CZ20004793A3 - Pressurized metered dose inhalers and pharmaceutical aerosol formulations - Google Patents

Abstract

The invention provides a pressurized metered dose inhaler containing a stable preparation of a drug acting as a β-agonist in the form of a solution or suspension. It also provides an aerosol preparation suitable for treatment by inhalation containing a β-agonist in the form of a solution or suspension.

Description

Pressurized metered dose inhalers and pharmaceutical aerosol preparations

Technical field

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

State of the art

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preparations in aerosol packages for medical use based on chlorinated hydrocarbons and chlorofluorocarbons have mostly been replaced by hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane (HFA134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea), which have been found to be safe for use in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

Such aerosol pharmaceutical preparations are generally of the solution or suspension type. Each such preparation is composed of at least a drug and a propellant. Some preparations further contain one or more adjuvants with a special purpose, such as an additional solvent, i.e. cosolvent, or a surfactant, i.e. surface-active agent (see EP 0 372 777). Conventional solution-based aerosol preparations (solution preparations) contain a low concentration of a cosolvent that is more polar than the propellant. Conventional suspension-based aerosol preparations (suspension preparations) contain a surfactant, rather than a cosolvent, on the theory that the surfactant will prevent particles from clumping and adhering to the walls of the pressurized container, and at the same time act as a lubricant for the spray valve (actuator) (see US 3 014 844).

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

The β-agonist drug (hereinafter referred to as β-agonist), formoterol (known as eformoterol in Europe) and its derivatives, are difficult to formulate into conventional aerosol formulations. Such formulations have been shown to have a short shelf life and require storage at low temperatures (in a refrigerator). However, refrigeration is undesirable because many patients have to carry a supply of the aerosol with them. This necessitates the development of aerosol formulations of β-agonists such as formoterol and its derivatives that are chemically and physically stable when stored at normal room temperature and humidity.

The essence of the invention

The object of the present invention is to provide a pressurized metered dose inhaler containing a stable β-agonist preparation that does not require refrigeration.

Another object is to provide a stable preparation formulated from a drug acting as a β-agonist(s), namely for use in the dosage form of an aerosol preparation in a pressurized container (spray), which does not require refrigeration during storage.

The above objectives have surprisingly been achieved in the present invention. The invention provides a novel pressurized inhaler comprising •· · · ·· «« • «··«· · · . · « » • ·»·» * · « ♦··«» ·»··· «· (a.

a container equipped with a dosing spray valve, which contains a filling - an aerosol preparation, formulated from a composition containing:

- β-agonist,

- at least one fluoroalkane propellant and

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

The invention further provides a novel pressurized metered dose inhaler comprising a reservoir container equipped with a metering valve, which contains a pressurized aerosol preparation formulated from a composition comprising:

- β-agonist particles,

- at least one fluoroalkane propellant and

- a surfactant that is capable of forming a suspension of β-agonist particles.

The invention also provides a novel aerosol formulation for use in a pressurized aerosol container, the aerosol formulation being 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 preparation, of a solvent capable of solubilizing or dissolving the β-agonist.

The invention further 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 a surfactant capable of forming a suspension of β-agonist particles.

Aerosol preparations according to the invention are surprisingly stable

* · 0 0 0 0 it

0 « 0 • 0 *· 0 in conditions of temperature up to 40 °C and relative humidity of 75% for at least 4 weeks.

Image description

Fig. 1 illustrates a chromatogram of formoterol fumarate that was formulated as a suspension.

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

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

Any solvent capable of solubilizing or dissolving the selected β-agonist can be used in the present invention. Examples of suitable solvents include alcohols, •»· « >

* · · · · · ethers, hydrocarbons and perfluorocarbons. Preferred solvents are polar, short-chain 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 cartridge fill). Preferably, the solvent is present in an amount of 10 to 15% (w/w). It will be apparent to those skilled in the art, based on the present invention, that lower drug concentrations typically require lower solvent concentrations and vice versa, in order to form a stable solution.

Any fluoroalkane propellant suitable for inhalation can 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 can be added as required to modify the properties of the propellant.

The propellant for solution formulations is typically present in an amount of 70 to 94% (w/w) based on the total weight of the aerosol formulation (i.e., the cartridge fill). A preferred aerosol formulation contains 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 of about 85% (w/w), about 15% (w/w), and about 0.01% (w/w).

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

Any metered dose inhaler suitable for pulmonary or nasal administration of a drug 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 μm. However, at the higher concentration of solvent used in the invention, it is desirable that the solvent evaporates as quickly as possible after inhalation. This can be achieved, for example, by reducing the diameter of the outlet opening to, for example, 250 μm, while using a solvent concentration of 10 to 15% (w/w). Based on the description of the present invention, the skilled person is able, without undue experimentation, to adjust the composition so that the desired dose of drug is delivered by the selected metering valve. For example, the vapor pressure of the formulation can be adjusted. The aerosol formulation and metering valve are typically selected to provide a therapeutically effective amount of β-agonist per valve actuation (valve actuation). An example of a therapeutically effective amount of formoterol fumarate is 12 μg per actuation.

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

A suitable propellant is any of the propellants described herein with respect to solution aerosol formulations. However, in a suspension aerosol formulation, the propellant may be used at a concentration of up to 99.9% (w/w) based on the weight of the aerosol formulation (i.e., the cartridge fill).

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 (i.e., the cartridge fill).

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

Any surfactant suitable for administration to the lungs of a patient that is capable of suspending the β-agonist particles used in the formulation can 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 ether (Brij 30) or other surfactants with a similar HLB. A preferred surfactant is polyoxyethylene-4-lauryl ether (Brij 30). The surfactant is typically present in an amount of 1% (w/w) or less.

A preferred suspension formulation contains HFA-134a in an amount greater than 99% (w/w), Brij 30 surfactant in an amount of about 0.002% (w/w) or more, and formoterol fumarate in an amount of 1% (w/w) or less. A preferred suspension formulation contains 99% (w/w) HFA-134a, Brij 30 in an amount of about 0.02% (w/w) or more, 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).

The following examples are given only to illustrate preferred embodiments and do not limit the scope of the present invention in any way, the invention being defined by the claims which are based on

• · • · ft full description.

Examples of embodiments of the invention

Examples 1 to 3

Three suspension aerosols according to 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 bottle or aluminum container.

2. adding the weighed drug.

3. Inserting the valve into the bottle or container.

4. adding a known amount of propellant through a valve into a bottle or container.

5. Sonicate the preparation for approximately 5 minutes.

A 19 ml aluminium Presspart metered dose inhaler canister with a 63 μΐ Bespak BK357 metering valve was used unless otherwise stated.

The properties of the aerosol packaging (sprays) from the example were tested using one or more of the following parameters:

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

- leakage according to the standards set forth in the US Pharmacopeia No. 23 and the National Pharmacopeia No. 18,

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

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

- the chemical test should be between 90.0 and 110% of the data stated on the label,

- weight per metered dose, spray dose content and content uniformity according to the standards set out in the Pharmacopeial Forum, Vol. 22, No. 6, and

M· • · ·· ·♦ 0·

4 · 0 0 0 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. Comparing the percentage of deposition in stage 2, it was found that the formulations containing Brij 30 and Tween 20 were better than the formulations containing PEG 300. In addition, the data show that the formulation with Tween 20 deposited a greater amount of drug on the nebulizer. Therefore, to minimize deposition on this type of nebulizer, Brij 30 was a more useful surfactant than Tween 20 in these formulations.

Examples 4 to 7

Four solution aerosol formulations (pressurized pack refills) of the present invention were formulated by mixing the ingredients listed in Table 2 using the method described in Example 1. To determine the stability of the solution aerosol formulations, Examples 6 and 7 were maintained for 1 month (28 days) at 40°C and 75% relative humidity, which is considered to be the severe conditions herein. The solution aerosol formulations were equilibrated at room temperature overnight before 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 delivered dose (using spray dose determination) after storage under harsh conditions was lower than the dose obtained with the original samples, due to adsorption of the drug onto the valve seal material. However, the solution aerosol formulations showed no signs of chemical degradation.

• ·

Examples 8 and 9 which is here with solution

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 kept for 1 month (28 days) at 40°C and 75% relative humidity, under harsh conditions. The formulations were equilibrated at room temperature overnight before 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 seal material, resulting in a loss of approximately 100% of the aerosols (by weight). However, the solution aerosol formulations showed no signs of chemical degradation.

Examples 10 to 13

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% relative humidity, which is considered to be the severe conditions herein. The suspension aerosol formulations were equilibrated at room temperature overnight before 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 (using 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 solution preparation examples.

Examples 14 to 17

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% relative humidity, which is considered to be the severe conditions herein. The suspension aerosol formulations were equilibrated at room temperature overnight before 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 that approximately 10% loss of drug occurred after storage under harsh conditions in Examples 16 and 17, relative to the starting Examples 14 and 15. This value is within acceptable limits and was in the region of 100% mass balance (container contents - drug in container). In addition, a particle size determination method (Andersen impactor) was used, which is permissible according to the United States Pharmacopeia (USP). The results show that no chemical (such as the appearance of a known degradation product or loss of parent compound) or physical instability occurred after storage, including 1) increase in particle size (MMAD - median aerodynamic diameter), 2) change in distribution (GSD - geometric standard deviation), 3) change in fine particle dose, or 4) change in fine particle fraction.

·*

• · • 9

9

Examples 18 and 19

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 suspension aerosol formulations 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 were recorded as Figures 1 and 2, respectively. Only one peak was observed in each figure, representing intact drug. No peaks representing degradation products were observed (expected to appear 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) spray dose weight (mg) valve/sprayer (mcg) throat/neck (mcg) stage 1 (mcg) stage 2 (mcg) mass balance (%) % in stage 2 spray dose weight (mg) iti ω 1—1 1 tj ÍC surfactant formoterol fumarate Test Contents of a spray dose Liquid fallout in a single stage Preparation i

polyethylene glycol 300 φφ

CN

Table • ·· ·· φφ ·· · · · · t · • · · « φ <

φ φφφφφ φ φ • φφφφ •·· ·· ·· φφφφ

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 About 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 About 20-24 0.00 96 'LZ 2.44 38.81 58 56.08 76.39 60-79 4.58 77 76.52 51-54 About 55-59 1 Starting 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 'OH > O Λ4 4-1 1—1 spray dose weight (mg) number of spray doses spray dose weight (mg) number of spray doses valve/sprayer (mcg) throat/neck (mcg) stage 1 (mcg) stage 2 (mcg) mass balance (%) % in stage 2 spray dose weight (mg) ! number of spray doses drug per dose (mcg) ¹ mass balance (%) spray dose weight (mg) number of spray doses spray dose weight (mg) ¹ number of spray doses humidity (ppm) Test Contents of a spray dose Weight of spray dose Liquid fallout in a single stage Contents of a spray dose Weight of spray dose 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 O τ—1 The tn O γΗ Γ-| 04 43 i—1 04 00 1 O 1 04 σ O χ ,— x οοο χ σ> O x 04 ιΌ O 40 ο θ' χ χ LQ The 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 I O Lf) O τ—i χ The χ 00 x O ο x ο 04 O 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 O O 04 t> χ ΟΟ χ 04 χ ο O x O 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 M μ μ 0 £ μ and η and Φ μ '«3 W V) ω V) The 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 Γ—I I £3 and £3 and S3 Φ μ 'φ > > 0 0 •γί ΓΊ Φ Φ μ M CU and 7) ω 44 At <υ υ] > O <0 £3 >, c: >1 μ (ϋ Li 4J λ; and W > 0 > I η 'β β 'ίθ >CI ο β S3 β ίΧι

ω β

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Data after 28 days Example 9 1,324 tn what 16,853 3.0269 0.00156 ftf 4-1 flj β WHAT I β cn N β cn 40 m 0 1—1 r- 0Ί 00 í—1 £3 A σ cn 00 about At I tn about X About about X about 40 X» X > and i—1 rH r-1 00 about Cn g -P <U 'Íú at Cl rs (0 0 b β en 'β M-l d 4-> rH β c 0 > A β β Cl >N 4-J β 0 >0) cn A 4-1 > 4-1 χ—1 oh 0 •H 1 M-4 β >at > Cl The '(1) and EN 0 Pl oP with n M-l >1 A rs About β A β CDs d > β £3 Cl £4 Ch M w I <U Ό >Cl H About 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 _ Starting data Example 11 14.22 89 82.9 1 kD O) r- 8-12 31, 36 27, 93 O Li) O) kD r* 90 54.32 81.7 13-22 15, 49 σι 81.4 50-51 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) mass balance (%) [spray dose weight (mg) [number of spray doses spray dose weight (mg) number of spray doses valve/sprayer (mcg) throat/neck (mcg) stage 1 (mcg) stage 2 (mcg) mass balance (%) % in stage 2 spray dose weight (mg) number of spray doses drug per dose (mcg) mass balance (%) spray dose weight (mg) number of spray doses spray dose weight (mg) number of spray doses Test Contents of a spray dose Weight of spray dose Liquid fallout in a single stage Contents of spray dose 1 Weight of spray dose

• ·

Table 4 - continued

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Table

X u Example 17 1 1 15.25 9.37 17.15 2.60 2.15 2.94 Γ' kD co I— 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 it r-H OO (TJ X kD 4J I About 00 <ie >M| *» About at CM CN rd 1 I 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 about to WHAT what Γ τ—1 CN kD what 00 UO r—1 !—1 that 00 00 WHAT ^sP to. ». to. 00 CN uf) <to i—1 LQ OY to. >P _with CY about with to, :—1 t—1 about to. κ »—1 WHAT about κ to. what what CM 1 1 cn i—1 CN what 00 τ—1 what CN rd About 00 rd about CN rd Γ- Γ· Π3 X fO xp TJ i—1 I Those N (0 0 i-1 cn Λ X what at I CN 00 >P · to. 1—1 > CM CN I—1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 I 1 1 1 I tn ____ Γ) Oy R σ· about at oP about g With — g B about ·*—* OJ .—, i—1 X oP υ •H g M| <u i—1 — •red X '0 >N —. 0) -P WHAT X G θ' about (Ie what '<Ie <u £1 44 at 43 'flj >0 at rO \ to. —in B 0 'WHAT >0 X TJ My m OY tTi θ' tn tr> tTi O» Oy > > 43 0 it About at about About t) at about About about about 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 it 0 fu 1 r—| 0 c To G g > about i—1 CN what ^p m kD Γ- about Ml g Φ > X about what '(D (LI •ΓΊ >N >cn β B B B g B B B B B G '(Those •year 0 ><1) 1-1 it Those G G G G G G G G G B Φ > <D > X My 0 H •H •H •H •H •H Φ >N 0 flj At 4-1 o. > Ό Ό TJ TJ in TJ τ) •σ Those X ><U X Q X X >at > G N I Π3 fO fO nJ it it Π3 you (TJ 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 Γ—I oP > Ml £2, what 10 10 WHAT WHAT WHAT WHAT WHAT what at > r-1 2 about T3 Md >1 X 42 0 > τ> ’G 'rtj G My C 0) 0 what At 43 My 44 X (Cj (ϋ fÚ WHAT what τ) & <u 42 β B E-i About < •H

• 0 ·

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0

0 and

*

Table 5 - continued

10,219 0.00241 0.00192 00 CN 00 cn what <— r—1 i—1 about About to. about about about kw rH about about CN 21 89 CN rH CDs About About To About About about kw kw !— about about cn 163 189 The About About 00 about about to» kw kw σϊ about about fO about erol fumarate what what 4-> i—1 1 •ΓΊ 0 seconds •H YOU ra M 0 and ra 4-1 Preparation

♦ · ·· * · * · > ♦ * • ·

Table 6

test Example 18 Example 19 Contents of a spray dose drug per dose (mcg) 10.87 9.55 mass balance (%) 89, 0 78.5 spray dose weight (mg) 78.6 78.0 number of spray doses 6-7 71-72 Contents of a spray dose drug per dose (mcg) 10.51 12.90 mass 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 nebulizer/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 recovered (mcg) 140.69 128.93 mass 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 - continued

Andersen impactor valve (mcg) 5, 64 - nebulizer/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 recovered (mcg) 132.98 - mass 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 Take 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 of the present invention may be made without departing from the original inventive concept, thus falling within the scope of the present invention.

Claims (19)

PATENT CLAIMS 1. A pressurized metered dose inhaler, characterized in that it comprises a container provided with a metering valve and a pressurized aerosol preparation 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 preparation, of a solvent capable of solubilizing or dissolving the β-agonist. 2. A pressurized metered dose inhaler according to claim 1, characterized in that the metering valve is constructed and arranged to provide metered doses of β-agonist in an amount that is therapeutically effective. 3. A pressurized metered dose inhaler according to claim 1, characterized in that the metering valve is constructed and arranged to provide metered doses of β-agonist in an amount of 12 μg per actuation of the metering valve. 4. A pressurized metered dose inhaler according to claim 1, characterized in that the fluoroalkane contains 1,1,1,2-tetrafluoroethane. 5. A pressurized metered dose inhaler according to claim 1, characterized in that the preparation is substantially free of chlorofluorocarbons. 9 4 6. A pressurized metered dose inhaler according to claim 1, characterized in that the propellant is present in an amount of 70 to 94% by weight. 7. A pressurized metered dose inhaler according to claim 1, characterized in that the solvent is present in an amount of at least 10% by weight. 8. A pressurized metered dose inhaler according to claim 1, characterized in that the solvent is present in an amount of at least 15% by weight. 9. A pressurized metered dose inhaler according to claim 1, characterized in that the solvent is present in an amount of greater than 5% to 30% by weight, based on the total weight of the aerosol preparation. 10. A pressurized metered dose inhaler according to claim 1, characterized in that the solvent is selected from the group consisting of ethers and alcohols. 11. A pressurized metered dose inhaler according to claim 1, characterized in that the solvent comprises an aliphatic alcohol having 1 to 6 carbon atoms. 12 . knows ethanol. Pressure sensor inhaler with c í se measured by the fact that dosages according to solvent claim 1 contains 13. Pressure inhaler with measured doses according to claim 1 confess listen feels by the fact that solvent there is more more polar than the propellant. 14. A pressurized metered dose inhaler according to claim 1, characterized in that the β-agonist comprises formoterol. 15. A pressurized metered dose inhaler according to claim 14, characterized in that formoterol is present in an amount of 1% by weight or less, based on the total weight of the aerosol preparation. 16. A pressurized metered dose inhaler according to claim 14, characterized in that formoterol is present in an amount of 0.01 to 0.02% by weight or less, based on the total weight of the aerosol preparation. 17. A pressurized metered dose inhaler according to claim 14, characterized in that the formoterol comprises formoterol fumarate. 18. A pressurized metered dose inhaler according to claim 1, wherein the aerosol formulation is substantially free of surfactant. 19. A pressurized metered dose inhaler according to claim 14, characterized in that formoterol contains formoterol fumarate in an amount of not more than 1% by weight, the solvent contains ethanol in an amount of more than 5% to 30% by weight and the propellant is present in an amount of 70 to 94% by weight, all based on the total weight of the aerosol preparation. 20. A pressurized metered dose inhaler according to claim 1, characterized in that the aerosol preparation is adapted to be stable in temperature conditions up to 40 °C * · · 9 · and relative humidity 75 % least for 4 weeks. 21. Pressure inhaler with measured doses mark u j i c i with t i m, that it contains container provided with a metering valve and a pressurized aerosol preparation formulated from a composition comprising: - β-agonist particles, - at least one fluoroalkane propellant and -surfactant capable of suspending β-agonist particles. 22. A pressurized metered dose inhaler according to claim 21, wherein the metering valve is constructed and arranged to deliver metered doses of the β-agonist in an amount that is therapeutically effective. 23. A pressurized metered dose inhaler according to claim 21, characterized in that the metering valve is constructed and arranged to provide metered doses 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. doses according to the claim fluoroalkane contains 25. A pressurized metered dose inhaler according to claim 21, wherein the aerosol formulation is substantially free of chlorofluorocarbons. 26. 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. 27. A pressurized metered dose inhaler according to claim 21, characterized in that the β-agonist comprises formoterol. 28. A pressurized metered dose inhaler according to claim 27, characterized in that the formoterol has an average particle size of less than 100 μm. 29. A pressurized metered dose inhaler according to claim 27, characterized in that the formoterol has an average particle size of less than 20 μm. 30. A pressurized metered dose inhaler according to claim 27, characterized in that the formoterol has an average particle size of 1 to 10 μm. 31. A pressurized metered dose inhaler according to claim 21, characterized in that the aerosol preparation forming the cartridge is substantially free of solvents. 32. A pressurized metered dose inhaler according to claim 27, characterized in that formoterol is present in an amount of 1% by weight, based on the total weight of the aerosol preparation. 33. A pressurized metered dose inhaler according to claim 27, characterized in that formoterol is present in an amount of 0.01 to 0.02% by weight, based on the total weight of the aerosol preparation. • · · · · 34. A pressurized metered dose inhaler according to claim 27, wherein the formoterol comprises formoterol fumarate. 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 pressurized 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. A pressurized metered dose inhaler according to claim 21, characterized in that the surfactant is at least one selected from the group consisting of polyalcohols. 38. The pressurized 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. 39. A pressurized metered dose inhaler according to claim 21, characterized in that the surfactant comprises polyoxyethylene-4-lauryl ether. 40. A pressurized metered dose inhaler according to claim 27, wherein the formoterol comprises 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, all based on the total weight of the aerosol preparation. 41. A pressurized metered dose inhaler according to claim 21, characterized in that the aerosol preparation is adapted to be stable under conditions of temperature up to 40°C and relative humidity of 75% for at least 4 weeks. 42. An aerosol preparation characterized in that it is adapted for use as a filling in a pressurized aerosol container, wherein it 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 preparation, of a solvent capable of solubilizing or dissolving the β-agonist. 43. Aerosol characterized by 1,1,1,2-tetrafluoroethane. a preparation e t 1 m, that according to claim 42 that the fluoroalkane contains 44. Aerosol characterized by chlorofluorocarbons. a preparation in that it is essentially free of, according to claim 42 45. An aerosol formulation according to claim 42, characterized in that 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. An aerosol formulation according to claim 42, wherein the solvent is present in an amount of at least 15% by weight. 48. An aerosol formulation according to 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. An aerosol preparation according to claim 42, characterized in that 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 preparation characterized in that ethanol. according to claim 42 the solvent comprises 52. Aerosol characterized by a polar non-propellant. a preparation according to claim 1, wherein the solvent is more 53. Aerosol mark ici formoterol. a preparation according to claim 42, wherein the β-agonist comprises 54. An aerosol formulation according to claim 53, wherein 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. An aerosol formulation according to claim 53, wherein 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 ΦΦΦΦΦΦΦ 56. Aerosol containing formoterol fumarate. a preparation according to claim 53, wherein formoterol contains 57. An aerosol formulation according to claim 53, characterized in that the aerosol formulation comprises 1% by weight of formoterol, which is substantially surfactant-free. 58. An aerosol preparation characterized in that formoterol fumarate is present in an amount of at most 5% to 30% by weight of ethanol, and the propellant is present in an amount of 70 to 94% by weight, all based on the total weight of the aerosol preparation. 59. An aerosol preparation according to claim 42, characterized in that it is adapted to be stable under conditions of temperature up to 40°C and relative humidity of 75% for at least 4 weeks. 60. An aerosol preparation 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. An aerosol preparation according to claim 60, characterized in that the fluoroalkane comprises 1,1,1,2-tetrafluoroethane. 62. Aerosol characterized by chlorofluorocarbons. a preparation in that it is essentially free of, according to claim 60 63. Aerosol preparation characterized in that in an amount of not more than 99.9% by weight. according to claim 60, the propellant is present 64. Aerosol characterized by formoterol. the preparation by containing, according to the claim, a β-agonist 65. Aerosol characterized by a particle size smaller than the preparation e by 100 pm. according to claim 64 formoterol has an average 66. Aerosol characterized by a particle size smaller than the preparation e by 2 0 pm. according to claim 64 formoterol has an average 67. An aerosol preparation according to claim 64, characterized in that the formoterol has an average particle size of 1 to 10 μm. 68. Aerosol indicating solvents. a preparation comprising, according to claim 60, substantially free of 0 · 000 69. An aerosol formulation according to claim 64, wherein formoterol is present in an amount of 1% by weight, based on the total weight of the aerosol formulation. 70. An aerosol formulation according to claim 64, wherein formoterol is present in an amount of 0.01 to 0.02% by weight, based on the total weight of the aerosol formulation. 71. Aerosol containing formoterol fumarate. a preparation according to claim 64, wherein formoterol comprises 72. The aerosol formulation of claim 60, wherein the surfactant is present in an amount of at least 0.002% by weight, based on the total weight of the aerosol formulation. 73. The aerosol formulation of 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. An aerosol preparation according to claim 60, characterized in that the surfactant is at least one selected from the group consisting of polyalcohols. 75. An aerosol formulation according to claim 60, characterized in that 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, 76. An aerosol preparation characterized by polyoxyethylene-4-lauryl ether. according to claim 60, the surfactant comprises 77. An aerosol formulation according to claim 64, wherein the formoterol comprises 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, all based on the total weight of the aerosol formulation. 78. An aerosol preparation according to claim 60, characterized in that it is adapted to be stable under conditions of temperature up to 40°C and relative humidity of 75% for at least 4 weeks.