Combo in vitro performance (ACI)

IN VITRO PERFORMANCE OF FORMOTEROL AND FLUTICASONE FROM AN INHALATION SOLUTION BY NEBULIZATION AND OTHER INHALATION DELIVERY SYSTEMS Tang Nguyen, Melisa Barron 1 , John Miyawa, and Partha S. Banerjee Dey L.P., Napa, CA, USA 1 current address: Theravance Inc., South San Francisco, CA, USA ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],The ACI method was adopted from USP <601> using apparatus 1 (Graseby Andersen, GA). The ACI was assembled (Fig. 1) with eight stages, induction port and cone. Filter support base was connected to the vacuum line with gauges and digital airflow meter. The airflow was adjusted to within  0.5 L/min of the nominal desired rate by opening or closing the toggle valve located between the two vacuum gauges. A nebulizer mouthpiece adapter was used to couple the nebulizer mouthpiece to the induction port inlet and create an airtight seal. The nebulizer/compressor was assembled according to manufacturer’s instructions. Prototype formoterol inhalation solution, 125  g/2 ml, was compared to 10 doses of the DPI product, Foradil  Aerolizer  , 12  g/dose (Novartis, NJ). Prototype fluticasone inhalation solution, 400  g/3 ml, was compared to Flixotide  suspension for inhalation, 0.5 mg/2 ml and 2 mg/2 ml (Allen & Hanburys, UK) and the MDI product, Flovent  110  g (GlaxoSmithKline, NC). The nebulizer systems used were Pari LC Star  / Proneb  (Pari, VA) jet nebulizer, and Omron MicroAir (Omron, IL) ultrasonic nebulizer for formoterol inhalation solution and Pari LC Plus  /Proneb  for fluticasone inhalation solution and Flixotide  suspension. Effect of temperature on aerodynamic size profile was studied by nebulizing formoterol inhalation solution, stored at 5  C and 25  C, using Pari LC Star  / Proneb  system immediately after the solution was pulled from the chamber. After nebulization to complete aerosolization, the ACI stages and plates and nebulizer were carefully rinsed with defined volume (5 to 20 ml) of solvent and analyzed by validated, stability indicating HPLC method (Table 1). The wash solvents were water for formoterol, and acetonitrile:water (1:1) for fluticasone. ACI vacuum flow rate was set at 28.3 L/min for all except the DPI product, Foradil  , in which case 60 L/min flow rate was used. The particle size of the Flixotide  suspensions was determined by laser diffraction spectrophotometry (Sympatec, NJ). The surface tension of the fluticasone inhalation solution and Flixotide  were measured at 25  C by a tensiometer (KSV instruments, Finland) using the Wilhelmy Plate method. Fig. 1 ACI set up Table 1. HPLC parameters of formoterol and fluticasone ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],ACKNOWLEDGEMENTS: The authors wish to acknowledge and thank Renee Yang, Lan Tran, Rahel Kahsey and Douglas Johnson for their technical support. REFERENCES: 1. Task Group on Lung Dynamics. Deposition and retention models for internal dosimetry of the human respiratory tract. Health Physics 1966; 12:173-208. 2. JG Hardy, SP Newman and M. Knoch. Lung deposition from four nebulizers. Respiratory Medicine 1993: 87; 461-465. 3. AR Clark. The use of laser diffraction for the evaluation of the aerosol clouds generated by medical nebulizers. Int J Pharm 1995; 115: 69-78. 4. T Fok, M Al-essa, S Monkman, et al. Pulmonary deposition of salbutamol aerosol delivered by metered dose inhaler, jet nebulizer and ultrasonic nebulizer in mechanically ventilated rabbits. Pediatr Res 1997; 42: 7210727. 5. U.S. Department of Health and Human Services. Guidance for Industry: Nasal spray and inhalation solution, suspension, and spray drug products – chemistry, manufacturing, and controls documentation. July 2002. Available from URL: http://www. fda . gov / cder /guidance/index. htm 6. WH Finlay and KW Stapleton. Undersizing of droplets from a vented nebulizer caused by aerosol heating during transit through an anderson impactor. J Aerosol Sci 1999; 30: 105-109. 7. MB Dolovich. Assessing nebulizer performance. Respiratory Care 2002; 47: 1290-1301. 8. RA Lewis and JS Fleming. Fractional deposition from a jet nebulizer: how it differs from a metered dose inhaler. Br J Dis Chest 1985; 79: 361-367. 9. BMZ Zainudin, M Biddiscombe et al. Comparison of bronchodilator responses and deposition patterns of salbutamol inhaled from a pressurized metered dose inhaler, as a dry powder, and as a nebulized solution. Thorax 1990; 45: 469-473. 10. TG O’Riordan. Formulations and nebulizer performance. Respiratory Care 2002; 47: 1305-1312. 11. PW Barry, and C O’Callaghan. An in vitro analysis of the output of budesonide from different nebulizers. J Allergy Clin Immunol 1999:104: 1168-1173. Correspondence : partha .banerjee@ dey .com Ultrasonic Nebulization System ACI House Vacuum Hose INTRODUCTION METHODS RESULTS Fig. 2..In vitro deposition profile (Anderson Cascade Impaction) of formoterol using PARI LC Star Jet Nebulizer Fig. 3. In vitro deposition (Anderson Cascade Impaction) profile of formoterol at 25C Fig. 5. In vitro deposition (Andersen Cascade Impaction) profile of Fluticasone by nebulization and MDI (@28.3 LPM) [First Study] [n = 3] Fig. 4. In vitro deposition profile of formoterol by nebulization (@ 28.3 LPM) vs DPI (@ 60 LPM) Table 2. Effect of temperature and type of nebulizer on comparative in vitro deposition (Andersen Cascade Impaction) profile of formoterol. Table 3. Comparative in vitro deposition (Andersen Cascade Impaction) data on formoterol by nebulization vs. DPI. Table 4. Comparative in vitro deposition (Andersen Cascade Impaction) data on fluticasone by nebulization (solution vs. suspension) and MDI product. Fig. 6. In vitro deposition (Andersen Cascade Impaction) profile of fluticasone by nebulization vs. MDI (@ 28.3 LPM) [Second Study] [n = 3] DISCUSSION DISCUSSION The total percent recovery for samples was within the range recommended in recent FDA guidance. 5 . The critical parameter of the comparative analysis was the amount of the respirable dose/fraction recovered from stages 2 to 5 of the ACI, which corresponded to particle sizes ranging from 1.1 µm to 5.8 µm at 28.3 L/min, and stages 1 to 4 corresponding to 1.1 µm to 6.5  m at 60 L/min flow rate. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were determined for all based on log probability of cumulative percentile distribution. Effect of temperature During jet nebulizer operation, solvent evaporation decreases the solution temperature and this has been suggested to cause undersizing of the particle size. 6,7 The nebulizer performance can also change due to the temperature dependency of the solution properties. The in vitro impactor deposition data (Fig. 2, Table 2), however, shows that respirable doses at 5  C and 25  C were not significantly different although higher temperature tends to increase the respirable dose. The increasing trend in respirable dose at higher temperature is not consistent with the temperature related undersizing theory. Fig. 7. In vitro deposition (Andersen Cascade Impaction @ 28.3 LPM) profile of fluticasone by nebulization: solution vs. suspension [Second Study] [n = 3] CONCLUSIONS ------- Vacuum Gauge 2 Vacuum Gauge 1 Air Jet Nebulization System Nebulizer Mouthpiece Adapter Toggle Valve

Combo in vitro performance (ACI)

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Combo in vitro performance (ACI)