MXPA00012655A

MXPA00012655A - Pressurized metered dose inhalers and pharmaceutical aerosol formulations

Info

Publication number: MXPA00012655A
Application number: MXPA/A/2000/012655A
Authority: MX
Inventors: Frank E Blondino; Michael Brucato; Maria W Buenafe
Original assignee: Baker Norton Pharmaceuticals Inc
Priority date: 1998-06-19
Filing date: 2000-12-18
Publication date: 2001-12-13

Abstract

Provided are pressurized metered dose inhalers containing stable formulations of a&bgr;-agonist drug in suspension or solution. Also provided are aerosol formulations suitable for inhalation therapy containing a&bgr;-agonist drug in suspension or solution.

Description

PRESSURIZED INHALERS WITH MEASURED DOSE AND PHARMACEUTICAL FORMULATIONS FOR AEROSOL 1. FIELD OF THE INVENTION The invention relates to pressurized inhalers with metered doses and aerosol formulations for inhalation treatment. 2. BACKGROUND OF THE INVENTION For environmental considerations, the chlorohydrocarbon and chlorofluorocarbon propellants for aerosol formulations for medical use have been displaced to a large extent by hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane ("HFA-134a") and 1,1 , 1,2,3,3,3-heptafluoropropane ("HFA-227ea") that have been identified as safe for use in pressurized inhalers with measured doses. These medicinal aerosol formulations are generally of the solution or suspension type. Each type is composed of, at least, the medicine and the propellant. Some formulations also include one or more adjuvants for special purposes such as a cosolvent or a surfactant (EP 0 372777). Traditional formulas of aerosol solutions contain low concentrations of a cosolvent more polar than the propellant Traditional formulations of aerosol suspensions contain a surfactant instead of a cosolvent according to a theory that the surfactant will prevent the agglomeration of the particles, their adhesion to the walls of the aerosol container and will provide lubrication of the metering valve ("activator"). (US 3,014,844). As a cosolvent, ethanol was used. However, the above teachings (see, for example, EP 0 616525) have stopped using ethanol concentrations greater than 5% for aerosol solution formulations for β-agonists. Traditionally, ethanol concentrations greater than 5% have been used only for formulations based on steroids with hydrofluoroalkane propellants. The drug ß-agonist, formoterol ("eformoterol" in Europe) and its derivatives have shown difficulty for formulations in conventional aerosols. These formulations have presented short storage lives and require refrigeration. Refrigeration is undesirable because many patients require the carrying of aerosol containers. Therefore, there remains a need for aerosol formulations for β-agonist drugs such as formoterol and its derivatives that remain chemically and physically stable during storage under ambient temperature and humidity conditions.

SUMMARY OF THE INVENTION An object of the present invention is to provide a pressurized inhaler for metered doses containing a stable formulation of a β-agonist drug, which does not require the use of refrigeration. Another objective of the present invention is to provide a stable formulation of a β-agonist drug which is convenient for use as an aerosol, which does not require the use of refrigeration. The above objectives and other objectives are achieved surprisingly by the following. The present invention provides a novel metered dose pressurized inhaler consisting of a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from the composition containing: a β-agonist medicament; at least one fluoroalkane propellant; and more than 5% by weight, based on the total weight of the aerosol formulation, of a solvent that is capable of solubilizing or dissolving the β-agonist drug. The invention further provides a novel pressurized inhaler for metered doses consisting of a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition containing: particles of a β-agonist drug; at least one fluoroalkane propellant; and a surfactant capable of forming a suspension of the β-agonist drug particles. The invention also offers a novel aerosol formulation adapted for use in a pressurized aerosol container; the aerosol formulation being formulated from a composition containing: a β-agonist drug; at least one fluoroalkane propellant; and more than 5% by weight, based on the total weight of the aerosol formulation, of a solvent that is capable of solubilizing or dissolving the β-agonist drug. The invention further provides a novel aerosol formulation adapted for use in a pressurized aerosol container, the aerosol formulation being formulated from a composition containing: particles of a β-agonist drug; at least one fluoroalkane propellant; and a surfactant that is capable of forming a suspension of the β-agonist drug particles. The aerosol formulations are surprisingly stable under the conditions of up to about 40 ° C and about 75% relative humidity during when less approximately four weeks.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates a formoterol fumarate chromatogram formulated as a suspension; and Figure 2 illustrates a chromatogram of formoterol fumarate after storage for 28 days at 40 ° C and 75% relative humidity.

DETAILED DESCRIPTION OF THE INVENTION Unexpectedly it has been discovered that the stability of aerosol formulations of solutions of a β-agonist drug can be significantly improved by using more than 5% by weight of a solvent capable of solubilizing or dissolving the β-agonist drug. The β-agonist drug can be any form that is convenient for application to the lungs or nasal passages of a human, such as the base form or the weak acid form. The present invention will be described with reference to the drug β-agonist formoterol. The term "formoterol" hereinafter is to be understood as the base form of formoterol as well as the weak acid form of formoterol, unless otherwise stated. A preferred weak acid form of formoterol is formoterol fumarate. The amount of the β-agonist drug used in the Aerosol formulation will depend on the type of medication selected. For the formoterol fumarate, the concentration used is usually about 1% by weight or less, preferably about 0.01% to about 0.02% by weight, based on the total weight of the aerosol formulation. Any solvent that is convenient for inhalation and capable of solubilizing or dissolving the β-agonist drug can be used. Examples of suitable solvents include alcohols, ethers, hydrocarbons and perfluorocarbons. Preferably, the solvent is short chain polar alcohols. More preferably, the solvent is an aliphatic alcohol having from 1 to 6 carbon atoms, such as ethanol and isopropanol. The most preferred solvent is ethanol. Examples of suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes. Examples of suitable ethers include dimethyl ether and diethyl ether. Examples of suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane and perfluoropentane. The solvent is normally present in an amount from about 6% to about 30% by weight, based on the total weight of the aerosol formulation. Preferably, the solvent is present in an amount of about 10% to about 15% by weight. With base in the description that is provided herein, one skilled in the art will realize that lower concentrations of the medicament will normally require lower concentrations of the solvent, and vice versa, to form a stable solution. Any fluoroalkane propellant that is suitable for inhalation may be used. Examples of suitable fluoroalkanes include HFA-134a, HFA-227ea, HFA-125 (pentafluoroethane), HFA-152a (1,1-difluoroethane), and HFA-32 (difluoromethane). Hydrocarbon and / or aliphatic gases can be added to modify the characteristics of the propellant as required. Preferably, the aerosol formulation is practically free of chlorofluorocarbons. However, chlorofluorocarbons may be used if desired. The propellant for the solution formulations is usually present in an amount from about 70% to about 94% by weight, based on the total weight of the aerosol formulation. A preferred aerosol formulation contains HFA-134a in an amount of less than about 90% by weight, ethanol in an amount greater than about 10% by weight and formoterol fumarate in an amount of about 0.01% by weight. A particularly preferred aerosol formulation contains about 85% by weight of HFA-134a, about 15% by weight ethanol and about 0.01% by weight of formoterol fumarate. Pressurized inhalers with metered doses are now well known in the art. It is possible to use any pressurized inhaler with metered doses that is convenient for application of medications to the lungs or nose of a patient. Pressurized inhalers with metered doses are usually equipped with a metering valve having a diameter in the spray orifice of approximately 460 μ. However, with the higher concentrations of the solvent employed in the present invention, it may be desirable for the solvent to evaporate as soon as possible after inhalation. This can be achieved by reducing the diameter of the sprinkler orifice, for example, to 250 μ, in combination with the use of solvent concentrations of from about 10 to about 15% by weight. Based on the description provided herein, one skilled in the art will be able to adjust the composition of the components to deliver a desired dose to the selected metering valve, without undue experimentation. For example, the composition can be altered to adjust the vapor pressure of the formulation. The aerosol formulation and the metering valve are usually selected to provide an effective amount for therapeutic use of the ß-agonist medication by activation. An example of an effective amount for therapeutic use of formoterol fumarate is about 12 μg per activation. It has also been unexpectedly discovered that stable aerosol formulations of the particle suspensions of a β-agonist drug can be formed using the β-agonist drug in combination with a surfactant that is capable of forming a suspension of the drug particles. β-agonist. The present invention will be described with reference to the drug β-agonist formoterol. The propellant can be any of the propellants described herein with reference to the aerosol solution formulations. However, the propellant in suspension aerosol formulations can be used in amounts up to about 99.9% by weight, based on the total weight of the aerosol formulation. The amount of the β-agonist drug used in the aerosol formulation will depend on the type of drug selected. For formoterol fumarate, the concentration used is usually about 1% by weight or less, preferably about 0.01% to about 0.02% by weight, based on the total weight of the aerosol formulation. The particle size of the β-agonist drug should be be suitable for inhalation in the nose or lung. Suitable average particle sizes are about 100 μ and less, about 20 μ and less, and most preferably in the range of about 1 to about 10 μ. It is possible to use any surfactant which is suitable for application to the lungs of a patient and which is capable of forming a suspension of the β-agonist drug particles. Examples of suitable surfactants include polyalcohols such as polyethylene glycol (PEG 300), diethylene glycol monoethyl ether (Transcutol), polyoxyethylene (20) sorbitan monolaurate (Tween 20) or sorbitan monooleate (Tween 80), propoxylated polyethylene glycol (Antarox 31R1) ), polyoxyethylene 4-lauryl ether (Brij 30), and surfactants having similar HLB. Preferably, the surfactant is polyoxyethylene 4-lauryl ether (Brij 30). The surfactant is usually present in an amount of about 1% by weight or less. A preferred suspension formulation contains HFA-134a in an amount greater than 99% by weight, Brij 30 surfactant in an amount of about 0.002% by weight or greater, and formoterol fumarate in an amount of about 1% or less. A particularly preferred suspension formulation contains about 99% by weight of HFA-134a, about 0.02% by weight of Brij 30 and about 0.02% by weight of formoterol fumarate. A particularly preferred formulation in a 19 ml container contains about 12.6 g / HFA-134a container, about 0.002 g / Brij 30 container and about 0.002 g / formoterol fumarate container. The following examples are presented only as an illustration of the particular embodiments of the invention and not to limit the clauses that are supported by the complete specification.

EXAMPLES 1-3 Three aerosols in suspension according to the present invention were formulated by combining the components shown in Table 1, using the following steps: 1. Weigh the solvent or surfactant in a glass bottle lined with plastic or a container of aluminum. 2. Add the heavy medication. 3. Attach a valve in a jar or container. 4. Add a known quantity of propellant through the valve to the bottle or container. 5. Sonify the formulation for approximately 5 minutes. A container for Presspart inhaler, with metered doses, of aluminum, of 19 ml was used with a metering valve of 63 μl Bespak BK357, unless it is established else. The properties of the aerosol formulations of the example were tested using one or more of the following: appearance (expert signs of leakage or deformation must not be present); leaks must comply with United States Pharmacopeia 23 and National Formulary standards; the contents of the container must be within 10% of the average; the medication per container must be within 25% of the average; the chemical test must be within 90.0-110% of what the label mentions; weight per measured dose; the content of the unit spraying and the uniformity of content must comply with the standards of the Pharmacopeial Forum, vol. 22, no. 6; and aerodynamic size distribution and water determination. The results of the tests are shown in Table 1.

By comparing the percent deposition in stage 2, it was determined that formulations containing Brij 30 and Tween 20 were superior to those containing PEG 300. In addition, the data show that the formulation with Tween 20 deposited a greater amount of the medication with activation. Therefore, to minimize deposition in this type of actuator, Brij 30 was a more useful surfactant in these formulations than was Tween 20.

Examples 4-7 Four aerosols in solution according to the present invention were formulated by combining the components shown in Table 2, using the method described in Example 1. To determine the stability of the formulations in solution for aerosol, the Examples 6 and 7 were maintained for one month (28 days) at 40 ° C and 75% relative humidity, conditions that were considered as accelerated conditions. The aerosol solution formulations were equilibrated at room temperature overnight before testing. The properties of the aerosol solution formulations were measured as in Example 1 and the results are shown in Table 2. The data indicate that the dose delivered (by determination of the unit spray) after storage under accelerated conditions was less than that obtained with the initial samples due to the adsorption of the medication on the material of the valve joint. However, the aerosol solution formulations showed no signs of chemical deterioration.

Examples 8 and 9 Two solutions for aerosol according to the present invention were formulated by combining the components shown in Table 3, using the method described in Example 1. To determine the stability of the formulations in aerosol solution, Example 9 was maintained for one month (28 days) at 40 ° C and 75% relative humidity, which was considered here as accelerated conditions. The aerosol solution formulations were equilibrated at room temperature overnight before testing. The properties of the aerosol solution formulations were measured as in Example 1 and the results are shown in Table 3. The medication could not be recovered from the joint materials during this study, which gave rise to a loss of about 15% by weight. However, the aerosol solution formulations showed no signs of chemical deterioration.

Examples 10-13 Four suspension formulations for aerosol according to the present invention were formulated by combining the components shown in Table 4, using the method described in Example 1. To determine the stability of the suspension formulations for aerosol, Examples 12 and 13 were maintained for one month (28 days) at 40 ° C and 75% relative humidity, which is considered herein as accelerated conditions. The aerosol suspension formulations were equilibrated at room temperature overnight before testing. The properties of aerosol suspension formulations were measured as in Example 1 and the results are shown in Table 4. After 28 days of storage, the dose delivered (by unit spray determination) in Examples 12 and 13 was lower than that obtained with the initial Examples 10 and 11, but was not reduced to the same extent as with the examples of the solution formulation. s Examples 14-17 Four suspension formulations for aerosol according to the present invention were formulated by combining the components shown in Table 5, using the method described in Example 1. To determine the stability of suspension formulations for aerosol, Examples 16 and 17 were maintained for one month (28 days) at 40 ° C and 75% relative humidity, which are considered here as accelerated conditions. Suspension formulations for aerosol were balanced at room temperature overnight before testing. The properties of the aerosol suspension formulations were measured as in Example .1 and the results are shown in Table 5. The data demonstrate that there was approximately 10% loss of the drug after storage under accelerated conditions in Examples 16 and 17, in relation to the initial Examples 14 and 15. This value is within the acceptable limits and was in the area of 100% materials difference (contents of the container - medication per container). In addition, the method accepted by the USP was used to determine the particle size (Andersen impactor). The results showed that there was no chemical instability (as appearance of a known degradation product or loss of precursor compound) or physical storage after included (1) as an increase in particle size (M AD - average aerodynamic diameter of the mass), (2) change in distribution (GSD - geometric standard deviation), (3) change in the dose of fine particles, or (4) change in the fraction of fine particles.

Examples 18 and 19 Two aerosols in suspension according to the present invention were formulated by combining the components that are shown in Table 6, using the method described in Example 1. The properties of suspension formulations for aerosol were measured as in Example 1 and the results are shown in Table 6.

Example 20 A suspension formulation for aerosol was formed by combining 99.96% by weight of HFA-134a, 0.02% by weight of formoterol fumarate and 0.02% by weight of Brij 30, using the method described in Example 1. Chromatograms HPLC of the aerosol suspension, before and after storage for 28 days at 40 ° C and 75% relative humidity, were obtained as in Figures 1 and 2, respectively. In each figure only one peak was observed representing the drug intact. No peaks were found representing fractional products of the drug (it was expected to be approximately 13 minutes). Thus, the aerosol suspension of formoterol showed long-term stability.

Table 1 B3 - Brij®30 T2 - Tween 20 P3 - Polyethylene glycol 300 Table 3 Table 6 Continuation Although the invention has been described in detail and with reference to the specific embodiments thereof, it will be apparent to those skilled in the art that it is possible to make different changes and modifications to the claimed invention without departing from the spirit and scope thereof.

Claims

CLAIMS A metered-dose pressurized inhaler consisting of a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition consisting of: a β-agonist medication; at least one fluoroalkane propellant; and more than 5% by weight, based on the total weight of the aerosol formulation, of a solvent that is capable of solubilizing or dissolving the β-agonist drug.
The metered dose pressurized inhaler according to claim 1, wherein the metering valve is constructed and arranged to provide metered doses of the β-agonist drug in an amount that is effective for therapeutic use.
The pressurized inhaler with metered doses according to claim 1, wherein the metering valve is constructed and arranged to provide metered doses of the β-agonist drug in an amount of about 12 μg by activation of the metering valve.
The pressurized inhaler with metered doses according to claim 1, wherein the fluoroalkane consists of 1,1,1,2-tetrafluoroethane.
The pressurized inhaler with metered doses according to claim 1, wherein the formulation is practically free of chlorofluorocarbons.
The pressurized inhaler with metered doses according to claim 1, wherein the propellant is present in an amount from about 70 to about 94% by weight.
The pressurized inhaler with metered doses according to claim 1, wherein the solvent is present in an amount of at least 10% by weight.
The pressurized inhaler with metered doses according to claim 1, wherein the solvent is present in an amount of at least 15% by weight.
The pressurized inhaler with metered doses according to claim 1, wherein the solvent is present in an amount ranging from more than 5% to about 30% by weight, based on the total weight of the aerosol formulation.
The pressurized inhaler with metered doses according to claim 1, wherein the solvent is selected from the group consisting of ethers and alcohols.
The pressurized inhaler with metered doses according to claim 1, wherein the solvent consists of an aliphatic alcohol having from 1 to about 6 carbon atoms.
12. The pressurized inhaler with metered doses according to claim 1, wherein the solvent consists of ethanol.
13. The pressurized inhaler with metered doses according to claim 1, wherein the solvent is more polar than the propellant.
14. The pressurized inhaler with metered doses according to claim 1, wherein the β-agonist drug consists of formoterol.
15. The pressurized inhaler with metered doses according to claim 14, wherein the formoterol is present in an amount of about 1% by weight or less, based on the total weight of the aerosol formulation.
16. The pressurized inhaler with metered doses according to claim 14, wherein the formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of the aerosol formulation.
17. The pressurized inhaler with metered doses according to claim 14, wherein formoterol consists of formoterol fumarate.
18. The pressurized inhaler with metered doses according to claim 1, wherein the aerosol formulation is practically without surfactant.
19. The pressurized inhaler with metered doses according to claim 14, wherein the formoterol consists of formoterol fumarate in an amount of up to about 1% by weight, the solvent consists of ethanol in an amount of greater than 5% to about 30% by weight. weight and the propellant is present in an amount from about 70% to about 94% by weight, all weights based on the total weight of the aerosol formulation.
20. The pressurized inhaler with metered doses according to claim 1, wherein the aerosol formulation is adapted to be stable under conditions of up to about 40 ° C and about 75% relative humidity for at least about four weeks.
21. A metered-dose pressurized inhaler consisting of a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition consisting of: particles of a beta-agonist drug; at least one fluoroalkane propellant; and a surfactant which is capable of forming a suspension of the β-agonist drug particles.
22. The pressurized inhaler with metered dose according to claim 21, wherein the metering valve it is constructed and arranged to provide measured doses of the β-agonist drug in an amount that is effective for therapeutic use.
23. The pressurized inhaler with metered doses according to claim 21, wherein the metering valve is constructed and arranged to provide metered doses of the β-agonist drug in an amount of about 12 μg by activation of the metering valve.
24. The pressurized inhaler with metered doses according to claim 21, wherein the fluoroalkane consists of 1,1,1,2-tetrafluoroethane.
25. The pressurized inhaler with metered doses according to claim 21, wherein the formulation is practically free of chlorofluorocarbons.
26. The pressurized inhaler with metered doses according to claim 21, wherein the propellant is present in an amount of about 99.9% by weight.
27. The pressurized inhaler with metered doses according to claim 21, wherein the β-agonist drug consists of formoterol.
28. The pressurized inhaler with metered doses according to claim 27, wherein the formoterol has an average particle size smaller than approximately 100 μ.
29. The pressurized inhaler with metered doses according to claim 27, wherein the formoterol has an average particle size of less than about 20 μ.
30. The pressurized inhaler with measured doses according to claim 27, wherein the formoterol has an average particle size from about 1 μ to about 10 μ.
31. The pressurized inhaler with metered doses according to claim 21, wherein the aerosol formulation is practically without solvent.
32. The pressurized inhaler with metered doses according to claim 27, wherein the formoterol is present in an amount of about 1% by weight or less, based on the total weight of the aerosol formulation.
33. The pressurized inhaler with metered doses according to claim 27, wherein the formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of the aerosol formulation. 4.
The pressurized inhaler with metered doses according to claim 27, wherein the formoterol consists of formoterol fumarate.
35. The pressurized inhaler with metered doses according to claim 21, wherein the surfactant is present in a [lacuna] of at least about 0.002% by weight, based on the total weight of the aerosol composition.
36. The pressurized inhaler with metered doses according to claim 21, wherein the surfactant is present in a [lacuna] of about 1% by weight or less, based on the total weight of the aerosol composition.
37. The pressurized inhaler with metered doses according to claim 21, wherein the surfactant is at least one selected from the group consisting of polyalcohols.
38. The pressurized inhaler with metered doses according to claim 21, wherein the surfactant consists of at least one selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene (20) monolaurate or sorbitan monooleate; and polyoxyethylene 4-lauryl ether.
39. The pressurized inhaler with metered doses according to claim 21, wherein the surfactant consists of polyoxyethylene 4-lauryl ether.
40. The pressurized inhaler with metered doses according to claim 27, wherein the formoterol consists of formoterol fumarate in an amount of up to about 1% by weight, the surfactant consists of polyoxyethylene 4-lauryl ether in an amount of about 1% by weight or less and the propellant is present in an amount of 99.9% by weight, all weights based on the total weight of the aerosol formulation.
The pressurized inhaler with metered doses according to claim 21, wherein the aerosol formulation is adapted to be stable under conditions of up to about 40 ° C and about 75% relative humidity for at least about four weeks.
An aerosol formulation adapted for use in a pressurized aerosol container, the aerosol formulation being formulated from a composition containing: a β-agonist drug; at least one fluoroalkane propellant; and more than 5% by weight, based on the total weight of the aerosol formulation, of a solvent that is capable of solubilizing or dissolving the β-agonist drug.
The aerosol formulation according to claim 42, wherein the fluoroalkane consists of 1,1,1,2-tetrafluoroethane.
The aerosol formulation according to claim 42, wherein the formulation is practically free of chlorofluorocarbons.
The aerosol formulation according to claim 42, wherein the propellant is present in an amount from about 70 to about 94% by weight.
The aerosol formulation according to claim 42, wherein the solvent is present in an amount of at least 10% by weight.
The aerosol formulation according to claim 42, wherein the solvent is present in an amount of at least 15% by weight.
The aerosol formulation according to claim 42, wherein the solvent is present in an amount ranging from more than 5% to about 30% by weight, based on the total weight of the aerosol formulation.
The aerosol formulation according to claim 42, wherein the solvent is selected from the group consisting of ethers and alcohols.
The aerosol formulation according to claim 42, wherein the solvent consists of an aliphatic alcohol having from 1 to about 6 carbon atoms.
51. The aerosol formulation according to claim 42, wherein the solvent consists of ethanol.
52. The aerosol formulation according to claim 42, wherein the solvent is more polar than the propellant.
53. The aerosol formulation according to claim 42, wherein the β-agonist drug consists of formoterol.
54. The aerosol formulation according to claim 53, wherein the formoterol is present in an amount of about 1% by weight or less, based on the total weight of the aerosol formulation.
55. The aerosol formulation according to claim 53, wherein the formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of the aerosol formulation.
56. The aerosol formulation according to claim 53, wherein the formoterol consists of formoterol fumarate.
57. The aerosol formulation according to claim 42, wherein the aerosol formulation is practically without surfactant.
58. The aerosol formulation according to claim 53, wherein the formoterol consists of formoterol fumarate in an amount of up to about 1% by weight, the solvent consists of ethanol in an amount greater than 5% to about 30% by weight and the propellant is present in an amount from about 70% to about 94% by weight, all weights based on the total weight of the aerosol formulation.
59. The aerosol formulation according to claim 42, wherein the aerosol formulation is adapted to be stable under conditions of up to about 40 ° C and about 75% relative humidity for at least about four weeks.
60. An aerosol formulation adapted for use in a pressurized aerosol container, the aerosol formulation being formulated from a composition consisting of: particles of a β-agonist drug; at least one fluoroalkane propellant; and a surfactant that is capable of forming a suspension of the β-agonist drug particles.
61. The aerosol formulation according to claim 60, wherein the fluoroalkane consists of 1,1,1,2-tetrafluoroethane.
62. The aerosol formulation according to claim 60, wherein the formulation is practically free of chlorofluorocarbons.
63. The aerosol formulation according to claim 60, wherein the propellant is present in an amount of about 99.9% by weight.
64. The aerosol formulation according to claim 60, wherein the β-agonist drug consists of formoterol.
65. The aerosol formulation according to claim 64, wherein the formoterol has an average particle size of less than about 100 μ.
66. The aerosol formulation according to claim 64, wherein the formoterol has an average particle size less than about 20 μ.
67. The aerosol formulation according to claim 64, wherein the formoterol has an average particle size from about 1 μ to about 10 μ.
68. The aerosol formulation according to claim 60, wherein the aerosol formulation is practically without solvent.
69. The aerosol formulation according to the claim 64, wherein formoterol is present in an amount of about 1% by weight or less, based on the total weight of the aerosol formulation.
70. The aerosol formulation according to claim 64, wherein the formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of the aerosol formulation.
71. The aerosol formulation according to claim 64, wherein the formoterol consists of formoterol fumarate.
72. The aerosol formulation according to claim 60, wherein the surfactant is present in a [lacuna] of at least about 0.002% by weight, based on the total weight of the aerosol composition.
73. The aerosol formulation according to claim 60, wherein the surfactant is present in a [lacuna] of about 1% by weight or less, based on the total weight of the aerosol composition. 4.
The aerosol formulation according to claim 60, wherein the surfactant is at least one selected from the group consisting of polyalcohols.
75. The aerosol formulation according to claim 60, wherein the surfactant consists of at least one selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene (20) monolaurate or sorbitan monooleate; and polyoxyethylene 4-lauryl ether.
76. The aerosol formulation according to claim 60, wherein the surfactant consists of polyoxyethylene 4-lauryl ether.
77. The aerosol formulation according to claim 64, wherein the formoterol consists of formoterol fumarate in an amount of up to about 1% by weight, the surfactant consists of polyoxyethylene 4-lauryl ether in an amount of about 1% by weight. weight or less and the propellant is present in an amount of 99.9% by weight, all weights based on the total weight of the aerosol formulation.
78. The aerosol formulation according to claim 60, wherein the aerosol formulation is adapted to be stable under conditions of up to about 40 ° C and about 75% relative humidity for at least about four weeks.