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Development of Temozolomide Dry Powder Formulations for Inhalation for the Treatment of Lung Tumours

par Wauthoz, Nathalie ;Deleuze, Philippe ;Saumet, Amandine;Duret, Christophe ;Amighi, Karim
Référence Journée doctorale pôle santé 2010 (23/12/2010: Campus Erasme)
Publication Non publié, 2010-12-23

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Development of Temozolomide Dry Powder Formulations for Inhalation for the Treatment of Lung Tumours Nathalie Wauthoz*, Philippe Deleuze, Amandine Saumet, Christophe Duret, Karim Amighi Laboratoire de Pharmacie Galénique et de Biopharmacie, Institut de Pharmacie, Université Libre de Bruxelles (ULB), CP207 bd du triomphe 1050 Bruxelles, Belgique. E-mail : nawautho@ulb.ac.be Lung cancer has been the leading fatal cancer in men and women for last decades [1][2] . Currently, non-specific, non-selective cytotoxic chemotherapy is delivered by infusion via the parenteral route and causes significant systemic toxicities to the patient with only a modest increase in survival time [3][4]. Another approach consits to deliver chemotherapeutic drugs to the lung by inhalation in order to maximize local drug concentration and to decrease the systemic toxicities. Recently, we demonstrated the in vivo antitumour activity of temozolomide (TMZ) against a mouse melanoma pulmonary pseudometastatic model by inhalation [5]. In this study, TMZ dry powders formulations for inhalation were produce by means of high pressure homogenizing and spray-drying without and with excipients (lactose, phospholipids and cholesterol), which could influence the aerodynamic and the dissolution characteristics of the powders in the lung. The dry powders for inhalation developed have a high TMZ content, from 70 until 100%. The aerodynamic particle size analysis by multi-stage liquid impinger showed good in vitro fine particle fractions (particles below 5 µm) from 25 until 51%. The crystalline state of TMZ remains unchanged in the dry-powders formulations as revealed by X-ray powder diffraction analysis and the moisture content was lower than 1%; these parameters are both important to ensure the long-term stability of the drug. Differential scanning calorimetry analysis revealed a lower melting point for dry-powders with lactose, which could increase the drug dissolution rate. An optimized in vitro dissolution test was used to discriminate dry powder formulations following their dissolution profile. References [1] A.Jemal, M. J. Thun, L. A. G. Ries, H. L. Howe, H. K. Weir, M. M. Center, E. Ward, X Wu, C. Eheman, R. Anderson, U. A. Ajani, B. Kohler, B. K. Edwards, Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control, JNCI. 100 (2008) 1672-1694 [2] A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, M.J. Thun, Cancer statistics, 2009, CA Cancer J. Clin. 59 (2009) 225-249. [3] S. Sharma, D. White, A.R. Imondi, M.E. Placke, D.M. Vail, M.G. Kris, Development of inhalational agents for oncologic use, J Clin. Oncology. 19 (2001) 1839-1847. [4] H.D.C. Smyth, I. Saleem, M. Donovan, C.F. Verschraegen, Pulmonary delivery of anti-cancer agents, in : R.O. Williams, D.R. Taft, J.T. McConville (Eds.), Advanced drug formulation design to optimize therapeutic outcomes, Informa Healthcare, New-York, 2008, pp. 81-111. [5] N. Wauthoz, P. Deleuze, J. Hecq, I. Roland, S. Saussez, I. Adanja, O. Debeir, C. Decaestecker, V. Mathieu, R. Kiss, K. Amighi, In vivo assessment of temozolomide local delivery for lung cancer inhalation therapy, Eur. J. Pharm. Sci. 29 (2010) 402-411.