Skip to main content
PMC home page
AAPS PharmSciTech logoLink to AAPS PharmSciTech
. 2004 Mar 10;5(2):17–23. doi: 10.1208/pt050227

Preparation and in vivo toxicity study of solid lipid microparticles as carrier for pulmonary administration

Vanna Sanna 1, Nathalie Kirschvink 2, Pascal Gustin 2, Elisabeta Gavini 1,✉, Isabelle Roland 3, Luc Delattre 3, Brigitte Evrard 3
PMCID: PMC2750462  PMID: 15760085

Abstract

The purpose of this research was to investigate the effects of processing conditions on the characteristics of solid lipid microparticles (SLM) with a potential application as carriers for pulmonary administration. Compritol (5.0% wt/wt) SLM dispersions were prepared by rotor-stator homogenization, at different surfactant concentrations and emulsification times. The SLM were characterized, in terms of morphology and size, after lyophilization and sterilization by autoclaving process. In vivo assessment was carried out in rats by intratracheal instillation of either placebo or SLM dispersion, and by bronchoalveolar lavage for cytological analysis. Mean particle size of 4 to 5 μm was achieved using 0.3% and 0.4% (wt/wt) of emulsifier (Poloxamer 188) and emulsification times of 2 and 5 minutes. The particles showed spherical shape and smooth surface. The morphology of microparticles, the size, and the size distribution were not substantially modified after lyophilization and sterilization. Total cell counts showed no significant differences between placebo and SLM 0.5% or 2.5% groups. Regarding cytology, percentage of polymorphonuclear neutrophils and macrophages did not significantly differ between groups. These results suggest that a single intratracheal administration of the SLMs does not induce a significant inflammatory airway response in rats and that the SLMs might be a potential carrier for encapsulated drug via the pulmonary route.

Keywords: solid lipid microparticles, pulmonary administration, lyophilization, sterilization, pulmonary toxicity

Full Text

The Full Text of this article is available as a PDF (477.6 KB).

References

  • 1.Reithmeier H, Hermann J, Gopferich A. Development and characterization of lipid microparticles as a drug carrier for somatostatin. Int J Pharm. 2001;218:133–143. doi: 10.1016/S0378-5173(01)00620-2. [DOI] [PubMed] [Google Scholar]
  • 2.Morel S, Ugazio E, Cavalli R, Gasco MR. Thymopentin in solid lypid nanoparticles. Int J Pharm. 1996;132:259–261. doi: 10.1016/0378-5173(95)04388-8. [DOI] [Google Scholar]
  • 3.Erni C, Suard C, Freitas S, Dreher D, Merkle HP, Elke W. Evaluation of cationic solid lipid microparticles as synthetic carriers for the targeted delivery of macromolecules to phagocytic antigen-presenting cells. Biomaterials. 2002;23:4667–4676. doi: 10.1016/S0142-9612(02)00216-8. [DOI] [PubMed] [Google Scholar]
  • 4.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]
  • 5.Hu FQ, Yuan H, Zhang HH, Fang M. Preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent diffusion method in aqueous system and physicochemical characterization. Int J Pharm. 2002;239:121–128. doi: 10.1016/S0378-5173(02)00081-9. [DOI] [PubMed] [Google Scholar]
  • 6.Lippacher A, Muller RH, Mader K. Preparation of semisolid drug carriers for topical application based on solid lipid nanoparticles. Int J Pharm. 2001;214:9–12. doi: 10.1016/S0378-5173(00)00623-2. [DOI] [PubMed] [Google Scholar]
  • 7.Muller RH, Mader K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery: a review of the state of the art. Eur J Pharm Biopharm. 2000;50:161–177. doi: 10.1016/S0939-6411(00)00087-4. [DOI] [PubMed] [Google Scholar]
  • 8.Cavalli R, Bargoni A, Podio V, Muntoni E, Zara GP, Gasco MR. Duodenal administration of solid lipid nanoparticles loaded with different percentages of tobramycin. J Pharm Sci. 2003;92:1085–1094. doi: 10.1002/jps.10368. [DOI] [PubMed] [Google Scholar]
  • 9.Reithmeier H, Herrmann J, Gopferich A. Lipid microparticles as a parenteral controlled release device for peptides. J Control Release. 2001;73:339–350. doi: 10.1016/S0168-3659(01)00354-6. [DOI] [PubMed] [Google Scholar]
  • 10.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]
  • 11.Savolainen M, Herder J, Khoo C, et al. Evaluation of polar lipid-hydrophilic polymer microparticles. Int J Pharm. 2003;262:47–62. doi: 10.1016/S0378-5173(03)00336-3. [DOI] [PubMed] [Google Scholar]
  • 12.Wissing SA, Muller RH. Solid lipid nanoparticles (SLN): a novel carrier for UV blockers. Pharmazie. 2001;56:783–786. [PubMed] [Google Scholar]
  • 13.Kunisawa J, Okudaira A, Tsutusmi Y, et al. Characterization of mucoadhesive microspheres for the induction of mucosal and systemic immune responses. Vaccine. 2000;19:589–594. doi: 10.1016/S0264-410X(00)00094-3. [DOI] [PubMed] [Google Scholar]
  • 14.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]
  • 15.Cavalli R, Caputo O, Parlotti ME, Trotta M, Scarnecchia C, Gasco MR. Sterilization and freeze-drying of drug-free and drug-loaded solid lipid nanoparticles. Int J Pharm. 1997;148:47–54. doi: 10.1016/S0378-5173(96)04822-3. [DOI] [Google Scholar]
  • 16.Schreier H, Gonzalez-Rothi RJ, Stecenko AA. Pulmonary delivery of liposomes. J Control Release. 1993;24:209–223. doi: 10.1016/0168-3659(93)90180-D. [DOI] [Google Scholar]
  • 17.Selek H, Sahin S, Ercan MT, Sargon M, Hincal AA, kas HS. Formulation and in vitro/in vivo evaluation of terbutaline sulphate incorporated in PLGA (25/75) and L-PLA microspheres. J Microencapsul. 2003;20:261–271. doi: 10.1080/0265204021000058465. [DOI] [PubMed] [Google Scholar]
  • 18.Joshi MR, Misra A. Liposomal Budesonide for Dry Powder Inhaler: Preparation and Stabilization. AAPS PharmSciTech. 2001;2(4):article 25. Available at: http://www.aapspharmscitech.org. [DOI] [PMC free article] [PubMed]
  • 19.Takeuchi H, Yamamoto H, Kawashima Y. Mucoadhesive nanoparticulate systems for peptide drug delivery. Adv Drug Deliv Rev. 2001;47:39–54. doi: 10.1016/S0169-409X(00)00120-4. [DOI] [PubMed] [Google Scholar]
  • 20.Davidson IG, Langner EJ, Plowman SV, Blair JA. Release mechanism of insulin encapsulated in trehalose ester derivative microparticles delivered via inhalation. Int J Pharm. 2003;254:211–222. doi: 10.1016/S0378-5173(03)00035-8. [DOI] [PubMed] [Google Scholar]
  • 21.Niven RW. Modulated drug therapy with inhalation aerosols. In: Hickey AJ, editor. Pharmaceutical Inhalation Aerosol Technology. New York, NY: Dekker; 1992. pp. 321–359. [Google Scholar]
  • 22.Muller RH, Ruhl D, Runge S, Schulze-Forster K, Mehnert W. Cytotoxicity of solid lipid nanoparticles as a function of the lipid matrix and the surfactant. Pharm Res. 1997;14:58–62. doi: 10.1023/a:1012043315093. [DOI] [PubMed] [Google Scholar]
  • 23.Mobley C, Hochhaus G. Methods used to assess pulmonary deposition and absorption of drugs. Drug Discov Today. 2001;6:367–375. doi: 10.1016/S1359-6446(01)01691-9. [DOI] [PubMed] [Google Scholar]
  • 24.Zeng XM, Martin GP, Marriott C. The controlled delivery of drugs to the lung. Int J Pharm. 1995;124:149–164. doi: 10.1016/0378-5173(95)00104-Q. [DOI] [Google Scholar]
  • 25.Larhrib H, Zeng XM, Martin GP, Marriott C, Pritchard J. The use of different grades of lactose as a carrier for aerosolised salbutamol sulphate. Int J Pharm. 1999;191:1–14. doi: 10.1016/S0378-5173(99)00164-7. [DOI] [PubMed] [Google Scholar]
  • 26.Mehnert W, Mader K. Solid lipid nanoparticles: production, characterization and applications. Adv Drug Deliv Rev. 2001;47:165–196. doi: 10.1016/S0169-409X(01)00105-3. [DOI] [PubMed] [Google Scholar]
  • 27.Muller R, Olbrich C. Solid lipid nanoparticles: Phagocytic uptake, in vitro cytotoxicity and in vitro biodegradation. Drugs. 1999;42:49–53. [Google Scholar]
  • 28.Heiati H, Tawashi R, Phillips NC. Drug retention and stability of solid lipid nanoparticles containing azidothymidine palmitate after autoclaving, storage and lyophilization. J Microencapsul. 1998;15:173–184. doi: 10.3109/02652049809006847. [DOI] [PubMed] [Google Scholar]
  • 29.Schwarz C, Freitas C, Mehnert W, Muller RH. Sterilisation and physical stability of drug-free and etomidate-loaded solid nanoparticles. Proceedings 33304 of the 22nd International Symposium on Controlled Release of Bioactive Materials. July 30–August 4, 1995. Seattle, WA. 766–767.
  • 30.Prinderre P, Piccerelle P, Cauture E, Kalantzis G, Reynier JP, Joachim J. Formulation and evaluation of o/w emulsions using experimental design. Int J Pharm. 1998;163:73–79. doi: 10.1016/S0378-5173(97)00368-2. [DOI] [Google Scholar]
  • 31.Roland I, Piel G, Delattre L, Evrard B. Systematic characterization of oil-in-water emulsions for formulation design. Int J Pharm. 2003;263:85–94. doi: 10.1016/S0378-5173(03)00364-8. [DOI] [PubMed] [Google Scholar]
  • 32.Zimmermann 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]
  • 33.Muller RH, Mehnert W, Lucks C, et al. Solid lipid nanoparticles (SLN) for controlled drug delivery: an alternative colloidal carrier system for controlled drug delivery. Eur J Pharm Biopharm. 1995;41:62–69. [Google Scholar]
  • 34.Siekmann B, Westesen K. Melt-homogenized solid lipid nanoparticles stabilized by the non-ionic surfactant tylxapol. I. Preparation and particle size determination. Pharm Pharmacol Lett. 1994;3:194–197. [Google Scholar]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES