Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M Taper DPI

Transcription

1 3M Drug Delivery Systems Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M Taper DPI Poster Reprint / Spring 2011 John Simons 1, Herbert Chiou 1, Louis Sigtermans 1, Tom Robison 1, Debra Wright 1, Jacqueline Ganser 1, Steve Stein 1, Les Harrison 1, Paul Ratner 2 1 3M Drug Delivery Systems, St. Paul, MN 2 Sylvana Research, San Antonio TX 3

2 Introduction Introduction In a previous paper, 3M s Taper dry powder inhaler (DPI) design and performance were described (1). This poster builds on that foundation and characterizes the uniformity of excipient-free fluticasone propionate(fp)/salmeterol xinafoate (SX) blends, the uniformity of the coated powder blends, and the performance of a FP/SX 3M Taper DPI. The in vitro results from a FP/SX 3M Taper DPI product are also compared with the 250/50 strength Advair Diskus * product. Table of Contents Methods...1 Blend/Coating Results...2 Performance Resutls...3 Future Work...5 Conclusions...5 References

3 Methods Methods Blending, Blend Uniformity Sampling: The blends were generated using a proprietary 3M process. Post processing samples were taken using customized sample thieves to collect μg of sample. Samples were taken from 20 locations throughout the blend. With regard to SX results, all numbers are reported as salmeterol base (SB) in accordance with how Advair product is labeled. Coating Process, Microstructured Carrier Tape (MCT): An asynchronous roller coating method (1) was used to fill the dimples in the MCT which is the primary packaging component of the Taper DPI device. Based on preliminary studies that were designed to estimate the delivered and fine particle doses of FP/SX blends with Taper, new MCT were manufactured (230 μg/dose [FP+SX] load capacity) to match the fine particle dose of the 250/50 Advair product. Next Generation Impactor (NGI): To measure the particle size distribution of the emitted doses from both the Taper and Advair products, NGIs were operated at 85 LPM (4 KPa pressure drop). Cups were coated to prevent particle bounce. Spring 2011 Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M Taper DPI 1

4 Blend/Coating Results Blend/Coating Results Blend Results: Table 1 shows the blend uniformity results obtained from a typical FP/SX blend (target blend ratio 6.3:1). Even when sampling a very small amount of the blend (~20-25 μg) relative to the size of the intended dose (~230 μg), a RSD of less than 2% was achieved. The results clearly demonstrate the capability of the blending process to mix excipient-free blends of micronized powders. In this particular example, the batch size was 80 g. Table 1: Blend uniformity of a typical FP/SX blend (n=20, sample size μg). Sample FP SB Ratio Ave :1 SD 0.1 RSD 1.7% Retention of Blend Uniformity: As with any blend there is the potential for segregation to occur if not properly handled or stored post processing. Because the powder feeding and coating processes for the Taper device impart some energy into the blends, it is necessary to demonstrate that the blends will remain unchanged or are changed in a predictable, reproducible manner. Table 2 lists the results of coating four separate blends on four separate days using the coating process described above. Blend 4 in Table 2 is the same blend referenced in Table 1. Table 2: Uniformity of coated microstructured carrier tape (MCT) with four FP/SX blends (n=36, 27, 72, 10) on four different days. Blend/Run 1 Blend/Run 2 Blend/Run 3 Blend/Run 4 Sample FP SB Ratio FP SB Ratio FP SB Ratio FP SB Ratio Ave : : : :1 SD RSD 2.8% 3.0% 1.3% 2.3% 2.3% 0.7% 3.3% 2.9% 1.7% Based on the content results, the powder coating method provides very good reproducibility for coating excipient-free FP/SX blends (within as well as across coating runs). There was also no significant change in the blend ratio due to coating, thus indicating that the powder feeding and coating processes used for Taper are compatible with the blends and will not cause them to segregate under normal processing conditions. Because of the cohesive nature of micronized powders and the similar particle size distributions (PSD) and densities of most relevant APIs considered for inhalation, the Taper coating process is expected to work well for a wide range of excipient-free API blends. Spring 2011 Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M Taper DPI 2

5 Product Performance Results Product Performance Results Product Performance: The NGI results of the FP/SX Taper product were compared with the 250/50 strength Advair product in Tables 3/4 and Figure 1. As intended, the fine particle masses (FPM) are well matched. Also as expected, the greatest differences in the data sets are the delivered doses from each device and the amount of FP/SX collected on the throat and pre-separator of the NGI. Table 3: Comparison of Taper and Advair Diskus in vitro data Fluticasone Propionate Salmeterol Base Delivered FPM < 5 µm MMAD Delivered FPM < 5 µm MMAD Dose, µg µg % µm Dose, µg µg % µm Taper Advair Figure 1: Comparison of NGI profiles for 3M Taper and Advair Diskus devices Drug Deposition (mcg) Fluticasone Propionate Particle Size Distribution by NGI Drug Depostion (mcg) Taper 6:1 Advair Diskus 250/50 Expanded View Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 0 T + PS Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC Salmeterol Base Particle Size Distribution by NGI Drug Deposition (mcg) Drug Depositon (mcg) Taper 6:1 Advair Diskus 250/50 Expanded View Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 0 T + PS Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC Spring 2011 Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M Taper DPI 3

6 Product Performance Results Cont. Product Performance Results Cont. Table 4. Average FP/SB NGI cup deposition for Advair and Taper (n = 5, μg) and normalized amount of FP/SB deposited from Taper device relative to Advair; (T/Adv%) = [Taper / Advair * 100] T+PS Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC FP Advair Taper T/Adv% 46% 77% 105% 96% 88% 91% 85% SB Advair Taper T/Adv% 29% 70% 89% 100% 96% 81% 0% As the data show, the 3M Taper device can be used to match a specified respirable dose target very accurately. As designed, the 3M Taper device is more efficient than the Advair Diskus product. As a result, less FP/SX needs to be loaded to deliver a set amount of drug and less drug is delivered from the device. In this specific example, only ~186 μg/dose for FP (~75% of Advair) and ~31 μg/dose of SB (~60% of Advair) are required to deliver the same respirable masses of FP and SB. Overall, there is good agreement between the Advair and FP/SX Taper products with regard to the amount of FP/SB collected on cups 1 to MOC. Although Advair begins with a 5:1 loading ratio for FP/SB (250 μg /50 μg), the respirable mass ratio for FP/SB is 6:1 (48 μg /8 μg). Since Taper maintains the same loaded and delivered ratios of FP/SB, it was necessary to start with a 6:1 (186 μg /31 μg) blend in order to match the 6:1 respirable mass ratio (47.9 μg /7.9 μg) of the Advair product. Spring 2011 Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M Taper DPI 4

7 Future Work Future Work Based on the results of this work, a clinical protocol has been written to explore the capability of the 3M Taper DPI to deliver a combination therapy to mild/moderate asthmatic patients with demonstrated reversibility. Per the protocol, sixteen subjects will receive two treatments separated by 7-16 days, according to a randomized, two-period crossover design: The reference treatment will be one inhalation from an Advair Diskus product (250/50 strength); the test treatment will be one inhalation from the 3M Taper device which contains approximately the same fine particle mass of each drug per dose. Pulmonary function and pharmacokinetics will be followed over 12.5 hr. Production of clinical supplies has been completed. Conclusions Conclusions As demonstrated by the results presented, 3M s Taper technology is capable of handling excipient-free powder blends and can be customized to match specific dosing targets. In comparing the performance of a FP/SX Taper product to Advair, there is a clear advantage of improved delivery efficiency which corresponds to less drug being required to deliver a target amount of drug to a patient s lungs. References References 1. Stein, S., Hodson, D., Alband, T., Sitz, R., Robison, T., Wang, Z. Chiou, H., Simons, J., McNally, R., and Ganser, J. (2010) The 3MTM Taper Dry Powder Inhaler Device, Bryon, P.R., Byron, P.R., Peart, J., Suman, J.D., Farr, S.J., Young, P.M., (eds), Respiratory Drug Delivery 2010, Vol 2, pp Spring 2011 Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M Taper DPI 5

8 Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems Drug Delivery Systems 3M Center, building E-10 St. Paul, MN USA FAX M.com/MTSDelivery 3M House, Morley Street, Loughborough, Leicestershire, LE11 1EP England +44 (0) FAX +44 (0) M.com/MTSDelivery 33-1, Tamagawadai 2-chrome Setagaya-ku, Tokyo Japan (81) FAX (81) M.com/MTSDelivery 3M Innovation Singapore Pte Ltd 1 Yishun Avenue 7 Singapore (65) FAX (65) M.com/MTSDelivery 3M All rights reserved. 3M is a trademark of 3M Company. Advair Diskus is a registered trademark of GlaxoSmithKline.