprasad DV, Metterville JJ, Rosenkratz H. Evaluation of polymeric hydroxamic acid iron chelators for treatment of iron overload. J Pharmacol Exp Ther. 1985;232(3):644-649.

Zhou T, Kang XL, Liu ZD, Liu DY, Hider RC. Synthesis and iron (III)-chelating properties of novel 3-hydroxypyridin-4-one hexadentate ligand-containing copolymers. Biomacromolecules. 2008;9(5):1372-1380.

Polomoscanik SC, Cannon CP, Neenan TX, Holmes-Farley SR, Manderille WH, Dhal PK. Hydroxamic acid-containing hydrogels for nanoabsorbed iron chelation therapy; synthesis, characterization and biological evaluation. Biomacromolecules. 2005;6(6):2946-2953.


Refbacks

  • There are currently no refbacks.


Creative Commons LicenseThis work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.