PHARMACEUTICAL COMPOSITION

Abstract

A pharmaceutical composition is described. The composition comprises: (i) a drug component comprising at least one tiotropium compound selected from tiotropium and the pharmaceutically acceptable derivatives thereof; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a).

Claims

1. A pharmaceutical composition comprising: (i) a drug component comprising tiotropium bromide monohydrate; and (ii) a propellant component at least 90 weight % of which is 1,1-difluoroethane (HFA-152a), wherein the composition is free of acid stabilisers, and wherein the composition is in the form of a suspension.

2. The pharmaceutical composition of claim 1, wherein the composition contains less than 500 ppm of water based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition of claim 2, wherein the composition contains greater than 0.5 ppm of water based on the total weight of the pharmaceutical composition.

4. The pharmaceutical composition of claim 1, wherein the composition contains less than 1000 ppm of oxygen based on the total weight of the pharmaceutical composition.

5. The pharmaceutical composition of claim 4, wherein the composition contains greater than 0.5 ppm of oxygen based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition of claim 1, wherein the drug component additionally comprises at least one long acting beta-2-agonist (LABA).

7. The pharmaceutical composition of claim 6, wherein the at least one long acting beta-2-agonist is selected from the group consisting of formoterol fumarate, formoterol fumarate dihydrate, salmeterol xinafoate, and olodaterol.

8. The pharmaceutical composition of claim 1, wherein the drug component additionally comprises at least one corticosteroid.

9. The pharmaceutical composition of claim 8, wherein the at least one corticosteroid is selected from mometasone, mometasone furoate, beclomethasone, beclomethasone dipropionate, fluticasone, and fluticasone propionate.

10. The pharmaceutical composition of claim 1, wherein at least 99 weight % of the propellant component is 1,1-difluoroethane (HFA-152a).

11. The pharmaceutical composition of claim 1, wherein the propellant component is entirely 1,1-difluoroethane (HFA-152a).

12. The pharmaceutical composition of claim 10, wherein the propellant component contains from 0.5 to 10 ppm of unsaturated impurities.

13. The pharmaceutical composition of claim 1, further comprising a surfactant component comprising at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin.

14. The pharmaceutical composition of claim 1, further comprising a polar excipient which is ethanol.

15. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is free of one or more of the following: (i) perforated microstructures; (ii) pharmaceutically acceptable salts of both cromoglycic acid and nedocromil; (iii) polar excipients; and (iv) ethanol.

16. The pharmaceutical composition of claim 1, wherein the composition after storage in uncoated aluminium containers at 40° C. and 75% relative humidity for 1 month will produce less than 0.05% by weight of impurities from the degradation of the tiotropium bromide monohydrate based on the total weight of the tiotropium bromide monohydrate and the impurities.

17. The pharmaceutical composition of claim 1, wherein the composition after storage in uncoated aluminium containers at 40° C. and 75% relative humidity for 3 months will produce less than 0.3% by weight of impurities from the degradation of the tiotropium bromide monohydrate based on the total weight of the tiotropium bromide monohydrate and the impurities.

18. The pharmaceutical composition of claim 1, wherein at least 97.0% by weight of the tiotropium bromide monohydrate that is contained originally in the pharmaceutical composition immediately following preparation will be present in the composition after storage in uncoated aluminium containers at 40° C. and 75% relative humidity for 3 months.

19. A metered dose inhaler (MDI) fitted with a sealed and pressurised aerosol container containing a pharmaceutical composition as claimed in claim 1.

20. The pharmaceutical composition of claim 1, which when delivered from a metered dose inhaler yields a fine particle fraction of the tiotropium bromide monohydrate which is at least 45 weight % of the emitted dose of the tiotropium bromide monohydrate even after storage of the pharmaceutical composition at 50° C. and 75% relative humidity for 15 days.

21. The pharmaceutical composition of claim 6 which is adapted to deliver the compounds making up the drug component in approximately the same proportions that they occur in the pharmaceutical composition.

22. A method of improving the aerosolization performance after storage of a pharmaceutical composition, said method comprising adding a propellant component at least 90 weight % of which is 1,1-difluoroethane (HFA-152a) to a pharmaceutical composition comprising a drug component comprising tiotropium bromide monohydrate, wherein the pharmaceutical composition is free of acid stabilizers, and wherein the composition is in the form of a suspension.

23. The method of claim 22, wherein the pharmaceutical composition when delivered from a metered dose inhaler yields a fine particle fraction of the tiotropium bromide monohydrate which is at least 45 weight % of the emitted dose of the tiotropium bromide monohydrate even after storage of the pharmaceutical composition at 50° C. and 75% relative humidity for 15 days.

24. The method of claim 22, wherein at least 99 weight % of the propellant component is 1,1-difluoroethane (HFA-152a).

Description

EXAMPLE 1

[0127] A number of experiments were conducted to investigate the in vitro aerosolization performance of pharmaceutical formulations of tiotropium bromide monohydrate delivered from a metered dose inhaler (MDI) using either HFA-134a or HFA-152a as the propellant.

[0128] Pharmaceutical formulations of tiotropium bromide monohydrate were prepared in either HFA-134a or HFA-152a (Mexichem, UK). The drug was weighed directly into standard uncoated 14 ml aluminium canisters (C128, Presspart, Blackburn, UK). The canisters were then crimped with a 50 μL valve (Bespak, Kings Lynn, UK) following which the propellant was filled into the canisters through the valve using a manual Pamasol crimper/filler (Pamasol, Switzerland). Finally, the canisters were sonicated for 20 minutes to aid dispersion of the drug in the suspension. The nominal dose of tiotropium bromide monohydrate was 10 μg.

[0129] High performance liquid chromatography (HPLC) was used to determine drug content following aerosolization studies (see below). A 150 mm×3 mm Zorbax SB-C3 propyl-silica column with a 3.5 μm particle size was used for the analysis. The column was coupled to a UV detector operating at a wavelength of 240 nm. The autosampler was operated at ambient temperature and 100 μl samples were injected into the column for the analyses. The chromatographic conditions are shown in Table 1 below.

TABLE-US-00001 TABLE 1 Pump UV Column Flow Rate Mobile Phase Wavelength Temperature Drug (ml.min.sup.−1) (gradient elution) (nm) (° C.) Tiotropium 1.20 Mobile Phase A: 240 50 Bromide Sodium methane Monohydrate sulphonate/ potassium dihydrogen phosphate Mobile Phase B: Methanol/ Acetonitrile (10:40 v/v)

[0130] The in vitro aerosolization performance of the formulations was studied using a Next Generation Impactor (NGI, Copley Scientific, Nottingham UK), which was connected to a vacuum pump (GE Motors, NJ, USA). Prior to testing, the cups of the NGI system were coated with 1% v/v silicone oil in hexane to eliminate particle bounce. For each experiment, three actuations of the valve were discharged into the NGI at 30 L.Math.min.sup.−1 as per pharmacopeia guidelines. Following aerosolization, the NGI apparatus was dismantled and the actuator and each part of the NGI was washed down into known volumes of the HPLC mobile phase. The mass of drug deposited on each part of the NGI was determined by HPLC using the methodology described above. This protocol was repeated three times for each canister, following which, the fine particle dose (FPD) and fine particle fraction of the emitted dose (FPF.sub.ED) were determined. The results are shown in Table 2 below.

TABLE-US-00002 TABLE 2 In vitro aerosolization performance of tiotropium bromide monohydrate in HFA-134a and HFA-152a as characterised by the emitted dose, fine particle dose, fine particle fraction of the emitted dose (FPF.sub.ED %), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). HFA-134a HFA-152a Emitted Dose 7.5 ± 0.1 7.2 ± 0.2 (μg ± S.D.) Fine Particle Dose 2.4 ± 0.2 2.7 ± 0.1 (μg ± S.D.) FPF.sub.ED % ± S.D 31.4 ± 2.5  38.0 ± 0.8  MMAD (μm) 4.8 4.5 GSD 2.1 2.1

EXAMPLE 2

[0131] A number of experiments were conducted to investigate the in vitro aerosolization performance of pharmaceutical formulations of tiotropium bromide monohydrate delivered from a metered dose inhaler (MDI) using either HFA-134a, HFA-227ea or HFA-152a as the propellant after initial preparation and after storing under stress storage conditions. The experimental protocol described above was used to prepare the pharmaceutical formulations and the in vitro aerosolization performance of the formulations was tested immediately after preparation (time t=zero) with a Next Generation Impactor using the method described in Example 1 above. The formulations were then stored under stress storage conditions (valve down) at 50° C. and 75% relative humidity for 5 days and 15 days. After storing for 5 days and 15 days under the stress storage conditions, the in vitro aerosolization performance of the pharmaceutical formulations was tested again as before with a Next Generation Impactor using the method described in Example 1 above. The results are shown in Tables 3 to 5 below.

TABLE-US-00003 TABLE 3 In vitro aerosolization performance of tiotropium bromide monohydrate delivered from a MDI using HFA-227ea, HFA-134a or HFA-152a as the propellant at time t = zero as characterised by the fine particle dose, fine particle fraction of the emitted dose (FPF.sub.ED %), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). HFA-227ea HFA-134a HFA-152a T = 0 T = 0 T = 0 Fine Particle 2.26 5.67 2.70 Dose (μg) FPF.sub.ED % 41.07 47.22 44.12 MMAD (μm) 3.12 2.68 2.59 GSD 1.84 1.68 1.65

TABLE-US-00004 TABLE 4 In vitro aerosolization performance of tiotropium bromide monohydrate after delivered from a MDI using HFA-227ea, HFA-134a or HFA-152a as the propellant storage (valve down) for 5 days at 50° C. and 75% relative humidity as characterised by the fine particle dose, fine particle fraction of the emitted dose (FPF.sub.ED %), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). HFA-227ea HFA-134a HFA-152a T = 5 days @ T = 5 days @ T = 5 days @ 50° C. 50° C. 50° C. and 75% RH and 75% RH and 75% RH Fine Particle 0.99 2.59 4.12 Dose (μg) FPF.sub.ED % 13.77 31.82 47.47 MMAD (μm) 8.57 2.07 2.73 GSD 2.06 1.80 1.72

TABLE-US-00005 In vitro aerosolization performance of tiotropium bromide monohydrate delivered from a MDI using HFA-227ea, HFA-134a or HFA-152a as the propellant after storage (valve down) for 15 days at 50° C. and 75 % relative humidity as characterised by the fine particle dose, fine particle fraction of the emitted dose (FPF.sub.ED %), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD). HFA-227ea HFA-134a HFA-152a T = 15 days @ T = 15 days @ T = 15 days @ 50° C. 50° C. 50° C. and 75% RH and 75% RH and 75% RH Fine Particle 0.79 3.72 5.51 Dose (μg) FPF.sub.ED % 13.02 41.10 50.27 MMAD (μm) 8.54 2.12 2.81 GSD 1.96 1.67 1.73

[0132] When HFA-227ea was used as the propellant to aerosolize the tiotropium bromide monohydrate, the aerosolization performance decreased dramatically after the pharmaceutical formulation containing the drug and the propellant had been stored under stress storage conditions for 5 days and 15 days at 50° C. and 75% relative humidity. In particular, the fine particle dose and fine particle fraction of the emitted dose decreased dramatically.

[0133] When HFA-134a was used as the propellant to aerosolize the tiotropium bromide monohydrate, the aerosolization performance decreased significantly after the pharmaceutical formulation containing the drug and the propellant had been stored under stress storage conditions for 5 days and 15 days at 50° C. and 75% relative humidity. In particular, the fine particle dose and fine particle fraction of the emitted dose decreased appreciably.

[0134] In contrast, when HFA-152a was used as the propellant to aerosolize the tiotropium bromide monohydrate, a good aerosolization performance was maintained after the pharmaceutical formulation containing the drug and the propellant had been stored under stress storage conditions for 5 days and 15 days at 50° C. and 75% relative humidity.

EXAMPLE 3

[0135] The chemical stability of tiotropium bromide monohydrate in HFA-134a and HFA-152a was investigated at time zero (T=0) and after storage, valve down, for 1 month (T=1M) and 3 months (T=3M) at 40° C. and 75% relative humidity (RH) and at 25° C. and 60% relative humidity (RH) in uncoated aluminium cans.

[0136] The drug formulations were prepared as described in Example 1 above and analysed using high performance liquid chromatography (HPLC). A 150 mm×4.6 mm Accucore C18 column with a 2.6 μm particle size was used for the analysis. The column was coupled to a UV detector operating at a wavelength of 240 nm. The autosampler was operated at ambient temperature and 100 μl samples were injected into the column for the analyses. The chromatographic conditions are shown in Table 6 below.

TABLE-US-00006 TABLE 6 Pump UV Column Flow Rate Mobile Phase Wavelength Temperature (mL.min.sup.−1) (gradient elution) (nm) (° C.) 1.0 Mobile Phase A: 240 45 10 mM Ammonium formate (pH 3.0) Mobile Phase B: Acetonitrile

[0137] The composition of the mobile phase was varied as shown in Table 7 below.

TABLE-US-00007 TABLE 7 Time (minutes) % Mobile phase A % Mobile phase B 0 95 5 1 95 5 21 0 100 22 0 100 23 95 5 28 95 5

[0138] The results of investigating the chemical stability of the tiotropium bromide monohydrate drug formulations in HFA-152a and HFA-134a in uncoated aluminium cans are shown, respectively, in Tables 8 and 9 below.

TABLE-US-00008 TABLE 8 Chemical stability of tiotropium bromide monohydrate in HFA-134a in uncoated aluminium cans based on percentage assay and total impurities upon storage at T and 25° C./60% RH. Time % Assay (LC) % total impurities Initial time T = 0 99.8 0.08 T = 1M @ 25/60 99.8 0.13 T = 1M @ 40/75 99.5 0.28 T = 3M @ 25/60 97.8 0.32 T = 3M @ 40/75 96.4 0.44

TABLE-US-00009 TABLE 9 Chemical stability of tiotropium bromide monohydrate (TBM) in HFA-152a in uncoated aluminium cans based on percentage assay and total impurities upon storage at T and 25° C./60% RH. Time % Assay (LC) % total impurities Initial time T = 0 100.5 <LoQ T = 1M @ 25/60 99.9 <LoQ T = 1M @ 40/75 99.8 <LoQ T = 3M @ 25/60 98.9 0.08 T = 3M @ 40/75 98.5 0.13

[0139] It can be seen from the above data that pharmaceutical formulations of tiotropium bromide monohydrate exhibit superior chemical stability when blended together with HFA-152a as the aerosolization propellant.

EXAMPLE 4

[0140] Formulations containing tiotropium bromide monohydrate and either HFA-134a or HFA-152a were prepared in PET vials and the suspension stability of the formulations determined using a Turbiscan MA 2000. The Turbiscan instrument has a reading head that moves along a flat-bottomed, 5 mL cylindrical glass cell, and takes readings of transmitted and backscattered light every 40 μm on a maximum sample height of 80 mm. The reading head uses a pulsed near infrared light source and two synchronous detectors. The transmission detector picks up light transmitted through the suspension tube at 0° and back scattering detector receives light back by the product at 135°.

[0141] The sedimentation and size of flocs for the different formulations are shown in Table 10 below.

TABLE-US-00010 TABLE 10 Suspension stability profiles of tiotropium bromide monohydrate formulations in HFA-134a and HFA-152a. Time to Size Start sediment Formulation (microns) (mins) Tiotropium bromide monohydrate and 3.45 0.82 HFA-134a Tiotropium bromide monohydrate and 3.55 0.91 HFA-152a