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AAPS PharmSciTech

, 20:128 | Cite as

Respiratory Administration of Infliximab Dry Powder for Local Suppression of Inflammation

  • Homa Faghihi
  • Abdolhossein Rouholamini Najafabadi
  • Zahra Daman
  • Elham Ghasemian
  • Hamed Montazeri
  • Alireza VatanaraEmail author
Research Article

Abstract

The airways are verified as a relevant route to improve antibody therapeutic index with superior lung concentration but limited passage into systemic blood stream. The current research aimed to process spray-dried (SD) powder of Infliximab to assess the feasibility of respiratory delivery of antibody for local suppression of lung-secreted tumor necrosis factor α (TNFα). Molecular and structural stability of powders were determined through size exclusion chromatography (SEC-HPLC) and Fourier transform infrared (FTIR) spectroscopy. Particle properties were characterized by laser light scattering, twin stage impinger (TSI), and scanning electron microscopy (SEM). In vitro biological activity was quantified applying L-929 cell line. Ovalbumin (OVA)-challenged balb/c mice were employed to evaluate the anti-TNFα activity of antibody formulation as in vivo experimental model. SD sample consisting of 36 mg trehalose, 12 mg cysteine, and 0.05% of Tween 20 was selected with minimum aggregation/fragmentation rate constants of 0.07 and 0.05 (1/month) based on 1 and 2 months of storage at 40°C and relative humidity of 75%. Fine particle fraction (FPF) value of this formulation was 67.75% with desired particle size and surface morphology for respiratory delivery. EC50 was 8.176 and 6.733 ng/ml for SD Infliximab and Remicade®, respectively. SD antibody reduced TNFα (26.56 pg/ml) secretion in mouse lung tissue, more than 2 orders of magnitudes comparing positive control group (TNFα, 68.34 pg/ml). The success of antibody inhalation mainly depended on the spray drying condition, formulation components, and stability of antibody within aerosolization. Inhaled Infliximab could be a potential drug for local inhibition of lung inflammation.

KEY WORDS

infliximab spray drying inflammation respiratory delivery bioactivity 

Abbreviations

SD

Spray-dried

FD

Freeze-dried

TNFα

Tumor necrosis factor alpha

mAb

Monoclonal antibody

IL5

Interleukin 5

AHR

Airway hyperresponsiveness

MDIs

Metered dose inhalers

DPIs

Dry powder inhalers

IgG

Immunoglobulin G

IVIG

Intravenous immunoglobulin

SEC-HPLC

Size exclusion high pressure liquid chromatography

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

FTIR

Fourier transform infrared

SEM

Scanning electron microscopy

MTT

Methyl tetrazolium

RPMI

Roswell Park Memorial Institute

ATCC

American Type Culture Collection

KBr

Potassium bromide

TSI

Twin stage impinger

ED

Emitted dose

FPD

Fine particle dose

FPF

Fine particle fraction

ADA

Anti-drug antibody

Notes

Supplementary material

12249_2019_1308_MOESM1_ESM.docx (147 kb)
ESM 1 (DOCX 146 kb)
12249_2019_1308_MOESM2_ESM.docx (59 kb)
ESM 2 (DOCX 58 kb)
12249_2019_1308_MOESM3_ESM.docx (33 kb)
ESM 3 (DOCX 33 kb)
12249_2019_1308_Fig7_ESM.png (227 kb)
Fig. 1A

supplement SEC-HPLC chromatogram of F1 (PNG 226 kb)

12249_2019_1308_MOESM4_ESM.tif (91 kb)
High Resolution Image (TIF 91 kb)
12249_2019_1308_Fig8_ESM.png (217 kb)
Fig. 1B

supplement SEC-HPLC chromatogram of F9 (PNG 217 kb)

12249_2019_1308_MOESM5_ESM.tif (93 kb)
High Resolution Image (TIF 93 kb)
12249_2019_1308_Fig9_ESM.png (230 kb)
Fig. 1C

supplement SEC-HPLC chromatogram of Remicade (PNG 229 kb)

12249_2019_1308_MOESM6_ESM.tif (98 kb)
High Resolution Image (TIF 97 kb)
12249_2019_1308_Fig10_ESM.png (176 kb)
Fig. 2

supplement (PNG 175 kb)

12249_2019_1308_MOESM7_ESM.tif (71 kb)
High Resolution Image (TIF 70 kb)

References

  1. 1.
    Catley MC, Coote J, Bari M, Tomlinson KL. Monoclonal antibodies for the treatment of asthma. Pharmacol Ther. 2011;132(3):333–51.PubMedCrossRefGoogle Scholar
  2. 2.
    Ricci M, Matucci A, Rossi O. New advances in the pathogenesis and therapy of bronchial asthma. Ann Ital Med Int. 1998;13(2):93–110.PubMedGoogle Scholar
  3. 3.
    Ramshaw HS, Woodcock JM, Bagley CJ, McClure BJ, Hercus TR, Lopez AF. New approaches in the treatment of asthma. Immunol Cell Biol. 2001;79(2):154–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Busse WW, Banks-Schlegel S, Wenzel SE. Pathophysiology of severe asthma. J Allergy Clin Immunol. 2000;106(6):1033–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Babu KS, Davies DE, Holgate ST. Role of tumor necrosis factor alpha in asthma. Immunol Allergy Clin N Am. 2004;24(4):583–97 v-vi.CrossRefGoogle Scholar
  6. 6.
    Bodey KJ, Semper AE, Redington AE, Madden J, Teran LM, Holgate ST, et al. Cytokine profiles of BAL T cells and T-cell clones obtained from human asthmatic airways after local allergen challenge. Allergy. 1999;54(10):1083–93.PubMedCrossRefGoogle Scholar
  7. 7.
    Feagan BG, Choquette D, Ghosh S, Gladman DD, Ho V, Meibohm B, et al. The challenge of indication extrapolation for infliximab biosimilars. Biologicals. 2014;42(4):177–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Erin EM, Leaker BR, Nicholson GC, Tan AJ, Green LM, Neighbour H, et al. The effects of a monoclonal antibody directed against tumor necrosis factor-alpha in asthma. Am J Respir Crit Care Med. 2006;174(7):753–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Wouters EF, Reynaert NL, Dentener MA, Vernooy JH. Systemic and local inflammation in asthma and chronic obstructive pulmonary disease: is there a connection? Proc Am Thorac Soc. 2009;6(8):638–47.PubMedCrossRefGoogle Scholar
  10. 10.
    Patil JS, Sarasija S. Pulmonary drug delivery strategies: a concise, systematic review. Lung India. 2012;29(1):44–9.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Lee G. Spray-drying of proteins. In: Carpenter JF, Manning MC, editors. Rational design of stable protein formulations: theory and practice. Boston: Springer US; 2002. p. 135–58.CrossRefGoogle Scholar
  12. 12.
    Respaud R, Marchand D, Pelat T, Tchou-Wong K-M, Roy CJ, Parent C, et al. Development of a drug delivery system for efficient alveolar delivery of a neutralizing monoclonal antibody to treat pulmonary intoxication to ricin. J Control Release. 2016;234(Supplement C):21–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Ramezani V, Vatanara A, Rouholamini Najafabadi A, Gilani K, Nabi-Meybodi M. Screening and evaluation of variables in the formation of antibody particles by spray drying. Powder Technol. 2013;233(Supplement C):341–6.CrossRefGoogle Scholar
  14. 14.
    Ramezani V, Vatanara A, Najafabadi AR, Shokrgozar MA, Khabiri A, Seyedabadi M. A comparative study on the physicochemical and biological stability of IgG1 and monoclonal antibodies during spray drying process. Daru. 2014;22(1):31.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Faghihi H, Vatanara A, Najafabadi AR, Ramezani V, Gilani K. The use of amino acids to prepare physically and conformationally stable spray-dried IgG with enhanced aerosol performance. Int J Pharm. 2014;466(1–2):163–71.CrossRefGoogle Scholar
  16. 16.
    Faghihi H, Najafabadi AR, Vatanara A. Optimization and characterization of spray-dried IgG formulations: a design of experiment approach. Daru. 2017;25(1):22.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Tian F, Middaugh CR, Offerdahl T, Munson E, Sane S, Rytting JH. Spectroscopic evaluation of the stabilization of humanized monoclonal antibodies in amino acid formulations. Int J Pharm. 2007;335(1):20–31.CrossRefGoogle Scholar
  18. 18.
    Islam N, Cleary MJ. Developing an efficient and reliable dry powder inhaler for pulmonary drug delivery—a review for multidisciplinary researchers. Med Eng Phys. 2012;34(4):409–27.PubMedCrossRefGoogle Scholar
  19. 19.
    Brightling C, Berry M, Amrani Y. Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol. 2008;121(1):5–10 quiz 1-2.PubMedCrossRefGoogle Scholar
  20. 20.
    Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond). 2005;109(2):135–42.CrossRefGoogle Scholar
  21. 21.
    Berry M, Brightling C, Pavord I, Wardlaw A. TNF-alpha in asthma. Curr Opin Pharmacol. 2007;7(3):279–82.PubMedCrossRefGoogle Scholar
  22. 22.
    Maury M, Murphy K, Kumar S, Mauerer A, Lee G. Spray-drying of proteins: effects of sorbitol and trehalose on aggregation and FT-IR amide I spectrum of an immunoglobulin G. Eur J Pharm Biopharm. 2005;59:251–61.CrossRefGoogle Scholar
  23. 23.
    Chang L, Shepherd D, Sun J, Ouellette D, Grant KL, Tang X, et al. 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. 2005;94(7):1427–44.PubMedCrossRefGoogle Scholar
  24. 24.
    Pourshahab PS, Gilani K, Moazeni E, Eslahi H, Fazeli MR, Jamalifar H. Preparation and characterization of spray dried inhalable powders containing chitosan nanoparticles for pulmonary delivery of isoniazid. J Microencapsul.Google Scholar
  25. 25.
    Le VNP, Thi THH, Robins E, Flament MP. Dry powder inhalers: study of the parameters influencing adhesion and dispersion of fluticasone propionate. AAPS PharmSciTech. 2012;13(2):477–84.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Maa Y-F, Costantino HR, Nguyen P-A, Hsu CC. The effect of operating and formulation variables on the morphology of spray-dried protein particles. Pharm Dev Technol. 1997;2(3):213–23.PubMedCrossRefGoogle Scholar
  27. 27.
    Lechuga-Ballesteros D, Charan C, Stults CL, Stevenson CL, Miller DP, Vehring R, et al. Trileucine improves aerosol performance and stability of spray-dried powders for inhalation. J Pharm Sci. 2008;97(1):287–302.PubMedCrossRefGoogle Scholar
  28. 28.
    Chew NY, Chan HK. Use of solid corrugated particles to enhance powder aerosol performance. Pharm Res. 2001;18(11):1570–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Goetze AM, Schenauer MR, Flynn GC. Assessing monoclonal antibody product quality attribute criticality through clinical studies. MAbs. 2010;2(5):500–7.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Kirman I, Whelan RL, Nielsen OH. Infliximab: mechanism of action beyond TNF-alpha neutralization in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2004;16(7):639–41.PubMedCrossRefGoogle Scholar
  31. 31.
    Kanojia G, Have RT, Bakker A, Wagner K, Frijlink HW, Kersten GF, et al. The production of a stable infliximab powder: the evaluation of spray and freeze-drying for production. PLoS One. 2016;11(10):e0163109.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Ramezani V, Vatanara A, Najafabadi AR, Shokrgozar MA, Khabiri A, Seyedabadi M. A comparative study on the physicochemical and biological stability of IgG(1) and monoclonal antibodies during spray drying process. Daru. 2014;22(1):31.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Cortez-Jugo C, Qi A, Rajapaksa A, Friend JR, Yeo LY. Pulmonary monoclonal antibody delivery via a portable microfluidic nebulization platform. Biomicrofluidics. 2015;9(5):052603.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Fellner RC, Terryah ST, Tarran R. Inhaled protein/peptide-based therapies for respiratory disease. Mol Cell Pediatr. 2016;3(1):16.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Mo JH, Kang EK, Quan SH, Rhee CS, Lee CH, Kim DY. Anti-tumor necrosis factor-alpha treatment reduces allergic responses in an allergic rhinitis mouse model. Allergy. 2011;66(2):279–86.PubMedCrossRefGoogle Scholar
  36. 36.
    Lahn M, Kanehiro A, Hahn YS, Wands JM, Aydintug MK, O'Brien RL, et al. Aerosolized anti-T-cell-receptor antibodies are effective against airway inflammation and hyperreactivity. Int Arch Allergy Immunol. 2004;134(1):49–55.PubMedCrossRefGoogle Scholar
  37. 37.
    Henderson WR, Chi EY, Albert RK, Chu SJ, Lamm WJ, Rochon Y, et al. Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. J Clin Investig. 1997;100(12):3083–92.PubMedCrossRefGoogle Scholar
  38. 38.
    Fahy JV, Cockcroft DW, Boulet LP, Wong HH, Deschesnes F, Davis EE, et al. Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects. Am J Respir Crit Care Med. 1999;160(3):1023–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Respaud R, Marchand D, Parent C, Pelat T, Thullier P, Tournamille JF, et al. Effect of formulation on the stability and aerosol performance of a nebulized antibody. MAbs. 2014;6(5):1347–55.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Benucci M, Li Gobbi F, Meacci F, Manfredi M, Infantino M, Severino M, et al. Antidrug antibodies against TNF-blocking agents: correlations between disease activity, hypersensitivity reactions, and different classes of immunoglobulins. Biologics. 2015;9:7–12.PubMedPubMedCentralGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Homa Faghihi
    • 1
  • Abdolhossein Rouholamini Najafabadi
    • 1
  • Zahra Daman
    • 1
  • Elham Ghasemian
    • 1
  • Hamed Montazeri
    • 2
  • Alireza Vatanara
    • 1
    • 3
    Email author
  1. 1.Department of Pharmaceutics, Faculty of PharmacyTehran University of Medical SciencesTehranIran
  2. 2.School of Pharmacy-International CampusIran University of Medical SciencesTehranIran
  3. 3.Aerosol Research Laboratory, Department of Pharmaceutics, School of PharmacyTehran University of Medical SciencesTehranIran

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