Formulations

Abstract

In a metered dose inhaler, comprising a canister and metering valve, containing a suspension aerosol formulation comprising particles of formoterol fumarate dihydrate and fluticasone propionate suspended in an HFA propellant, a method of reducing deposition of particles on the surfaces of the canister and the metering valve, the method comprising the step of adding a wetting agent to the formulation.

Claims

1-46. (canceled)

47. A method of reducing the deposition of drug particles of a suspension aerosol formulation on the surfaces of a canister and metering valve of a metered dose inhaler, the method comprising incorporating ethanol in an amount of less than 2% by weight based on the total weight of the formulation, the formulation comprising particles of formoterol fumarate dihydrate and fluticasone propionate suspended in an HFA propellant, said particles having a mean aerodynamic particle diameter of from 1 to 6 microns.

48. A method according to claim 47 wherein the ethanol is employed in an amount of 1.99 to 0.01% by weight based on the total weight of the suspension aerosol formulation.

49. A method according to claim 47 wherein the ethanol is employed in an amount of 1.5% to 1.0% by weight based on the total weight of the suspension aerosol formulation.

50. A method according to claim 47 wherein the HFA propellant is HFA 227.

51. A method according to claim 47 wherein the formoterol fumarate dihydrate is employed in an amount of 0.003-0.04% by weight.

52. A method according to claim 47 wherein fluticasone propionate is employed in an amount of 0.01-0.6% by weight.

53. A method according to claim 47 wherein the suspension aerosol formulation comprises a salt selected from the group consisting of nedocromil and cromoglycic acid.

54. A method according to claim 53 wherein the salt is sodium cromoglycate (DSCG).

55. A method according to claim 53 wherein the sodium cromoglycate is employed in an amount of 0.01-0.1% by weight based on the total weight of the formulation.

56. The method of claim 47, wherein the canister after filling and being stored for at least two weeks at a temperature of about 17 to about 25 degrees centigrade and a relative humidity of about 29 to 63% contains a residue of formoterol fumarate dehydrate, wherein said formoterol fumarate dehydrate is not more than about 12% based on the amount of formoterol fumarate dihydrate filled into the canister.

57. The method of claim 47, wherein the canister after filling and being stored for at least two weeks at a temperature of about 17 to about 25 degrees centigrade and a relative humidity of about 29 to 63% contains a residue of fluticasone propionate, wherein said fluticasone propionate is not more than about 12% based on the amount of fluticasone propionate filled into the canister.

Description

EXAMPLE 1

[0085] The following compositions shown below in Table 3 were prepared.

TABLE-US-00003 TABLE 3 Compositions of pharmaceutical formulations. Flutiform Flutiform Flutiform Flutiform Flutiform 25/5 50/5 125/5 250/5 250/10 Nominal 50 mcg FP and 100 mcg FP and 250 mcg FP and 500 mcg FP and 500 mcg FP and dose 10 mcg FF 10 mcg FF 10 mcg FF 10 mcg FF 20 mcg FF Fluticasone 0.0357 0.0714 0.1785 0.3570 0.3570 Formoterol 0.0071 0.0071 0.0071 0.0071 0.0142 Cromolyn 0.0343 0.0343 0.0343 0.0343 0.0343 sodium Ethanol 1.43  1.43  1.43  1.43  1.43  HFA 227 qs ad 100.0 qs ad 100.0 qs ad 100.0 qs ad 100.0 qs ad 100.0

[0086] The appropriate amounts of the micronised active substances were weighed and transferred into the batching vessel. The appropriate amount of micronised sodium cromolyn, (DSCG) was added and the vessel closed. The propellant mixture of HFA 227 (apaflurane) with 1.43% alcohol was made in a separate vessel and transferred into the batching vessel. The solid materials were dispersed in the liquefied propellant by use of a rotor-stator homogenizer at 2900 rpm for 30 min. The homogeneous bulk suspension was cooled to 4° C. and re-circulated between the vessel and the Pamasol aerosol filling machine P2001.

[0087] Pharmaceutical aerosol canisters with 14 ml brim full volume were crimped with 50 mcl metering valves using a Pamasol P2005 crimping machine. Aliquots of 11 g suspension were filled into the crimped canisters by the P2001 filling machine. The weight of each filled canister was checked; all filled canisters were subjected to a heat stress test at about 50 to 60° C. and stored one month prior to assembly with an actuator for testing.

EXAMPLE 2

[0088] The Flutiform 50/5 composition shown in Table 2 above, was tested against a comparator product identical to the 50/5 formulation but for the ethanol being removed from the comparator product.

[0089] MDI canisters filled with these compositions were tested for assay of both drugs in the canister, dose uniformity through inhaler life up to the last nominal dose, aerodynamic particle size distribution of the aerosol medication by Andersen Cascade Impactor, and for drug deposition on the internal surfaces of the canister and valve (CCS).

[0090] The results are shown in Table 3:

TABLE-US-00004 TABLE 3 Effect of Ethanol on dose uniformity and Aerodynamic Particle Size Distribution (APSD). Results at initial. Flutiform 50/5 Comparator Total drug content per container FP assay % of target (RSD[%}); n = 3 95.1 (0.4) 95.4 (1.0) FF assay % of target (RSD[%}); n = 3 95.5 (0.4) 100.8 (1.1) dose uniformity through container life (intra inhaler) Mean FP dose μg/actuation (RSD[%]); n = 9 45 (8.0) 31 (13.7) Mean FF dose μg/actuation (RSD[%]); n = 9 4.4 (7.7) 3.5 (13.5) APSD by Anderson cascade impactor Mean metered FP dose μg/actuation (n = 5) 44.9 34.2 Mean FP dose μg/actuation (n = 5) 42.5 30.3 Mean fine particle dose FP μg/actuation (n = 5) 16.7 12.5 Mean metered FF dose μg/actuation (n = 5) 4.6 4.4 Mean FF dose μg/actuation (n = 5) 4.2 3.4 Mean fine particle dose FF μg/actuation (n = 5) 2.13 1.55 Residue in CCS* FP assay % of target (RSD[%}); n = 3 7.8 (13.6) 14.5 (12.8) FF assay % of target (RSD[%}); n = 3 8.1 (13.8) 14.7 (14.1) Cromolyn sodium assay % of target (RSD[%}); 7.7 (15.1) 15.9 (13.3) n = 3

[0091] The purpose of this experiment was to test the effect of a wetting agent, in this case dehydrated ethanol, on critical parameters such as dose uniformity and particle size distribution. The results show that at initial (results at t=0, after at least 2 weeks storage at ambient conditions of 17 to 25 degrees centigrade and 29 to 63% relative humidity for the formulation without ethanol, the mean dose and fine particle dose was reduced. Furthermore, the assay of residual material in exhausted containers indicated a marked increase in deposition on internal surfaces of the container closure system for the formulation not containing ethanol.

[0092] Testing a product at initial is an important benchmark for formulators. If a product fails in key parameters such as dose and aerodynamic particle size distribution at this stage, it is extremely unlikely that the product will be stable under conditions of accelerated storage.

EXAMPLE 3.

[0093] The following batches were made up using the process described in Example 1:

TABLE-US-00005 TABLE 14 Description Fluticasone/formoterol Fluticasone/formoterol formulation formulation (nominal dose 500 μg (nominal dose 500 μg fluticasone/20 μg fluticasone/10 μg formoterol) formoterol) Composition % w/w % w/w Fluticasone propionate 0.3571 0.3571 Formoterol fumarate 0.0143 0.0071 dihydrate DSCG 0.0343 0.0343 Ethanol 1.43 1.43 HFA 227 qs to 100.0 qs to 100.0

[0094] The results of the stability investigation up to 12 months demonstrated good product quality and robustness of both formulations, as shown by the results displayed in Tables 15 and 16, below.

TABLE-US-00006 TABLE 15 Summary of ACI results of fluticasone/formoterol formulation Flutiform 250/10 up to 12 months at 25° C./60% RH and 40° C./75% RH. Each result is the mean of 6 determinations (beginning and end of 3 canisters). 25° C./60% RH 40° C./75% RH Initial 3 months 6 months 12 months 1 month Fluticasone Metered dose [μg] 428.9 419.8 426.8 427.7 425.9 454.8 429.3 437.1 412.6 Delivered dose [μg] 407.5 400.9 407.3 413.9 408.5 434.2 413.5 417.0 392.2 FPD (Stage 3- 173.6 184.0 179.1 181.8 184.0 186.1 177.0 180.1 177.0 Filter) [μg] Group 1 186.2 172.6 185.2 179.5 180.3 195.9 182.6 185.6 164.9 (Mouthpiece-USP throat) [μg] Group 2 (Stage 0- 60.2 52.3 52.6 56.7 53.5 65.0 60.8 60.7 61.3 Stage 2) [μg] Group 3 (Stage 3- 168.8 178.5 174.2 177.1 179.2 181.1 172.1 175.1 172.4 Stage 5) [μg] Group 4 (Stage 6- 4.9 5.5 5.0 4.7 4.8 5.0 4.8 5.0 4.6 Filter) [μg] Formoterol Metered dose [μg] 18.50 18.27 18.12 18.22 18.00 19.25 17.60 18.15 17.51 Delivered dose [μg] 16.89 16.71 16.47 16.89 16.57 17.54 16.34 16.76 16.05 FPD (Stage 3- 8.40 8.87 8.66 8.90 9.04 9.01 8.29 8.61 8.48 Filter) [μg] Group 1 8.06 7.61 7.67 7.42 7.21 8.16 7.30 7.49 7.01 (Mouthpiece-USP throat) [μg] Group 2 (Stage 0- 1.75 1.41 1.45 1.57 1.45 1.81 1.68 1.68 1.70 Stage 2) [μg] Group 3 (Stage 3- 8.18 8.60 8.43 8.68 8.81 8.77 8.08 8.36 8.27 Stage 5) [μg] Group 4 (Stage 6- 0.22 0.27 0.23 0.23 0.23 0.23 0.21 0.25 0.21 Filter) [μg] 40° C./75% RH 3 months 6 months 12 months Fluticasone Metered dose [μg] 442.3 449.8 430.0 431.2 447.9 Delivered dose [μg] 423.2 417.3 415.6 414.1 429.8 FPD (Stage 3- 193.2 183.1 174.7 181.0 172.1 Filter) [μg] Group 1 179.9 206.5 182.6 179.6 196.6 (Mouthpiece-USP throat) [μg] Group 2 (Stage 0- 59.7 52.5 63.3 61.5 69.9 Stage 2) [μg] Group 3 (Stage 3- 188.6 178.1 170.7 176.6 168.5 Stage 5) [μg] Group 4 (Stage 6- 4.7 5.0 3.9 4.4 3.7 Filter) [μg] Formoterol Metered dose [μg] 18.59 19.05 18.42 18.21 18.43 Delivered dose [μg] 17.13 16.56 17.04 16.76 16.81 FPD (Stage 3- 9.23 8.92 8.64 9.00 8.23 Filter) [μg] Group 1 7.42 8.44 7.72 7.23 8.03 (Mouthpiece-USP throat) [μg] Group 2 (Stage 0- 1.61 1.42 1.74 1.67 1.85 Stage 2) [μg] Group 3 (Stage 3- 9.00 8.69 8.44 8.79 8.05 Stage 5) [μg] Group 4 (Stage 6- 0.23 0.23 0.20 0.21 0.18 Filter) [μg] indicates data missing or illegible when filed

TABLE-US-00007 TABLE 16 Summary of ACI results of fluticasone/formoterol formulation Flutiform 250/5 up to 12 months at 25° C./60% RH and 40° C./75% RH. Each result is the mean of 6 determinations (beginning and end of 3 canisters). 25° C./60% RH 40° C./75% RH Initial 6 months 12 months 1 month 6 months 12 months Fluticasone Metered dose [μg] 402.2 432.1 426.9 433.0 420.3 419.0 417.1 431.4 428.9 417.9 Delivered dose [μg] 378.4 413.9 411.6 416.2 405.5 404.5 401.0 412.1 417.3 402.7 FPD (Stage 3-Filter) [μg] 181.0 203.2 195.1 193.6 185.6 185.0 181.2 194.1 193.9 178.9 Group 1 (Mouthpiece-USP throat) [μg] 171.5 175.9 180.1 175.6 178.9 181.4 183.7 179.9 175.5 171.2 Group 2 (Stage 0-Stage 2) [μg] 42.1 46.3 46.2 54.2 47.8 43.6 45.0 50.8 52.3 58.1 Group 3 (Stage 3-Stage 5) [μg] 177.1 199.1 190.8 189.9 182.0 181.0 177.2 190.7 190.3 175.7 Group 4 (Stage 6-Filter) [μg] 3.8 4.0 4.4 3.7 3.6 4.0 4.0 3.4 3.5 3.2 Formoterol Metered dose [μg] 8.47 9.28 9.22 9.22 8.78 9.09 9.10 9.13 9.07 8.49 Delivered dose [μg] 7.62 8.38 8.40 8.45 8.03 8.36 8.26 8.23 8.37 7.76 FPD (Stage 3-Filter) [μg] 3.81 4.42 4.28 4.27 4.04 4.08 4.00 4.19 4.20 3.82 Group 1 (Mouthpiece-USP throat) [μg] 3.78 3.91 4.01 3.84 3.79 4.04 4.14 3.94 3.84 3.59 Group 2 (Stage 0-Stage 2) [μg] 0.75 0.82 0.81 0.92 0.81 0.79 0.81 0.86 0.89 0.92 Group 3 (Stage 3-Stage 5) [μg] 3.75 4.34 4.19 4.17 3.97 3.96 3.89 4.11 4.11 3.75 Group 4 (Stage 6-Filter) [μg] 0.06 0.08 0.10 0.10 0.08 0.11 0.11 0.08 0.09 0.07 indicates data missing or illegible when filed