Computational intelligence for prediction of biological effects of drugs absorption in lungs


  • Adam Pacławski Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, Medyczna 9 St, 30-688 Cracow, Poland
  • Jakub Szlęk Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, Medyczna 9 St, 30-688 Cracow, Poland
  • Aleksander Mendyk Department of Pharmaceutical Technology and Biopharmaceutics, Jagiellonian University Medical College, Medyczna 9 St, 30-688 Cracow, Poland



empirical model, absorption enhancers, pulmonary drugs, genetic programming, symbolic regression, computational intelligence


Lungs are recently extensively examined as a route for delivering drugs (active pharmaceutical ingredients, API) into the bloodstream mainly due to the possibility of noninvasive administration of macromolecules, such as proteins and peptides. Absorption mechanisms of chemical compounds in lungs are still not fully understood, what makes pulmonary formulation composition development challenging. The manuscript presents development of an empirical model capable of predicting the excipients’ influence on the absorption of the drug in lungs. Due to complexity of the problem and not fully understood mechanisms of absorption, computational intelligence tools were applied. As a result, a mathematical formula was established and analyzed. The normalized root-mean-squared error (NRMSE) and R2 of the model were 4.57%, and 0.83, respectively. The presented approach is beneficial both practically by developing \textit{in sillico} predictive model and theoretically by gaining knowledge about the influence of API and excipient structure on absorption in lungs.


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Agu R.U., Ugwoke M.I., Armand M., Kinget R., Verbeke N.: The lung as a

route for systemic delivery of therapeutic proteins and peptides. In: Respiratory research, vol. 2(4), pp. 198–209, 2001. ISSN 1465-9921. URL http://dx.doi.


Al-Tabakha M.M.: Future prospect of insulin inhalation for diabetic patients: The case of Afrezza versus Exubera. In: Journal of Controlled Release, vol. 215, pp. 25–38, 2015. ISSN 18734995. URL


Banaei A., Pourbasheer E., Haggi F.: QSAR studies and application of genetic algorithm -multiple linear regressions in prediction of novel p2x7 receptor antagonists’ activity. In: Iranian Chemical Communication, vol. 98, pp. 318–336, 2016.

Bienert S., Waterhouse A., deBeer T., Tauriello G., Studer G., Bordoli L., Schwede T.: The SWISS-MODEL Repositorynew features and functionality. In: Nucleic Acids Research, vol. 45(D1), pp. D313–D319, 2017. ISSN 0305-1048. URL

Bluemke D.A.: Radiology in 2018:Are You Working with AI or Being Replaced by AI? In: Radiology, vol. 287(2), pp. 365–366, 2018. ISSN 15271315. URL

Cannon A.J.: monmlp: Monotone multi-layer perceptron neural network., 2012. URL

Core R.D.: R: A language and environment for statistical computing. In: R

Foundation for Statistical Computing, vol. 1, 2008. URL http://www.r-project.

Dong Z., Hamid K.A., Gao Y., Lin Y., Katsumi H., Sakane T., Yamamoto A.:

Polyamidoamine dendrimers can improve the pulmonary absorption of insulin and calcitonin in rats. In: Journal of Pharmaceutical Sciences, vol. 100(5), pp. 1866–1878, 2011. ISSN 15206017. URL

Edwards C.D., Luscombe C., Eddershaw P., Hessel E.M.: Development of a Novel Quantitative Structure-Activity Relationship Model to Accurately Predict Pulmonary Absorption and Replace Routine Use of the Isolated Perfused Respiring Rat Lung Model. In: Pharmaceutical Research, 2016. ISSN 0724-8741. URL

European Medicines Agency: Scientific discussion in marketing authorisation document for the product EXUBERA, insulin inhalation powder, 2006. URL{_}GB/document{_}library/EPAR{_ }-{_}Scientific{_}Discussion/human/000588/WC500054634.pdf.

Flasch O., Mersmann O., Bartz-Beielstein T., Stork J., Zaefferer M.: R geneticprogramming framework. R package version 0.4-1, 2015. URL

Geerts T., Vander Heyden Y.: In silico predictions of ADME-Tox properties: drug absorption. In: Combinatorial chemistry & high throughput screening, vol. 14(5), pp. 339–61, 2011. ISSN 1875-5402. URL 2174/138620711795508359.

He L., Gao Y., Lin Y., Katsumi H., Fujita T., Yamamoto A.: Improvement of

pulmonary absorption of insulin and other water-soluble compounds by polyamines in rats. In: Journal of Controlled Release, vol. 122(1), pp. 94–101, 2007. ISSN 01683659. URL

Hussain A., Arnold J.J., Khan M.A., Ahsan F.: Absorption enhancers in pulmonary protein delivery. In: Journal of Controlled Release, vol. 94(1), pp. 15–24, 2004. ISSN 01683659. URL

Hussain A., Yang T., Zaghloul A.A., Ahsan F.: Pulmonary Absorption of Insulin Mediated by Tetradecyl-β-Maltoside and Dimethyl-β-Cyclodextrin. In: Pharmaceutical Research, vol. 20(10), pp. 1551–1557, 2003. ISSN 07248741. URL

Kerlin R.L., Li X.: Pathology in Non-Clinical Drug Safety Assessment. In:

H. Wanda M. Haschek, Colin G. Rousseaux, Matthew A. Wallig, Rousseaux’s, eds., Haschek and Rousseaux’s Handbook of Toxicologic Pathology, chap. Chapter 24, pp. 725–750. Academic Press, third etit ed., 2013. ISBN 9780124157590. URL

Kim S., Thiessen P.A., Bolton E.E., Chen J., Fu G., Gindulyte A., Han L., He J., He S., Shoemaker B.A., Wang J., Yu B., Zhang J., Bryant S.: PubChem Substance and Compound databases: CID 70095. In: Nucleic Acids Research, vol. 44, pp. 1202–1213, 2016. URL

Kobayashi S., Kondo S., Juni K.: Pulmonary delivery of salmon calcitonin dry powders containing absorption enhancers in rats. In: Pharmaceutical Research, vol. 13(1), pp. 80–83, 1996. ISSN 07248741. URL

Kraljevich T.: h2o: R interface for H20, 2018. URL https://cran.r-project.


Kuhn M., Weston S.: Cubist: Rule- And Instance-Based Regression Modeling, 2016. URL

Kumar T.M., Misra A.: Pulmonary absorption enhancement of salmon Calcitonin. In: Journal of Drug Targeting, vol. 12(3), pp. 135–144, 2004. ISSN 1061186X. URL

Li Y., Mitra A.K.: Effects of phospholipid chain length, concentration, charge, and vesicle size on pulmonary insulin absorption. In: Pharmaceutical Research, vol. 13(1), pp. 76–79, 1996. ISSN 07248741. URL

Liaw a., Wiener M.: Classification and Regression by randomForest. In: R news, vol. 2(December), pp. 18–22, 2002. ISSN 16093631. URL

Machida M., Hayashi M., Awazu S.: The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats. In: Biological & Pharmaceutical Bulletin, vol. 23(1), pp. 84–86, 2000. ISSN 0918-6158. URL

Mitra R., Pezron I., Li Y., Mitra a.K.: Enhanced pulmonary delivery of insulin by lung lavage fluid and phospholipids. In: International journal of pharmaceutics, vol. 217(1-2), pp. 25–31, 2001. ISSN 0378-5173. URL

Morales J.O., Fathe K.R., Brunaugh A., Ferrati S., Li S., Montenegro-Nicolini M., Mousavikhamene Z., McConville J.T., Prausnitz M.R., Smyth H.D.C.: Challenges and Future Prospects for the Delivery of Biologics: Oral Mucosal, Pulmonary, and Transdermal Routes. In: The AAPS Journal, vol. 19(3), pp. 652–668, 2017. ISSN 1550-7416. URL

Morita T., Yamamoto A., Hashida M., Sezaki H.: Effects of Various Absorption Promoters on Pulmonary Absorption of Drugs with Different Molecular Weights. In: Biological & Pharmaceutical Bulletin, vol. 16(3), pp. 259–262, 1993. ISSN 13475215. URL

Moriwaki H., Tian Y.S., Kawashita N., Takagi T.: Mordred: A molecular descriptor calculator. In: Journal of Cheminformatics, vol. 10(1), 2018. ISSN 17582946.URL

Nahar K., Gupta N., Gauvin R., Absar S., Patel B., Gupta V., Khademhosseini A., Ahsan F.: In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals. In: European Journal ofPharmaceutical Sciences, vol. 49(5), pp. 805–818, 2013. ISSN 09280987 18790720. URL

Nakate T., Yoshida H., Ohike A., Tokunaga Y., Ibuki R., Kawashima Y.: Improvement of pulmonary absorption of cyclopeptide FK224 in rats by co-formulatingwith β-cyclodextrin. In: European Journal of Pharmaceutics and Biopharmaceutics, vol. 55(2), pp. 147–154, 2003. ISSN 09396411. URL

Okumura K., Iwakawa S., Yoshida T., Seki T., Komada F.: Intratracheal delivery of insulin Absorption from solution and aerosol by rat lung. In: International Journal of Pharmaceutics, vol. 88(1-3), pp. 63–73, 1992. ISSN 03785173. URL

Onoue S., Yamamoto K., Kawabata Y., Hirose M., Mizumoto T., Yamada S.:Novel dry powder inhaler formulation of glucagon with addition of citric acid for enhanced pulmonary delivery. In: International Journal of Pharmaceutics, vol. 382(1-2), pp. 144–150, 2009. ISSN 03785173. URL

Pacławski A., Szlȩk J., Mendyk A.: Absorption EnhancementPredictor,


Pfützner A., Forst T.: Pulmonary insulin delivery by means of the Technosphere„ drug carrier mechanism. In: Expert Opinion on Drug Delivery, vol. 2(6), pp. 1097–1106, 2005. ISSN 1742-5247. URL

Quinlan J.R.: Learning with continuous classes. In: Machine Learning, vol. 92,pp. 343–348. 1992. URL

Rave K P.A.S.S.W.B.R.H.O.H.L., Steiner S., Pfützner A., Wilson B.R., Harzer O., Heinemann L., Rave K.: Technosphere/Insulin–proof of concept study with a new insulin formulation for pulmonary delivery. In: Exp Clin Endocrinol Diabetes, vol. 110(1), pp. 17–21, 2002. ISSN 0947-7349. URL

Sanders M.: Inhalation therapy: an historical review. In: Prim. Care Respir. J.,vol. 16(2), pp. 71–81, 2007. ISSN 14714418. URL

Singh P., Kumar R., Sharma B.K., Prabhakar Y.S.: Topological descriptors in modeling malonyl coenzyme A decarboxylase inhibitory activity: N-Alkyl-N-(1,1,1,3,3,3-hexafluoro-2-hydroxypropylphenyl) amide derivatives. In: Journal ofEnzyme Inhibition and Medicinal Chemistry, vol. 24(1), pp. 77–85, 2009. ISSN 14756366. URL

Suarez S., Garcia-Contreras L., Sarubbi D., Flanders E., O’Toole D., Smart J.,Hickey A.J.: Facilitation of pulmonary insulin absorption by H-MAP: Pharmacokinetics and pharmacodynamics in rats. In: Pharmaceutical Research, vol. 18(12), pp. 1677–1684, 2001. ISSN 07248741. URL

Szlȩk J., Pacławski A., Lau R., Jachowicz R., Kazemi P., Mendyk A.: Empirical search for factors affecting mean particle size of PLGA microspheres containing macromolecular drugs. In: Computer Methods and Programs in Biomedicine, vol.134, pp. 137–147, 2016. ISSN 18727565. URL

Szlek J., Pacławski A., Llau R., Jachowicz R., Mendyk A.: Heuristic modeling of macromolecule release from PLGA microspheres. In: International Journal of Nanomedicine, vol. 8, pp. 4601–4611, 2013. ISSN 11782013. URL

Tai L., Li S., Liu M.: Autonomous exploration of mobile robots through de

ep neural networks. In: International Journal of Advanced Robotic Systems,

vol. 14(4), pp. 1–9, 2017. ISSN 17298814. URL

Takano M., Kawami M., Aoki A., Yumoto R.: Receptor-mediated endocytosis of macromolecules and strategy to enhance their transport in alveolar epithelial cells. In: Expert Opinion on Drug Delivery, vol. 12(5), pp. 813–825, 2015. ISSN1742-5247. URL

Wiśniowska B., Mendyk A., Szlek J., Kołaczkowski M., Polak S.: Enhanced QSAR models for drug-triggered inhibition of the main cardiac ion currents. In: Journal of Applied Toxicology, vol. 35(9), pp. 1030–1039, 2015. ISSN 10991263. URL

Y. Li A.M.: Effcects of phospholipid chain length concentration charge and vesicels size on pulmonary insulin absorption. In: Pharm. Res., vol. 13, pp. 76–79,1996.

Yamamoto A., Fujita T., Muranishi S.: Pulmonary absorption enhancement of peptides by absorption enhancers and protease inhibitors. In: Journal of Con trolled Release, vol. 41(1-2), pp. 57–67, 1996. ISSN 01683659. URL http: //

Yamamoto A., Okumura S., Fukuda Y., Fukui M., Takahashi K., Muranishi S.:Improvement of the pulmonary absorption of (Asu1,7)-eel calcitonin by various absorption enhancers and their pulmonary toxicity in rats. In: Journal of Pharmaceutical Sciences, vol. 86(10), pp. 1144–1147, 1997. ISSN 00223549. URL




How to Cite

Pacławski, A., Szlęk, J., & Mendyk, A. (2019). Computational intelligence for prediction of biological effects of drugs absorption in lungs. Computer Science, 20(1).