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. 2005 Sep 30;6(2):E158–E166. doi: 10.1208/pt060224

Etoposide-loaded nanoparticles made from glyceride lipids: Formulation, characterization, in vitro drug release, and stability evaluation

L Harivardhan Reddy 1, R S R Murthy 1,✉
PMCID: PMC2750527  PMID: 16353973

Abstract

The aim of the study was to prepare etoposide-loaded nanoparticles with glyceride lipids and then characterize and evaluate the in vitro steric stability and drug release characteristics and stability. The nanoparticles were prepared by melt emulsification and homogenization followed by spray drying of nanodispersion. Spray drying created powder nanoparticles with excellent redispersibility and a minimal increase in particle size (20–40 nm). Experimental variables, such as homogenization pressure, number of homogenization cycles, and surfactant concentration, showed a profound influence on the particle size and distribution. Spray drying of Poloxamer 407-stabilized nanodispersion lead to the formation of matrix-like structures surrounding the nanoparticles, resulting in particle growth. The in vitro steric stability test revealed that the lipid nanoparticles stabilized by sodium tauroglycocholate exhibit excellent steric stability compared with Poloxamer 407. All 3 glyceride nanoparticle formulations exhibited sustained release characteristics, and the release pattern followed the Higuchi equation. The spray-dried lipid nanoparticles stored in black polypropylene containers exhibited excellent long-term stability at 25°C and room light conditions. Such stable lipid nanoparticles with in vitro steric stability can be a beneficial delivery system for intravenous administration as long circulating carriers for controlled and targeted drug delivery.

Keywords: lipid nanoparticles, high-pressure homogenization, spray drying, Poloxamer 407, steric stability

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References

  • 1.Muller RH, Olbrich C. Solid lipid nanoparticles: phagocytic uptake, in vitro cytoxicity and in vitro biodegradation. Drugs Made in Germany. 1999;42:49–53. [Google Scholar]
  • 2.Lim SJ, Kim CK. Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid. Int J Pharm. 2002;243:135–146. doi: 10.1016/S0378-5173(02)00269-7. [DOI] [PubMed] [Google Scholar]
  • 3.Freitas C, Muller RH. Spray drying of solid lipid nanoparticles (SLN TM) Eur J Pharm Biopharm. 1998;46:145–151. doi: 10.1016/S0939-6411(97)00172-0. [DOI] [PubMed] [Google Scholar]
  • 4.Magenheim B, Levy MY, Benita S. A new in vitro technique for evaluation of drug release profile from colloidal carriers-ultrafiltration technique at low pressure. Int J Pharm. 1993;94:115–123. doi: 10.1016/0378-5173(93)90015-8. [DOI] [Google Scholar]
  • 5.Muller RH, Ruhl D, Runge S, Schulze-Foster K, Mehnert W. Cytotoxicity of solid lipid nanoparticles as a function of the lipid matrix and the surfactant. Pharm Res. 1997;14:458–462. doi: 10.1023/A:1012043315093. [DOI] [PubMed] [Google Scholar]
  • 6.zur Muhlen A, Schwarz C, Mehnert W. Solid lipid nanoparticles (SLN) for controlled drug delivery—drug release and release mechanism. Eur J Pharm Biopharm. 1998;45:149–155. doi: 10.1016/S0939-6411(97)00150-1. [DOI] [PubMed] [Google Scholar]
  • 7.Muller RH, Maassen S, Weyhers H, Mehnert W. Phagocytic uptake and cytotoxicity of solid lipid nanoparticles (SLN) sterically stabilized with poloxamine 908 and poloxamer 407. J Drug Target. 1996;4:161–170. doi: 10.3109/10611869609015973. [DOI] [PubMed] [Google Scholar]
  • 8.Schwarz C, Mehnert W. Solid lipid nanoparticles (SLN) for controlled drug delivery II. Drug incorporation and physicochemical characterization. J Microencapsul. 1999;16:205–213. doi: 10.1080/026520499289185. [DOI] [PubMed] [Google Scholar]
  • 9.Schwarz C, Mehnert W, Lucks JS, Muller RH. Solid lipid nanoparticles (SLN) for controlled drug delivery I: production, characterization and sterilization. J Control Release. 1994;30:83–96. doi: 10.1016/0168-3659(94)90047-7. [DOI] [Google Scholar]
  • 10.Siekmann B, Westesen K. Thermoanalysis of the recrystallization process of melt-homogenized glyceride nanoparticles. Colloid Surf B: Biointerfac. 1994;3:159–175. doi: 10.1016/0927-7765(94)80063-4. [DOI] [Google Scholar]
  • 11.Westesen K, Bunjes H, Koch MHJ. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. J Control Release. 1997;48:223–236. doi: 10.1016/S0168-3659(97)00046-1. [DOI] [Google Scholar]
  • 12.Bunjes H, Drechsler M, Koch MHJ, Westesen K. Incorporation of the model drug ubidecarenone into solid lipid nanoparticles. Pharm Res. 2001;18:287–293. doi: 10.1023/A:1011042627714. [DOI] [PubMed] [Google Scholar]
  • 13.Bunjes H, Koch MHJ, Westesen K. Effect of surfactants on the crystallization and polymorphism of lipid nanoparticles. Progr Colloid Polym Sci. 2002;121:7–10. doi: 10.1007/3-540-47822-1_2. [DOI] [Google Scholar]
  • 14.Bunjes H, Koch MHJ, Westesen K. Influence of emulsifiers on the crystallization of solid lipid nanoparticles. J Pharm Sci. 2003;92:1509–1520. doi: 10.1002/jps.10413. [DOI] [PubMed] [Google Scholar]
  • 15.Bunjes H, Koch MHJ, Westesen K. Effect of particle size on colloidal solid triglycerides. Langmuir. 2000;16:5234–5241. doi: 10.1021/la990856l. [DOI] [Google Scholar]
  • 16.Freitas C, Muller RH. Correlation between long-term stability of nanoparticles (SLN) and crystallinity of the lipid phase. Eur J Pharm Biopharm. 1999;47:125–132. doi: 10.1016/S0939-6411(98)00074-5. [DOI] [PubMed] [Google Scholar]
  • 17.Zimmerman E, Muller RH, Mader K. Influence of different parameters on reconstitution of lyophilized SLN. Int J Pharm. 2000;196:211–213. doi: 10.1016/S0378-5173(99)00424-X. [DOI] [PubMed] [Google Scholar]
  • 18.Bodmeier R, Chen H. Preparation of biodegradable poly(+/−) lactide microparticles using a spray drying technique. J Pharm Pharmacol. 1988;40:754–757. doi: 10.1111/j.2042-7158.1988.tb05166.x. [DOI] [PubMed] [Google Scholar]
  • 19.Eldem T, Speiser P, Hincal A. Optimization of spray-dried and congealed lipid micropellets and characterization of their surface morphology by scanning electron microscopy. Pharm Res. 1991;8:47–54. doi: 10.1023/A:1015874121860. [DOI] [PubMed] [Google Scholar]
  • 20.Forni F, Coppi G, Vandelli MA, Cameroni R. Drug release from spray-dried and spray-embedded microparticles of diltiazem hydrochloride. Chem Pharm Bull. 1991;39:2091–2095. [Google Scholar]
  • 21.Moghimi SM, Porter CJH, Muir IS, Illum L, Davis SS. Non-phagocytic uptake of intravenously injected microspheres in rat spleen: influence of particle size and hydrophilic coating. Biochem Biophys Res Commun. 1991;127:861–866. doi: 10.1016/0006-291X(91)91869-E. [DOI] [PubMed] [Google Scholar]
  • 22.Porter CJH, Moghimi SM, Illum L, Davis SS. The polyoxyethylene/polyoxypropylene block co-polymer poloxamer 407 selectively redirects intravenously injected microspheres to sinusoidal endothelial cells of rabbit bone marrow. FEBS Lett. 1992;305:62–66. doi: 10.1016/0014-5793(92)80655-Z. [DOI] [PubMed] [Google Scholar]
  • 23.Artursson P, Illum L, Davis SS. Polymers in controlled drug delivery. Bristol, London: Butterworth-Heinemann; 1987. The fate of microparticulate drug carriers after intravenous administration; pp. 15–24. [Google Scholar]
  • 24.Lin W, Coombes AGA, Garnett MC, et al. Preparation of sterically stabilized human serum albumin nanospheres using a novel Dextranox-MPEG crosslinking agent. Pharm Res. 1994;11:1589–1592. doi: 10.1023/a:1018957704209. [DOI] [PubMed] [Google Scholar]
  • 25.Olbrich C, Kayser O, Muller RH. Lipase degradation of Dynasan 114 and 116 solid lipid nanoparticles (SLN)—effect of surfactants, storage time and crystallinity. Int J Pharm. 2002;237:119–128. doi: 10.1016/S0378-5173(02)00035-2. [DOI] [PubMed] [Google Scholar]
  • 26.Jenning V, Lippacher A, Gohla SH. Medium scale production of solid lipid nanoparticles (SLN) by high pressure homogenization. J Microencapsul. 2002;19:1–10. doi: 10.1080/713817583. [DOI] [PubMed] [Google Scholar]
  • 27.Yang SC, Lu LF, Cai Y, Zhu JB, Liang BW, Yang CZ. Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain. J Control Release. 1999;59:299–307. doi: 10.1016/S0168-3659(99)00007-3. [DOI] [PubMed] [Google Scholar]
  • 28.Muller RH, Ruhl D, Runge SA. Biodegradation of solid lipid nanoparticles as a function of lipase incubation time. Int J Pharm. 1996;144:115–121. doi: 10.1016/S0378-5173(96)04731-X. [DOI] [Google Scholar]
  • 29.Siekmann B, Westesen K. Submicron-sized parenteral carrier systems based on solid lipids. Pharm Pharmacol Lett. 1992;1:123–126. [Google Scholar]
  • 30.Young TJ, Johnston KP, Pace GW, Mishra AK. Phospholipi-stabilized nanoparticles of cyclosporine A by rapid expansion from supercritical to aqueous solution.AAPS Pharm Sci Tech. 2004;5(1):Article 11. Available at: <http://www.aapspharmscitech.org.> [DOI] [PMC free article] [PubMed]
  • 31.Kabanov AV, Batrakova EV, Alakhov VY. Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery. J Control Release. 2002;82:189–212. doi: 10.1016/S0168-3659(02)00009-3. [DOI] [PubMed] [Google Scholar]
  • 32.Reddy LH, Murthy RSR. Polymerization of n-butyl cyanoacrylate in presence of surfactant: study of influence of polymerization factors on particle properties, drug loading and evaluation of its drug release kinetics. ARS Pharmaceutica. 2003;44:351–369. [Google Scholar]
  • 33.Schwarz C, Freitas C, Mehnert W, Muller RH. Sterilization and physical stability of drug-free and etomidate-loaded solid lipid nanoparticles. Proc Int Symp Cont Rel Bioact Mater. 1995;22:766–767. [Google Scholar]
  • 34.Bunjes H, Westesen K, Koch MHJ. Crystallization tendency and polymorphic transitions in triglyceride nanoparticles. Int J Pharm. 1996;129:159–173. doi: 10.1016/0378-5173(95)04286-5. [DOI] [Google Scholar]
  • 35.Westesen K, Bunjes H. Do nanoparticles prepared from lipids solid at room temperature always possess a solid lipid matrix? Int J Pharm. 1995;115:129–131. doi: 10.1016/0378-5173(94)00347-8. [DOI] [Google Scholar]
  • 36.Moghimi SM, Hunter AC, Murray JC. Long-circulating and target-specific nanoparticles: theory to practice. Pharmacol Rev. 2001;53:283–318. [PubMed] [Google Scholar]
  • 37.Hamdani J, Moes AJ, Amighi K. Physical and thermal characterisation of Precirol and Compritol as lipophilic glycerides used for the preparation of controlled-release matrix pellets. Int J Pharm. 2003;260:47–57. doi: 10.1016/S0378-5173(03)00229-1. [DOI] [PubMed] [Google Scholar]

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