The lung as a route for systemic delivery of therapeutic proteins and peptides

Respiratory Research

Norbert Verbeke²  Renaat Kinget²  Michoel Armand²  Michael Ikechukwu Ugwoke¹  Remigius Uchenna Agu² 

[1] Octoplus Pharmaceutical Development, Leiden, The Netherlands;Laboratorium voor Farmacotechnologie en Biofarmacie, KU Leuven, Leuven, Belgium

关键词: systemic delivery;    pulmonary absorption;    proteins;    peptides;    lung;   

Others  :  1227447
DOI  :  10.1186/rr58

 received in 2001-01-25, accepted in 2001-03-13,  发布年份 2001

【 摘 要 】

The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium are unique features of the lung that can facilitate systemic delivery via pulmonary administration of peptides and proteins. Physical and biochemical barriers, lack of optimal dosage forms and delivery devices limit the systemic delivery of biotherapeutic agents by inhalation. Current efforts to overcome these difficulties in order to deliver metabolic hormones (insulin, calcitonin, thyroid-stimulating hormone [TSH], follicle-stimulating hormone [FSH] and growth hormones) systemically, to induce systemic responses (immunoglobulins, cyclosporin A [CsA], recombinant-methionyl human granulocyte colony-stimulating factor [r-huG-CSF], pancreatic islet autoantigen) and to modulate other biological processes via the lung are reviewed. Safety aspects of pulmonary peptide and protein administration are also discussed.

【 授权许可】

   
2001 BioMed Central Ltd

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Wearley LL: Recent progress in protein and peptide delivery by non-invasive routes. Crit Rev Ther Drug Carrier Syst 1991, 8:1331-1394.
• [2]Wilson CG, Washington N: Physiological Pharmaceutics. England: John Wiley;. 1989.
• [3]Banga AK: Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems. Lancaster: Technomic;. 1995.
• [4]Weibel ER: Morphometry of the Human Lung. Berlin: Springer Verlag;. 1963.
• [5]Chrystyn H: Is total particle dose more important than particle distribution. Respir Med 1997, 91(suppl):17-19.
• [6]Gupta S, Moussy F, Dalby RN, Meikka SI, Bruley DF: Pulmonary delivery of human protein C and factor IX. In: Textbook of Advances in Experimental Medicine and Biology or Oxygen Transport to Tissue, vol 411. Edited by Nemoto EM, LaManna J. New York: Plenum Press; 1997, 429-435.
• [7]Engel T, Heinig JH, Malling HJ, Scharling B, Nikander K, Madsen F: Clinical comparison of inhaled busesonide delivered either via pressurized metered dose inhaler or Turbuhaler®. Allergy 1989, 44:220-225.
• [8]Nielsen KG, Skov M, Klug B, Ifversen M, Bisgaard H: Flow-dependent effect of formoterol dry powder inhaled from the Aerolizer®. Eur Respir J 1997, 10:2105-2109.
• [9]Niven RW: Delivery of biotherapeutics by inhalation aerosol. Crit Rev Ther Drug Carrier Syst 1995, 12:151-231.
• [10]Sayani AP, Chien YW: Systemic delivery of peptides and proteins across absorptive mucosae. Crit Rev Ther Drug Carrier Syst 1996, 13:85-184.
• [11]Zhou XH: Overcoming enzymatic and absorption barriers to non-parenterally administered protein and peptide drugs. J Contr Rel 1994, 29:239-252.
• [12]Liu FY, Kildsig DO, Mitra AK: Pulmonary biotransformation of insulin in rat and rabbit. Life Sci 1992, 51:1683-1689.
• [13]Shen Z, Zhang Q, Wei S, Nagai T: Proteolytic enzymes as a limitation for pulmonary absorption of insulin: in vitro and in vivo investigations. Int J Pharm 1999, 192:115-121.
• [14]Fukuda F, Tsuji T, Fujita T, Yamamoto A, Muranishi S: Susceptibility of insulin to proteolysis in rat lung homogenates and its protection from proteolysis by various protease inhibitors. Biol Pharm Bull 1995, 18:891-894.
• [15]Wigley FM, Londono JH, Wood SH, Shipp JC, Waldman RH: Insulin across respiratory mucosa by aerosol delivery. Diabetes 1971, 20:552-556.
• [16]Colthorpe P, Farr SJ, Taylor G, Smith IJ, Wyatt D: The pharmacokinetics of pulmonary-delivered insulin: a comparison of intratracheal and aerosol administration to the rabbit. Pharm Res 1992, 9:764-768.
• [17]Okumura k, Iwaka S, Tsuguchika Y, Toshimitsu S, Komada F: Intratracheal delivery of insulin absorption from solution and aerosol by rat lung. Int J Pharm 1992, 88:63-73.
• [18]Sakr FM: A new approach for insulin delivery via the pulmonary route: design and pharmacokinetics in non-diabetics rabbits. Int J Pharm 1992, 86:1-7.
• [19]Jendle JH, Karlberg BE, Arborelius M: An exploration of intrapulmonary insulin administration in anaesthetized and mechanically ventilated pigs. Scand J Clin Lab Invest 1996, 56:251-258.
• [20]Gansslen M: About inhalation of insulin [abstract; in German]. Klin Wochenschr 1925, 4:71.
• [21]Jendle JH, Karlberg BE: Intrapulmonary administration of insulin to healthy volunteers. J Intern Med 1996, 240:93-98.
• [22]Laube BL, Georgopoulos A, Adams GK: Preliminary study of the efficiency of insulin aerosol delivered by oral inhalation in diabetic patients. JAMA 1993, 269:2106-2109.
• [23]Laube BL, Benedict GW, Dobs AS: The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes. Chest 1998, 114:1734-1739.
• [24]Laube BL, Benedict GW, Dobs AS: Time to peak insulin level, relative bioavailability, and effect of site of deposition of nebulized insulin in patients with noninsulin-dependent diabetes mellitus. J Aerosol Med 1998, 11:153-173.
• [25]Pfützner A, Heise T, Steiner S, Heinemann L, Rave K: Inhaled technosphere: insulin shows a low variability in metabolic action in type 2 diabetic patients [abstract]. Diabetes 2000, 49 (suppl):A121.
• [26]Rave KM, Heise T, Pfützner A, Steiner S, Heinemann L: Results of a dose-response study with a new insulin inhaler formulation [abstract]. Diabetes 2000, 49(suppl):A75.
• [27]Elliot RB, Edgar BW, Pitcher CC, Quested C, McMaster J: Parenteral absorption of insulin from the lung in diabetic children. Aust Paediatr J 1987, 23:293-297.
• [28]Gelfand AG, Schwartz SL, Horton M, Law CG, Pun EF: Pharmacological reproducibility of inhaled human insulin pre-meal dosing in patients with type 2 diabetes mellitus (NIDDM) [abstract]. Diabetes 1998, 47(suppl):A99.
• [29]Skyler JS, Gelfand RA, Kourides IA: Treatment of type 1 diabetes mellitus with inhaled human insulin: a 3-month, multicenter trial [abstract]. Diabetes 1998, 47(suppl):A61.
• [30]Cefalu WT, Gelfand RA, Kourides I: Treatment of type 2 diabetes mellitus with inhaled human insulin: a 3-month, multicenter trial [abstract]. Diabetes 1998, 47(suppl):A61.
• [31]Cappelleri JC, Gerber RA, Bell-farrow AD, English JS, Agramonte RF, Kourides IA: Improved patient satisfaction with inhaled insulin in subjects with type 2 diabetes mellitus: results from a multicenter randomized controlled trial [abstract]. Diabetes 2000, 49(suppl):A100.
• [32]Gerber RA, Cappelleri JC, Bell-farrow AD, English JS, Agramonte RF, Gelfand RA: Improved patient satisfaction with inhaled insulin in subjects with type 1 diabetes mellitus after one year: results from a multicenter extension trial [abstract]. Diabetes 2000, 49(suppl):A108.
• [33]Cefalu WT, Balagtas CC, Landschulz WH, Gelfand RA: Sustained efficacy and pulmonary safety of inhaled insulin during two years of outpatient therapy [abstract]. Diabetes 2000, 49 (suppl):A101.
• [34]Farr S, McElduff A, Ward E, Okumu F, Mather L, Gonda I, Rubsamen R: A comparison of the pharmacokinetics and pharmacodynamics of inhaled insulin administered as different strength solutions to healthy volunteers [abstract]. Diabetes 1998, 47(suppl):A61.
• [35]Farr S, McElduff A, Ward E, Okikawa J, Lloyd P, Schuster J, Mather L, Gonda I: The mode of inhalation influences the pharmacokinetics and pharmacodynamics of pulmonary delivered insulin in healthy fasted volunteers [abstract]. Pharm Res 1997, 14(suppl):S136.
• [36]Kipnes M, Otulana B, Clauson P, Fischer J, Farr S, Hatorp V, Schwartz S: A comparison of the pharmacodynamic effects of inhaled insulin versus subcutaneous insulin in type 1 diabetic patients [abstract]. Diabetes 1999, 48(suppl):A95.
• [37]Brunner GA, Balent B, Sendlhofer G, Ellmerer M, Schaupp L, Jendle JH, Kristensen A, Okikawa J, Pieber TR: Pharmacokinetics and pharmcodynamics of inhaled versus subcutaneous insulin in subjects with type 1 diabetes: a glucose clamp study [abstract]. Diabetes 2000, 49(suppl):A76.
• [38]Weiss SR, Berger S, Cheng S, Kourides I, Landschulz WH, Gelfand R: Adjunctive therapy with inhaled human insulin in type 2 diabetic patients failing oral agents: a multicenter phase II trial [abstract]. Diabetes 1999, 48(suppl):A12.
• [39]Patton JS, Trinchero P, Platz RM: Bioavailability of pulmonary delivered peptides and proteins: α-interferon, calcitonins and parathyroid hormone. J Contr Rel 1994, 28:79-85.
• [40]Komada F, Iwakawa S, Yamamoto N, Sakakibara H, Okumura K: Intratracheal delivery of peptide and protein agents: absorption from solution and dry powder by rat lung. J Pharm Sci 1994, 83:863-867.
• [41]Folkesson HG, Hedin L, Westrom BR, Pierzynowski SG, Karlsson BW: Lung to blood passage of human growth hormone after intratracheal instillation: stimulation of growth in hypophysectomized rats. J Endocrinol 1992, 134:197-203.
• [42]Colthorpe P, Farr SJ, Smith IJ, Wyatt D, Taylor G: The influence of regional deposition on the pharmacokinetics of pulmonary-delivered human growth hormone in rabbits. Pharm Res 1995, 12:356-359.
• [43]Shao Z, Li Y, Mitra AK: Cyclodextrins as mucosal absorption promoters of insulin III: pulmonary route of delivery. Eur J Pharm Biopharm 1994, 40:283-288.
• [44]Shen Z, Cheny Y, Zhang Q: Lanthanides enhance pulmonary absorption of insulin. Biol Trace Element Res 2000, 75:215-225.
• [45]Heinemann L, Klappoth W, Rave K, Hompesch B, Linkeschowa R, Heis T: Intra-individual variability of metabolic effect of inhaled insulin together with an absorption enhancer. Diabetes Care 2000, 23:1343-1347.
• [46]Kobayashi S, Kondo S, Juni K: Study of pulmonary delivery of salmon calcitonin in rats: effects of protease inhibitors and absorption enhancers. Pharm Res 1994, 11:1239-1243.
• [47]Morita T, Yamamoto A, Takakura Y, Hashida M, Sekaki H: Improvement of pulmonary absorption of (ASU1,7)-Eel calci-tonin by various protease inhibitors in rats. Pharm Res 1994, 11:909-913.
• [48]Yamamoto A, Okumura S, Fukuda Y, Fukui M, Takahashi K, Muran-ishi S: Improvement of the pulmonary absorption of (ASU1,7)-Eel calcitonin by various absorption enhancers and their pulmonary toxicity in rats. J Pharm Sci 1997, 86:1144-1147.
• [49]Edwards DA, Hanes J, Caponetti G, Hrkach J, Ben-Jebria A, Eskew ML, Mintzes J, Deaver D, Lotan N, Langer R: Large porous particles for pulmonary drug delivery. Science 1997, 276:1868-1871.
• [50]Kawashima Y, Yamamoto H, Takeuchi H, Fujoka S, Hino T: Pulmonary delivery of insulin with nebulized DL-lactide/glycolide copolymer (PLGA) nanosphere to prolong hypoglycemic effect. J Contr Rel 1999, 62:279-287.
• [51]Liu F, Shao Z, Kildsig DO, Mitra AK: Pulmonary delivery of free and liposomal insulin. Pharm Res 1993, 10:228-232.
• [52]Li Y, Mitra AK: Effect of phospholipid chain length, concentration, charge, and vesicle size on pulmonary insulin absorption. Pharm Res 1996, 13:76-79.
• [53]Smith PL, Yeulet SE, Citerone DR, Drake F, Cook K, Wall DA, Marcello J: SK&F 110679: comparison of absorption following oral or respiratory administration. J Contr Rel 1994, 28:67-77.
• [54]Ajei A, Garren J: Pulmonary delivery of peptide drugs: effect of particle size on bioavailability of leuprolide acetate in healthy voluteers. Pharm Res 1990, 7:565-569.
• [55]Adjei A, Johnson E, Doyle R, Sims K: Formulations of a non-apeptide: in vitro and in vivo studies [abstract]. J Pharm Sci 1987, 76(suppl):PS47.
• [56]Adjei A, Hui J, Finley R, Lin T, Lancaster J, Fort F: Pulmonary bioavailability of leuprolide acetate following multiple dosing to beagle dogs: some pharmacokinetic and clinical issues. Int J Pharm 1994, 107:57-66.
• [57]Bennett DB, Tyson E, Nuremberg CA, Mah S, De Groot JS, Teitelbaum Z: Pulmonary delivery of detirelix by intratracheal instillation and aerosol inhalation in briefly anesthetized dog. Pharm Res 1994, 11:1048-1055.
• [58]Schreier H, McNicol KJ, Bennette DB, Teitelbaum Z, Derendorf H: Pharmacokinetics of detirelix following intratracheal instillation and aerosol inhalation in the unanesthethized awake sheep. Pharm Res 1994, 11:1056-1059.
• [59]Lizio R, Klenner T, Borchard G, Romeis P, Sarlikiotis AW, Reissmann T, Lehr C: Systemic delivery of the GnRH antagonist cetrorelix by intratracheal instillation in anesthetized rat. Eur J Pharm Sci 2000, 9:253-258.
• [60]Folkesson HG, Westrom BR, Karlsson BW: Permeability of the respiratory tract to different sized macromolecules after intratracheal instillation in young and adult rats. Acta Physiol Scand 1990, 139:347-354.
• [61]Folkesson HG, Westrom BR, Pierzynowski SG, Svendsen J, Karlsson BW: Lung to blood passage of albumin and a nonapeptide after intratracheal instillation in the young developing pig. Acta Physiol Scand 1993, 147:173-178.
• [62]Bot AI, Tarara TE, Smith DJ, Bot SR, Woods CM, Weers JG: Novel lipid-based hollow-porous microparticles as a platform for immunoglobulin delivery to the respiratory tract. Pharm Res 2000, 17:275-283.
• [63]Hänninen A, Harisson LC: γδ T cells as mediators of mucosal tolerance: the autoimmune diabetes model. Immunol Rev 2000, 173:109-119.
• [64]Harrison LC, Dempsey-Collier , Kramer DR, Takahashi K: Aerosol insulin induces regulatory CD8 γδ T cells that prevent murine insulin-dependent diabetes. J Exp Med 1996, 184:2167-2174.
• [65]Altrock BW, Fagin KD, Hockman HR, Fish EN, Goldstein L, Chang D, Duker K, Stebbing N: Antiviral and antitumor effects of human interferon analog, IFN-α Con1, assessed in hamsters. J Interferon Res 1986, 6:405-415.
• [66]Niven RW, Whitcomb KL, Woodwards M, Liu J, Jornacion C: Systemic absorption and activity of recombinant consensus interferons after intratracheal intillation and aerosol administration. Pharm Res 1995, 12:1889-1895.
• [67]Niven RW, Lott FD, Cribbs JM: Pulmonary absorption of recombinant methionyl human granulocyte colony stimulating factor (r-huG-CSF) after intratracheal instillation to the hamster. Pharm Res 1993, 10:1604-1610.
• [68]Niven RW, Lott FD, Ip AY, Cribbs JM: Pulmonary delivery of powders and solutions containing granulocyte colony-stimulating factor (r-huG-CSF) to the rabbit. Pharm Res 1994, 11:1101-1109.
• [69]Taljanski W, Pierzynowki SG, Lundin PD, Westrom BR, Eirefelt S, Podlesny J, Dahlback M, Siwinska-Golebiowska H, Karlsson BW: Pulmonary delivery of intratracheally instilled and aerosolized cyclosporin A to young and adult rats. Drug Metab Dis 1997, 25:917-920.
• [70]Niven RW, Whitcomb KL, Shaner LD, Ralph LD, Habberfield AD, Wilson JV: Pulmonary absorption of polyethylene glycolated recombinant human granulocyte colony stimulating factor (PEGr-huG-CSF). J Contr Rel 1994, 32:177-189.
• [71]Wolff RK: Safety of inhaled proteins for therapeutic use. J Aerosol Med 1998, 11:197-219.
• [72]Myers MA, Thomas DA, Straub L, Soucy DW, Niven RW, Kaltenback M, Hood CI: Pulmonary effect of chronic exposure to liposome aerosols in mice. Exp Lung Res 1993, 19:1-19.
• [73]Dokka S, Toledo D, Shi X, Castranova V, Rojanasakul Y: Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes. Pharm Res 2000, 17:521-525.