Search tips
Search criteria 


Logo of aapspharmspringer.comThis journalToc AlertsSubmit OnlineOpen Choice
AAPS PharmSciTech. 2002 September; 3(3): 16–26.
Published online 2015 February 19. doi:  10.1007/BF02830616
PMCID: PMC2784047

Preparation of budesonide and budesonide-PLA microparticles using supercritical fluid precipitation technology


The objective of this study was to prepare and characterize microparticles of budesonide alone and budesonide and polylactic acid (PLA) using supercritical fluid (SCF) technology. A precipitation with a compressed antisolvent (PCA) technique employing supercritical CO2 and a nozzle with 100-μm internal diameter was used to prepare microparticles of budesonide and budesonide-PLA. The effect of various operating variables (temperature and pressure of CO2 and flow rates of drug-polymer solution and/or CO2) and formulation variables (0.25%, 0.5%, and 1% budesonide in methylene chloride) on the morphology and size distribution of the microparticles was determined using scanning electron microscopy. In addition, budesonide-PLA particles were characterized for their surface charge and drug-polymer interactions using a zeta meter and differential scanning calorimetry (DSC), respectively. Furthermore, in vitro budesonide release from budesonide-PLA microparticles was determined at 37°C. Using the PCA process, budesonide and budesonide-PLA microparticles with mean diameters of 1 to 2 μm were prepared. An increase in budesonide concentration (0.25%–1% wt/vol) resulted in budesonide microparticles that were fairly spherical and less aggiomerated. In addition, the size of the microparticles increased with an increase in the drug-polymer solution flow rate (1.4–4.7 mL/min) or with a decrease in the CO2 flow rate (50–10 mL/min). Budesonide-PLA microparticles had a drug loading of 7.94%, equivalent to ~80% encapsulation efficiency. Budesonide-PLA microparticles had a zeta potential of— 37±4 mV, and DSC studies indicated that SCF processing of budesonide-PLA microparticles resulted in the loss of budesonide crystallinity. Finally, in vitro drug release studies at 37°C indicated 50% budesonide release from the budesonide-PLA microparticles at the end of 28 days. Thus, the PCA process was successful in producing budesonide and budesonide-PLA microparticles. In addition, budesonide-PLA microparticles sustained budesonide release for 4 weeks.

Keywords: budesonide, carbon dioxide, microparticles, supercritical, sustained release

Full Text

The Full Text of this article is available as a PDF (842K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Brogden RN, McTavish D. Budesonide: an updated review of its pharmacological properties, and therapeutic efficacy in asthma and rhinitis. Drugs. 1992;44:375–407. doi: 10.2165/00003495-199244030-00007. [PubMed] [Cross Ref]
2. Erlansson M, Svensjo E, Bergqvist D. Leukotriene B4-induced permeability increase in postcapillary venules and its inhibition by three different antiinflammatory drugs. Inflammation. 1989;13:693–705. doi: 10.1007/BF00914313. [PubMed] [Cross Ref]
3. Svensjo E. The hamster cheek pouch as a model in microcirculation research. Eur Respir J. 1990;12:595s. Abstract. [PubMed]
4. Bandi N, Kompella UB. Budesonide reduces vascular endothelial growth factor secretion and expression in airway (Calu-1) and alveolar (A549) epithelial cells. Eur J Pharmacol. 2001;425:109–116. doi: 10.1016/S0014-2999(01)01192-X. [PubMed] [Cross Ref]
5. Bandi N, Kompella UB. Budesonide reduces multidrug resistance-associated protein 1 expression in an airway epithelial cell line (Calu-1) Eur J Pharmacol. 2002;437:9–17. doi: 10.1016/S0014-2999(02)01267-0. [PubMed] [Cross Ref]
6. Langer R. Drug delivery and targeting. Nature. 1998;392(6679, suppl):5–10. [PubMed]
7. Tom JW, Lim G, Debenedetti PG, Prudhomme RK. Applications of supercritical fluids in controlled release of drugs. In: Brennecke JF, Kiran E, editors. Supercritical Engineering Science: Fundamentals and Applications. Cary, NC: Oxford University Press; 1993. pp. 238–257.
8. Bodmeier R, Wang H, Dixon DJ, Mawson S, Johnston KP. Polymeric microspheres prepared by spraying into compressed carbon dioxide. Pharm Res. 1995;12:1211–1217. doi: 10.1023/A:1016276329672. [PubMed] [Cross Ref]
9. Bleich J, Kleinebudde P, Mueller BW. Influence of gas density and pressure on microparticles produced with the ASES process. Int J Pharm. 1994;106:77–84. doi: 10.1016/0378-5173(94)90278-X. [Cross Ref]
10. Bleich J, Mueller BW. Production of drug loaded microparticles by the use of supercritical gases with the aerosol solvent extraction system (ASES) process. J Microencapsulation. 2002;13:131–139. doi: 10.3109/02652049609052902. [PubMed] [Cross Ref]
11. Falk R, Randolph TW, Meyer JD, Kelly RM, Manning MC. Controlled release of ionic compounds from poly (L-lactide) microspheres produced by precipitation with a compressed antisolvent. J Control Rel. 1997;44:77–85. doi: 10.1016/S0168-3659(96)01508-8. [Cross Ref]
12. Sunkara G, Kompella UB. Drug delivery applications of supercritical fluid technology. Drug Del. Technol. 2002;2:44–50.
13. Young TJ, Johnston KP, Mishima K, Tanaka H. Encapsulation of lysozyme in a biodegradable polymer by precipitation with a vaporover-liquid antisolvent. J Pharm Sci. 1999;88:640–650. doi: 10.1021/js980237h. [PubMed] [Cross Ref]
14. Dixon DJ, Johnston KP, Bodmeier RA. Polymeric materials formed by precipitation with a compressed fluid antisolvent. AIChE J. 1993;39:127–139. doi: 10.1002/aic.690390113. [Cross Ref]
15. Randolph TW, Randolph AD, Mebes M, Yeung S. Sub-micrometer-sized biodegradable particles of poly (L-lactic acid) via the gas antisolvent spray precipitation process. Biotechnol Prog. 1993;9:429–435. doi: 10.1021/bp00022a010. [PubMed] [Cross Ref]
16. Bleich J, Mueller BW, Wabmus W. Aerosol solvent extraction system: a new microparticle production technique. Int J Pharm. 1993;97:111–117. doi: 10.1016/0378-5173(93)90131-X. [Cross Ref]
17. Kompella UB, Koushik K. Preparation of drug delivery systems using supercritical fluid technology. Crit Rev Ther Drug Carrier Syst. 2001;18:173–199. [PubMed]
18. Mawson S, Kanakia S, Johnston KP. Coaxial nozzle for control of particle morphology in precipitation with a compressed fluid antisolvent. J Appl Polym Sci. 1997;64:2105–2118. doi: 10.1002/(SICI)1097-4628(19970613)64:11<2105::AID-APP6>3.0.CO;2-N. [Cross Ref]
19. Steckel H, Thies J, Mueller BW. Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide. Int J Pharm. 1997;152:99–110. doi: 10.1016/S0378-5173(97)00071-9. [Cross Ref]
20. Palakodaty S, York P, Pritchard J. Supercritical fluid processing of materials from aqueous solutions: the application of SEDS to lactose as a model substance. Pharm Res. 1998;15:1835–1843. doi: 10.1023/A:1011949805156. [PubMed] [Cross Ref]
21. Reverchon E, Celano C, Porta GD. Supercritical antisolvent precipitation: a new technique for preparing submicronic yttrium powders to improve YBCO superconductors. J Mater Res. 1998;13:284–289. doi: 10.1557/JMR.1998.0039. [Cross Ref]
22. Benedetti L, Bertucco A, Pallado P. Production of micronic particles of biocompatible polymer using supercritical carbon dioxide. Biotechnol Bioeng. 1997;53:232–237. doi: 10.1002/(SICI)1097-0290(19970120)53:2<232::AID-BIT15>3.0.CO;2-M. [PubMed] [Cross Ref]
23. Mawson S, Johnston KP, Betts DE, McClain JB, DeSimone JM. Stabilized polymer microparticles by precipitation with a compressed fluid antisolvent, 1: polyfluoro acrylates. Macromolecules. 1997;30:71–77. doi: 10.1021/ma961048t. [Cross Ref]
24. Mawson S, Yates MZ, O_Neill ML, Johnston KP. Stabilized polymer microparticles by precipitation with a compressed fluid antisolvent 2: polypropylene oxide- and polybutylene oxide-based copolymers. Langmuir. 1997;13:1519–1528. doi: 10.1021/la961017r. [Cross Ref]
25. Faouzi MA, Dine T, Luyckx M, Brunet C, Gressier B, Cazin M, Wallaert B, Cazin JC. High performance liquid chromatographic method for the determination of budesonide in bronchoalveolar lavage fluids of asthmatic patients. J Chromatogr B Biomed Appl. 1995;664:463–467. doi: 10.1016/0378-4347(94)00473-I. [PubMed] [Cross Ref]
26. Lengsfeld CS, Delplanque JP, Borocas VH, Randolph TW. Mechanism governing microparticle morphology during precipitation by a compressed antisolvent: atomization vs nucleation and growth. J Phys Chem B. 2000;104:2725–2735. doi: 10.1021/jp9931511. [Cross Ref]
27. Reaves JT, Griffith AT, Roberts CB. Critical properties of dilute carbon dioxide plus entrainer and ethane plus entrainer mixtures. J Chem Eng Data. 1998;43:683–686. doi: 10.1021/je9702753. [Cross Ref]
28. Angus S., Armstrong B., de Reuck K.M., editors. International Thermodynamic Tables of the Fluid State: Carbon Dioxide. Oxford: Pergamon Press; 1976.
29. Mu L, Feng SS. Fabrication, characterization and in vitro release of paclitaxel (Taxol) loaded polylactic-co-glycolic acid microspheres prepared by spray drying technique with lipid/cholesterol emulsifiers. J Control Rel. 2001;76:239–254. doi: 10.1016/S0168-3659(01)00440-0. [PubMed] [Cross Ref]
30. Kompella UB, Bandi N, Ayalasomayajula SP. Polylactic acid nanoparticles for sustained release of budesonide. Drug Del Technol. 2001;1:28–34.
31. Van Hees T, Piel G, Evrard B, Otte X, Thunus L, Delattre L. Application of supercritical carbon dioxide for the preparation of a piroxicambeta-cyclodextrin inclusion compound. Pharm Res. 1999;16:1864–1870. doi: 10.1023/A:1018955410414. [PubMed] [Cross Ref]
32. Ghaderi R, Artursson P, Carlfors J. Preparation of biodegradable microparticles using solution-enhanced dispersion by supercritical fluids (SEDS) Pharm Res. 1999;16:676–681. doi: 10.1023/A:1018868423309. [PubMed] [Cross Ref]

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