Performance of a Fluticasone Propionate/Salmeterol ... - 3M Company

3M Drug Delivery Systems

Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M™ Taper DPI Poster Reprint / Spring 2011

John Simons1, Herbert Chiou1, Louis Sigtermans1, Tom Robison1, Debra Wright1, Jacqueline Ganser1, Steve Stein1, Les Harrison1, Paul Ratner2 1 3M Drug Delivery Systems, St. Paul, MN 2Sylvana Research, San Antonio TX

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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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

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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 20-25 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

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Drug Deposition (mc Drug Deposition (m

LPM (4 KPa pressure drop). Cups were coated to prevent particle bounce. LPM (4 KPa pressure drop). Cups were coated to prevent particle bounce.

Blend/Coating Results

8

6

4

2

Blend Results: Table 1 shows the blend uniformity results obtained from a typical FP/SX blend (target blend

Blend Results: Table 1 shows the blend uniformity results obtained from a typical 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 the blend µg)ofrelative thewas sizeachieved. of the intended dose (~230demonstrate µg), a RSDthe of capability intended dose (~230(~20-25 μg), a RSD less thanto2% The results clearly less than 2% was achieved. The results clearly demonstrate the capability of the less than 2% was achieved. The results clearly demonstrate the capability of the of the blending process to mixtoexcipient-free blendsblends of micronized powders. In this particular blending process mix excipient-free of micronized powders. In this example, the blending process to mix excipient-free blends of micronized powders. In this particular example, the batch size was 80 g. batch sizeparticular was 80 g. example, the batch size was 80 g. ratio 6.3:1).FP/SX Even when a veryratio small6.3:1). amount of the blend (~20-25aμg) relative the sizeofof the blendsampling (target blend Even when sampling very smalltoamount

Drug Deposition (mcg) Drug Deposition (mcg)

Blend/Coating Results

Blend/Coating Results Results Blend/Coating

1 12 1 10

Table 1: Blend uniformity of a typical FP/SX blend (n=20, sample size 20-25 µg).

Tableuniformity 1: Blendofuniformity of a typical FP/SXsample blend (n=20, sample Table 1: Blend a typical FP/SX blend (n=20, size 20-25 μg). size 20-25 µg). Sample FP SB Sample FP SB Ave 16.8 2.7 Ave 16.8 2.7 SD SD RSD RSD

Ratio Ratio 6.3:1 6.3:1 0.1 0.1 1.7% 1.7%

Figure 1: Comp Figure 1: Comp

Retention of Blend Uniformity: As with any blend there is the potential for segregation to occur if not properly

Retention of Blend Uniformity: As with any blend there is the potential for of processing. Blend Uniformity: Asthewith any blend there is the potential forfor the Taper device handled orRetention stored post Because powder andpost coating processes segregation to occur if not properly handledfeeding or stored processing. Because the 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 impart some energy into theand blends, it is processes necessary to that theimpart blendssome will remain powder feeding coating fordemonstrate the Taper device energyunchanged or into the blends, it is necessary to demonstrate that the blends will remain intointhe blends, it isreproducible necessary to demonstrate thatthe theresults blendsofwill remain are changed a predictable, Table 2reproducible lists coating four2 separate unchanged or are changed in amanner. predictable, manner. Table lists the blends on unchanged or are changed in a predictable, reproducible manner. Table 2 lists the results ofusing coating four separate blends on four separate days using the coating four separate daysof the four coating processblends described above. Blend 4days in Table 2 isthe thecoating same blend referenced results coating separate on four separate using process described above. Blend 4 in Table 2 is the same blend referenced in Table in Table 1.process described above. Blend 4 in Table 2 is the same blend referenced in Table 1. 1.

Table 4. Avera Table 4. Avera (n = 5, µg) and (n = 5, µg) and relative to Adva relative to Adva

T+PS T+PS

FP FP Advair 159.5 Advair 159.5 Taper 72.8 Taper 72.8 T/Adv% 46% T/Adv% 46% SB SB Advair 35.5 Advair 35.5 Taper 10.2 Taper 10.2 T/Adv% 29% T/Adv% 29%

Table 2: Uniformity of coated microstructured carrier four FP/SX Table 2: Uniformity coated microstructured carrier tape (MCT) withtape four(MCT) FP/SX with blends (n=36, 27, 72, 10) on Table 2: ofUniformity of coated microstructured carrier tape (MCT) with four FP/SX blends four different days.(n=36, 27, 72, 10) on four different days. blends (n=36, 27, 72, 10) on four different days.

Blend/Run 1 Blend/Run 1 Sample FP SB Sample FP SB Ave 186.1 30.4 Ave 186.1 30.4 SD 5.2 0.9 SD 5.2 0.9 RSD 2.8% 3.0% RSD 2.8% 3.0%

Ratio Ratio 6.1:1 6.1:1 0.1 0.1 1.3% 1.3%

Blend/Run 2 Blend/Run 2 FP SB FP SB 191.1 31.9 191.1 31.9 4.3 0.7 4.3 0.7 2.3% 2.3% 2.3% 2.3%

Ratio Ratio 6.0:1 6.0:1 0.04 0.04 0.7% 0.7%

Blend/Run 3 Blend/Run 3 FP SB FP SB 186.2 30.7 186.2 30.7 6.2 0.9 6.2 0.9 3.3% 2.9% 3.3% 2.9%

Ratio Ratio 6.1:1 6.1:1 0.1 0.1 1.7% 1.7%

Blend/Run 4 Blend/Run 4 FP SB Ratio FP SB Ratio 182.8 29.4 6.2:1 182.8 29.4 6.2:1 3.4 0.8 0.1 3.4 0.8 0.1 1.8 2.7 2.0 1.8 2.7 2.0

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.



4 4 4 4 3 3 3 3 2 2 2 2 1 1 1 1

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is good agreem ~186 µg/dose fo ~186 µg/dose the amounttooffod are required are5:1 required toratd loading is agreeme is good good agreeme 6:1 (48 µgof/8FPµ the amount theFP/SB, amountit was of FP 5:1 loading ratio 5:1match loading the/8ratio 6:1 6:1 (48 µg 6:1 (48 µg /8 µg µg FP/SB, it was FP/SB, it was ne ne match match the the 6:1 6:1 re re

Product Performance Results

Product Performance Results Product Performance Results

Product Performance Results Product Performance: NGI results of the FP/SX Taperofproduct wereTaper compared withwere the 250/50 strength Product The Performance: The NGI results the FP/SX product withand theFigure 250/50 Advair product in Tables andare Figure As Advair productcompared in Tables 3/4 1. strength As intended, the fine particle masses3/4 (FPM) well 1. matched. intended, the fine particle masses (FPM) well matched. Also as expected, Product Performance: The NGI results of theareFP/SX Taper product were compared with the 250/50 Advair in Tables 3/4 and compared withthe theamount 250/50ofstrength strength Advair product product inthroat Tables 3/4pre-separator and Figure Figure 1. 1.ofAs As device and FP/SX collected on the and the amount of FP/SX collected on the throat and pre-separator of the NGI. intended, the fine particle masses (FPM) are well matched. Also as expected, intended, the fine particle masses (FPM) are well matched. Also as expected, NGI. the the greatest greatest differences differences in in the the data data sets sets are are the the delivered delivered doses doses from from each each device and the amount of FP/SX collected on the throat and pre-separator device the amount ofofFP/SX collected on the throat and pre-separator of of the the Tableand 3:of Taper Comparison Advair Table 3: Comparison and AdvairTaper Diskusand in vitro dataDiskus in vitro data NGI. NGI.

Product TheinNGI results ofsets the FP/SX Taper product wereeach Also as expected, thePerformance: greatest differences in the data thedelivered delivered doses from from the greatest differences the data sets areare the doses eachdevice and the

Fluticasone Propionate

Based on the the capability mild/moderate Based on re Based on the the re protocol, sixte the capability of theaccording capabilitytoofa mild/moderate aa mild/moderate will be one inh protocol, sixteen protocol, sixteen treatment will according to aa rr according to approximately will be one inha willfunction be one and inhap treatment will be treatment will be supplies has approximately approximately th th function and ph function and ph supplies supplies has has be be

Salmeterol Base

Table Comparison of and Diskus Table 3: 3:Delivered ComparisonFPM of Taper Taper and Advair Advair Diskus in in vitro vitro data data FPM < 5 µm MMAD Delivered < 5 µm

MMAD µm

Dose,Fluticasone µg µm Dose, µgSalmeterol % % µg Propionate µg Base Fluticasone Propionate Salmeterol Base Taper Delivered 128.9 47.9< 5 µm37.1 MMAD 2.97 Delivered 19.6 7.9 < 5 µm40.0 MMAD 2.92 FPM FPM Delivered MMAD Delivered MMAD FPM < 5 µm FPM < 5 µm Advair Dose,224 48.0 3.12 Dose,46.7 3.36 µg µm µg µm %21.4 %17.0 µg µg8.0 Dose, µg µm Dose, µg µm % % µg µg Taper 128.9 47.9 37.1 2.97 19.6 7.9 40.0 2.92 Taper 128.9 47.9 37.1 2.97 19.6 40.0 2.92 Fluticasone Propionate Particle Size Distribution7.9 by NGI Advair 224 48.0 21.4 3.12 46.7 8.0 17.0 3.36 Advair 224 1: Comparison 48.0 3.12 46.7 and Advair 8.0 17.0 3.36 Figure of21.4 NGI profiles for6:1 3M Taper ® 250/50Diskus devices Taper Advair Diskus 180

20 Fluticasone Propionate Particle Size Distribution by NGI 160

d from a typical y small amount of 30 µg), a RSD of from from aa typical typical capability of the mall amount of mall amount of ers. In this µg), a RSD µg), a RSD of of pability of the pability of the s. In s.size In this this 20-25 µg).

Drug Drug Depostion Depostion (mcg) (mcg)

45

35 30 25 20 15

Drug Drug Depositon Depositon (mcg) (mcg)

Drug DrugDeposition Deposition(mcg) (mcg) Drug Deposition (mcg)

45 45 40 40 35 35 30 30 25 25

Taper 6:1

As demonstr handling exc dosing target As demonstrate AsAdvair, demonstrate there handling excipi handling excipi corresponds dosing targets. dosing targets. patient’s lung Advair, Advair, there there is is corresponds to corresponds to patient’s patient’s lungs. lungs.

Advair Diskus® 250/50

Salmeterol Base Particle Size Distribution by NGI 4 Salmeterol Base Particle Size Distribution by NGI Drug Depositon (mcg)

40

ze ze 20-25 20-25 µg). µg).

ntial for sing. Because the t some energy al for alremain for g. Because the g.Table Because the 2 lists the ome energy ome energy g the coating main main ferenced in11060735 TablePerformance Taper.indd able able 22 lists lists the the

Drug Depostion (mcg)

Fluticasone Propionate Particle Size Distribution by NGI Expanded View

15 140 Taper 6:1 Advair Diskus ® 250/50 180 Taper 6:1 Advair Diskus ® 250/50 180 120 20 10 160 20 Expanded View 160 100 Expanded View 15 5 140 15 140 80 10 0 120 10 Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 120 60 100 5 100 5 40 80 0 80 0 20 Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 60 Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 60 0 40 T + PS Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 40 20 20 0 0 T + PS Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC Base Particle Size Distribution NGI7 MOC T + PSSalmeterol Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 byCup

Drug DrugDeposition Deposition(mcg) (mcg) Drug Deposition (mcg)

Product Performance Results

sing a customized from ng aa 20 ng rs are reported stomized stomized belled. m m 20 20 are are reported nousreported roller lled. lled.primary he y studies that ous roller ous roller P/SX blends primary primary d capacity) to studies studies that that SX SX blends blends capacity) to ution of the capacity) to operated at 85 ounce. ion ion of of the the erated erated at at 85 85 nce. nce.

normal conditions. of theAPI cohesive of micronized work processing well forthea similar wide range of Because excipient-free blends.nature powders and particle size distributions (PSD) and densities powders and the similar particle size distributions (PSD) and densities of of most most relevant APIs considered for inhalation, the Taper coating process is expected relevant APIs considered for inhalation, the Taper coating process is expected to to work work well well for for aa wide wide range range of of excipient-free excipient-free API API blends. blends.

3

4 4

2

3 3

1

2 2

0

Taper 6:1 Taper 6:1

1.

® 250/50 Advair Diskus Expanded View Advair Diskus® 250/50

1. 1.

Expanded View Expanded View Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC

1 1

20 10 0 20 0 Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 15 5 Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 15 10 0 10 T + PS Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC 5 5 0 0 T + PS Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC T + PS Cup 1 Cup 2 Cup 3 Cup 4 Cup 5 Cup 6 Cup 7 MOC

* Advair Disku

Figure 1: Comparison of NGI profiles for 3M Taper and Advair Diskus devices

3

Table1:4.Comparison Average FP/SB NGI cup deposition for Advair and Taper Figure of NGI profiles for 3M Taper and Advair Diskus devices Figure 1: Comparison of NGI profiles for 3M Taper and Advair Diskus devices Spring 2011 | Performance of a Fluticasone Propionate/Salmeterol Xinafoate 3M device Taper DPI (n = 5, µg) and normalized amount of FP/SB deposited from Taper relativeAverage to Advair; (T/Adv%) = [Taper / Advair * 100] and Taper Table Table 4. 4. Average FP/SB FP/SB NGI NGI cup cup deposition deposition for for Advair Advair and Taper (n = 5, µg) and normalized amount of FP/SB deposited from Taper device (n = 5, µg) and normalized FP/SB from T+PS Cup 1 amount Cup 2 ofCup 3 deposited Cup 4 Cup 5 Taper Cup 6device Cup 7 MOC relative to Advair; (T/Adv%) == [Taper // Advair ** 100] relative to Advair; (T/Adv%) [Taper Advair 100] FP

Stein, H., Sim Powde Stein, S. Stein, S.S Farr, H., Simo H.,377-38 Simo Powder Powder II Farr, Farr, S.J S.J 377-380. 377-380.

* Advair Diskus® * Advair Diskus® 3

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Dr

5 0 T + PS Cup 1

Cup 2

Cup 3

Cup 4

Cup 5

Cup 6

Cup 7

* Advair Disku

MOC

Product Performance Results Cont.

Figure 1: Comparison of NGI profiles for 3M Taper and Advair Diskus devices

Product Performance Results Cont.

ntial for sing. Because the t some energy remain Table 2 lists the g the coating ferenced in Table

Table 4. Average FP/SB NGI cup deposition for Advair and Taper

(n =FP/SB 5, µg) amount FP/SB Taper device Table 4. Average NGIand cupnormalized deposition for Advairofand Taperdeposited (n = 5, μg)from and normalized amount of FP/SB relative to Advair; (T/Adv%) = [Taper / Advair * 100] deposited from Taper device relative to Advair; (T/Adv%) = [Taper / Advair * 100]

SB

Ratio

:1 182.8

29.4

6.2:1

1

3.4

0.8

0.1

%

1.8

2.7

2.0

Cup 1

Cup 2

Cup 3

Cup 4

Cup 5

Cup 6

Cup 7

MOC

Advair

159.5

7.5

15.9

18.6

17.0

4.7

0.8

0.0

0.0

Taper

72.8

5.8

16.7

17.8

14.9

4.2

0.7

0.1

0.1

T/Adv%

46%

77%

105%

96%

88%

91%

85%

--

--

Advair

35.5

1.7

2.9

3.1

2.8

0.7

0.0

0.0

0.0

Taper

10.2

1.2

2.6

3.1

2.7

0.6

0.0

0.0

0.0

T/Adv%

29%

70%

89%

100%

96%

81%

0%

--

--

SB

Blend/Run 4 FP

T+PS FP

with four FP/SX

io

377-38

10

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.



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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. 377-380.



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