Inhaled theophylline: old drug new tricks?


  • Maria Malamatari Department of Pharmacy, Frederick University, Nicosia 1036, Cyprus; Institute for Globally Distributed Open Research and Education (IGDORE), London, UK



Theophylline, Respiratory disease, Pulmonary drug delivery


Theophylline and aminophylline (i.e., the soluble complex of theophylline with ethylenediamine) have been used in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease for more than 90 years. Theophylline’s narrow therapeutic index and side effects, as well as the discovery of more potent and safer bronchodilators, made it to fall out of favour with healthcare professionals and patients. New scientific knowledge on the molecular mechanism of action of theophylline, along with increasing clinical evidence suggest that theophylline should be exploited as an anti-inflammatory agent rather than a bronchodilator. This review covers the journey of theophylline from rise to fall and back to its potential re-emergence as a combination formulation with inhaled corticosteroids in the management of chronic inflammatory lung diseases. Several approaches to formulate theophylline either as a monotherapy or as a combination therapy for delivery to the lungs are presented.


Hirsch S. Klinischer und Experimenteller Beitrag zur Krampflösenden Wirkung der Purinderivate. Klin Wochenschr. 1922;1:615-8.

May CD. History of the introduction of theophylline into the treatment of asthma. Clin Allergy. 1974;4:211-7.

Weinberger M. The pharmacology and therapeutic use of theophylline. J Allergy Clin Immunol. 1984;73:525-40.

Henriksen DP, Davidsen JR, Laursen CB. Nationwise use of theophylline among adults – A 20-year Danish drug utilisation study. Respir Med. 2018;140:57-62.

Newhouse MT. Is Theophylline Obsolete? Chest. 1990;98:1-3.

Cazzola M, Matera MG. The effect of doxofylline in asthma and COPD. Respir Med. 2020;164:105904.

Ozoh OB, Eze JN, Garba BI, Ojo OO, Okorie E-M, Yiltok E, et al. Nationwide survey of the availability and affordability of asthma and COPD medicines in Nigeria. Trop Med Int Health. 2021;26:54-65.

Spiller HA. Theophylline. In: Wexler P, eds. Encyclopedia of Toxicology. 2nd ed. New York: Elsevier; 2005:167-8.

Ma YJ, Jiang DQ, Meng JX, Li MX, Zhao HH, Wang Y, et al. Theophylline: a review of population pharmacokinetic analyses. J Clin Pharm Ther. 2016;41:594-601.

Global Strategy for Asthma and Prevention. Global Initiative for Asthma. Available at: https:// Accessed on 14 July 2023.

Global initiative for chronic obstructive lung disease. Available at: Accessed on 14 July 2023.

BNF content. Available at: Accessed on 14 July 2023.

Wen H, Park K. Introduction and Overview of Oral Controlled Release Formulation Design. In: Wen H, Park K, eds. Oral Controlled Release Formulation Design and Drug Delivery. USA: John Wiley & Sons Ltd; 2010:1-19.

Cheng Y, Qin H, Acevedo NC, Jiang X, Shi X. 3D printing of extended-release tablets of theophylline using hydroxypropyl methylcellulose (HPMC) hydrogels. Inter J Pharm. 2020;591:119983.

Hendeles L, Iafrate RP, Weinberger M. A clinical and pharmacokinetic basis for the selection and use of slow release theophylline products. Clin Pharmacokinet. 1984;9:95-135.

Tilley SL. Methylxanthines in Asthma. In: Fredholm BB, eds. Methylxanthines. Heidelberg: Springer; 2011:439-56.

Barnes PJ. Theophylline. Pharmaceuticals. 2010;3:725-47.

Boswell-Smith V, Cazzola M, Page CP. Are phosphodiesterase 4 inhibitors just more theophylline? J Allergy Clin Immunol. 2006;117:1237-43.

Fabbri LM, Beghé B, Yasothan U, Kirkpatrick P. Roflumilast. Nat Rev Drug Discov. 2010;9:761-2.

Currie GP, Butler CA, Anderson WJ, Skinner C. Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: a new approach to oral treatment. Br J Clin Pharmacol. 2008;65:803-10.

Mascali JJ, Cvietusa P, Negri J, Borish L. Anti-inflammatory effects of theophylline: modulation of cytokine production. Ann Allergy Asthma Immunol. 1996;77:34-8.

Finnerty JP, Lee C, Wilson S, Madden J, Djukanovic R, Holgate ST. Effects of theophylline on inflammatory cells and cytokines in asthmatic subjects: a placebo-controlled parallel group study. Eur Respir J. 1996;9:1672-7.

Jaffar ZH, Sullivan P, Page C, Costello J. Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J. 1996;9:456-62.

Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O’Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med. 1997;337:1412-8.

Ukena D, Harnest U, Sakalauskas R, Magyar P, Vetter N, Steffen H, et al. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J. 1997;10:2754-60.

Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, et al. A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA. 2002;99:8921-6.

Shapiro SD. The macrophage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160:S29-32.

Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med. 1996;153:530-4.

Barnes PJ. Emerging pharmacotherapies for COPD. Chest. 2008;134:1278-86.

Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med. 2004;200:689-95.

Thomson NC. The role of environmental tobacco smoke in the origins and progression of asthma. Curr Allergy Asthma Rep. 2007;7:303-9.

Spears M, Donnelly I, Jolly L, Brannigan M, Ito K, McSharry C, et al. Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study. Eur Respir J. 2009;33:1010-7.

Devereux G, Cotton S, Fielding S, McMeekin N, Barnes PJ, Briggs A, et al. Effect of Theophylline as Adjunct to Inhaled Corticosteroids on Exacerbations in Patients With COPD: A Randomized Clinical Trial. JAMA. 2018;320:1548-59.

Shuai T, Zhang C, Zhang M, Wang Y, Xiong H, Huang Q, et al. Low-dose theophylline in addition to ICS therapy in COPD patients: A systematic review and meta-analysis. PLoS One. 2021;16:e0251348.

Zhu B, Haghi M, Goud M, Young PM, Traini D. The formulation of a pressurized metered dose inhaler containing theophylline for inhalation. Eur J Pharm Sci. 2015;76:68-72.

Zhu B, Haghi M, Nguyen A, Goud M, Yeung S, Young PM, et al. Delivery of theophylline as dry powder for inhalation. Asian J Pharm Sci. 2015;10:520-7.

El-Gendy N, Pornputtapitak W, Berkland C. Nanoparticle agglomerates of fluticasone propionate in combination with albuterol sulfate as dry powder aerosols. Eur J Pharm Sci. 2011;44:522-33.

Salem H, Abdelrahim M, Eid KA, Sharaf M. Nanosized rods agglomerates as a new approach for formulation of a dry powder inhaler. Int J Nanomed. 2011;6:311-20.

Malamatari M, Somavarapu S, Kachrimanis K, Bloxham M, Taylor KMG, Buckton G. Preparation of theophylline inhalable microcomposite particles by wet milling and spray drying: The influence of mannitol as a co-milling agent. Int J Pharm. 2016;514:200-11.

Leng D, Kissi EO, Löbmann K, Thanki K, Fattal E, Rades T, et al. Design of inhalable solid dosage forms of budesonide and theophylline for pulmonary combination therapy. AAPS Pharm Sci Tech. 2019;20:137.

Mizoe T, Ozeki T, Okada H. Application of a Four-fluid Nozzle Spray Drier to Prepare Inhalable Rifampicin-containing Mannitol Microparticles. AAPS Pharm Sci Tech. 2008;9:755-61.

Leng D, Thanki K, Foged C, Yang M. Formulating Inhalable Dry Powders Using Two-Fluid and Three-Fluid Nozzle Spray Drying. Pharm Res. 2018;35:247.

Ehrick JD, Wylie J, Goodey AP, Li Y, Liu O, Donovan B. Orally inhaled fixed-dose combination products for the treatment of asthma and chronic obstructive pulmonary disease: not simple math. Ther Deliv. 2014;5:297-317.

Focaroli S, Jiang G, O’Connell P, Fahy JV, Healy A-M. The Use of a Three-Fluid Atomising Nozzle in the Production of Spray-Dried Theophylline/Salbutamol Sulphate Powders Intended for Pulmonary Delivery. Pharmaceutics. 2020;12:1116.

Salama RO, Young PM, Traini D. Concurrent oral and inhalation drug delivery using a dual formulation system: the use of oral theophylline carrier with combined inhalable budesonide and terbutaline. Drug Deliv Transl Res. 2014;4:256-67.

Mueller-Walz R, Fridez M, Balaxi M. Pharmaceutical composition for inhalation. WO2017033032A1;2017.




How to Cite

Malamatari, M. (2023). Inhaled theophylline: old drug new tricks?. International Journal of Basic & Clinical Pharmacology, 13(1), 174–180.



Review Articles