Abstract
This investigation aimed to develop nimesulide (NMS)-loaded poly(lactic-co-glycolic acid) (PLGA)-based nanoparticulate formulations as a biodegradable polymeric drug carrier to treat rheumatoid arthritis. Polymeric nanoparticles (NPs) were prepared with two different nonionic surfactants, vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) and poly(vinyl alcohol) (PVA), using an ultrasonication solvent evaporation technique. Nine batches were formulated for each surfactant using a 32 factorial design for optimal concentration of the emulsifying agents, 0.03–0.09% for vitamin E TPGS and 2–4% for PVA. The surfactant percentage and the drug/polymer ratio (1:10, 1:15, 1:20) of the NMS-loaded NPs were investigated based on four responses: encapsulation efficiency, particle size, the polydispersity index, and the surface charge. The response surface plots and linearity curves indicated a relationship between the experiment’s responses and a set of independent variables. The NPs produced with both surfactants exhibited a negative surface charge, and scanning electron micrographs revealed that all of the NPs were spherical in shape. A narrower size distribution and higher drug loadings were achieved in PVA-emulsified PLGA NPs than in the vitamin E TPGS emulsified. Decreasing amounts of both nonionic surfactants resulted in a reduction in the emulsion’s viscosity, which led to a decrease in the particle size of NPs. According to the ANOVA results obtained in this present research, vitamin E TPGS exhibited the best correlation between the independent variables, namely drug/polymer ratio and the surfactant percentage, and the dependent variables (encapsulation efficiency R 2 = 0.9603, particle size R 2 = 0.9965, size distribution R 2 = 0.9899, and surface charge R 2 = 0.8969) compared with PVA.
Similar content being viewed by others
References
Manjanna KM, Shivakumar B, Pramod Kumar TM. Microencapsulation: an acclaimed novel drug-delivery system for NSAIDs in arthritis. Crit Rev Ther Drug Carr Syst. 2010;27:509–45.
Zhang Z, Huang G. Micro- and nano-carrier mediated intra-articular drug delivery systems for the treatment of osteoarthritis. J Nanotechnol. 2012;2012:1–11. Article ID 748909.
Bianchi M, Ehrlich GE, Facchinetti F, Huskisson EC, Jenoure P, La Marca A, et al. Clinical applications of nimesulide in pain, arthritic conditions and fever. In: Rainsford KD, editor. Nimesulide actions and uses. Basel: Birkhäuser; 2005. p. 245–314.
Zhang Z, Bi XB, Huang G. Enhanced targeting efficiency of PLGA microspheres loaded with lornoxicam for intra-articular administration. Drug Deliv. 2011;18(7):536–44.
Schulze K, Koch A, Schöpf B, Petri A, Steitz B, Chastellain M, et al. Intrarticular application of superparamagnetic nanoparticles and their uptake by synovial membrane-an experimental study in sheep. J Magn and Magn Mater. 2005;293:419–32.
Gerwin N, Hops C, Lucke A. Intraraticular drug delivery in osteoarthritis. Adv Drug Deliv Rev. 2006;58:226–42.
Liang LS, Jackson J, Min W, Risovic V, Wasan KM, Burt HM. Methotrexate loaded poly(L-lactic acid) microspheres for intra-articular delivery of methotrexate to joint. J Pharm Sci. 2004;93:943–56.
Horisawa E, Kubota K, Tuboi I, Sato K, Yamamoto H, Takeuchi H, et al. Size-dependency of D, L-lactide/glycolide copolymer particulates for intra-articular delivery system on phagocytosis in rat synovium. Pharm Res. 2002;19:132–9.
Ratcliffe JH, Hunneyball M, Smith A, Wilson CG, Davis SS. Preparation and evaluation of biodegradable polymeric systems for the intra-articular delivery of drugs. J Pharm Pharmacol. 1984;36:431–6.
Rothenfluh DA, Bermudez H, O’Neil CP, Hubbell JA. Bifunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nat Mater. 2008;7:248–54.
Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Préat V. PLGA-based nanoparticles: an overview of biomedical applications. J Control Release. 2012;161:505–22.
Wang JX, Fan YB, Gao Y, Hu QH, Wang TC. TiO2 nanoparticles translocation and potential toxicological effect in rats after intraarticular injection. Biomater. 2009;30:4590–600.
Wang J, Gao Y, Hou Y, Zhao F, Pu F, Liu X, et al. Evaluation on cartilage morphology after intra-articular injection of titanium dioxide nanoparticles in rats. J Nanomater. 2012;452767:1–11.
Crowe LA, Tobalem F, Gramoun A, Delattre BMA, Grosdemange K, Salaklang J, et al. Improved dynamic response assessment for intra-articular injected iron oxide nanoparticles. Magn Reson Med. 2012;68:1544–52.
Ding YDH, Shangli L, Ruofan M. The efficacy and safety of lornoxicam in treatment of rheumatoid arthritis and osteoarthritis. Chin J New Drugs. 2004;13:562–4.
Betre H, Liu W, Zalutsky MR, Chilkoti A, Kraus VB, Setton LA. A thermally responsive biopolymer for intra-articular drug delivery. J Control Release. 2006;115:175–82.
Horisawa E, Hirota T, Kawazoe S, Yamada J, Yamamoto H, Takeuchi H, et al. Prolonged anti-inflammatory action of DL-lactide/glycolide copolymer nanospheres containing betamethasone sodium phosphate for an intra-articular delivery system in antigen-induced arthritic rabbit. Pharm Res. 2002;19:403–10.
Higaki M, Ishihara T, Izumo N, Takatsu M, Mizushima Y. Treatment of experimental arthritis with poly(D, L-lactic/glycolic acid) nanoparticles encapsulating betamethasone sodium phosphate. Ann Rheum Dis. 2005;64:1132–6.
Gohel M, Patel M, Amin A, Agrawal R, Dave R, Bariya N. Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS Pharm Sci Tech. 2004;5(3). Article 36
Freitas MN, Marchetti JM. Nimesulide PLA microspheres as a potential sustained release system for the treatment of inflammatory diseases. Int J Pharm. 2005;295:201–11.
Ravikumara NR, Madhusudhan B, Nagaraj TS, Hiremat SR, Raina G. Preparation and evaluation of nimesulide-loaded ethylcellulose and methylcellulose nanoparticles and microparticles for oral delivery. J Biomater Appl. 2009;24:47–64.
Sengel Turk CT, Hascicek C, Dogan AL, Esendagli G, Guc D, Gönül N. Preparation and in vitro evaluation of meloxicam-loaded PLGA nanoparticles on HT-29 human colon adenocarcinoma cells. Drug Dev Ind Pharm. 2012;38:1107–16.
Dong Y, Zhang Z, Feng SS. D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) modified poly(L_lactide) (PLLA) films for localized delivery of paclitaxel. Int J Pharm. 2008;350:166–71.
Sengel CT, Hascicek C, Gönül N. Design of vitamin E d-a tocopheryl polyethylene Glycol 1000 succinate-emulsified poly (DL–lactide–co-glycolide) nanoparticles: influence of duration of ultrasonication energy. J Young Pharm. 2011;3:171–5.
Alayoubi A, Nazzal M, Sylvester PW, Nazzal S. “Vitamin E” fortified parenteral lipid emulsions: Plackett-Burman screening of primary process and composition parameters. Drug Dev Ind Pharm. 2013;39:363–73.
Gómez-Gaete C, Bustos GL, Godoy RR, Saez CK, Novoa GP, Fernández EM, et al. Successful factorial design for the optimization of methylprednisolone encapsulation in biodegradable nanoparticles. Drug Dev Ind Pharm. 2013;39:310–20.
United States Pharmacopoeia 23 – National Formulary 18, 1995
Nie H, Wang CH. Fabrication and characterization of PLGA/Hap composite scaffolds for delivery of BMP-2 plasmid DNA. J Control Release. 2007;120:111–21.
El Gamal SS, Naggar VF, Allam AN. Optimization of acyclovir tablets based on gastroretention technology: factorial design analysis and physicochemical characteristics studies. Drug Dev Ind Pharm. 2011;37:855–67.
Blasi P, Giovagnoli S, Schoubben A, Puglia C, Bonina F, Rossi C, et al. Lipid nanoparticles for brain targeting I. formulation optimization. Int J Pharm. 2011;419:287–95.
Yadav KS, Sawant KK. Modified nanoprecipitation method for preparation of cytarabine-loaded PLGA nanoparticles. AAPS PharmSciTech. 2010;11:1456–65.
Yadav KS, Jacob S, Sachdeva G, Chunttani K, Mishra AK, Sawant KK. Long circulating PEGylated PLGA nanoparticles of cytarabine for targeting leukemia. J Microencapsul. 2011;28:729–42.
Sengel CT, Hascicek C, Gönül N. Development and in-vitro evaluation of modified release tablets including ethylcellulose microspheres loaded with diltiazem hydrochloride. J Microencapsul. 2006;23:135–52.
Sengel-Turk CT, Hascicek C, Gönül N. Microspheres-based once-daily modified release matrix tablets for oral administration in angina pectoris. J Microencapsul. 2008;25:257–66.
Budhian A, Siegel SJ, Winey KI. Haloperidol-loaded PLGA nanoparticles: systematic study of particle size and drug content. Int J Pharm. 2007;336:367–75.
Zhang Z, Tan S, Feng SS. Vitamin E TPGS as a molecular biomaterial for drug delivery. Biomater. 2012;33:4889–906.
Mu L, Feng SS. A novel controlled release formulation for the anticancer drug paclitaxel (Taxol®): PLGA nanoparticles containing vitamin E TPGS. J Control Release. 2003;86:33–48.
Vega E, Egea MA, Valls O, Espina M, García ML. Flurbiprofen loaded biodegradable nanoparticles for opthalmic administration. J Pharm Sci. 2006;95:2393–405.
Xu Q, Crossley A, Czernuszka J. Preparation and characterization of negatively charged poly(lactic-co-glycolic acid) microspheres. J Pharm Sci. 2009;98:2377–89.
Chen JL, Yeh MK, Chiang CH. Dichloromethane evaporative behaviour during the solidifying process of ovalbumin-loaded poly (DL lactic-co-glycolic acid) microparticles. J Food and Drug Anal. 2004;12:291–8.
Turk CT, Hascicek C, Gonul N. Evaluation of drug-polymer interaction in polymeric microspheres containing diltiazem hydrochloride. J Therm Anal Cal. 2009;95:865–9.
Nalluri BN, Chowdary KPR, Murthy KVR, Hayman AR, Becket G. Physicochemical characteristics and dissolution properties of nimesulide cyclodextrin binary systems. AAPS PharmSciTech. 2003;4: Article 2.
Mccarron P, Donnelly RF, Marouf W. Celecoxib-loaded poly(D, L-lactide-co-glycolide) nanoparticles prepared using a novel and controllable combination of diffusion and emulsification steps as part of the salting-out procedure. J Microencapsul. 2006;23:480–98.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Turk, C.T.S., Oz, U.C., Serim, T.M. et al. Formulation and Optimization of Nonionic Surfactants Emulsified Nimesulide-Loaded PLGA-Based Nanoparticles by Design of Experiments. AAPS PharmSciTech 15, 161–176 (2014). https://doi.org/10.1208/s12249-013-0048-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12249-013-0048-9