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. 2003 Oct 11;4(4):565–573. doi: 10.1208/pt040471

Optimization of polylactic-co-glycolic acid nanoparticles containing itraconazole using 23 factorial design

Mukdavan Prakobvaitayakit 1,✉, Ubonthip Nimmannit 1
PMCID: PMC2750664  PMID: 15198566

Abstract

This study investigated the utility of a 23 factorial design and optimization process for polylactic-co-glycolic acid (PLGA) nanoparticles containing itraconazole with 5 replicates at the center of the design. Nanoparticles were prepared by solvent displacement technique with PLGAX1 (10, 100 mg/mL), benzyl benzoateX2 (5, 20 μg/mL), and itraconazoleX3 (200, 1800 μg/mL). Particle size (Y1), the amount of itraconazole entrapped in the nanoparticles (Y2), and encapsulation efficiency (Y3) were used as responses. A validated statistical model having significant coefficient figures (P<.001) for the particle size (Y1), the amount of itraconazole entrapped in the nanoparticles (Y2), and encapsulation efficiency (Y3) as function of the PLGA (X1), benzyl benzoate (X2), and itraconazole (X3) were developed: Y1=373.75+66.54X1+52.09X2+105.06X3−4.73X1X2+46.30X1X3; Y2=472.93+73.45X1+ 169.06X2+333.03X3+62.40X1X3+141.49X2X3; Y3= 57.36+6.53X1+15.52X2−12.59X3+1.01X1X3+ 1.73X2X3.X1,X2, andX3 had a significant effect (P<.001) onY1,Y2, andY3. The particle size, the amount of itraconazole entrapped in the nanoparticles, and the encapsulation efficiency of the 4 formulas were in agreement with the predictions obtained from the models (P<.05). An overlay plot for the 3 responses shows the boundary in whichY1 shows the boundary in which a number of combinations of concentration of PLGA, benzyl benzoate, and itraconazole will result in a satisfactory process. Using the desirability approach with the same constraints, the solution composition having the highest overall desirability (D=0.769) was 10 mg/mL of PLGA, 16.94 μg/mL of benzyl benzoate, and 1001.01 μg/mL of itraconazole. This approach allowed the selection of the optimum formulation ingredients for PLGA nanoparticles containing itraconazole of 500 μg/mL.

Keywords: itraconazole, nanoparticles, PLGA, 23 factorial design, formulation optimization

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References

  • 1.Allemann E, Leroux RG. Biodegradable nanoparticles of particles of poly(lactic acid) and poly(lactic-co-glycolic acid) for parenteral administration. In: Gregoridas G, editor. Pharmaceutical Dosage Form. New York, NY: Marcel Dekker; 1999. pp. 163–186. [Google Scholar]
  • 2.Wise DL, Fellmann TD, Sanderson JE, Wentworth RL. Lactic /glycolic acid polymers. In: Gregoridas G, editor. Drug Carriers in Biology and Medicine. London, UK: Academic Press; 1979. pp. 237–270. [Google Scholar]
  • 3.Fessi H, Puisieux F, Devissagnet JP, Ammoury N, Betina S. Nanocapsule formation by interfacial deposition following solvent displacement. Int J Pharm. 1989;55:R1–R4. doi: 10.1016/0378-5173(89)90281-0. [DOI] [Google Scholar]
  • 4.Cauchetier E, Deniau M, Fessi H, Astier A, Paul A. Atovaquone-loaded nanocapsules: influence of the polymer on their in vitro characteristics. Int J Pharm. 2003;250:273–281. doi: 10.1016/S0378-5173(02)00556-2. [DOI] [PubMed] [Google Scholar]
  • 5.Barichello JM, Morishita M, Takayama K, Nagai T. Encapsulation of hydrophilic and lipophilic drugs in PLGA nanoparticles by the nanoprecipitation method. Drug Dev Ind Pharm. 1999;25(4):471–476. doi: 10.1081/DDC-100102197. [DOI] [PubMed] [Google Scholar]
  • 6.Fawaz F, Bonini F, Guyot M, Lagueny AM, Fessi H, Devissaguet JP. Influence of poly(DL-lactide) nanocapsules on the biliary clearance and enterohepatic circulation of indomethacin in the rabbit. Pharm Res. 1993;10:750–756. doi: 10.1023/A:1018924219540. [DOI] [PubMed] [Google Scholar]
  • 7.Chasteigner DS, Fessi H, Devissaguet JP, Puisieux F. Comparative study of the association of itraconazole with colloidal drug carriers. Drug Dev Res. 1996;38:125–133. doi: 10.1002/(SICI)1098-2299(199606)38:2&#x0003c;125::AID-DDR7&#x0003e;3.0.CO;2-L. [DOI] [Google Scholar]
  • 8.Heykants J, Peer V, van de Velde V, Rooy PV, Meuldermans W, Lavrijsen K, Woestenborghs R, Van Cutsem J, Cauwenbergh G. The clinical pharmacokinetics of itraconazole: an overview. Mycoses. 1989;32(suppl. 1):67–68. doi: 10.1111/j.1439-0507.1989.tb02296.x. [DOI] [PubMed] [Google Scholar]
  • 9.Stetsko G. Statistical experimental design and its application to pharmaceutical development problems. Drug Dev Ind Pharm. 1986;12:1109–1123. doi: 10.3109/03639048609065848. [DOI] [Google Scholar]
  • 10.Dawoodbhai S, Suryanarayan ER, Woodruff CW, Rhodes CT. Optimization of tablet formulations containing talc. Drug Dev Ind Pharm. 1991;17(10):1343–1371. doi: 10.3109/03639049109057301. [DOI] [Google Scholar]
  • 11.Bos CE, Bolhuis GK, Lerk CF. Optimization of tablet formulations based on starch/lactose granulations for use in tropical countries. Drug Dev Ind Pharm. 1991;17(17):2373–2389. doi: 10.3109/03639049109048081. [DOI] [Google Scholar]
  • 12.Ceschel GC, Maffei P, Badiello R. Optimization of hydrochlorothiazide tablets. Drug Dev Ind Pharm. 1999;25(11):1167–1176. doi: 10.1081/DDC-100102284. [DOI] [PubMed] [Google Scholar]
  • 13.Zaghloul AA, Vaithiyalingam SR, Faltinek J, Reddy IK, Khan MA. Response surface methodology to obtain naproxen controlled release tablets from its microspheres with Eudragit L 100-55. J Microencapsul. 2001;18(5):651–662. doi: 10.1080/02652040110055630. [DOI] [PubMed] [Google Scholar]
  • 14.Arica B, Kas HS, Orman MN, Hincal AA. Biodegradable bromocryptine mesylate microspheres prepared by a solvent evaporation technique. I. Evaluation of formulation variables on microspheres characteristics for brain delivery. J Microencapsul. 2002;19(4):473–484. doi: 10.1080/02652040210144216. [DOI] [PubMed] [Google Scholar]
  • 15.Adinarayana K, Ellaiah P. Response surface optimization of the critical medium components for the production of alkaline protease by a newly isolatedBacillus sp. J Pharm Pharm Sci. 2002;5(3):272–278. [PubMed] [Google Scholar]
  • 16.Nangia A, Lam F, Hung CT. Formulation optimization of a hydrocolloid dressing. Drug Dev Ind Pharm. 1990;16(14):2109–2123. doi: 10.3109/03639049009023643. [DOI] [Google Scholar]
  • 17.Elkheshen SA, Badawi SS, Badawi AA. Optimization of a reconstitutable suspension of rifampicin using 24 factorial design. Drug Dev Ind Pharm. 1996;22(7):623–630. doi: 10.3109/03639049609063216. [DOI] [Google Scholar]
  • 18.Montgomery DC, editor. Design and Analysis of Experiments. 5th ed. New York, NY: Wiley & Sons; 2001. [Google Scholar]
  • 19.Law D, Moore CB, Denning DW. Bioassay for serum itraconazole concentrations using hydroxyitraconazole standars. Antimicrob Agents Chemother. 1994;38:1561–1566. doi: 10.1128/aac.38.7.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Akhnazarova S, Kafaro V, editors. Experiment Optimization in Chemistry and Chemical Engineering. Moscow, Russia: Mir House Publications; 1982. [Google Scholar]
  • 21.Box GEP, Hunter WG, Hunter JS, editors. Statistic for Experiments. New York, NY: John Wiley and Sons; 1978. [Google Scholar]
  • 22.Box GEP, Wilson KB. On the experimental attainment of optimum conditions. J Roy Stat Soc B. 1951;13:1–45. [Google Scholar]

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