Respirable Low-Density Microparticles Formed In Situ from Aerosolized Brittle Matrices
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
Inhalation of low-density porous particles enables deep lung delivery with less dependence on device design and patient inspiration. The purpose of this study was to implement Thin Film Freezing (TFF) to investigate a novel approach to dry powder inhalation.
Powders produced by TFF were evaluated for aerodynamic and geometric particle size by cascade impaction and laser light scattering, respectively. Density measurements were conducted according to USP methods and calculated using data from particle size measurements. Excipient inclusion and its effect on moisture sorption was measured by Dynamic Vapor Sorption (DVS).
TFF-produced brittle matrix powders were sheared apart into respirable microparticles using a passive DPI device, producing fine particle fractions (FPF) up to 69% and mass median aerodynamic diameters (MMAD) as low as 2.6 μm. Particles had a mean geometric diameter ranging from 25 μm to 50 μm and mass densities of approximately 0.01 g/cm3. Powders were susceptible to moisture-induced matrix collapse, capillary forces and electrostatic charging; although formulations containing mannitol or no sugar excipient proved to be more robust.
Aerosolized brittle matrices produced by TFF may prove to be a useful platform for highly efficient pulmonary delivery of thermally labile, highly potent, and poorly soluble drugs.
- Kling, J (2008) Inhaled insulin’s last gasp?. Nat Biotech 26: pp. 479-480 CrossRef
- Crowder, TM, Rosati, JA, Schroeder, JD, Hickey, AJ, Martonen, TB (2002) Fundamental effects of paritcle morphology on lung delivery: predictions of Stoke’s Law and the particular relevance to dry powder inhaler formulation and development. Pharm Res 19: pp. 239-245 CrossRef
- Edwards, DA, Hanes, J, Caponetti, G, Hrkach, J, Ben-Jebria, A, Eskew, ML (1997) Large Porous Particles for Pulmonary Drug Delivery. Science 276: pp. 1868 CrossRef
- Geiser, M, Casaulta, M, Kupferschmid, B, Schulz, H, Semmler-Behnke, M, Kreyling, W (2008) The Role of Macrophages in the Clearance of Inhaled Ultrafine Titanium Dioxide Particles. Am J Respir Cell Mol Biol 38: pp. 371-376 CrossRef
- Scarpelli, EM (2003) Physiology of the alveolar surface network. Comp Biochem Physiol A Mol Integr Physiol 135: pp. 39-104 CrossRef
- Tam, JM, McConville, JT, Robert, O, Williams, I, Johnston, KP (2008) Amorphous cyclosporin nanodispersions for enhanced pulmonary deposition and dissolution. J Pharm Sci 97: pp. 4915-4933 CrossRef
- Engstrom, J, Tam, J, Miller, M, Williams, R, Johnston, K (2009) Templated Open Flocs of Nanorods for Enhanced Pulmonary Delivery with Pressurized Metered Dose Inhalers. Pharm Res 26: pp. 101-117 CrossRef
- Crisp, MT, Tucker, CJ, Rogers, TL, Williams, RO, Johnston, KP (2007) Turbidimetric measurement and prediction of dissolution rates of poorly soluble drug nanocrystals. J Control Release 117: pp. 351-359 CrossRef
- Matteucci, ME, Brettmann, BK, Rogers, TL, Elder, EJ, Williams, RO, Johnston, KP (2007) Design of Potent Amorphous Drug Nanoparticles for Rapid Generation of Highly Supersaturated Media. Mol Pharm 4: pp. 782-793 CrossRef
- Matteucci, ME, Paguio, JC, Miller, MA (2009) Williams Iii RO, and Johnston KP. Highly Supersaturated Solutions from Dissolution of Amorphous Itraconazole Microparticles at pH 6.8. Mol Pharm 6: pp. 375-385 CrossRef
- McConville, J, Overhoff, K, Sinswat, P, Vaughn, J, Frei, B, Burgess, D (2006) Targeted High Lung Concentrations of Itraconazole Using Nebulized Dispersions in a Murine Model. Pharm Res 23: pp. 901-911 CrossRef
- Sinswat, P, Overhoff, KA, McConville, JT, Johnston, KP, Williams, RO (2008) Nebulization of nanoparticulate amorphous or crystalline tacrolimus - Single-dose pharmacokinetics study in mice. Eur J Pharm Biopharm 69: pp. 1057-1066 CrossRef
- Vaughn, JM, Wiederhold, NP, McConville, JT, Coalson, JJ, Talbert, RL, Burgess, DS (2007) Williams Iii RO, and Peters JI. Murine airway histology and intracellular uptake of inhaled amorphous itraconazole. Int J Pharm 338: pp. 219-224 CrossRef
- Chiou, WL, Riegelman, S (1969) Preparation and dissolution characteristics of several fast-release solid dispersions of griseofulvin. J Pharm Sci 58: pp. 1505-1510 CrossRef
- Yang, JZ, Young, AL, Chiang, P-C, Thurston, A, Pretzer, DK (2008) Fluticasone and budesonide nanosuspensions for pulmonary delivery: preparation, characterization, and pharmacokinetic studies. J Pharm Sci 97: pp. 4869-4878 CrossRef
- Tsapis N, Bennett D, Jackson B, Weitz DA, and Edwards DA. Trojan particles: Large porous carriers of nanoparticles for drug delivery. 2002;99:12001–12005.
- Velaga, SP, Berger, R, Carlfors, J (2002) Supercritical fluids crystallization of budesonide and flunisolide. Pharm Res 19: pp. 1564-1571 CrossRef
- Cheng, YS, Marshall, TC, Henderson, RF, Newton, GJ (1985) Use of a jet mill for dispersing dry powder for inhalation studies. Am Ind Hyg Assoc J 46: pp. 449-454 CrossRef
- Chawla, A, Taylor, KMG, Newton, JM, Holbrook, P (1994) Production of spray dried salbutamol sulfate for use in dry powder aerosol formulation. Int J Pharm 108: pp. 233-240 CrossRef
- Overhoff, KA, Johnston, KP, Tam, J, Engstrom, J, Williams, RO (2009) Use of thin film freezing to enable drug delivery: a review. J Drug Deliv Sci Tech 19: pp. 89-98
- Engstrom, J, Lai, E, Ludher, B, Chen, B, Milner, T, Williams, R (2008) Formation of Stable Submicron Protein Particles by Thin Film Freezing. Pharm Res 25: pp. 1334-1346 CrossRef
- Patton, JS (1996) Mechanisms of macromolecule absorption by the lungs. Adv Drug Delivery Rev 19: pp. 3-36 CrossRef
- Overhoff, KA, Engstrom, JD, Chen, B, Scherzer, BD, Milner, TE, Johnston, KP (2007) Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs. Eur J Pharm Biopharm 65: pp. 57-67 CrossRef
- Marple, VA, Olson, BA, Santhanakrishnan, K, Mitchell, JP, Murray, SC, Hudson-Curtis, BL (2003) Next Generation Pharmaceutical Impactor (A New Impactor for Pharmaceutical Inhaler Testing). Part II: archival calibration. J Aerosol Med 16: pp. 301-324 CrossRef
- Mitchell, JP (2003) Practices of coating collection surfaces of cascade impactors: a survey of members of the european pharmaceutical aerosol group (EPAG). Drug Deliv Lung 14: pp. 75-78
- Akashi, T, Nefuji, T, Yoshida, M, Hosoda, J (1996) Quantitative determination of tautomeric FK506 by reversed-phase liquid chromatography. J Pharm Biomed Anal 14: pp. 339-346 CrossRef
- Christopher, D, Curry, P, Doub, B, Furnkranz, K, Lavery, M, Lin, K (2003) Considerations for the Development and Practice of Cascade Impaction Testing, Including a Mass Balance Failure Investigation Tree. J Aerosol Med 16: pp. 235-247 CrossRef
- Berg, E, Svensson, JO, Asking, L (2007) Determination of nebulizer droplet size distribution: a method based on impactor refrigeration. J Aerosol Med 20: pp. 97-104 CrossRef
- Dunbar, C, Kataya, A, Tiangbe, T (2005) Reducing bounce effects in the Andersen cascade impactor. Int J Pharm 301: pp. 25-32 CrossRef
- Kamiya A, Sakagami M, Hindle M, and Byron PR. Aerodynamic sizing of metered dose inhalers: An evaluation of the andersen and next generation pharmaceutical impactors and their USP methods. 2004;93:1828–1837.
- Choi H-G, Lee B-J, Han J-H, Lee M-K, Park K-M, Yong CS, Rhee J-D, Kim Y-B, and Kim C-K. Terfenadine β-Cyclodextrin Inclusion Complex with Antihistaminic Activity Enhancement. 2001;27:857–862.
- Overhoff, K, McConville, J, Yang, W, Johnston, K, Peters, J, Williams, R (2008) Effect of stabilizer on the maximum degree and extent of supersaturation and oral absorption of tacrolimus made by ultra-rapid freezing. Pharm Res 25: pp. 167-175 CrossRef
- Miller, DA, DiNunzio, JC, Yang, W, McGinity, JW, Williams, RO (2008) Targeted intestinal delivery of supesaturated itraconazole for improved oral absorption. Pharm Res 25: pp. 1450-1459 CrossRef
- Yang, W, Tam, J, Miller, DA, Zhou, J, McConville, JT, Johnston, KP (2008) High bioavailability from nebulized itraconazole nanoparticle dispersions with biocompatible stabilizers. Int J Pharm 361: pp. 177-188 CrossRef
- Birchall, JC, Jones, BE, Morrissey, A, Jones, BE (2008) A Comparison of the Puncturing Properties of Gelatin and Hypromellose Capsules for Use in Dry Powder Inhalers. Drug Dev Ind Pharm 34: pp. 870-876 CrossRef
- Pilcer, G, Sebti, T, Amighi, K (2006) Formulation and Characterization of Lipid-Coated Tobramycin Particles for Dry Powder Inhalation. Pharm Res 23: pp. 931-940 CrossRef
- Berchane, NS, Carson, KH, Rice-Ficht, AC, Andrews, MJ (2007) Effect of mean diameter and polydispersity of PLG microspheres on drug release: experiment and theory. Int J Pharm 337: pp. 118-126 CrossRef
- Kajiwara, K, Franks, F, Echlin, P, Greer, AL (1999) Structural and dynamic properites of crystalline and amorphous phases in raffinose-water mixtrues. Pharm Res 16: pp. 1441-1448 CrossRef
- Gohel, MC (2005) A review of co-processed directly compressible excipients. J Pharm Pharm Sci 8: pp. 76-93
- Young, P, Sung, A, Traini, D, Kwok, P, Chiou, H, Chan, H-K (2007) Influence of Humidity on the Electrostatic Charge and Aerosol Performance of Dry Powder Inhaler Carrier based Systems. Pharm Res 24: pp. 963-970 CrossRef
- Hogan, SE, Buckton, G (2001) Water sorption/desorption–near IR and calorimetric study of crystalline and amorphous raffinose. Int J Pharm 227: pp. 57-69 CrossRef
- Lechuga-Ballesteros, D, Charan, C, Stults, CLM, Stevenson, CL, Miller, DP, Vehring, R (2007) Trileucine Improves Aerosol Performance and Stability of Spray-Dried Powders for Inhalation. J Pharm Sci 97: pp. 287-302 CrossRef
- Sastry, SV, Nyshadham, JR, Fix, JA (2000) Recent technological advances in oral drug delivery—a review. Pharmaceut Sci Tech Today 3: pp. 138-145 CrossRef
- Jennings, T (1999) Lyophilization: Introduction and basic priciples. CRC Press LLC, Bcoa Raton
- Gohel MC, Jogani PD, and Bariya SH. Development of Agglomerated Directly Compressible Diluent Consisting of Brittle and Ductile Materials. 2003;8:143–151.
- Booy, MPWM, Ruiter, RA, Meere, ALJ (1992) Evaluation of the Physical Stability of Freeze-Dried Sucrose-Containing Formulations by Differential Scanning Calorimetry. Pharm Res 9: pp. 109-114 CrossRef
- Hancock BC, Zografi G. Characteristics and significance of the amorphous state in pharmaceutical systems. 1997;86:1–12.
- Respirable Low-Density Microparticles Formed In Situ from Aerosolized Brittle Matrices
Volume 30, Issue 3 , pp 813-825
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- dry powder inhalation
- low-density particles
- particle engineering
- respirable powder
- Industry Sectors
- Author Affiliations
- 1. Drug Dynamics Institute, The University of Texas at Austin, 1 University Station, Mail Stop A1915, Austin, Texas, 78712, USA
- 2. College of Pharmacy, The University of Texas at Austin, 1 University Station, Mail Stop A1920, Austin, Texas, 78712, USA
- 3. Department of Chemical Engineering, The University of Texas at Austin, 1 University Station, Mail Stop C0400, Austin, Texas, 78712, USA