CZ20004793A3 - Pressure inhalators with metered dosages and pharmaceutical aerosol preparations - Google Patents

Abstract

The solution provides a pressurized metered dose inhaler which contains a stable drug preparation acting as a antagonist in the form of a solution or suspension. It also provides an aerosol formulation suitable for inhalation therapy, which contains a β-agonist in solution or suspension.

Description

Pressurized metered-dose inhalers and pharmaceutical aerosol preparations

Technical field

The present invention relates to metered dose inhalers and aerosol formulations suitable for inhalation therapy.

BACKGROUND OF THE INVENTION

Due to environmental requirements, propellants (propellants) of aerosol packs for medical use based on chlorinated hydrocarbons and chlorofluorocarbons have already been mostly replaced by hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (HFA134a) or 1 1,1,2,3,3,3-heptafluoropropane (HFA-227ea), which have been found to be safe for use in metered dose inhalers.

Such aerosol formulations are generally of the solution or suspension type. Each such composition is composed of at least a drug and a propellant. Some formulations contain yet another one or more special purpose adjuvants, such as an additional solvent, e.g. a co-solvent or a surfactant, i. a surfactant (see EP 0 372 777). Conventional solution-based aerosol formulations (solution formulations) contain a cosolvent in a low concentration that is more polar than the propellant. Conventional suspension-based aerosol formulations (suspension formulations) contain a surfactant, rather than a cosolvent, according to the theory that the surfactant will prevent the particles from sticking together and adhering to the walls of the pressure vessel, while acting as a lubricant ( a lubricant) for the actuator valve (see US 3 014 844).

Ethanol was often used as a co-solvent. However, the prior art (see e.g. EP 0 616 525) has shown that ethanol in concentrations of 5% was not used in solution aerosol formulations of β-agonists. Historically, ethanol concentrations above 5% have been used only for steroid-based formulations with hydrofluoroalkane propellants.

A medicament acting as a β-agonist (hereafter called β-agonist), formoterol (known as eformoterol in Europe) and its derivatives, is difficult to formulate into conventional aerosol formulations. Such formulations have been shown to have a short shelf life and require storage at a low temperature (refrigerator). However, cooling is undesirable because many patients have to carry the aerosol canister with them. This implies a need for aerosol formulations of β-agonists such as formoterol and derivatives thereof, which are chemically and physically stable when stored at ambient room temperature and humidity.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a pressurized metered-dose inhaler comprising a stable β-agonist formulation that does not require refrigerator storage.

Another object is to provide a stable formulation formulated from a medicament acting as a β-agonist (s) for use as an aerosol formulation in a pressurized container (spray) that does not require refrigeration upon storage.

Surprisingly, the above objectives have been met in the present invention. The present invention provides a novel pressure inhaler comprising a pressurized inhaler. · «» »» (A.

a container equipped with a metering spray valve comprising a cartridge - an aerosol formulation, formulated from a composition comprising:

- β-agonist,

at least one fluoroalkane propellant, and

- more than 5% (w / w), based on the total weight of the aerosol formulation, of a solvent capable of solubilizing or dissolving a β-agonist.

The invention further provides a novel pressurized metered-dose inhaler comprising a canister equipped with a metering valve, comprising a compressed aerosol formulation formulated from a composition comprising:

- β-agonist particles,

at least one fluoroalkane propellant, and

a surfactant capable of suspending from β-agonist particles.

The invention also provides a novel aerosol formulation for use in a pressurized aerosol container, wherein the aerosol formulation is formulated from a composition comprising

- β-agonist particles,

at least one fluoroalkane propellant, and

- more than 5% (w / w), based on the total weight of the aerosol formulation, of a solvent capable of solubilizing or dissolving a β-agonist.

The invention also provides a novel aerosol formulation for use in a pressurized aerosol container, wherein the aerosol formulation is formulated from a composition comprising

- β-agonist particles,

at least one fluoroalkane propellant and surfactant capable of suspending from β-agonist particles.

The aerosol formulations of the invention are surprisingly stable

* · 0 0 0 0 it

0 0 0 0 0 v 0 0 at a temperature of up to 40 ° C and a relative humidity of 75% for at least 4 weeks.

Description of the picture

Giant. 1 illustrates a chromatogram of formoterol fumarate which has been formulated as a suspension.

Giant. 2 illustrates a chromatogram of formoterol fumarate after storage for 28 days at 40 ° C and 75% relative humidity.

Surprisingly, it has been found that the stability of solution β-agonist solution aerosol formulations can be significantly improved by using more than 5% (w / w) solvent that is capable of solubilizing or dissolving the β-agonist. A β-agonist, i.e., a medicament acting as a β-agonist, is any form suitable for administration to the lungs or nasal cavity of a human, eg, a basic or weakly acid form. In the description of the present invention, formoterol is used as an example of a β-agonist. Thus, the term formoterol is used herein to mean the basic or weakly acidic form of formoterol, unless expressly stated otherwise. A preferred weakly acid form of formoterol is formoterol fumarate.

The amount of β-agonist used in the aerosol formulation of the invention depends on the type of drug selected. For formoterol fumarate, the concentration is usually less than 1% (w / w), preferably 0.01% to 0.02% (w / w) based on the total weight of the aerosol formulation (ie, the pressurized fill).

Any solvent capable of solubilizing or dissolving the selected β-agonist may be used in the present invention. Examples of suitable solvents include alcohols

Ethers, hydrocarbons and perfluorinated hydrocarbons. Preferred solvents are short chain polar alcohols. More preferred are aliphatic alcohols having 1 to 6 carbon atoms such as ethanol and isopropanol. The most preferred solvent is ethanol. Examples of suitable hydrocarbons further include n-butane, isobutane, pentane, neopentane and isopentanes. Examples of suitable ethers include dimethyl ether and diethyl ether. Examples of suitable fluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane and perfluoropentane.

The solvent is typically present in an amount of from 6 to 30% (w / w) based on the total weight of the aerosol formulation (i.e. the pressurized fill). Preferably, the solvent is present in an amount of 10-15% (w / w). The skilled artisan will appreciate that lower drug concentrations usually require lower solvent concentrations and vice versa in order to form a stable solution.

Any fluoroalkane propellant suitable for inhalation may be used in the invention. Examples of suitable fluoroalkanes include HFA-134a, HFA-227ea, HFA-125 (pentafluoroethane), HFA152a (1,1-difluoroethane) and HFA-32 (difluoromethane). Hydrocarbons and / or aliphatic gases may be added as required to modify the properties of the propellant.

The propellant for solution preparations is usually present in an amount of 70 to 94% (w / w) based on the total weight of the earosol preparation (i.e. the pressurized fill). A preferred earosol formulation comprises HFA-134a in an amount of less than 90% (w / w), ethanol in an amount of greater than 10% (w / w), and formoterol fumarate in an amount of about 0.01% (w / w).

A particularly preferred aerosol formulation comprises HFA-134a (w / w), ethanol formoterol fumarate in an amount in an amount of about 85 about 15% (w / w) and about 0.01% (w / w).

Pressurized metered dose inhalers are now well known in the art.

Any metered-dose metered-dose inhaler suitable for administration to the lung or nose may be used in the invention. A metered dose inhaler is typically provided with a metering valve having an orifice with a radius of approximately 460 μια. However, at a higher concentration of the solvent used according to the invention, the solvent needs to evaporate as quickly as possible after inhalation. This can be achieved, for example, by reducing the diameter of the outlet orifice to, for example, 250 gm, while using a solvent in a concentration of 10 to 15% (w / w). Based on the teachings of the present invention, one skilled in the art is able, without undue experimentation, to adjust the composition of the composition so that the desired dose of medicament is delivered via the selected metering valve. For example, it is possible to adjust the vapor pressure of the formulation. The aerosol formulation and metering valve are typically selected to provide a therapeutically effective amount of a β-agonist to no valve activation (valve compression). An example of a therapeutically effective amount of formoterol fumarate is 12 µg per activation.

It has unexpectedly been found that stable aerosol formulations from suspensions with β-agonist particles can be prepared using a β-agonist in combination with a surfactant capable of forming a suspension of β-agonist particles. The present invention is explained in more detail by way of example of a β-agonist which is formoterol.

A suitable propellant is any propellant described herein with respect to solution aerosol formulations. However, the propellant of the suspension aerosol formulation can be used up to a concentration of 99.9% (w / w) based on the weight of the aerosol formulation (ie, the pressurized cartridge).

The amount of β-agonist drug used in the aerosol formulation depends on the type of drug selected. For formoterol fumarate, the concentration used is usually 1% (w / w) or less, preferably 0.01 to 0.02% (w / w) based on the total weight of the aerosol formulation (ie the pressurized fill).

The β-agonist particle size must be such that the drug is suitable for inhalation into the nose or lungs. A suitable average particle size is 100 microns and less, preferably 20 microns and less, most preferably in the range of 1 to 10 microns.

Any surfactant suitable for administration to the lungs of a patient capable of suspending the β-agonist particle used in the formulation may be used in the invention. Suitable surfactants include polyalcohols such as polyethylene glycol (PEG 300), diethylene glycol monoethyl ether (Transcutol), polyoxyethylene (20) sorbitan monolaurate (Tween 20) or monooleate (Tween 80), propoxylated polyethylene glycol (Antarox 31R1), polyoxyethylene-4-lauryl Brij 30) or other HLB-like surfactants. A preferred surfactant is polyoxyethylene-4-lauryl ether (Brij 30). The surfactant is usually present in an amount of 1% (w / w) or less.

A preferred suspension formulation comprises HFA-134a in an amount of greater than 99% (w / w), Brij 30 surfactant in an amount of about 0.002% (w / w) or greater, and formoterol fumarate in an amount of 1% (w / w) or less. A preferred suspension formulation comprises 99% (w / w) HFA-134a, Brij 30 in an amount of about 0.02% (w / w) or higher, and formoterol fumarate in an amount of 0.2% (w / w). A particularly preferred suspension formulation contains 12.6 g of HFA-134a, 0.002 g of Brij 30 and 0.002 g of formoterol fumarate (all in g per container) in a 19 ml pressure vessel.

The following examples are given merely to illustrate preferred embodiments and do not limit the scope of the present invention, the invention being defined by the claims that are based

• · • · ft full description.

DETAILED DESCRIPTION OF THE INVENTION

Examples 1 to 3

The three suspension aerosols of the present invention were formulated by mixing the ingredients listed in Table 1 as follows:

1. weighing the diluent or surfactant into a plastic coated glass vial or aluminum container.

2. adding the weighed drug.

3. insert the valve into the vial or container.

4. adding a known amount of propellant through the valve to the vial or container.

5. sonication of the preparation for approximately 5 minutes.

A 19 ml aluminum canister of a Presspart metered dose inhaler was used, with a valve measuring 63 μak Bespak BK357 unless otherwise stated.

The properties of the formulations in the aerosol package (sprays) of the example were tested using one or more of the following parameters:

appearance (there should be no external signs of leakage or deformation),

- a leak according to the standards of US Pharmacopoeia No 23 and National Pharmacopoeia No 18,

- the content of the container should be within 10% of the diameter,

- the drug in the container should be within 25% of the diameter,

- the chemical test should be within the range of 90,0 to 110% of the information given on the label,

- metered dose weight, spray dose content and content uniformity according to the standards provided in the Pharmacopeial Forum, Volume 22, No. 6, and

Μ · · · · ·

4 · 0 0 0 0

4 0 0 0 0 • 00 00 0 0000 00 0

- aerodynamic size distribution and water content.

The test results are shown in Table 1. By comparing the deposit percentage at stage 2, the formulations containing Brij 30 and Tween 20 were found to be superior to those containing PEG 300. In addition, the data show that the formulation with Tween 20 deposited more drug on the nebulizer. Therefore, to minimize deposition on this type of nebulizer, Brij 30 was more useful in these formulations as a surfactant than Tween 20.

Examples 4 to 7

The four solution aerosol formulations of the present invention were formulated by mixing the ingredients listed in Table 2 using the method described in Example 1. The stability of the solution aerosol formulations was determined. Examples 6 and 7 were maintained for 1 month (28 days) at 40 ° C and 75% relative humidity, which is considered to be difficult here. Solution aerosol formulations were equilibrated at room temperature overnight prior to testing. The properties of the solution aerosol formulations were measured as in Example 1 and the results are shown in Table 2.

The data show that the dose administered (by spray dose determination) after storage under severe conditions was lower than the dose obtained with the initial samples due to drug adsorption to the valve seal material. However, the solution aerosol formulations did not show any signs of chemical decay.

• ·

Examples 8 and 9 which is here with solution

The two solution aerosol formulations of the present invention were formulated by mixing the ingredients listed in Table 3 using the method described in Example 1. To determine the stability of the solution aerosol formulations, Example 9 was maintained for 1 month (28 days) at 40 ° C and 75% relative. humidity, under severe conditions. The formulations were equilibrated at room temperature overnight prior to testing. The properties of the solution aerosol formulations were measured as in Example 1 and the results are shown in Table 3.

In this study, the drug could not be recovered from the gasket material, resulting in a loss of approximately weighted aerosols. However, the solution aerosol formulations did not show any signs of chemical decay.

Examples 10 to 13

The four suspension aerosol formulations of the present invention were formulated by mixing the ingredients listed in Table 4 using the method described in Example 1. To determine the stability of the suspension aerosol formulations, Examples 12 and 13 were maintained for 1 month (28 days) at 40 ° C and 75 ° C. % relative humidity, which is considered to be harsh conditions here. Suspension aerosol formulations were equilibrated at room temperature overnight prior to testing. The properties of the suspension aerosol formulations were measured as in Example 1 and the results are shown in Table 4.

After 28 days of storage, the dose administered (by spray dose determination) in Examples 12 and 13 was lower than the dose

Obtained with starting examples 10 and 11, but was not reduced to the same extent as the examples of solution formulations.

Examples 14 to 17

The four suspension aerosol formulations of the present invention were formulated by mixing the ingredients listed in Table 5 using the method described in Example 1. To determine the stability of the suspension aerosol formulations, Examples 16 and 17 were maintained for 1 month (28 days) at 40 ° C and 75 ° C. % relative humidity, which is considered to be harsh conditions here. Suspension aerosol formulations were equilibrated at room temperature overnight prior to testing. The properties of the suspension aerosol formulations were measured as in Example 1 and the results are shown in Table 5.

The test data shows approximately 10% loss of drug after storage under severe conditions in Examples 16 and 17, relative to starting examples 14 and 15. This value is within acceptable limits and was within 100% of the material balance container). In addition, a particle size determination method (Andersen impactor) that is permissible according to USP was used. The results show that there was no chemical (such as occurrence of known degradation product or loss of parent compound) or physical instability after storage including 1) particle size increase (MMAD - median aerodynamic diameter), 2) change in distribution (GSD - geometric standard deviation), 3 ) changing the fine particle dose; or 4) changing the fine particle fraction.

· *

9

9

Examples 18 and 19

The two suspension aerosol formulations of the present invention were formulated by mixing the ingredients listed in Table 6 using the method described in Example 1. The properties of the formulation with suspension aerosols were measured as in Example 1 and the results are shown in Table 6.

Example 20

The suspension aerosol formulation was formed by mixing 99.96% (w / w) HFA-134a, 0.02% (w / w) formoterol fumarate and 0.02% (w / w) Brij 30, using the method described in Example 1. HPLC chromatograms of the suspension aerosol before and after storage for 28 days at 40 ° C and 75% relative humidity as Figures 1 and 2, respectively. Only one peak representing an intact drug was observed in each figure. No peaks representing decay products were detected (expected occurrence after approximately 13 minutes). Thus, the formoterol suspension aerosol exhibited long-term stability.

9 ·

> · · · ·

49 9 9

Table

Example 3 1 r * LD 80.70 11.27 13.59 96 27.71 O kC r-H 48.17 77.90 8.53550 0.0018 (P3) 0.00076 Example 2 8.53 81.10 40.73 16.36 7.99 39, 92 73.50 38.02 78, 90 8,71860 0.0017 (T2) 0.00079 Example 1 8.27 82.15 26.59 25,00 7, 94 40.87 66.50 40.71 80.80 8.55550 0.0017 (B3) 08000 '0 drug per dose (mcg) weight of spray dose (mg) valve / atomizer (mcg) throat / neck (mcg) stage 1 (mcg) stage 2 (mcg) substance balance (%) % at stage 2 weight of spray dose (mg) iti ω 1—1 1 i.e ÍC surfactant formoterol fumarate Test Content spray benefits Liquid fallout in an individual stage Preparation and

polyethylene glycol 300 φφ

CN

Table • ·· ·· φφ ·· · · · · · · · · <

φ φ φ · · · · · • ·

Data after 28 days Example 7 4.26 72 71.38 11-14 73.1 35-39 0, 00 46, 47 0, 00 37.37 O 44.57 09 'ZL 15-34 4.33 CN r- 73.10 51-57 73.8 55-59 1 Example 6 4.37 78 72.58 6-9 ΟΊ O 20-24 0, 00 96 'LZ 2.44 38.81 58 56.08 76.39 60-79 4.58 77 76.52 51-54 O 55-59 1 Default data Example 5 1—1 00 00 70.35 7-10 71.3 10-14 0, 00 36, 67 3, 69 54.99 80 57, 67 VO (Ti CN 64-83 5.53 93 00 CN Γ 54-57 what CN 54-58 rH CN VO Example 4 5.21 90 72.05 7-10 70, 0 21-25 6.14 38.63 O O 56.54 91 cn vo ω lD 72.10 68-87 O cn 102 Lf) O CN r * 54-57 71.1 58-62 drug per dose (mcg) o \ o rtf X! 'Π3 > O C 0 'OJ > O Λ4 4-1 1—1 spray dose weight (mg) number of spray doses spray dose weight (mg) number of spray doses valve / atomizer (mcg) throat / neck (mcg) stage 1 (mcg) stage 2 (mcg) substance balance (%) % at stage 2 spray dose weight (mg)! number of spray doses drug per dose (mcg) ¹ substance balance (%) spray dose weight (mg) number of spray doses weight of the spray dose (mg) ¹ number of spray doses humidity (ppm) Test Content spray benefits Weight spray benefits Liquid fallout in an individual stage Content spray benefits Weight spray benefits Water content!

· · · · · · · · · · · · · · · · ·

Table 2 - continued

4.79 CTi r » 73.52 101-104 X C4 [ 110-114 16,753 3,0267 0.00163 04 / 04 / Γ Ο τ — 1 ΟΊ tn Ο γΗ Γ- | 04 / 43 i — 1 04 / 00 1 Ο 1 04 / σ Ο χ , - x οο χ σ> Ο x 04 / ιΌ Ο 40 ο θ ' χ χ LQ ΟΊ Γ r — 1 Γ · ι — 1 r ~ 1 04 / ο 04 / 04 / t-1 04 / γ ~ 1 40 04 / γ ^- 1 γΗ 40 00 rH ΟΟ σι AND Ο Lf) Ο τ — i χ ΟΊ χ 00 x Ο ο x ο 04 / Ο 04 / γΗ Γ · χ χ 40 ι — 1 Ι> γΗ θ ' ι — 1 t-4 00 ο 40 40 ο ι — 1 04 / 04 / 04 / 40 00 r-H ι — 1 γΉ 40 r4 04 / 1 Lf) 1 σ Ο Ο 04 / t> χ ΟΟ χ 04 / χ ο Ο x Ο 04 / γΗ γΗ 04 / 40 X X 40 ι — 1 Γ- γ ~ Η Γ <—1 ι — 1 οί ο Cn rr> β β !> ί > 1 44 44 44 44 .-X > <υ > 0) Cn οΡ 'β > 'ÍÚ > 0 Ό 'β β '(0 β β ίϋ 'Φ 'φ μ β > £ 3 > £ 3 'Φ β 'ίϋ ο υ 0 υ μ 44 > • ΓΊ '> 1 ‘ΓΊ ίΰ > 0 dl > Φ > β 'fl β μ 0 μ 0 β β > and • ΓΊ and • ΓΊ 4-1 0 W Φ W Φ Γ—} π3 Μ μ μ 0 £ μ and η and Φ μ '«3 W IN) ω IN) Η φ 0 > 0 0 0Ί 0 4-1 > 0 β μ ΰ -μ r — f C 0 • Η 44 μ (1) η Φ 1 β > υ μ 0 > υ 0 > υ < £ 3 μ '1) 'β β 0 β 0 and 4-> 0 I — I Ή £ 3 and £ 3 and S3 Φ μ 'φ > > 0 0 • γί ΓΊ Φ Φ μ Μ CU and 7) ω 44 AT <υ υ] > Ο <0 £ 3 >, C: > 1 μ (ϋ Λί 4J λ; and W > 0 > Ή η 'β β 'ίθ > CI ο β S3 β ίΧι

ω β

AND!

I — I β

Λ β

Η

Data after 28 days Example 9 1,324 tn what 16,853 3,0269 0.00156 ftf 4-1 flj β WHAT Ή β cn N β cn 40 m 0 1—1 r- 0Ί 00 í — 1 £ 3 AND σ cn 00 O AT Ή tn O X O O X O 40 X » X > and i — 1 rH r-1 00 O Cn G -P <U 'Íú at Cl rs (0 0 b β cs 'β M-1 d 4-> rH β C 0 > AND β β Cl > N 4-J β 0 > 0) cn AND 4-1 > 4-1 χ — 1 oj 0 • H 1 M-4 β > u > Cl Η '(1) and CS 0 Pl oP se n M-1 > 1 AND rs O β AND β CD d > β £ 3 Cl 4 £ Ch M w Ή <U Ό > Cl H O and

• 4 • 4

Table

Data after 28 days Example 13 11.10 r- r- 80.75 r * · * 1 81, 9 8-12 27, 90 17.47 5, 60 69.57 WHAT WHAT 57.72 Q £ 18-27 13, 42 92 81.2 43-44 52-56 Example 12 13.32 85 80.75 6-7 80.9 18-22 23.36 19.11 3, 95 78.58 8Δ 62.86 82.1 8-17 13.72 87 81, 4 50-51 80, 9 52-56 i _ Default data Example 11 14.22 89 82.9 1 kD O) r- 8-12 31, 36 27, 93 O If) O) kD r * 90 54.32 81.7 13-22 15, 49 σι 81.4 50-51 and 00 oo 52-56 Example 10 14.45 92 80, 0 Γ * 1 kD LD kQ 8-12 32.72 31.21 6.20 75.95 94 51.99 i — 1 ΟΊ r * 13-22 15, 03 96 79.7 50-51 78.9 52-56 drug per dose (mcg) substance balance (%) [spray dose weight (mg) [number of spray doses spray dose weight (mg) number of spray doses valve / atomizer (mcg) throat / neck (mcg) stage 1 (mcg) stage 2 (mcg) substance balance (%) % at stage 2 spray dose weight (mg) number of spray doses drug per dose (mcg) substance balance (%) spray dose weight (mg) number of spray doses spray dose weight (mg) number of spray doses Test Content spray benefits Weight spray benefits Liquid fallout in an individual stage Content spray benefits 1 Weight spray benefits

• ·

Table 4 - Continuation

1 14.73 116 CD O Γ- 91-92 73, 0 93-97 10,825 0.00152 0.00194 LO LO CM CD σ LO LO CM CM and- i — 1 LO LO σι ΟΊ O O O TO. 1 1 O O O CM LO i — 1 cr> CQ O 1 τ— r · Γ ΟΊ r * · ΟΊ r ^- O O E ~ LO rd r-1 CM σ CM r- CQ CQ CM CM rd CD 00 LO ΟΊ i — 1 O O CM TO. l *. 1 with O O CM rd Q CM O ΟΊ O * » «>. 00 rd 00 with 00 00 00 i — 1 O O O i — 1 LO σ σ 00 Γ * r * LO CM rd TO, LO 00 CQ σι 00 O O 00 TO. TO 1 and 00 O O CD CQ Γ σι CD ΟΊ CQ TO 1—1 oo r * 00 CD σ ΟΊ O O m Ln G G «-. > 1 >, 44 44 44 44 .—. > > <u m oP 'fÚ > 'Io > υ · - Ti 'Io Ό G Ti Ό flj 'Φ 'Φ 4-J X > X > X Μΰ G 'ίΰ O υ 0 at Jd 44 > • m '> 1 • γί ___ > 0 <u > 1) > b G 'Io b Jd 0 Jd 0 G and Ό > and • ΓΊ and • γί * 4d and O cn <u <n <U rd flj Jd J4 J-l 0 G 4-J and 4-1 and fÚ Jd 4-J 'íú ω w w w O <D IN) O > O 0 CQ CQ 4-J 0 > 0 and 4-J G 4-J rH 0 44 X + J <U X 1) 1 • ΓΊ G Λ > 0 4-J O > u 0 > u • H Jd rd '<U 'fO G 0 b 0 [0057] Ib M 0 > r — 1 • —1 X and X and TO CQ Md '<u '<u > > 0 0 • n • ΓΊ (AT <u M J-l CU and w IN) Í> 1 Ό 44 0 4-J 0) > W > 0 Π3 xi xi >. G > 1 Jd (ΰ ίΰ 44 4-J and VJ w > 0 > Ή n Ω 'flj b oj > b O O Ό w Ό Oj

Table

X at Example 17 1 1 15.25 9.37 17.15 2.60 2.15 2.94 Γ ' kD what AND- 27.20 19.80 3.82 0.75 0, 00 72.93 114.70 75 2.5 Γ rd 68.18 75 C τ> WHAT kD CN 1— 0 TJ - ft nj r-H OO (I.E X kD 4J Ή O 00 <ie > M | * » O at CM CN rd 1 AND 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Lf) t — 1 Those Π3 kD u0 r- r- ~ what Γ- CN O kO WHAT what Γ τ — 1 CN kD what 00 UO r — 1 ! —1 it 00 00 WHAT ^ sP to. ». to. 00 CN uf) <k i — 1 LQ OY to. > P _with CY O with to, : —1 t — 1 O to. κ »—1 WHAT O κ to. what what CM 1 1 cn i — 1 CN what 00 τ — 1 what CN rd O 00 rd O CN rd Γ- Γ · Π3 X fO xp I.E i — 1 Ή Those N (0 0 i-1 cn Λ X what at Ή CN 00 > P · to. 1—1 > CM CN I — 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 AND 1 1 1 AND tn ____ Γ) Oy R σ · O at oP O G WITH - G (B) O · * - * OJ .—, i — 1 X oP υ • H G M | <u i — 1 - • rd X '0 > N -. 0) -P WHAT X G θ ' O (I.e what '<Ie <u £ 1 44 at 43 'flj > 0 at rO \ to. .-in (B) 0 'WHAT > 0 X I.E Me m OY tTi θ ' tn tr> tTi Ο » Oy > > 43 0 her O at O O (t) at O O O O 0 43 0 Those > G G G G G G G, G G r- > 0 G ϋ '> 1 'three tn > 0 X ** - * what 'Φ > 'ί> Ί G G 0 nj 0 fu 1 r— | 0 C TO G G > O i — 1 CN what ^ p m kD Γ- O Ml G Φ > X O what '(D (IF • ΓΊ > N > cn β (B) (B) (B) G (B) (B) (B) (B) (B) G '(Those • ro 0 > <1) 1-1 nj Those G G G G G G G G G (B) Φ > <D > X Me 0 H • H • H • H • H • H Φ > N 0 flj AT 4-1 O. > Ό Ό I.E I.E in I.E τ) • σ Those X > <U X Q X X > u > G N Ή Π3 fO fO nJ nj nj Π3 σί (I.E 1—1 X X Q > OJ Ό) 11 0 > MJ 44 44 44 44 44 44 44 X 44 1) > 1 'ftí § WHAT 'ftf P I — I oP > Ml £ 2, what 10 10 WHAT WHAT WHAT WHAT WHAT what at > r-1 2 O T3 Md > 1 X 42 0 > τ> 'G 'rtj G Me C 0) 0 what AT 43 Me 44 X (Cj (ϋ fÚ WHAT what τ) & <u 42 β (B) E-i O < • H

• 0 ·

• · • 0 0 ♦ · 0 0

0

0 i

*

Table 5 - continued

10,219 0.00241 0.00192 00 CN 00 cn what <- r — 1 i — 1 O O to. O O O kw rH O O CN 21 89 CN rH CD O O TO O O O kw kw ! - O O cn 163 189 ΟΊ O O 00 O O to" kw kw σϊ O O fO O erolfumarate what what 4-> i — 1 1 • ΓΊ 0 with • H TI ra M 0 ac ra 4-1 Preparation

♦ · · · • •

Table 6

test Example 18 Example 19 Content spray benefits drug per dose (mcg) 10.87 9.55 substance balance (%) 89, 0 78.5 spray dose weight (mg) 78.6 78.0 number of spray doses 6-7 71-72 Content spray benefits drug per dose (mcg) 10.51 12.90 substance balance (%) 86.0 104, 8 spray dose weight (mg) 78.7 78.9 number of spray doses 8-9 73-74 Andersen impactor valve (mcg) 5.93 9, 14 spray / adapter (mcg) 28.91 29, 02 inlet / cone (mcg) 30.03 20.18 stage 0 (mcg) 1.33 0, 96 stage 1 (mcg) 1, 64 1.32 stage 2 (mcg) 2.28 1.72 stage 3 (mcg) 9, 54 8.45 stage 4 (mcg) 29.37 27.25 stage 5 (mcg) 27.71 27.52 stage 6 (mcg) 3.27 3.38 stage 7 (mcg) 0, 00 0, 00 stage F (mcg) 0.68 0.00 total S0-S7 (mcg) 75.14 70, 60 total drug withdrawn (mcg) 140.69 128.93 substance balance (%) 107, 7 103, 8 MMAD 2.3 2.5 GSD 1.6 1.5 fine particle dose (mcg) 73 68 fine particle fraction (%) 69 75

Table 6 - Continuation

Andersen impactor valve (mcg) 5, 64 - spray / adapter (mcg) 28.58 inlet / cone (mcg) 23.56 - stage 0 (mcg) 1.13 - stage 1 (mcg) 1.56 - stage 2 (mcg) 1, 97 - stage 3 (mcg) 9, 95 - stage 4 (mcg) 30.04 - stage 5 (mcg) 27.51 - stage 6 (mcg) 3, 05 - stage 7 (mcg) 0.00 - stage F (mcg) 0.00 - total S0-S7 (mcg) 75.21 total drug withdrawn (mcg) 132.98 - substance balance (%) 103.3 MMAD 2.5 - GSD 1.5 - fine particle dose (mcg) 73 - fine particle fraction (%) 74 - Preparation HFA-134a 12.8169 12.6705 Brij 30 0.00230 0, 00220 formoterol fumarate 0.002044 0.001970

While the invention has been described in detail including examples of specific embodiments, it will be apparent to those skilled in the art that various changes and modifications to the present invention may be made without departing from the original inventive concept, and thus falling within the scope of the present invention.

Claims (19)

PATENT CLAIMS 1. A pressurized metered-dose inhaler comprising a container having a metering valve and a compressed aerosol formulation formulated from a composition comprising: - β-agonist, at least one fluoroalkane propellant, and - more than 5% by weight, based on the total weight of the aerosol formulation, of a solvent capable of solubilizing or dissolving a β-agonist. A pressurized metered dose inhaler according to claim 1, wherein the metering valve is designed and arranged to provide metered doses of the β-agonist in an amount that is therapeutically effective. The metered dose inhaler of claim 1, wherein the metering valve is designed and arranged to provide metered doses of β-agonist in an amount of 12 µg per actuation of the metering valve. A pressurized metered-dose inhaler according to claim 1, characterized in that it comprises fluoroalkane 1,1,1,2-tetrafluoroethane. A metered dose inhaler according to claim 1, wherein the formulation is substantially free of chlorofluorocarbons. 9 4 A metered dose inhaler according to claim 1, wherein the propellant is present in an amount of 70 to 94% by weight. A pressurized metered dose inhaler according to claim 1, wherein the solvent is present in an amount of at least 10% by weight. A metered dose inhaler according to claim 1, wherein the solvent is present in an amount of at least 15% by weight. A metered dose inhaler according to claim 1, wherein the solvent is present in an amount of greater than 5% to 30% by weight, based on the total weight of the aerosol formulation. A metered dose inhaler according to claim 1, wherein the solvent is selected from the group consisting of ethers and alcohols. A pressurized metered-dose inhaler according to claim 1, wherein the solvent comprises an aliphatic alcohol having 1 to 6 carbon atoms. 12. confesses ethanol. Pressure č u j í inhaler s c í se measured that benefits according to solvent of claim 1 contain e 13. Pressure inhaler s measured benefits according to of claim 1 confesses č u j í c í se that solvent is more polar than propellant. A pressurized metered dose inhaler according to claim 1, wherein the β-agonist comprises formoterol. A pressurized metered-dose inhaler according to claim 14, characterized in that the formoterol is present in an amount of 1% by weight or less, based on the total weight of the aerosol formulation. A pressurized metered-dose inhaler according to claim 14, characterized in that the formoterol is present in an amount of 0.01 to 0.02% by weight or less, based on the total weight of the aerosol formulation. A pressurized metered-dose inhaler according to claim 14, characterized in that the formoterol comprises formoterol fumarate. A pressurized metered dose inhaler according to claim 1, wherein the aerosol formulation is substantially free of surfactant. A pressurized metered-dose inhaler according to claim 14, characterized in that the formoterol contains formoterol fumarate in an amount of not more than 1% by weight, wherein the solvent contains ethanol in an amount of more than 5% to 30% by weight and the propellant is present in 70 to 94% by weight. and all based on the total weight of the aerosol formulation. A pressurized metered-dose inhaler according to claim 1, characterized in that the aerosol formulation is adapted to be stable at temperatures of up to 40 ° C. and relative humidity 75 % at least for 4 weeks. 21. Pressure inhaler with measured benefits marked u j i c i se t i m that it contains jar provided with a metering valve and a compressed aerosol formulation formulated from a composition comprising: - β-agonist particles, at least one fluoroalkane propellant, and -surfactant capable of suspending the β-agonist particle. A pressurized metered-dose inhaler according to claim 21, characterized in that the metering valve is designed and arranged to provide metered doses of the β-agonist in an amount that is therapeutically effective. A metered dose inhaler according to claim 21, wherein the metering valve is designed and arranged to provide a metered dose of β-agonist in an amount of 12 µg per actuation of the metering valve. 24. A pressurized metered-dose inhaler (21) characterized in that 1,1,1,2-tetrafluoroethane. dosages according to claim fluoroalkane comprises 25. The metered dose inhaler of claim 21, wherein the aerosol formulation is substantially free of chlorofluorocarbons. A pressurized metered-dose inhaler according to claim 21, characterized in that the propellant is present in an amount of not more than 99.9% by weight. A pressurized metered-dose inhaler according to claim 21, wherein the β-agonist comprises formoterol. A metered dose inhaler according to claim 27, wherein the formoterol has an average particle size of less than 100 µπι. The metered dose inhaler of claim 27, wherein the formoterol has an average particle size of less than 20 µπι. A metered dose inhaler according to claim 27, wherein the formoterol has an average particle size of 1 to 10 µπι. A metered dose inhaler according to claim 21, wherein the cartridge-forming aerosol formulation is substantially free of solvents. A metered dose inhaler according to claim 27, wherein the formoterol is present in an amount of 1% by weight relative to the total weight of the aerosol formulation. A pressurized metered-dose inhaler according to claim 27 wherein formoterol is present in an amount of 0.01 to 0.02% by weight based on the total weight of the aerosol formulation. • · · · · 34. A pressurized metered dose inhaler according to claim 27, wherein the formoterol comprises formoterofumarate. 35. A pressurized metered dose inhaler according to claim 21, wherein the surfactant is present in an amount of at least 0.002% by weight, based on the total weight of the aerosol formulation. 36. A metered dose inhaler according to claim 21, wherein the surfactant is present in an amount of 1% by weight or less, based on the total weight of the aerosol formulation. 37. The metered dose inhaler of claim 21, wherein the surfactant is at least one selected from the group consisting of polyalcohols. 38. The metered dose inhaler of claim 21, wherein the surfactant is at least one selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene (20) sorbital monolaurate or monooleate, and polyoxyethylene-4-lauryl ether. A pressurized metered-dose inhaler according to claim 21, characterized in that the surfactant comprises polyoxyethylene-4-lauryl ether. A pressurized metered-dose inhaler according to claim 27, wherein the formoterol contains formoterol fumarate in an amount of at most 1% by weight, the surfactant comprises polyoxyethylene-4-lauryl ether in an amount of 1% by weight or less, and the propellant is present in an amount. 99.9% by weight, all based on the total weight of the aerosol formulation. 41. A metered dose inhaler according to claim 21, wherein the aerosol formulation is adapted to be stable at a temperature of up to 40 ° C and a relative humidity of 75% for at least 4 weeks. 42. An aerosol formulation, characterized in that it is adapted for use as a cartridge in a pressurized aerosol container, and is formulated from a composition comprising: - β-agonist, at least one fluoroalkane propellant, and - more than 5% by weight, based on the total weight of the aerosol formulation, of a solvent capable of solubilizing or dissolving a β-agonist. 43. Aerosol characterized p 1,1,1,2-tetrafluoroethane. The composition according to claim 42, which comprises fluoroalkane 44. An aerosol characterized by chlorofluorocarbons. wherein the composition is substantially free of the composition of claim 42 The aerosol formulation of claim 42, wherein the solvent is present in an amount of 70 to 94% by weight. 46. An aerosol formulation according to claim 42, wherein the solvent is present in an amount of at least 10% by weight. · · * * * * * * »» »» »» »» »» · · 47. The aerosol formulation of claim 42 wherein the solvent is present in an amount of at least 15% by weight. 48. The aerosol formulation of claim 42, wherein the solvent is present in an amount of greater than 5% to 30% by weight based on the total weight of the aerosol formulation. 49. The aerosol formulation of claim 42, wherein the solvent is selected from the group consisting of ethers and alcohols. 50. An aerosol formulation according to claim 42 wherein the solvent comprises an aliphatic alcohol having 1 to 6 carbon atoms. 51. An aerosol formulation wherein the ethanol. according to claim 42, the solvent comprises 52. Aerosol characterized as polar than propellant. The composition of claim 1 wherein the solvent is more than one 53. Aerosol characterized formoterol. The composition of claim 42 wherein the β-agonist comprises 54. The aerosol formulation of claim 53, wherein the formoterol is present in an amount of 1% by weight or less, based on the total weight of the aerosol formulation. Φ Φ Φ • φφ Φ Φ 55. Aerosol preparation. according to claim 53, characterized in that the formoterol is present in an amount of 0.01 to 0.02% by weight or less, based on the total weight of the aerosol formulation. • Φ φφ • 9 4 Φ • Φ Φ Φ Φ Φ Φ Φ Φ ΦΦ ΦΦΦΦ 56. An aerosol indicating formoterol fumarate. The composition of claim 53 wherein the formoterol comprises 57. An aerosol comprising substantially free of a surfactant formulation according to claim 1 wherein the formoterol comprises 1% by weight, wherein the formulation comprises: 58. An aerosol formulation comprising at most solvent formoterol fumarate in an amount of greater than 5% to 30% by weight of ethanol, and a propellant present in an amount of 70 to 94% by weight, based on the total weight of the aerosol formulation. 59. An aerosol formulation according to claim 42, characterized in that it is adapted to be stable at a temperature of up to 40 ° C and a relative humidity of 75% for at least 4 weeks. 60. An aerosol formulation adapted for use in a pressurized aerosol container, characterized in that it is formulated from a composition comprising: - β-agonist particles, at least one fluoroalkane propellant, and - a surfactant capable of forming a suspension of β-agonist particles. ··· ···· 61. The aerosol formulation of claim 60, wherein the fluoroalkane comprises 1,1,1,2-tetrafluoroethane. 62. Aerosol characterized by chlorofluorocarbons. wherein the composition is substantially free of the composition of claim 60 63. An aerosol formulation wherein the amount is at most 99.9% by weight. according to claim 60, a propellant is present 64. An aerosol characterized by formoterol. A composition according to claim 1 comprising a β-agonist of claim 65. An aerosol characterized with a particle size smaller than formulation e by 100 µm. according to formoterol of claim 64 has an average 66. An aerosol having a particle size smaller than formulation e by 20 µm. according to formoterol of claim 64 has an average 67. The aerosol formulation of claim 64, wherein the formoterol has an average particle size of 1 to 10 μπι. 68. Aerosol indicating solvents. The composition of claim 60 substantially free 0 · 000 69. An aerosol formulation according to claim 64 wherein the formoterol is present in an amount of 1% by weight relative to the total weight of the aerosol formulation. 70. An aerosol formulation according to claim 64 wherein the formoterol is present in an amount of 0.01 to 0.02% by weight relative to the total weight of the aerosol formulation. 71. An aerosol indicating formoterol fumarate. The composition of claim 64 comprising formoterol 72. An aerosol formulation according to claim 60, wherein the surfactant is present in an amount of at least 0.002% by weight relative to the total weight of the aerosol formulation. 73. An aerosol formulation according to claim 60 wherein the surfactant is present in an amount of 1% by weight or less, based on the total weight of the aerosol formulation. 74. The aerosol formulation of claim 60, wherein the surfactant is at least one selected from the group consisting of polyalcohols. 75. The aerosol formulation of claim 60 wherein the surfactant is at least one selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene sorbital (20) sorbital monolaurate or monooleate, and polyoxyethylene 4-lauryl ether; 76. An aerosol formulation comprising polyoxyethylene-4-lauryl ether. according to claim 60 that the surfactant comprises 77. An aerosol formulation according to claim 64 wherein formoterol contains formoterol fumarate in an amount of not more than 1% by weight, the surfactant comprises polyoxyethylene-4-lauryl ether in an amount of 1% by weight or less and the propellant is present in an amount of 99.9% by weight. to the total weight of the aerosol formulation. 78. The aerosol formulation of claim 60, wherein the aerosol formulation is adapted to be stable at temperatures of up to 40 ° C and 75% relative humidity for at least 4 weeks.