Abstract
Non-invasive delivery systems are desirable for routine administration of therapeutic protein and peptides. The large absorptive surface area of the lungs, thin alveolar epithelial barrier, and extensive vasculature makes the pulmonary route a promising option. For many years, drug delivery to the lungs has been achieved by nebulizers and metered dose inhalers. Two rapidly expanding fields of aerosol drug delivery are liquid-spray systems and dry-powder delivery systems. The selection of an aerosolization system for protein and peptide active compounds will be driven by several inter-related factors that include: physicochemical properties of the macromolecule, the principle of aerosolization of the device, and patient- and disease-related properties. Although novel liquid spray systems may have aerosol and delivery advantages over current inhalation aerosol technologies, rigorous scientific evaluation has not yet been performed due to the relatively recent introduction of these systems. Alternatively, dry-powder inhaler systems for protein and peptide therapeutics have undergone significantly more scientific evaluation. Dry-powder systems for protein and peptide therapeutics may have stability and sterility advantages. However, with currently used excipients and passive dispersion mechanisms, these devices are relatively inefficient. A convergence of improved particle manufacturing methods and technologies with active dispersion technologies may lead to more efficient delivery options. Alongside these delivery considerations, issues pertaining to economic viability, regulatory approval, and patient factors are equally important for selection of an appropriate delivery system. Thus, with our current understanding, there is no acceptable decision tree or algorithm that can be used to derive the most appropriate device technology for inhaled protein and peptide therapy. This review aims to provide guidance to select the best formulation alternative to deliver a candidate protein/peptide drug through the pulmonary route.
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References
Lien S, Lowman HB. Therapeutic peptides. Trends Biotechnol 2003; 21: 556–62
Johnson KA. Preparation of peptide and protein powders for inhalation. Adv Drug Deliv Rev 1997; 26: 3–15
Byron PR, Patton JS. Drug delivery via the respiratory tract. J Aerosol Med 1994; 7: 49–75
RW Niven. Atomization and nebulizers, inhalation aerosols: physical and biological basis for therapy. In: Hickey AJ, editor. New York: Marcel Dekker, 1996: 273–312
Hess DR. Nebulizers: principles and performance. Respir Care 2000; 45: 609–22
Raul JL. Design principles of liquid nebulization devices currently in use. Respir Care 2002; 47: 1257–75
Wolff RK, Niven RW. Generation of aerosolized drugs. J Aerosol Med 1994; 7: 89–106
Everard ML. CFC transition: the Emperor’s new clothes. Each class of drug deserves a delivery system that meets its own requirements. Thorax 2000; 55(10): 811–4
Smyth HDC. The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers. Adv Drug Deliv Rev 2003; 55: 807–28
Quinn EA, Forbes RT, Williams AC, et al. Protein conformational stability in the hydrofluoroalkane propellants tetrafluoroethane and heptafluoropropane analyzed by Fourier transform Raman spectroscopy. Int J Pharm 1999; 186: 31–41
Stefely JS, Brown B, Hammerbeck DM, et al. Equiping the MDI for the 21st century by expanding its formulation options. In: Dalby RN, Byron PR, Peart J, editors. Respiratory drug delivery VIII. Raleigh (NC): Davis Horwood International Publishing Ltd, 2002: 207–14
Geller DE. New liquid aerosol generation devices: systems that force pressurized liquids through nozzles. Respir Care 2002; 47: 1392–405
Crockford DR. Adaptive Aerosol Delivery (AAD™) Technology: approaching drug delivery from the patient’s perspective. Drug Deliv Technol 2002; 2: 44–9
Byrne NM, Keavey PM, Perry JD, et al. Comparison of lung deposition of colomycin using the HaloLite and the Pari LC Plus nebulisers in patients with cystic fibrosis. Arch Dis Child 2003; 88: 715–8
Aerogen technology: customization of aerosol particle size distribution [online]. Available at URL: http://www.aerogen.com/pdf/scipresl3.pdf [Accessed 2005 Jan 13]
Geller D, Rosenfeld M, Waltz DA, et al. Efficiency of pulmonary administration of tobramycin solution for inhalation in cystic fibrosis using an improved drug delivery system. Chest 2003; 123: 28–36
Dhand R. Nebulizers that use a vibrating mesh or plate with multiple apertures to generate aerosol. Respir Care 2002; 47: 1406–16
Smart J, Berg E, Nerbrink O, et al. Touchspray technology: comparison of the droplet size measured with cascade impaction and laser diffraction. In: Dalby RN, Byron PR, Peart J, editors. Respiratory drug delivery VIII. Tucson (AZ): Davis Horwood International Publishers Ltd, 2002: 525–7
Geller D, Thipphawong J, Otulana B, et al. Bolus inhalation of rhDNase with the AERx system in subjects with cystic fibrosis. J Aerosol Med 2003; 16: 175–82
Perera AD, Kapitza C, Nosek L, et al. Absorption and metabolic effect of inhaled insulin: intrapatient variability after inhalation via the Aerodose insulin inhaler in patients with type 2 diabetes. Diabetes Care 2002; 25: 2276–81
Gomez A. The electrospray and its application to targeted drug inhalation. Respir Care 2002; 47: 1419–31
Zierenberg B. Optimizing the in vitro performance of Respimat. J Aerosol Med 1999; 12Suppl. 1: S19–24
Deshpande D, Blanchard J, Srinivasan S, et al. Aerosolization of lipoplexes using AERx Pulmonary Delivery System. AAPS PharmSci 2002; 4(3): E13
Henry RR, Mudaliar SR, Howland WC, et al. Inhaled insulin using the AERx Insulin Diabetes Management System in healthy and asthmatic subjects. Diabetes Care 2003; 26: 764–9
Thipphawong J, Otulana B, Clauson P, et al. Pulmonary insulin administration using the AERx insulin diabetes system. Diabetes Technol Ther 2002; 4: 515–8
Farr SJ, Reynolds D, Nat A, et al. Technical development of AERx diabetes management system: essential characteristics for diabetes treatment with pulmonary insulin. In: Dalby RN, Byron PR, Peart J, editors. Respiratory drug delivery VIII. Vol. I. Richmond (VA): Virginia Commonwealth University, 2002: 51–60
Goodall S, Chew N, Chan K, et al. Aerosolization of protein solutions using thermal inkjet technology. J Aerosol Med 2002; 15: 351–7
Elias CB, Joshi JB. Role of hydrodynamic shear on activity and structure of proteins. Adv Biochem Eng Biotechnol 1998; 59: 47–71
Maa Y-F, Hsu CC. Protein denaturation by combined effect of shear and air-liquid interface. Biotechnol Bioeng 1997; 54: 503–12
Edwards RA, Huber RH. Surface denaturation of proteins: the thermal inactivation of beta-galactosidase (Escherichia coll) on wall-liquid surfaces. Biochem Cell Biol 1992; 70: 63–9
Porter WR. Chemical and physical properties of peptide and protein drugs. In: Adjei A, Gupta PK, editors. Inhalation delivery of therapeutic peptides and proteins. Vol. 107. New York: Marcel Dekker Inc., 1997: 59–87
Arakawa T, Prestrelski SJ, Kenney WC, et al. Factors affecting short-term and long-term stabilities of proteins. Adv Drug Deliv Rev 1993; 10: 1–28
Courrier HM, Butz N, Vandamme TF. Pulmonary drug delivery systems: recent developments and prospects. Crit Rev Ther Drug Carrier Syst. 2002; 19(4-5): 425–98
Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br J Clin Pharmacol 2003; 56: 600–12
Ceh B, Winterhalter M, Frederik PM, et al. Stealth liposomes: from theory to product. Adv Drug Deliv Rev 1997; 24: 165–77
Alton EW, Middleton PG, Caplen NJ, et al. Noninvasive liposome-mediated gene delivery can correct the ion transport defect in cystic fibrosis mutant mice. Nat Genet 1993; 5: 135–42
Hyde SC, Gill DR, Higgins CF, et al. Correction of the ion transport defect in cystic fibrosis transgenic mice by gene therapy. Nature 1993; 362: 250–5
Logan JJ, Bebok Z, Walker LC, et al. Cationic lipids for reporter gene and CFTR transfer to rat pulmonary epithelium. Gene Ther 1995; 2: 38–49
Rich DP, Anderson MP, Gregory RJ, et al. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature 1990; 347: 358–63
Yoshimura K, Rosenfeld MA, Nakamura H, et al. Expression of the human cystic fibrosis transmembrane conductance regulator gene in the mouse lung after in vivo intratracheal plasmid-mediated gene transfer. Nucleic Acids Res 1992; 20: 3233–40
Gregoriadis G, McCormack B, Obrenovic M, et al. Vaccine entrapment in liposomes. Methods 1999; 19: 156–62
Mbawuike IN, Wyde PR, Anderson PM. Enhancement of the protective efficacy of inactivated influenza A virus vaccine in aged mice by IL-2 liposomes. Vaccine 1990; 8: 347–52
Khanna C, Anderson PM, Hasz DE, et al. Interleukin-2 liposome inhalation therapy is safe and effective for dogs with spontaneous pulmonary metastases. Cancer 1997; 79: 1409–21
Ten RM, Anderson PM, Zein NN, et al. Interleukin-2 liposomes for primary immune deficiency using the aerosol route. Int Immunopharmacol 2002; 2: 333–44
Hussain A, Yang T, Zaghloul AA, et al. Pulmonary absorption of insulin mediated by tetradecyl-beta-maltoside and dimethyl-beta-cyclodextrin. Pharm Res 2003; 20: 1551–7
Kuhn RJ. Formulation of aerosolized therapeutics. Chest 2001; 120: 94S–8S
O’Riordan TG. Formulations and nebulizer performance. Respir Care 2002; 47: 1305–12
Brambilla G, Berrill S, Davies RJ, et al. Formulation of leuprolide as an HFA solution pMDI. J Aerosol Med 2003; 16(2): 209
Williams RO, Liu J. Formulation of a protein with propellant HFA 134a for aerosol delivery. Eur J Pharm Sci 1999; 7: 137–44
Meyer RJ. Bringing new nebulizer technologies to market: regulatory issues. Respir Care 2002; 47: 1334–6
Dunne PJ. Economic aspects of introducing new nebulizer technology. Respir Care 2002; 47: 1321–31
Niven RN. Dry powder inhalers: preface. Adv Drug Deliv Rev 1997; 26: 1–2
Peart J, Clarke MJ. New developments in dry powder inhaler technology. Am Pharm Rev 2001; 4: 37–45
Louey MD. Particle interactions in powder mixtures for inhalation. Parkville, Australia: Department of Pharmaceutics, Monash University, 2000: 242
Hersey A. Ordered mixing: a new concept in powder mixing practice. Powder Tech 1975; 11: 41–4
Ganderton D, Kassem NM. Dry powder inhalers. In: Ganderton D, Jones T, editors. Advances in pharmaceutical sciences. London: Academic Press, 1992: 165–91
Staniforth JN. Improvements in dry powder inhaler performance: surface passivation effectseditors: drug delivery to the lungs VII. London: The Aerosol Society, 1996: 86–9
Chan HK, Chew NYK. Novel alternative methods for the delivery of drugs for the treatment of asthma. Adv Drug Deliv Rev 2003; 55: 793–805
Staniforth JN, Rees JE. Electrostatic charge interactions in ordered powder mixes. J Pharm Pharmacol 1982; 34: 69–76
Thiel WJ, Nguyen LT. Fluidized bed granulation of an ordered powder mixture. J Pharm Pharmacol 1982; 34: 692–9
Zeng XM, Martin GP, Tee SK, et al. Effects of particle size and adding sequence of fine lactose on the deposition of salbutamol sulphate from a dry powder formulation. Int J Pharm 1999; 182: 133–44
Zeng XM, Martin GP, Tee SK, et al. The role of fine particle lactose on the dispersion and deaggregation of salbutamol sulphate in an air stream in vitro. Int J Pharm 1998; 176: 99–110
Crowder TM, Louey MD, Sethuraman VV, et al. 2001: an Odyssey in inhaler formulation and design. Pharm Tech 2001; 25(7): 113
Atkins PJ, Crowder TM. The design and development of inhalation drug delivery systems. In: Hickey AJ, editors. Pharmaceutical inhalation aerosol technology. 2nd ed. New York: Marcel Dekker, 2004: 279–309
Phillips E, Allsopp E, Christensen T, et al. Size reduction of peptides and proteins by jet milling. In: Dalby RN, Byron PR, Farr SJ, editors. Respiratory drug delivery VI. Buffalo Grove (IL): Interpharm Press, 1998: 161–8
Wang W. Lyophilization and development of solid protein Pharmaceuticals. Int J Pharm 2000; 203: 1–60
Tang X, Pikal MJ. Design of freeze-drying processes for Pharmaceuticals: practical advice. Pharm Res 2004; 21: 191–200
Carpenter JF, Pikal MJ, Chang BS, et al. Rational design of stable lyophilized protein formulations: some practical advice. Pharm Res 1997; 14: 969–75
Hatley RHM, Blair JA. Stabilization and delivery of labile materials by amorphous carbohydrates and their derivatives. J Mol Catal B Enzym 1999; 7: 11–9
Zeng XM, Martin GP, Marriott C. Effects of molecular weight of polyvinylpyrrolidone on the glass transition and crystallization of co-lyophilized sucrose. Int J Pharm 2001; 218: 63–73
Immamura K, Iwai M, Ogawa T, et al. Evaluation of hydration states of protein in freeze-dried amorphous sugar matrix. J Pharm Sci 2001; 90: 1955–63
Chang BS, Beauvais RM, Dong A, et al. Physical factors affecting the storage stability of freeze-dried interleukin-1 receptor antagonist: class transition and protein conformation. Arch Biochem Biophys 1996; 331: 249–58
Shamblin SL, Huang EY, Zografi G. The effects of co-lyophilized polymeric additives on the glass transition temperature and crystallization of amorphous sucrose. J Therm Anal 1996; 47: 1567–79
Ward KR, Adams GDJ, Alpar HO, et al. Protection of the enzyme L-asparaginase during lyophilization: a molecular modeling approach to predict required level of lyoprotectant. Int J Pharm 1999; 187: 153–62
Carpenter JF, Crowe JH. An infrared spectroscopy study of the interactions of carbohydrates with dried protein. Biochemistry 1989; 28: 3916–22
Sacchetti M, Van Oort MM. Sray-drying and supercritical fluid particle generation techniques. In: Hickey AJ, editor. Inhalation aerosols. New York: Marcel Dekker, 1996: 337–84
Liao YH, Brown MB, Quader A, et al. Investigation of the physical properties of spray dried stabilized lysozyme particles. J Pharm Pharmacol 2003; 55: 1213–21
Broadhead J, Rouan SKE, Hau I, et al. The effect of process and formulation variables on the properties of spray-dried beta-galactosidase. J Pharm Pharmacol 1994; 46: 458–67
Mumenthaler M, Hsu M, Pearlman R. Feasibility study on spray-drying protein Pharmaceuticals: recombinant human growth hormone and tissue-type plasminogenic factor. Pharm Res 1994; 11: 12–20
Patton JS, Foster LC, Platz RM. Methods and composition for pulmonary delivery of insulin. International patent application WO 1995; 95/24: 183
Chan HK, Clark A, Gonda I, et al. Spray dried powders and powder blends of recombinant human deoxyribonuclease (rhDNase) for aerosol delivery. Pharm Res 1997; 14: 431–7
Chew NYK, Chan HK. Use of solid corrugated particles to enhance powder aerosol performance. Pharm Res 2001; 18: 1570–7
Codrons V, Vanderbist F, Verbeeck RG, et al. Systemic delivery of parathyroid hormone (1-34) using inhalation dry powder in rats. J Pharm Sci 2003; 92: 938–50
Maa YF, Nguyen PA, Sweeney T, et al. Protein inhalation powders: spray drying vs spray freeze drying. Pharm Res 1999; 16: 249–54
Sunkara G, Kompella UB. Drug delivery applications of supercritical fluid technology. Drug Deliv Tech 2002; 2: 44–50
Kompella UB, Koushik K. Preparation of drug delivery systems using supercritical fluid technology. Crit Rev Ther Drug Carrier Sys 2001; 18: 173–99
Winters MA, Debenedetti PG, Carey J, et al. Long-term and high temperature storage of supercritically processed microparticulate protein powders. Pharm Res 1997; 14: 1370–8
Moshashaee S, Bisrat M, Forbes R, et al. Supercritical fluid processing of proteins: lysozyme precipitation from aqueous solution. J Pharm Pharmacol 2003; 55: 185–92
Yeo SD, Lim GB, Debenedetti PG, et al. Formation of microparticulate protein powders using a supercritical fluid antisolvent. Biotechnol Bioeng 1993; 41: 341–6
Okamoto H, Todo H, Iida K, et al. Dry powders for pulmonary delivery of peptides and proteins. KONA 2002; 20: 71–82
Bustami RT, Chan HK, Foster NR. Aerosol delivery of protein powders processed by supercritical fluid technology. In: Byron, PR, Farr, SJ, Dalby RN, editors. Respiratory drug delivery VII. Palm Harbor (FL): Serentec Press, 2000: 611–3
Sellers SP, Clark GS, Sievers RE, et al. Dry powders of stable protein formulations from aqueous solutions prepared using supercritical CO2 assisted aerosolization. J Pharm Sci 2001; 90: 785–97
Ribeiro Dos Santos I, Richard J, Pech B, et al. Microencapsulation of protein particles within lipids using a novel supercritical fluid process. Int J Pharm 2002; 242: 69–78
Meziani MJ, Sun YP. Protein-conjugated nanoparticles from rapid expansion of supercritical fluid solution into aqueous solution. J Am Chem Soc 2003; 125: 8015–8
Edwards DE, Ben-Jebria A, Langer R. Recent advances in pulmonary drug delivery using large, porous inhaled particles. J Appl Physiol 1997; 84: 379–85
Edwards DE, Hanes J, Caponetti G, et al. Large porous particles for pulmonary drug delivery. Science 1997; 276: 1868–71
Vanbever R, Mintzes JD, Wang J, et al. Formulation and physical characterization of large porous particles for inhalation. Pharm Res 1999; 16: 1735–42
Thiering R, Dehghani F, Dillow A, et al. The influence of operating conditions on the dense gas precipitation of model proteins. J Chem Technol Biotechnol 2000; 75: 29–41
Bot AI, Tarara TE, Smith DJ, et al. Novel lipid-based hollow-porous microparticles as a platform for immunoglobulin delivery to the respiratory tract. Pharm Res 2000; 17: 275–83
Garcia-Contreras L, Morcol TM, Bell SJD, et al. Evaluation of novel particles as pulmonary delivery systems for insulin in rats. AAPS PharmSci 2003; 5(2): E9
Steiner SS, Pfutzner A, Wilson B, et al. Technosphere™/insulin: proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endocrinol Diabetes 2002; 110: 17–21
Brown LR, Rashba-Step J, Scott T, et al. Pulmonary delivery of novel insulin microspheres. In: Dalby RN, Byron PR, Peart J, et al., editors. Respiratory drug delivery VIII. Raleigh (NC): Davis Horwood International Publishing Ltd, 2002: 431–3
Blair J, Coghlan D, Langner E, et al. Sustained delivery of insulin via the lung using Solidose technology. In: Dalby RN, Byron PR, Peart J, Farr SJ, editors. Respiratory drug delivery VIII. Raleigh (NC): Davis Horwood International Publishing Ltd, 2002: 411–413
Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications. Br J Pharmacol 2003; 56: 588–99
Patton JS. Mechanisms of macromolecule absorption by the lungs. Adv Drug Deliv Rev 1996; 19: 3–36
Hussain A, Arnold JJ, Khan MA, et al. Absorption enhancers in pulmonary protein delivery. J Control Release 2004; 94: 15–24
Garcia-Contreras L, Sarubbi D, Flanders E, et al. Immediate and short-term cellular and biochemical responses to pulmonary single-dose studies of insulin and H-MAP. Pharm Res 2001; 18: 1685–93
Manning MC, Patel K, Borchardt R. Stability of protein pharmaceuticals. Pharm Res 1989; 6: 903–18
Geigert J. Overview of the stability and handling of recombinant protein drugs. J Parenter Sci Technol 1989; 43: 220–4
Martin A, Swarbrick J, Cammarata A. Physical pharmacy. Philadelphia (PA): Lea & Febiger, 1983
Atkins PJ, Crowder TM, Hickey AJ, et al. Recent technical advances and formulation strategies in pulmonary drug delivery [online]. Available at URL: http://www.inpharm.com/static/intelligence/pdf/MAG_142029.pdf [Accessed 2005 Feb 18]
The United States Pharmacopieal Convention, Inc. Patient safety. Rockville (MD): The United States Pharmacopieal Convention, Inc. Quality Review, 2000
Physicians’ Desk Reference. 56th ed. Montvale (NJ): Medical Economics Company, Inc., 2002
Hickey AJ, Garcia-Contreras L. Immunological and toxicological implications of short term studies in animals of pharmaceutical aerosol delivery to the lungs. Crit Rev Ther Drug Carrier Syst 2001; 18: 387–431
Wolff RK. Safety of inhaled proteins for therapeutic use. J Aerosol Med 1998; 11: 197–219
Gonda I. Drugs administered directly into the respiratory tract: modeling of the duration of effective drug levels. J Pharm Sci 1988; 77: 340–6
Clark A. Pulmonary delivery technology: recent advantages and potential for the new millenium. In: Hickey AJ, editor. Pharmaceutical inhalation aerosol technology. 2nd ed. New York: Marcel Dekker, 2004: 571–91
Corkery K. Inhalable drugs for systemic therapy. Respir Care 2000; 45: 831–5
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Garcia-Contreras, L., Smyth, H.D.C. Liquid-spray or dry-powder systems for inhaled delivery of peptide and proteins?. Am J Drug Deliv 3, 29–45 (2005). https://doi.org/10.2165/00137696-200503010-00004
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DOI: https://doi.org/10.2165/00137696-200503010-00004