REVIEW
Formulation Design of Dry Powders for Inhalation
Jeffry G. Weers,
Danforth P. Miller,
Jeffry G. Weers
Novartis Pharmaceuticals Corporation, San Carlos, California, 94070
Search for more papers by this authorCorresponding Author
Danforth P. Miller
Novartis Pharmaceuticals Corporation, San Carlos, California, 94070
Telephone: +650-622-1533; Fax: +650-622-3609; E-mail: [email protected]Search for more papers by this authorJeffry G. Weers,
Danforth P. Miller,
Jeffry G. Weers
Novartis Pharmaceuticals Corporation, San Carlos, California, 94070
Search for more papers by this authorCorresponding Author
Danforth P. Miller
Novartis Pharmaceuticals Corporation, San Carlos, California, 94070
Telephone: +650-622-1533; Fax: +650-622-3609; E-mail: [email protected]Search for more papers by this authorAbstract
Drugs for inhalation are no longer exclusively highly crystalline small molecules. They may also be amorphous small molecules, peptides, antibodies, and myriad types of engineered proteins. The evolution of respiratory therapeutics has created a need for flexible formulation technologies to engineer respirable particles. These technologies have enabled medicinal chemists to focus on molecular design without concern regarding compatibility of physicochemical properties with traditional, blend-based technologies. Therapeutics with diverse physicochemical properties can now be formulated as stable and respirable dry powders. Particle engineering technologies have also driven the deployment of new excipients, giving formulators greater control over particle and powder properties. This plays a key role in enabling efficient delivery of drugs to the lungs. Engineered powder and device combinations enable aerosols that largely bypass the mouth and throat, minimizing the inherent variability among patients that arises from differences in oropharyngeal and airway anatomies and in breathing profiles. This review explores how advances among molecules, particles, and powders have transformed inhaled drug product development. Ultimately, this scientific progress will benefit patients, enabling new classes of therapeutics to be formulated as dry powder aerosols with improved efficacy, reduced variability and side effects, and improved patient adherence. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3259–3288, 2015
REFERENCES
- 1Childs SL, Stahly GP, Park A. 2007. The salt-cocrystal continuum: The influence of crystal structure on ionization state. Mol Pharm 4(3): 323–338.
- 2Ahlneck C, Zografi G. 1990. The molecular basis for moisture effects on the physical and chemical stability of drugs in the solid-state. Int J Pharm 62: 87–95.
- 3Brodka-Pfeiffer K, Hausler H, Grass P, Langguth P. 2003. Conditioning following powder micronization: Influence on particle growth of salbutamol sulfate. Drug Dev Ind Pharm 29(10): 1077–1084.
- 4Young PM, Chan HK, Chiou H, Edge S, Tee TH, Traini D. 2007. The influence of mechanical processing of dry powder inhaler carriers on drug aerosolization performance. J Pharm Sci 96(5): 1331–1341.
- 5Patton JS, Byron PR. 2007. Inhaling medicines: Delivering drugs to the body through the lungs. Nat Rev Drug Dis 6(1): 67–74.
- 6Sadrzadeh N, Miller DP, Lechuga-Ballesteros D, Harper NJ, Stevenson CL, Bennett DB. 2010. Solid-state stability of spray-dried insulin powder for inhalation: Chemical kinetics and structural relaxation modeling of Exubera above and below the glass transition temperature. J Pharm Sci 99(9): 3698–3710.
- 7Maa YF, Costantino HR, Nguyen PA, Hsu CC. 1997. The effect of operating and formulation variables on the morphology of spray-dried protein particles. Pharm Dev Technol 2(3): 213–223.
- 8Mumenthaler M, Hsu CC, Pearlman R. 1994. Feasibility study on spray-drying protein pharmaceuticals: Recombinant human growth hormone and tissue-type plasminogen activator. Pharm Res 11(1): 12–20.
- 9Kawakami K, Usui T, Hattori M. 2012. Understanding the glass-forming ability of active pharmaceutical ingredients for designing supersaturating dosage forms. J Pharm Sci 101(9): 3239–3248.
- 10Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. 2001. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46(1–3): 3–26.
- 11Choy YB, Prausnitz MR. 2011. The rule of five for non-oral routes of drug delivery: Ophthalmic, inhalation and transdermal. Pharm Res 28(5): 943–948.
- 12Ritchie TJ, Luscombe CN, MacDonald SJF. 2009. Analysis of the calculated physicochemical properties of respiratory drugs: Can we design for inhaled drugs yet? J Chem Inf Model 49: 1025–1032.
- 13Tronde A, Nordén B, Marchner H, Wendel A-K, Lennernäs H, Bengtsson UH. 2003. Pulmonary absorption rate and bioavailability of drugsin vivo in rats: Structure–absorption relationships and physicochemical profiling of inhaled drugs. J Pharm Sci 92: 1216–1233.
- 14Eixarch H, Haltner-Ukomadu E, Beisswenger C, Bock U. 2010. Drug delivery to the lung: Permeability and physicochemical characteristics of drugs as the basis for a pulmonary biopharmaceutical classification system (pBCS). J Epithelial Biol Pharm 3: 1–14.
- 15Amidon GL, Lennernas H, Shah VP, Crison JR. 1995. A theoretical basis for a biopharmaceutic drug classification: The correlation of in-vitro drug product dissolution and in-vivo bioavailability. Pharm Res 12(3): 413–420.
- 16Hastedt J. 2014. The lungs as a dissolution vessel? Inhalation 8(6): 1–5.
- 17Glossop PA, Lane CA, Price DA, Bunnage ME, Lewthwaite RA, James K, Brown AD, Yeadon M, Perros-Huguet C, Trevethick MA, Clarke NP, Webster R, Jones RM, Burrows JL, Feeder N, Taylor SC, Spence FJ. 2010. Inhalation by design: Novel ultra-long-acting beta(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup. J Med Chem 53(18): 6640–6652.
- 18Yeadon M. 2011. The paradox of respiratory R&D, and why ‘inhaled-by-design' heralds a new dawn in asthma and chronic obstructive pulmonary disease treatments. Future Med Chem 3: 1581–1583.
- 19Daley-Yates PT, Price AC, Sisson JR, Pereira A, Dallow N. 2001. Beclomethasone dipropionate: Absolute bioavailability, pharmacokinetics and metabolism following intravenous, oral, intranasal and inhaled administration in man. Br J Clin Pharmacol 51(5): 400–409.
- 20Selby MD, de Koning PD, Roberts DF. 2011. A perspective on synthetic and solid-form enablement of inhalation candidates. Future Med Chem 13: 1679–1701.
- 21Baird JA, Van Eerdenbrugh B, Taylor LS. 2010. A classification system to assess the crystallization tendency of organic molecules from undercooled melts. J Pharm Sci 99(9): 3787–3806.
- 22Patton JS, Nagarajan S, Clark A. 1998. Pulmonary absorption and metabolism of peptides and proteins. In Respiratory Drug Delivery. RN Dalby, PR Byron, SJ Farr, Eds. vol. VI. Interpharm Press, Buffalo Grove, Illinois, USA. pp 17–24.
- 23Patton JS, Platz RM. 1992. Pulmonary delivery of peptides and proteins for systemic action. Adv Drug Deliv Rev 8: 179–228.
- 24Patton JS. 1996. Mechanisms of macromolecule absorption by the lungs. Adv Drug Deliv Rev 19: 3–36.
- 25Niven RW, Whitcomb KL, Shaner L, Ip AY, Kinstler OB. 1995. The pulmonary absorption of aerosolized and intratracheally instilled rhG-CSF and MonoPEGylated rhG-CSF. Pharm Res 12(9): 1343–1349.
- 26Meyer K, Zimmermann I. 2004. Effect of glidants in binary powder mixtures. Powder Technol 139(1): 40–54.
- 27Finlay WH. 2001. The mechanics of inhaled pharmaceutical aerosols: An introduction. London, UK: Academic Press.
- 28Hersey JA. 1975. Ordered mixing: A new concept in powder mixing practice. Powder Technol 11(1): 41–44.
- 29Geldart D. 1973. Types of gas fluidization. Powder Technol 7(5): 285–292.
- 30Weers J, Clark A, Challoner P. 2004. High dose inhaled powder delivery: Challenges and techniques. In Respiratory Drug Delivery; RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, Eds. Vol. IX. Amy Davis Biggs, River Grove, Illinois, USA. pp 281–288.
- 31Borgström L, Olsson B, Thorsson L. 2006. Degree of throat deposition can explain the variability in lung deposition of inhaled drugs. J Aerosol Med Pulm Drug Deliv 19: 473–483.
- 32Weers JG, Tarara TE, Clark AR. 2007. Design of fine particles for pulmonary drug delivery. Expert Opin Drug Deliv 4: 297–313.
- 33Ganderton D. 1992. The generation of respirable clouds from coarse powder aggregates. J Biopharm Sci 3: 101–105.
- 34Ganderton D, Kassem NM. 1992. Dry powder inhalers. In Advances in pharmaceutical sciences; D Ganderton, T Jones, Eds. London, UK: Academic Press, pp 165–191.
- 35Zeng XM, Martin GP, Marriott C, Pritchard J. 2000. The influence of carrier morphology on drug delivery by dry powder inhalers. Int J Pharm 200(1): 93–106.
- 36Jones MD, Price R. 2006. The influence of fine excipient particles on the performance of carrier-based dry powder inhalation formulations. Pharm Res 23(8): 1665–1674.
- 37Begat P, Morton DAV, Shur J, Kippax P, Staniforth JN, Price R. 2009. The role of force control agents in high-dose dry powder inhaler formulations. J Pharm Sci 98(8): 2770–2783.
- 38Pilcer G, Wauthoz N, Amighi K. 2012. Lactose characteristics and the generation of the aerosol. Adv Drug Deliv Rev 64(3): 233–256.
- 39Kou X, Chan LW, Steckel H, Heng PW. 2012. Physico-chemical aspects of lactose for inhalation. Adv Drug Deliv Rev 64(3): 220–232.
- 40Larhrib H, Zeng XM, Martin GP, Marriott C, Pritchard J. 1999. The use of different grades of lactose as a carrier for aerosolised salbutamol sulphate. Int J Pharm 191(1): 1–14.
- 41Zhou Q, Morton DAV. 2012. Drug-lactose binding aspects in adhesive mixtures: Controlling performance in dry powder inhaler formulations by altering lactose carrier surfaces. Adv Drug Deliv Rev 64(3): 275–284.
- 42Dunbar C. 2002. Dry powder formulations for inhalation. Drug Deliv Syst Sci 2: 78–80.
- 43Vehring R. 2008. Pharmaceutical particle engineering via spray drying. Pharm Res 25(5): 999–1022.
- 44Zeng XM, Martin GP, Tee SK, Abu Ghoush A, Marriott C. 1999. Effects of particle size and adding sequence of fine lactose on the deposition of salbutamol sulphate from a dry powder formulation. Int J Pharm 182(2): 133–144.
- 45Zeng XM, Martin GP, Tee SK, Marriott C. 1998. The role of fine particle lactose on the dispersion and deaggregation of salbutamol sulphate in an air stream in vitro. Int J Pharm 176(1): 99–110.
- 46Begat P, Morton DAV, Staniforth JN, Price R. 2004. The cohesive-adhesive balances in dry powder inhaler formulations I: Direct quantification by atomic force microscopy. Pharm Res 21(9): 1591–1597.
- 47Adi H, Larson I, Chiou H, Young P, Traini D, Stewart P. 2008. Role of agglomeration in the dispersion of salmeterol xinafoate from mixtures for inhalation with differing drug to fine lactose ratios. J Pharm Sci 97(8): 3140–3152.
- 48Jones MD, Hooton JC, Dawson ML, Ferrie AR, Price R. 2008. An investigation into the dispersion mechanisms of ternary dry powder inhaler formulations by the quantification of interparticulate forces. Pharm Res 25(2): 337–348.
- 49Louey MD, Stewart PJ. 2002. Particle interactions involved in aerosol dispersion of ternary interactive mixtures. Pharm Res 19(10): 1524–1531.
- 50Adi H, Larson I, Stewart PJ. 2007. Adhesion and redistribution of salmeterol xinafoate particles in sugar-based mixtures for inhalation. Int J Pharm 337(1–2): 229–238.
- 51Begat P, Price R, Harris H, Morton DAV, Staniforth JN. 2005. The influence of force control agents on the cohesive-adhesive balance in dry powder inhaler formulations. KONA 23: 109–121.
- 52Staniforth JN, Morton DAV. 2002. Powder technology research leading to improvements in inhaler products. Powder Sci Eng 34: 60–64.
- 53Pfeffer R, Dave RN, Wei DG, Ramlakhan M. 2001. Synthesis of engineered particulates with tailored properties using dry particle coating. Powder Technol 117(1–2): 40–67.
- 54Zhou QT, Morton DA. 2012. Drug-lactose binding aspects in adhesive mixtures: Controlling performance in dry powder inhaler formulations by altering lactose carrier surfaces. Adv Drug Deliv Rev 64(3): 275–284.
- 55Stewart PJ, Adi H, Larson I. 2005. Dry powder inhaler formulations: Simple two component powder mixtures or a multi-particulate nightmare? Proceedings of the International Conference of Drug Delivery to the Lungs 16. The Aerosol Society, Edinburgh, UK. pp 81–84.
- 56Taki M, Marriott C, Zeng XM, Martin GP. 2010. Aerodynamic deposition of combination dry powder inhaler formulations in vitro: A comparison of three impactors. Int J Pharm 388(1–2): 40–51.
- 57Anderson GJM, Bonney SG, Davies MB, Lintell DTD, Wilson AA. 2005. Medicament dispenser. Patent US 20050154491 A1.
- 58Bell JH, Hartley PS, Cox JSG. 1971. Dry powder aerosols. I—A new powder inhalation device. J Pharm Sci 60: 1559–1564.
- 59Borgström L, Bondesson E, Moren F, Trofast E, Newman SP. 1994. Lung deposition of budesonide inhaled via Turbuhaler: A comparison with terbutaline sulphate in normal subjects. Eur Respir J 7(1): 69–73.
- 60Everard ML, Devadason SG, Le Souef PN. 1997. Flow early in the inspiratory manoeuvre affects the aerosol particle size distribution from a Turbuhaler. Respir Med 91(10): 624–628.
- 61Shekunov BY, Chattopadhyay P, Tong HH, Chow AH. 2007. Particle size analysis in pharmaceutics: Principles, methods and applications. Pharm Res 24(2): 203–227.
- 62Vanbever R, Mintzes JD, Wang J, Nice J, Chen DH, Batycky R, Langer R, Edwards DA. 1999. Formulation and physical characterization of large porous particles for inhalation. Pharm Res 16(11): 1735–1742.
- 63Edwards DA, Hanes J, Caponetti G, Hrkach J, Ben-Jebria A, Eskew ML, Mintzes J, Deaver D, Lotan N, Langer R. 1997. Large porous particles for pulmonary drug delivery. Science 276(5320): 1868–1872.
- 64Dunbar C. 2006. Porous particles for inhalation: The science behind their improved dispersibility. In Respiratory Drug Delivery; RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, Eds. Vol. X. Davis Healthcare International Publishing, River Grove, Illinois, USA, pp 307–315.
- 65Duddu SP, Sisk SA, Walter YH, Tarara TE, Trimble KR, Clark AR, Eldon MA, Elton RC, Pickford M, Hirst PH, Newman SP, Weers JG. 2002. Improved lung delivery from a passive dry powder inhaler using an engineered PulmoSphere® powder. Pharm Res 19(5): 689–695.
- 66Rietema K. 1991. The dynamics of fine powders. New York: Elsevier.
- 67Weiler C, Egen M, Trunk M, Langguth P. 2010. Force control and powder dispersibility of spray dried particles for inhalation. J Pharm Sci 99(1): 303–316.
- 68Stout G, Pham X, Rocchio MJ, Naydo KA, Parks DJ, Reich P. 2001. Powder filling apparatus and methods for their use. Patent US 6182712 B1.
- 69Geller DE, Weers J, Heuerding S. 2011. Development of an inhaled dry-powder formulation of tobramycin using PulmoSphere technology. J Aerosol Med Pulm Drug Deliv 24(4): 175–182.
- 70Kendall K, Stainton C. 2001. Adhesion and aggregation of fine particles. Powder Technol 121(2–3): 223–229.
- 71Chow AH, Tong HH, Chattopadhyay P, Shekunov BY. 2007. Particle engineering for pulmonary drug delivery. Pharm Res 24(3): 411–437.
- 72Weers J, Tarara T. 2014. The PulmoSphere™ platform for pulmonary drug delivery. Therap Deliv 5(3): 277–295.
- 73DeLong M, Wright J, Dawson M, Meyer T, Sommerer K, Dunbar C. 2005. Dose delivery characteristics of the AIR pulmonary delivery system over a range of inspiratory flow rates. J Aerosol Med 18(4): 452–459.
- 74Dunbar C, Scheuch G, Sommerer K, DeLong M, Verma A, Batycky R. 2002. In vitro and in vivo dose delivery characteristics of large porous particles for inhalation. Int J Pharm 245(1–2): 179–189.
- 75Newhouse MT, Hirst PH, Duddu SP, Walter YH, Tarara TE, Clark AR, Weers JG. 2003. Inhalation of a dry powder tobramycin PulmoSphere formulation in healthy volunteers. Chest 124(1): 360–366.
- 76Pilcer G, Sebti T, Amighi K. 2006. Formulation and characterization of lipid-coated tobramycin particles for dry powder inhalation. Pharm Res 23(5): 931–940.
- 77Chew NYK, Chan HK. 2001. Use of solid corrugated particles to enhance powder aerosol performance. Pharm Res 18(11): 1570–1577.
- 78Rumpf H. 1974. Die wissenschaft des agglomerierens. Chemie-Ingenieur Technik 46: 1–11.
- 79Cantor AS, Stefely JS, Jinks PA, Baran JR, Ganser JM, Mueting MW, Gabrio BJ, Stein SW. 2008. Modifying interparticulate interactions using surface-modified excipient nanoparticles. In Respiratory Drug Delivery; RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, PM Young, Eds. Davis Healthcare International Publishing, River Grove, Illinois, USA. pp 309–318.
- 80Zhang J, Wu L, Chan HK, Watanabe W. 2011. Formation, characterization, and fate of inhaled drug nanoparticles. Adv Drug Deliv Rev 63(6): 441–455.
- 81Descamps M, Willart JF, Dudognon E, Caron V. 2007. Transformation of pharmaceutical compounds upon milling and comilling: The role of Tg. J Pharm Sci 96(5): 1398–1407.
- 82Koch CC. 2003. Top-down synthesis of nanostructured materials: Mechanical and thermal processing methods. Rev Adv Mater Sci 5: 91–99.
- 83Verma S, Gokhale R, Burgess DJ. 2009. A comparative study of top-down and bottom-up approaches for the preparation of micro/nanosuspensions. Int J Pharm 380(1–2): 216–222.
- 84Garcia A, Mack P, Williams S, Fromen C, Shen T, Tully J, Pillai J, Kuehl P, Napier M, Desimone JM, Maynor BW. 2012. Microfabricated engineered particle systems for respiratory drug delivery and other pharmaceutical applications. J Drug Deliv 2012: 941243.
- 85Pitchayajittipong C, Shur J, Price R. 2009. Engineering of crystalline combination inhalation particles of a long-acting beta2-agonist and a corticosteroid. Pharm Res 26(12): 2657–2666.
- 86Tsapis N, Bennett D, Jackson B, Weitz DA, Edwards DA. 2002. Trojan particles: Large porous carriers of nanoparticles for drug delivery. Proc Natl Acad Sci USA 99(19): 12001–12005.
- 87York P. 1999. Strategies for particle design using supercritical fluid technologies. Pharm Sci Technol Today 2(11): 430–440.
- 88Maa YF, Ameri M, Shu C, Payne LG, Chen DX. 2004. Influenza vaccine powder formulation development: Spray-freeze-drying and stability evaluation. J Pharm Sci 93(7): 1912–1923.
- 89Merkel TJ, Herlihy KP, Nunes J, Orgel RM, Rolland JP, DeSimone JM. 2010. Scalable, shape-specific, top-down fabrication methods for the synthesis of engineered colloidal particles. Langmuir 26(16): 13086–13096.
- 90Matteucci ME, Hotze MA, Johnston KP, Williams III RO. 2006. Drug nanoparticles by antisolvent precipitation: Mixing energy versus surfactant stabilization. Langmuir 22(21): 8951–8959.
- 91Ruecroft G, Hipkiss D, Ly T, Maxted N, Cains PW. 2005. Sonocrystallization: The use of ultrasound for improved industrial crystallization. Org Proc Res Dev 9(6): 923–932.
- 92Woo MW, Mansouri S, Chen XD. 2014. Antisolvent vapor precipitation: The future of pulmonary drug delivery particle production? Expert Opin Drug Deliv 11(3): 307–311.
- 93Masters K. 1985. Spray drying handbook. Fourth Edition. Halsted Press, New York.
- 94Sacchetti MJ, van Oort MM. 1996. Spray-drying and supercritical fluid generation techniques. In Inhalation aerosols: Physical and biological basis for therapy; AJ Hickey, Ed. New York, New York: Marcel Dekker, pp 337–384.
- 95Snyder HE, Lechuga-Ballesteros D. 2008. Spray drying: Theory and pharmaceutical applications. In Pharmaceutical Dosage Forms: Tablets. Volume 1, Third Edition.; LL Augsburger, SW Hoag, Eds. New York, New York: Informa Healthcare, pp 227–260.
- 96Vidgren MT, Vidgren PA, Paronen TP. 1987. Comparison of physical and inhalation properties of spray-dried and mechanically micronized disodium-cromoglycate. Int J Pharm 35(1–2): 139–144.
- 97White S, Bennett DB, Cheu S, Conley PW, Guzek DB, Gray S, Howard J, Malcolmson R, Parker JM, Roberts P, Sadrzadeh N, Schumacher JD, Seshadri S, Sluggett GW, Stevenson CL, Harper NJ. 2005. Exubera: Pharmaceutical development of a novel product for pulmonary delivery of insulin. Diabetes Technol Ther 7(6): 896–906.
- 98Maa YF, Nguyen PA, Sweeney T, Shire SJ, Hsu CC. 1999. Protein inhalation powders: Spray drying vs spray freeze drying. Pharm Res 16(2): 249–254.
- 99Rogers TL, Hu J, Yu Z, Johnston KP, 3rd Williams RO. 2002. A novel particle engineering technology: Spray-freezing into liquid. Int J Pharm 242(1–2): 93–100.
- 100Pilcer G, Amighi K. 2010. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm 392(1–2): 1–19.
- 101Wauthoz N, Amighi K. 2014. Phospholipids in pulmonary drug delivery. Eur J Lipid Sci Technol 116(9): 1114–1128.
- 102Wang YY, Lai SK, Suk JS, Pace A, Cone R, Hanes J. 2008. Addressing the PEG mucoadhesivity paradox to engineer nanoparticles that “slip” through the human mucus barrier. Angew Chem Int Ed Engl 47(50): 9726–9729.
- 103Guchardi R, Frei M, John E, Kaerger JS. 2008. Influence of fine lactose and magnesium stearate on low dose dry powder inhaler formulations. Int J Pharm 348(1–2): 10–17.
- 104Elversson J, Millqvist-Fureby A. 2006. In situ coating—An approach for particle modification and encapsulation of proteins during spray-drying. Int J Pharm 323(1–2): 52–63.
- 105Vehring R, Foss WR, Lechuga-Ballesteros D. 2007. Particle formation in spray drying. J Aerosol Sci 38(7): 728–746.
- 106Wright JL, Clements JS. 1989. Lung surfactant turnover and factors that affect turnover. In Lung cell biology; D Massaro, Ed. New York, New York: Marcel Dekker, pp 655–699.
- 107Begat P, Morton DA, Shur J, Kippax P, Staniforth JN, Price R. 2009. The role of force control agents in high-dose dry powder inhaler formulations. J Pharm Sci 98(8): 2770–2783.
- 108Rabbani NR, Seville PC. 2004. The use of amino acids as formulation excipients in lactose-based spray-dried powders. J Pharm Pharmacol 56: S32–S33.
- 109Lechuga-Ballesteros D, Kuo M-C. 2003. Dry powder compositions having improved dispersivity. Patent US 6518239 B1.
- 110Aquino RP, Prota L, Auriemma G, Santoro A, Mencherini T, Colombo G, Russo P. 2012. Dry powder inhalers of gentamicin and leucine: Formulation parameters, aerosol performance and in vitro toxicity on CuFi1 cells. Int J Pharm 426(1–2): 100–107.
- 111Seville PC, Learoyd TP, Li HY, Williamson IJ, Birchall JC. 2007. Amino acid-modified spray-dried powders with enhanced aerosolisation properties for pulmonary drug delivery. Powder Technol 178(1): 40–50.
- 112Feng AL, Boraey MA, Gwin MA, Finlay PR, Kuehl PJ, Vehring R. 2011. Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery. Int J Pharm 409(1–2): 156–163.
- 113Boraey MA, Hoe S, Sharif H, Miller DP, Lechuga-Ballesteros D, Vehring R. 2012. Improvement of the dispersibility of spray-dried budesonide powders using leucine in an ethanol–water cosolvent system. Powder Technol 236: 171–178.
- 114Lechuga-Ballesteros D, Charan C, Stults CL, Stevenson CL, Miller DP, Vehring R, Tep V, Kuo MC. 2008. Trileucine improves aerosol performance and stability of spray-dried powders for inhalation. J Pharm Sci 97(1): 287–302.
- 115Karhu M, Kuikka J, Kauppinen T, Bergstrom K, Vidgren M. 2000. Pulmonary deposition of lactose carriers used in inhalation powders. Int J Pharm 196(1): 95–103.
- 116Edge S, Mueller S, Price R, Shur J. 2008. Factors affecting defining the quality and functionality of excipients used in the manufacture of dry powder inhaler products. Drug Dev Ind Pharm 34(9): 966–973.
- 117Kumar V, Banker GS. 1994. Maillard reaction and drug stability. In Maillard reactions in chemistry, food, and health; TP Labuza, GA Reineccius, VM Monnier, O'Brien J, JW Baynes, Eds. Cambridge, United Kingdom: Royal Society of Chemistry, Information Services, pp 6.
- 118Hodge JE. 1953. Dehydrated foods: Chemistry of browning reactions in model systems. J Agric Food Chem 1(15): 928–943.
- 119Badawy SI, Hussain MA. 2007. Microenvironmental pH modulation in solid dosage forms. J Pharm Sci 96(5): 948–959.
- 120Shalaev EY, Zografi G. 1996. How does residual water affect the solid-state degradation of drugs in the amorphous state? J Pharm Sci 85(11): 1137–1141.
- 121Ohtake S, Shalaev E. 2013. Effect of water on the chemical stability of amorphous pharmaceuticals: I. Small molecules. J Pharm Sci 102(4): 1139–1154.
- 122Ewing GE. 2004. Thin film water. J Phys Chem B 108(41): 15953–15961.
- 123Dai Q, Hu J, Salmeron M. 1997. Adsorption of water on NaCl (100) surfaces: Role of atomic steps. J Phys Chem B 101(11): 1994–1998.
- 124Badawy SIF, Williams RC, Gilbert DL. 1999. Effect of different acids on solid-state stability of an ester prodrug of a IIb/IIIa glycoprotein receptor antagonist. Pharm Dev Technol 4(3): 325–331.
- 125Pudipeddi M, Zannou EA, Vasanthavada M, Dontabhaktuni A, Royce AE, Joshi YM, Serajuddin AT. 2008. Measurement of surface pH of pharmaceutical solids: A critical evaluation of indicator dye-sorption method and its comparison with slurry pH method. J Pharm Sci 97(5): 1831–1842.
- 126Song Y, Schowen RL, Borchardt RT, Topp EM. 2001. Effect of ‘pH' on the rate of asparagine deamidation in polymeric formulations: ‘pH'-rate profile. J Pharm Sci 90(2): 141–156.
- 127Strickley RG, Visor GC, Lin LH, Gu L. 1989. An unexpected pH effect on the stability of moexipril lyophilized powder. Pharm Res 6(11): 971–975.
- 128Glombitza BW, Oelkrug D, Schmidt PC. 1994. Surface-acidity of solid pharmaceutical excipients. 1: Determination of the surface-acidity. Eur J Pharm Biopharm 40(5): 289–293.
- 129Glombitza BW, Schmidt PC. 1995. Surface-acidity of solid pharmaceutical excipients. 2: Effect of the surface-acidity on the decomposition rate of acetylsalicylic-acid. Eur J Pharm Biopharm 41(2): 114–119.
- 130Harper NJ, Gray S, De Groot J, Parker JM, Sadrzadeh N, Schuler C, Schumacher JD, Seshadri S, Smith AE, Steeno GS, Stevenson CL, Taniere R, Wang M, Bennett DB. 2007. The design and performance of the Exubera pulmonary insulin delivery system. Diabetes Technol Ther 9(Suppl 1): S16–S27.
- 131Schanker LS, Less MJ. 1977. Lung pH and pulmonary absorption of nonvolatile drugs in rat. Drug Metab Dispos 5(2): 174–178.
- 132Mallanack DT. 2007. The pKa distribution of drugs: Application to drug discovery. Perspect Med Chem 1: 25–38.
- 133Wong CH, Matai R, Morice AH. 1999. Cough induced by low pH. Respir Med 93(1): 58–61.
- 134Angell CA. 1995. Formation of glasses from liquids and biopolymers. Science 267(5206): 1924–1935.
- 135Aso Y, Yoshioka S, Kojima S. 2000. Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by their enthalpy relaxation and H-1 NMR relaxation times. J Pharm Sci 89(3): 408–416.
10.1002/(SICI)1520-6017(200003)89:3<408::AID-JPS11>3.0.CO;2-# CAS PubMed Web of Science® Google Scholar
- 136Duddu SP, DalMonte PR. 1997. Effect of glass transition temperature on the stability of lyophilized formulations containing a chimeric therapeutic monoclonal antibody. Pharm Res 14(5): 591–595.
- 137Hancock BC, Zografi G. 1997. Characteristics and significance of the amorphous state in pharmaceutical systems. J Pharm Sci 86(1): 1–12.
- 138Slade L, Levine H. 1995. Glass transitions and water-food structure interactions. Adv Food Nutr Res 38: 103–269.
- 139Marsac PJ, Konno H, Taylor LS. 2006. A comparison of the physical stability of amorphous felodipine and nifedipine systems. Pharm Res 23(10): 2306–2316.
- 140Duddu SP, Zhang GZ, DalMonte PR. 1997. The relationship between protein aggregation and molecular mobility below the glass transition temperature of lyophilized formulations containing a monoclonal antibody. Pharm Res 14(5): 596–600.
- 141Hancock BC, Shamblin SL, Zografi G. 1995. Molecular mobility of amorphous pharmaceutical solids below their glass-transition temperatures. Pharm Res 12(6): 799–806.
- 142Yoshioka S, Aso Y, Kojima S. 2004. Temperature- and glass transition temperature-dependence of bimolecular reaction rates in lyophilized formulations described by the Adam-Gibbs-Vogel equation. J Pharm Sci 93(4): 1062–1069.
- 143Roy ML, Pikal MJ, Rickard EC, Maloney AM. 1992. The effects of formulation and moisture on the stability of a freeze-dried monoclonal antibody-vinca conjugate: A test of the WLF glass transition theory. Dev Biol Stand 74: 323–340.
- 144Guo YS, Bryn SR, Zografi G. 2000. Physical characteristics and chemical degradation of amorphous quinapril hydrochloride. J Pharm Sci 89(1): 128–143.
10.1002/(SICI)1520-6017(200001)89:1<128::AID-JPS13>3.0.CO;2-Z CAS PubMed Web of Science® Google Scholar
- 145Chang LQ, Shepherd D, Sun J, Ouellette D, Grant KL, Tang XL, Pikal MJ. 2005. Mechanism of protein stabilization by sugars during freeze-drying and storage: Native structure preservation, specific interaction, and/or immobilization in a glassy matrix? J Pharm Sci 94(7): 1427–1444.
- 146Shamblin SL, Hancock BC, Pikal MJ. 2006. Coupling between chemical reactivity and structural relaxation in pharmaceutical glasses. Pharm Res 23(10): 2254–2268.
- 147Yoshioka S, Miyazaki T, Aso Y. 2006. Degradation rate of lyophilized insulin, exhibiting an apparent Arrhenius behavior around glass transition temperature regardless of significant contribution of molecular mobility. J Pharm Sci 95(12): 2684–2691.
- 148Yoshioka S, Aso Y. 2005. A quantitative assessment of the significance of molecular mobility as a determinant for the stability of lyophilized insulin formulations. Pharm Res 22(8): 1358–1364.
- 149Yoshioka S, Miyazaki T, Aso Y. 2006. Beta-relaxation of insulin molecule in lyophilized formulations containing trehalose or dextran as a determinant of chemical reactivity. Pharm Res 23(5): 961–966.
- 150Yoshioka S, Aso Y, Miyazaki T. 2006. Negligible contribution of molecular mobility to the degradation rate of insulin lyophilized with poly(vinylpyrrolidone). J Pharm Sci 95(4): 939–943.
- 151Bras AR, Noronha JP, Antunes AMM, Cardoso MM, Schonhals A, Affouard F, Dionisio M, Correia NT. 2008. Molecular motions in amorphous ibuprofen as studied by broadband dielectric spectroscopy. J Phys Chem B 112(35): 11087–11099.
- 152Bhattacharya S, Suryanarayanan R. 2009. Local mobility in amorphous pharmaceuticals—Characterization and implications on stability. J Pharm Sci 98(9): 2935–2953.
- 153Dranca I, Bhattacharya S, Vyazovkin S, Suryanarayanan R. 2009. Implications of global and local mobility in amorphous sucrose and trehalose as determined by differential scanning calorimetry. Pharm Res 26(5): 1064–1072.
- 154Johari GP, Goldstein M. 1970. Viscous liquids and the glass transition. J Chem Phys 53: 2372–2388.
- 155Ngai KL. 2003. An extended coupling model description of the evolution of dynamics with time in supercooled liquids and ionic conductors. J Phys Condens Matter 15(11): S1107–S1125.
- 156Sun Y, Xi H, Ediger MD, Yu L. 2008. Diffusionless crystal growth from glass has precursor in equilibrium liquid. J Phys Chem B 112(3): 661–664.
- 157Alie J, Menegotto J, Cardon P, Duplaa H, Caron A, Lacabanne C, Bauer M. 2004. Dielectric study of the molecular mobility and the isothermal crystallization kinetics of an amorphous pharmaceutical drug substance. J Pharm Sci 93(1): 218–233.
- 158Cleland JL, Lam X, Kendrick B, Yang J, Yang TH, Overcashier D, Brooks D, Hsu C, Carpenter JF. 2001. A specific molar ratio of stabilizer to protein is required for storage stability of a lyophilized monoclonal antibody. J Pharm Sci 90(3): 310–321.
- 159Carpenter JF, Pikal MJ, Chang BS, Randolph TW. 1997. Rational design of stable lyophilized protein formulations: Some practical advice. Pharm Res 14(8): 969–975.
- 160Chan HK, Clark AR, Feeley JC, Kuo MC, Lehrman SR, Pikal-Cleland K, Miller DP, Vehring R, Lechuga-Ballesteros D. 2004. Physical stability of salmon calcitonin spray-dried powders for inhalation. J Pharm Sci 93(3): 792–804.
- 161Cicerone MT, Soles CL. 2004. Fast dynamics and stabilization of proteins: Binary glasses of trehalose and glycerol. Biophys J 86(6): 3836–3845.
- 162Cicerone MT, Tellington A, Trost L, Sokolov A. 2003. Substantially improved stability of biological agents in dried form. BioProc Int 1: 36–47.
- 163Matveev YI, Grinberg VY, Sochava IV, Tolstoguzov VB. 1997. Glass transition temperature of proteins. Calculation based on the additive contribution method and experimental data. Food Hydrocolloids 11(2): 125–133.
- 164Cicerone MT, Douglas JF. 2012. β-Relaxation governs protein stability in sugar-glass matrices. Soft Matter 8(10): 2983.
- 165Kerc J, Srcic S. 1995. Thermal analysis of glassy pharmaceuticals. Thermochim Acta 248: 81–95.
- 166Roos YH. 1995. Phase transitions in foods. San Diego, California: Academic Press.
- 167Greenhalgh DJ, Williams AC, Timmins P, York P. 1999. Solubility parameters as predictors of miscibility in solid dispersions. J Pharm Sci 88(11): 1182–1190.
- 168Van Eerdenbrugh B, Lo M, Kjoller K, Marcott C, Taylor LS. 2012. Nanoscale mid-infrared evaluation of the miscibility behavior of blends of dextran or maltodextrin with poly(vinylpyrrolidone). Mol Pharm 9(5): 1459–1469.
- 169Loira-Pastoriza C, Todoroff J, Vanbever R. 2014. Delivery strategies for sustained drug release in the lungs. Adv Drug Deliv Rev 75: 81–91.
- 170Jacobsen JR. 2011. Third-generation long-acting beta(2)-adrenoceptor agonists: medicinal chemistry strategies employed in the identification of once-daily inhaled beta(2)-adrenoceptor agonists. Future Med Chem 3(13): 1607–1622.
- 171Hirschmann R, Nicolaou KC, Pietranico S, Leahy EM, Salvino J, Arison B, Cichy MA, Spoors PG, Shakespeare WC, Sprengeler PA, Hamley P, Smith AB, Reisine T, Raynor K, Maechler L, Donaldson C, Vale W, Freidinger RM, Cascieri MR, Strader CD. 1993. De novo design and synthesis of somatostatin non-peptide peptidomimetics utilizing beta-d-glucose as a novel scaffolding. J Am Chem Soc 115(26): 12550–12568.
10.1021/ja00079a039 Google Scholar
- 172Niven RW. 1995. Delivery of biotherapeutics by inhalation aerosol. Crit Rev Ther Drug Carrier Syst 12(2–3): 151–231.
- 173Harris JM, Chess RB. 2003. Effect of PEGylation on pharmaceuticals. Nat Rev Drug Discov 2(3): 214–221.
- 174Leach CL, Kuo M, Bueche B, Fishburn S, Viegas T, Bossard M, Guo L, Bentley MD, Hobbs CH, Cherrington AD, Patton JS. 2004. Modifying the pulmonary absorption and retention of proteins through PEGylation. In Respiratory Drug Delivery; RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, Eds. Vol. IX. Amy Davis Biggs, River Grove, Illinois, USA. pp 69–77.
- 175Biggadike K. 2011. Fluticasone furoate/fluticasone propionate—Different drugs with different properties. Clin Respir J 5(3): 183–184.
- 176Pfannkuch F, Rettig H, Stahl PH. 2011. Biological effects of the API salt form. In Handbook of pharmaceutical salts—Properties, selection, and use; PH Stahl, CG Wermuth, Eds. Weinheim, Germany: Wiley-VCH, pp 128.
- 177Palmer JBD. 1993. Medicaments. Patent US 5270305 A.
- 178Chilton AS, Godward RE, Carey PF. 1995. The determination in human plasma of 1-hydroxy-2-naphthoic acid following administration of salmeterol xinafoate. J Pharm Biomed Anal 13(2): 165–169.
- 179Thackaberry EA. 2012. Non-clinical toxicological considerations for pharmaceutical salt selection. Expert Opin Drug Metab Toxicol 8(11): 1419–1433.
- 180El-Sherbiny IM, Villanueva DG, Herrera D, Smyth HDC. 2011. Overcoming lung clearance mechanisms for controlled release drug delivery. In Controlled pulmonary drug delivery; HDC Smyth, AJ Hickey, Eds. New York: Springer, pp 101–126.
- 181Kawaguchi H, Koiwai N, Ohtsuka Y, Miyamoto M, Sasakawa S. 1986. Phagocytosis of latex particles by leucocytes. I. Dependence of phagocytosis on the size and surface potential of particles. Biomaterials 7(1): 61–66.
- 182Champion JA, Mitragotri S. 2006. Role of target geometry in phagocytosis. Proc Natl Acad Sci USA 103(13): 4930–4934.
- 183Evora C, Soriano I, Rogers RA, Shakesheff KN, Hanes J, Langer R. 1998. Relating the phagocytosis of microparticles by alveolar macrophages to surface chemistry: The effect of 1,2-dipalmitoylphosphatidylcholine. J Control Release 51(2–3): 143–152.
- 184Jones BG, Dickinson PA, Gumbleton M, Kellaway IW. 2002. The inhibition of phagocytosis of respirable microspheres by alveolar and peritoneal macrophages. Int J Pharm 236(1–2): 65–79.
- 185Gelperina S, Kisich K, Iseman MD, Heifets L. 2005. The potential advantages of nanoparticle drug delivery systems in chemotherapy of tuberculosis. Am J Respir Crit Care Med 172(12): 1487–1490.
- 186Sung JC, Padilla DJ, Garcia-Contreras L, Verberkmoes JL, Durbin D, Peloquin CA, Elbert KJ, Hickey AJ, Edwards DA. 2009. Formulation and pharmacokinetics of self-assembled rifampicin nanoparticle systems for pulmonary delivery. Pharm Res 26(8): 1847–1855.
- 187Devitt A, Pierce S, Oldreive C, Shingler WH, Gregory CD. 2003. CD14-dependent clearance of apoptotic cells by human macrophages: The role of phosphatidyiserine. Cell Death Differ 10(3): 371–382.
- 188Bot AI, Smith DJ, Bot S, Dellamary L, Tarara TE, Harders S, Phillips W, Weers JG, Woods CM. 2001. Receptor-mediated targeting of spray-dried lipid particles coformulated with immunoglobulin and loaded with a prototype vaccine. Pharm Res 18(7): 971–979.
- 189Fiegel J, Brenza T, Hamed R. 2011. Controlled transport for pulmonary drug delivery. In Controlled pulmonary drug delivery; HDC Smyth, AJ Hickey, Eds. New York: Springer, pp 143–163.
10.1007/978-1-4419-9745-6_7 Google Scholar
- 190Lai YL, Mehta RC, Thacker AA, Yoo SD, Mcnamara PJ, Deluca PP. 1993. Sustained bronchodilation with isoproterenol poly (glycolide-co-lactide) microspheres. Pharm Res 10(1): 119–125.
- 191Alpar HO, Somavarapu S, Atuah KN, Bramwell V. 2005. Biodegradable mucoadhesive particulates for nasal and pulmonary antigen and DNA delivery. Adv Drug Deliv Rev 57(3): 411–430.
- 192Sakagami M, Kinoshita W, Sakon K, Sato J, Makino Y. 2002. Mucoadhesive beclomethasone microspheres for powder inhalation: Their pharmacokinetics and pharmacodynamics evaluation. J Control Release 80(1–3): 207–218.
- 193Learoyd TP, Burrows JL, French E, Seville PC. 2009. Sustained delivery by leucine-modified chitosan spray-dried respirable powders. Int J Pharm 372(1–2): 97–104.
- 194Patton JS, Fishburn CS, Weers JG. 2004. The lungs as a portal of entry for systemic drug delivery. Proc Am Thorac Soc 1(4): 338–344.
- 195Zeng XM, Martin GP, Marriott C. 1995. The controlled delivery of drugs to the lung. Int J Pharm 124(2): 149–164.
- 196Salama RO, Traini D, Chan HK, Sung A, Ammit AJ, Young PM. 2009. Preparation and evaluation of controlled release microparticles for respiratory protein therapy. J Pharm Sci 98(8): 2709–2717.
- 197 HDC Smyth, AJ Hickey, Eds. 2011. Controlled pulmonary drug delivery. 1st ed. New York: Springer, pp 557.
- 198Sheth P, Myrdal PB. 2011. Excipients utilized for modifying pulmonary drug release. In Controlled pulmonary drug delivery; HDC Smyth, AJ Hickey, Eds. New York: Springer, pp 237–263.
10.1007/978-1-4419-9745-6_11 Google Scholar
- 199Hickey AJ, Suarez S, Bhat M, O'Hara P, Lalor CB, Atkins K, Hopfer R, McMurray DN. 1998. Efficacy of rifampicin-poly(lactide-co-glycolide) microspheres in treating tuberculosis. In Respiratory Drug Delivery; RN Dalby, PR Byron, SJ Farr, Eds. Vol. VI. Interpharm Press, Buffalo Grove, Illinois, USA. pp 201–209.
- 200Sung JC, Padilla DJ, Garcia-Contreras L, VerBerkmoes JL, Durbin D, Peloquin CA, Elbert KJ, Hickey AJ, Edwards DA. 2009. Formulation and pharmacokinetics of self-assembled rifampicin nanoparticle systems for pulmonary delivery. Pharm Res 26(8): 1847–1855.
- 201Cook RO, Pannu RK, Kellaway IW. 2005. Novel sustained release microspheres for pulmonary drug delivery. J Control Release 104(1): 79–90.
- 202Courrier HM, Butz N, Vandamme TF. 2002. Pulmonary drug delivery systems: Recent developments and prospects. Crit Rev Ther Drug Carrier Syst 19(4–5): 425–498.
- 203Sivadas N, O'Rourke D, Tobin A, Buckley V, Ramtoola Z, Kelly JG, Hickey AJ, Cryan SA. 2008. A comparative study of a range of polymeric microspheres as potential carriers for the inhalation of proteins. Int J Pharm 358(1–2): 159–167.
- 204Fu J, Fiegel J, Hanes J. 2004. Synthesis and characterization of PEG-based ether-anhydride terpolymers: Novel polymers for controlled drug delivery. Macromolecules 37(19): 7174–7180.
- 205Misra A, Jinturkar K, Patel D, Lalani J, Chougule M. 2009. Recent advances in liposomal dry powder formulations: Preparation and evaluation. Expert Opin Drug Deliv 6(1): 71–89.
- 206Swaminathan J, Ehrhardt C. 2011. Liposomes for pulmonary drug delivery. In Controlled pulmonary drug delivery; HDC Smyth, AJ Hickey, Eds. New York: Springer, pp 313–334.
- 207Willis L, Hayes D, Mansour HM. 2012. Therapeutic liposomal dry powder inhalation aerosols for targeted lung delivery. Lung 190(3): 251–262.
- 208Li Z, Zhang Y, Wurtz W, Lee JK, Malinin VS, Durwas-Krishnan S, Meers P, Perkins WR. 2008. Characterization of nebulized liposomal amikacin (Arikace) as a function of droplet size. J Aerosol Med Pulm Drug Deliv 21(3): 245–254.
- 209Serisier DJ, Bilton D, De Soyza A, Thompson PJ, Kolbe J, Greville HW, Cipolla D, Bruinenberg P, Gonda I, investigators O. 2013. Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): A randomised, double-blind, placebo-controlled trial. Thorax 68(9): 812–817.
- 210Shah SP, Misra A. 2004. Liposomal amikacin dry powder inhaler: Effect of fines on in vitro performance. AAPS PharmSciTech 5(4): 107–113.
- 211Joshi M, Misra A. 2003. Disposition kinetics of ketotifen from liposomal dry powder for inhalation in rat lung. Clin Exp Pharmacol Physiol 30(3): 153–156.
- 212Lo YL, Tsai JC, Kuo JH. 2004. Liposomes and disaccharides as carriers in spray-dried powder formulations of superoxide dismutase. J Control Release 94(2–3): 259–272.
- 213Lu DM, Hickey AJ. 2005. Liposomal dry powders as aerosols for pulmonary delivery of proteins. AAPS Pharm Sci Tech 6(4): E641–E648.
- 214Bi R, Shao W, Wang Q, Zhang N. 2008. Spray-freeze-dried dry powder inhalation of insulin-loaded liposomes for enhanced pulmonary delivery. J Drug Target 16(9): 639–648.
- 215Desai TR, Wong JP, Hancock REW, Finlay WH. 2002. A novel approach to the pulmonary delivery of liposomes in dry powder form to eliminate the deleterious effects of milling. J Pharm Sci 91(2): 482–491.
- 216 ISO/TS 80004-2:2015. Nanotechnologies—Vocabulary—Part 2: Nano-objects. Accessed July 27, 2015, at: http://www.iso.org/.
- 217 Food and Drug Administration. June 2014. Guidance for industry: Considering whether an FDA-regulated product involves the application of nanotechnology. Accessed July 27, 2015, at: http://www.fda.gov/RegulatoryInformation/Guidances/ucm257698.htm.
- 218Thomson SW. 1871. On the equilibrium of vapour at a curved surface of liquid. Philos Mag 42(282): 448–452.
- 219Noyes AA, Whitney WR. 1897. The rate of solution of solid substances in their own solutions. J Am Chem Soc 19: 930–934.
10.1021/ja02086a003 Google Scholar
- 220Gumbleton M. 2001. Caveolae as potential macromolecule trafficking compartments within alveolar epithelium. Adv Drug Deliv Rev 49(3): 281–300.
- 221Oberdorster G. 2001. Pulmonary effects of inhaled ultrafine particles. Int Arch Occup Environ Health 74(1): 1–8.
- 222Watts AB, Williams RO. 2011. Nanoparticles for pulmonary delivery. In Controlled Pulmonary Drug Delivery; HDC Smyth, AJ Hickey, Eds. NewYork: Springer, pp 335–366.
- 223Weers J, Tarara T, Malcolmson R, Leung D. 2006. Embedded crystals in low density particles: Formulation, manufacture, and properties. In Respiratory Drug Delivery; RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, Eds. Vol. X. Davis Healthcare International Publishing, River Grove, Illinois, USA. pp 297–305.
- 224El-Gendy N, Berkland C. 2009. Combination chemotherapeutic dry powder aerosols via controlled nanoparticle agglomeration. Pharm Res 26(7): 1752–1763.
- 225El-Gendy N, Gorman EM, Munson EJ, Berkland C. 2009. Budesonide nanoparticle agglomerates as dry powder aerosols with rapid dissolution. J Pharm Sci 98(8): 2731–2746.
- 226Packhaeuser C, Lahnstein K, Sitterberg J, Schmehl T, Gessler T, Bakowsky U, Seeger W, Kissel T. 2009. Stabilization of aerosolizable nano-carriers by freeze-drying. Pharm Res 26(1): 129–138.
- 227Mehnert W, Mader K. 2001. Solid lipid nanoparticles: Production, characterization and applications. Adv Drug Deliv Rev 47(2–3): 165–196.
- 228Muller RH, Mader K, Gohla S. 2000. Solid lipid nanoparticles (SLN) for controlled drug delivery: A review of the state of the art. Eur J Pharm Biopharm 50(1): 161–177.
- 229Westesen K, Bunjes H, Koch MHJ. 1997. Physicochemical characterization of lipid nanoparticles and evaluation of their drug loading capacity and sustained release potential. J Control Release 48(2–3): 223–236.
- 230Videira MA, Botelho MF, Santos AC, Gouveia LF, de Lima JJP, Almeida AJ. 2002. Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles. J Drug Target 10(8): 607–613.
- 231Mezzena M, Scalia S, Young PM, Traini D. 2009. Solid lipid budesonide microparticles for controlled release inhalation therapy. AAPS J 11(4): 771–778.
- 232Spiekermann GM, Finn PW, Ward ES, Dumont J, Dickinson BL, Blumberg RS, Lencer WI. 2002. Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: Functional expression of FcRn in the mammalian lung. J Exp Med 196(3): 303–310.
- 233Sakagami M, Nicholson KL, Byron PR. 2015. Quantifying monoclonal antibody disposition following aerosol administration: Systemic and airway exposure in non-human primates. Proc Respir Drug Deliv Europe 1: 27–36.
- 234Low SC, Nunes SL, Bitonti AJ, Dumont JA. 2005. Oral and pulmonary delivery of FSH-Fc fusion proteins via neonatal Fc receptor-mediated transcytosis. Hum Reprod 20(7): 1805–1813.
- 235Bitonti AJ, Dumont JA. 2006. Pulmonary administration of therapeutic proteins using an immunoglobulin transport pathway. Adv Drug Deliv Rev 58(9–10): 1106–1118.
- 236Boss AH, Petrucci R, Lorber D. 2012. Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin. J Diabetes Sci Technol 6(4): 773–779.
- 237Blair JA, Coghlan D, Langner E, Jansen M, Askey-Sarvar A. 2002. Sustained delivery of insulin via the lung using Solidose® technology In Respiratory Drug Delivery; RN Dalby, PR Byron, J Peart, SJ Farr, Ed. Vol. VIII. Raleigh, North Carolina: Davis Horwood International Publishing, pp 411–413.
- 238Telko MJ, Hickey AJ. 2005. Dry powder inhaler formulations. Respir Care 50: 1209–1227.
- 239Aswania O, Ritson S, Iqbal SM, Bhatt J, Rigby AS, Everard ML. 2004. Intra-subject variability in lung dose in healthy volunteers using five conventional portable inhalers. J Aerosol Med 17(3): 231–238.
- 240Cochrane MG, Bala MV, Downs KE, Mauskopf J, Ben-Joseph RH. 2000. Inhaled corticosteroids for asthma therapy: Patient compliance, devices, and inhalation technique. Chest 117(2): 542–550.
- 241Stahlhofen W, Rudolf G, James AC. 1989. Intercomparison of experimental regional deposition data. J Aerosol Med 2: 285–308.
10.1089/jam.1989.2.285 Google Scholar
- 242Rudolf G, Köbrich R, Stahlhofen W, James AC. 1994. Regional aerosol deposition in man—A statistical and algebraic model. Ann Occup Hyg 38(Inhaled particles VII): 1–14.
10.1093/annhyg/38.inhaled_particles_VII.1 Google Scholar
- 243Frijlink HW, De Boer AH. 2004. Dry powder inhalers for pulmonary drug delivery. Expert Opin Drug Deliv 1(1): 67–86.
- 244Dunbar CA, Hickey AJ, Holzner P. 1998. Dispersion and characterization of pharmaceutical dry powder aerosols. KONA 16: 7–45.
- 245Hill M, Vaughan L, Dolovich M. 1996. Dose targeting for dry powder inhalers. In Respiratory Drug Delivery; RN Dalby, PR Byron, SJ Farr, Eds. Vol. V. Interpharm Press, Buffalo Grove, Illinois, USA. pp 197–208.
- 246Weers J, Ung K, Le J, Rao N, Ament B, Axford G, Maltz D, Chan L. 2013. Dose emission characteristics of placebo PulmoSphere® particles are unaffected by a subject's inhalation maneuver. J Aerosol Med Pulm Drug Deliv 26(1): 56–68.
- 247Weers JG, Bell J, Chan HK, Cipolla D, Dunbar C, Hickey AJ, Smith IJ. 2010. Pulmonary formulations: What remains to be done? J Aerosol Med Pulm Drug Deliv 23(Supplement 2): S5–S23.
- 248Dinh K, Myers DJ, Glazer M, Shmidt T, Devereaux C, Simis K, Noymer PD, He M, Choosakul C, Chen Q, Cassella JV. 2011. In vitro aerosol characterization of Staccato® loxapine. Int J Pharm 403(1–2): 101–108.
- 249Zanen P, Go LT, Lammers JW. 1996. Optimal particle size for beta 2 agonist and anticholinergic aerosols in patients with severe airflow obstruction. Thorax 51(10): 977–980.
- 250Usmani OS, Biddiscombe MF, Barnes PJ. 2005. Regional lung deposition and bronchodilator response as a function of beta2-agonist particle size. Am J Respir Crit Care Med 172(12): 1497–1504.
- 251Usmani OS, Biddiscombe MF, Nightingale JA, Underwood SR, Barnes PJ. 2003. Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols. J Appl Physiol 95(5): 2106–2112.
- 252Clark AR. 2012. Understanding penetration index measurements and regional lung targeting. J Aerosol Med Pulm Drug Deliv 25(4): 179–187.
- 253Clark AR, Hartman MS. 2012. Regional lung deposition: Can it be controlled and have an impact on safety and efficacy? In Respiratory Drug Delivery; RN Dalby, PR Byron, J Peart, JD Suman, SJ Farr, PM Young, Eds. Davis Healthcare International Publishing, River, Grove, Illinois, USA. pp 89–100.
- 254Longest PW, Hindle M. 2012. Condensational growth of combination drug-excipient submicrometer particles for targeted high efficiency pulmonary delivery: Comparison of CFD predictions with experimental results. Pharm Res 29(3): 707–721.
