Is) are presently being evaluated as to whether they could be used as a treatmentfor PH.6 Imatinib has been investigated in several studies to determine if it is effective against PH.71 Moreover, other agents, such erlotinib and gefitinib, which have been used effectively in the treatment of lung cancer, could be also considered for PH.6,12,13 However, orally administered TKIs have serious side effects, which has generated a quest for alternative routes of administration, such as inhalation.14 In this work, we investigated whether erlotinib, gefitinib, and imatinib could be modified for aerosol administration using jet and ultrasound nebulizers. We also sought to determine the best combination of residual cup design, residual cup loading, and nebulizer, for producing droplets less than 5 m in size.Materials and methods DrugsErlotinib (150 mg tablets; Tarceva ; Roche, Basel, Switzerland), gefitinib (250 mg tablets; Iressa AstraZeneca, London, UK), and imatinib (400 mg tablets; Glivec Novartis, Basel, Switzerland) were sourced from our oncology department.aerosol production systemsJet nebulizers and residual cupsThree jet nebulizers, ie, Maxineb(Flexicare Medical Ltd., Mountain Ash, UK; 6 L per minute and 35 psi); Sunmist(Nursing Hygiene, Southwater, UK; 5 L per minute and 35 psi); and Invacare(Invacare Corporation, Elyria, OH, USA; 4 L per minute and 36 psi) were chosen for the experiment (Figure 1). We opted to use seven residual cups, of which four had a capacity of no more than 6 mL and two had a capacity of no more than 10 mL. The large cups were designated using the letters A, D, and E, and the small residual cups were designated C, F, B, and G (Figures 2 and 3). Large residual cups with a capacity of 2 mL were used. The residual cup loadings were 2, 4, 6, and 8 mL (8 mL only for the large cups).Ultrasound nebulizersThree ultrasound nebulizers were selected. The first was the NE-U07 (Omron, Tokyo, Japan), which is compact and weighs less than 350 g, includes a 10 mL medication cup, and generates uniform micrometer-sized vapor particles. The second was a portable Gima device (Gima SpA, Gessate, Italy). The third was a portable EASYnebII (Flaem Nuova, Martino, Italy). The loadings were 2 mL and 4 mL, since this is the amount held by the residual cup for each of the three ultrasound nebulizers.submit your manuscript | www.dovepressDrug Design, Development and Therapy 2014:DovepressDovepressinhaled TKis for pulmonary hypertensionFigure 1 Ultrasound nebulizers (upper row) and jet nebulizers (lower row).Figure 2 large residual cups.Drug Design, Development and Therapy 2014:submit your manuscript | www.Levomepromazine dovepressDovepressPitsiou et alDovepressFigure 3 small residual cups.Droplet measurementThe size distribution of the droplets and their mean diameter (d32) were calculated using a Mastersizer 2000 (Malvern Instruments Ltd.Artemether , Malvern, UK) equipped with a Scirocco module (Malvern).PMID:24818938 A refractive index of 1.33 was used for the sprayed droplets. Several experiments were performed repeatedly until optimal measurements were obtained, as in our previously reported experiments159 (Figure 4).MillingThe erlotinib and imatinib tablets were milled in a planetary ball mill (Pulverisette-5; Frisch GmbH, M chen, Germany) equipped with agate bowls (500 mL) and eight balls (20 mm, 20 g) with a rotational speed of approximately 200 rpm, resulting in an acceleration of about 7.5 g. We initiated our milling at 60 minutes for erlotinib and at 80 minutes for imatin.