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Temozolomide by inhalation for the treatment of lung tumors : Preclinical investigation and development of dry powder formulations for inhalation

par Wauthoz, Nathalie
Référence Forum des sciences pharmaceutiques de la société belge des sciences pharmaceutiques (15ème: 13 et 14/05/2011: Spa)
Publication Non publié, 2011-05-13

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Résumé :

Lung cancer has been the leading fatal cancer in men and women for last decades [1][2] . Currently, non-specific and 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, the efficacy of local drug delivery by inhalation to intravenous delivery was made with temozolomide (TMZ) in a mouse B16F10 melanoma pulmonary pseudometastatic model [5]. The mode of delivery was optimized for the uniformity of delivered dose, the droplet size distribution and the distribution of droplets in the lungs [5]. In the present 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. An optimized in vitro dissolution test for inhaler products was used to evaluate the dissolution profiles of the different formulations which are similarly fast [6]. These dry powder formulations, based on the use of acceptable excipients for inhalation and showing good dispersion and dissolution properties, represent an attractive alternative for use in local lung cancer therapy. [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] Jemal A., Siegel R., Xu J., Ward E., Cancer Statistics, 2010. CA Cancer J Clin 2010; 60:277-300. [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. [6] N. Wauthoz, P. Deleuze, A. Saumet, C. Duret, R. Kiss, K. Amighi, Temozolomide-based dry powder formulations for lung tumor-related inhalation treatment, Pharm. Res. (2010) DOI 10.1007/s 1095-010-0329-x.