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AAPS PharmSciTech. 2004 June; 5(2): 17–23.
Published online 2004 March 10. doi:  10.1208/pt050227
PMCID: PMC2750462

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

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

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
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. [PubMed] [Cross Ref]
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. [Cross Ref]
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. [PubMed] [Cross Ref]
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. [Cross Ref]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
12. Wissing SA, Muller RH. Solid lipid nanoparticles (SLN): a novel carrier for UV blockers. Pharmazie. 2001;56:783–786. [PubMed]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
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. [Cross Ref]
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. [Cross Ref]
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. [PubMed] [Cross Ref]
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. [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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
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.
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. [PubMed]
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. [PubMed] [Cross Ref]
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. [Cross Ref]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
27. Muller R, Olbrich C. Solid lipid nanoparticles: Phagocytic uptake, in vitro cytotoxicity and in vitro biodegradation. Drugs. 1999;42:49–53.
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. [PubMed] [Cross Ref]
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. [Cross Ref]
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. [PubMed] [Cross Ref]
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. [PubMed] [Cross Ref]
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.
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.

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