WO1999065460A2 - Pressurized metered dose inhalers and pharmaceutical aerosol formulations comprising a beta-agonist - Google Patents

Pressurized metered dose inhalers and pharmaceutical aerosol formulations comprising a beta-agonist Download PDF

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Publication number
WO1999065460A2
WO1999065460A2 PCT/US1999/013863 US9913863W WO9965460A2 WO 1999065460 A2 WO1999065460 A2 WO 1999065460A2 US 9913863 W US9913863 W US 9913863W WO 9965460 A2 WO9965460 A2 WO 9965460A2
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WO
WIPO (PCT)
Prior art keywords
aerosol formulation
weight
metered dose
dose inhaler
amount
Prior art date
Application number
PCT/US1999/013863
Other languages
French (fr)
Other versions
WO1999065460A3 (en
Inventor
Frank E. Blondino
Michael Brucato
Maria W. Buenafe
Original Assignee
Baker Norton Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE69911602T priority Critical patent/DE69911602T2/en
Priority to IL14034099A priority patent/IL140340A0/en
Application filed by Baker Norton Pharmaceuticals, Inc. filed Critical Baker Norton Pharmaceuticals, Inc.
Priority to AU48259/99A priority patent/AU762927B2/en
Priority to CA002335303A priority patent/CA2335303A1/en
Priority to DK02026980T priority patent/DK1306082T3/en
Priority to DK99931837T priority patent/DK1085856T3/en
Priority to SK1944-2000A priority patent/SK19442000A3/en
Priority to AT99931837T priority patent/ATE250409T1/en
Priority to JP2000554340A priority patent/JP2002518100A/en
Priority to BR9912170-0A priority patent/BR9912170A/en
Priority to EP99931837A priority patent/EP1085856B1/en
Priority to KR1020007014438A priority patent/KR20010053025A/en
Priority to HU0102468A priority patent/HUP0102468A3/en
Publication of WO1999065460A2 publication Critical patent/WO1999065460A2/en
Publication of WO1999065460A3 publication Critical patent/WO1999065460A3/en
Priority to NO20006466A priority patent/NO20006466L/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A61K9/124—Aerosols; Foams characterised by the propellant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers

Definitions

  • the invention relates to pressurized metered dose inhalers and aerosol formulations for inhalation therapy.
  • chlorohydrocarbon and chlorofluorocarbon propeilants for aerosol formulations for medical uses have been largely replaced by hydrofluoroalkanes such as 1 ,1 ,1 ,2- tetrafluoroethane ("HFA-134a”) and 1 ,1 ,1 ,2,3,3,3,-heptafluoropropane ("HFA-134a")
  • HFA-134a hydrofluoroalkanes
  • HFA-134a 1 ,1 ,1 ,2,3,3,3,3,-heptafluoropropane
  • Such medicinal aerosol formulations are generally of the solution or suspension type. Each type is composed of, at least, the medicament and the propellant. Some formulations also include one or more special purpose adjuvants such as a cosolvent or a surfactant (EP O 372777).
  • Conventional aerosol solution formulations contain low concentrations of a cosolvent more polar than the propellant.
  • Conventional aerosol suspension formulations contain a surfactant rather than a cosolvent on a theory that the surfactant would prevent agglomeration of the particles, their adhesion to the walls of the aerosol container, and provide for lubrication of the dispensing valve ("actuator"). (US 3,014,844).
  • Ethanol has been used as a cosolvent.
  • previous teachings see, e.g., EP 0 616525 have taught away from using concentrations of ethanol greater than 5% for solution aerosol formulations for ⁇ -agonists. Historically, ethanol concentrations greater than 5% have been used only for steroid-based formulations with hydrofluoroalkane propellants.
  • An objective of the present invention is to provide a pressurized metered dose inhaler that contains a stable formulation of a ⁇ -agonist drug, which does not require the use of refrigeration.
  • the present invention provides a novel pressurized metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition comprising: a ⁇ -agonist drug; at least one fluoroalkane propellant; and greater than 5% by weight, based on total weight of the aerosol formulation, of a solvent that is capable of solubilizing or dissolving the ⁇ - agonist drug.
  • the invention further provides a novel pressurized metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition comprising: particles of a ⁇ -agonist drug; at least one fluoroalkane propellant; and a surfactant that is capable of forming a suspension of the particles of ⁇ -agonist drug.
  • the invention also provides a novel aerosol formulation adapted for use in a pressurized aerosol container, said aerosol formulation being formulated from a composition comprising: a ⁇ -agonist drug; at least one fluoroalkane propellant; and greater than 5% by weight, based on total weight of the aerosol formulation, of a solvent that is capable of solubilizing or dissolving the ⁇ - agonist drug.
  • the invention further provides a novel aerosol formulation adapted for use in a pressurized aerosol container, said aerosol formulation being formulated from a composition comprising: particles of a ⁇ -agonist drug; at least one fluoroalkane propellant; and a surfactant that is capable of forming a suspension of the particles of ⁇ -agonist drug.
  • the aerosol formulations are surprisingly stable under conditions up to about 40°C and about 75% relative humidity for at least about four weeks.
  • Fig. 1 illustrates a chromatogram of formoterol fumarate formulated as a suspension
  • Fig. 2 illustrates a chromatogram of the formoterol fumarate after storage for 28 days at 40°C and 75% relative humidity.
  • the stability of aerosol formulations of solutions of a ⁇ -agonist drug can be significantly improved by utilizing more than 5% by weight of a solvent capable of solubilizing or dissolving the ⁇ -agonist drug.
  • the ⁇ -agonist drug can be any form that is suitable for application to the lungs or nasal passages of a human, such as base form or weak acid form.
  • the present invention will be described with reference to the ⁇ -agonist drug formoterol.
  • the term "formoterol" is hereinafter understood to mean the base form of formoterol as well as the weak acid form of formoterol, unless stated otherwise.
  • a preferred weak acid form of formoterol is formoterol fumarate.
  • the amount of ⁇ -agonist drug utilized in the aerosol formulation will depend on the type of drug selected.
  • the concentration utilized 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 suitable for inhalation and capable of solubilizing or dissolving the selected ⁇ -agonist drug can be used.
  • suitable solvents include alcohols, ethers, hydrocarbons, and perfluorocarbons.
  • the solvent is short chain polar alcohols. More preferably, the solvent is an aliphatic alcohol having from one to six carbon atoms, such as ethanol and isopropanol. The most preferred solvent is ethanol.
  • suitable hydrocarbons include n-butane, isobutane, pentane, neopentane and isopentanes.
  • suitable ethers include dimethyl ether and diethyl ether.
  • suitable perfluorocarbons include perfluoropropane, perfluorobutane, perfluorocyclobutane, and perfluoropentane.
  • the solvent is usually present in an amount of 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. Based on the disclosure provided herein, one skilled in the art will recognize that lower concentrations of medicament usually require lower concentrations of solvent, and vice versa, in order to form a stable solution.
  • fluoroalkane propellant that is suitable for inhalation
  • suitable fluoroalkanes include HFA-134a, HFA-227ea, HFA-125
  • the aerosol formulation is substantially free of chlorofluorocarbons. However, if desired chlorofluorocarbons can be utilized.
  • the propellant for solution formulations is usually present in an amount of from about 70% to about 94% by weight, based on the total weight of the aerosol formulation.
  • a preferred aerosol formulation comprises HFA-134a in an amount 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 comprises about 85 % by weight of HFA-134a, about 15 % by weight of ethanol, and about 0.01 % by weight of formoterol fumarate.
  • Pressurized metered dose inhalers are now well known in the art. Any pressurized metered dose inhalerthat is suitable for application of drugs to the lungs or nose of a patient can be used. Pressurized metered dose inhalers usually are equipped with a metering valve having a spray orifice diameter of about 460 ⁇ m. However, with the higher concentrations of solvent employed in the present invention, it may be desirable that the solvent evaporates as soon as possible after inhalation. This can be achieved by reducing the spray orifice diameter, for example, to 250 ⁇ m, in combination with using solvent concentrations of about 10 to about 15% by weight.
  • the component composition may be altered to adjust the vapor pressure of the formulation.
  • the aerosol formulation and metering valve are usually selected to provide a therapeutically effective amount of the ⁇ -agonist drug per activation.
  • An example of a therapeutically effective amount of formoterol fumarate is about 12 ⁇ g per activation.
  • the propellant can be any of the propellants described herein with reference to solution aerosol formulations.
  • the propellant in suspension aerosol formulations can be utilized in amounts up to about 99.9% by weight, based on the total weight of the aerosol formulation.
  • the amount of ⁇ -agonist drug utilized in the aerosol formulation will depend on the type of drug selected.
  • the concentration utilized 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 ⁇ -agonist drug should be suitable for inhalation into the nose or lung. Suitable average particle sizes are about 10O ⁇ m and less, preferably about 20 ⁇ m and less, and more preferably in the range of about 1 to about 10 ⁇ m.
  • any surfactant that is suitable for application to the lungs of a patient and which is capable of forming a suspension of particles of the ⁇ -agonist drug can be utilized.
  • suitable surfactants include polyalcohols such as polyethylene glycol (PEG 300), diethylene glycol monoethyl ether (Transcutol), poiyoxyethylene(20) sorbitan monolaurate (Tween 20) or monooleate (Tween 80), propoxylated polyethylene glycol (Antarox 31 R1 ), polyoxyethylene 4-lauryi ether (Brij 30), and surfactants having similar HLBs.
  • the surfactant is polyoxyethylene 4-lauryl ether (Brij 30).
  • a preferred suspension formulation comprises 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 comprises 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 canister comprises about 12.6 g/canister of HFA-134a, about
  • Bespak BK357, 63 ⁇ L metered valve was used, unless otherwise stated.
  • Example aerosol formulations were tested using one or more of the following: appearance (no external signs of leaking or deformation should be present); leakage to meet United States Pharmacopeia 23 and National Formulary 18 standards; canister contents to be within 10% of the mean; drug per container to be within 25% of the mean; chemical assay to be within 90.0-110% of label claim; weight per metered dose; unit spray content and content uniformity to meet Pharmacopeial Forum, vol. 22, no. 6 standards; and aerodynamic size distribution and water determination.
  • the test results 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 demonstrated that the Tween 20 formulation deposited a greater amount of drug on the actuator. Therefore, in order to minimize deposition on this type of actuator, Brij 30 was a more useful surfactant in these formulations than was Tween 20.
  • Examples 4-7 Four solution aerosols according to 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 solution aerosol formulations, Examples 6 and 7 were maintained for 1 month (28 days) at 40°C and 75% relative humidity, which are considered herein as accelerated conditions. 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.
  • Example 8 and 9 Two solution aerosols according to 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 solution aerosol formulations, Example 9 was maintained for 1 month (28 days) at 40°C and 75% relative humidity, which are considered herein as accelerated conditions. 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 3.
  • Example 12 and 13 were maintained for 1 month (28 days) at 40°C and 75% relative humidity, which are considered herein as accelerated conditions.
  • the suspension aerosol formulations were ,0 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.
  • Example 16 and 17 were maintained for 1 month (28 days) at 40°C and 75% relative humidity, which are considered herein as accelerated conditions.
  • the suspension aerosol formulations were 25 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.
  • test data demonstrates that there was about a 10% loss of drug after storage under accelerated conditions in Examples 16 and 17, relative to the initial Examples 14 and 15. This value is within acceptable limits and was in the area of 100% material balance (canister contents - drug per canister).
  • USP accepted method for determining particle size was employed. The results showed that there was no chemical (as appearance of a known degradation product or loss of parent compound) or physical instability after storage including (1 ) as an increase in particle size (MMAD - mass median aerodynamic diameter), (2) change in the distribution (GSD - geometric standard deviation), (3) change in fine particle dose, or (4) change in fine particle fraction.
  • Example 20 A suspension aerosol formulation was formed by combining 99.96 % by weight of HFA-134a, 0.02 % by weight formoterol fumarate, and 0.02 % by weight of 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 obtained as Figs. 1 and 2 respectively. In each Figure, only a single peak, representing the intact drug, was observed. No peaks representing breakdown products of the drug (expected to be at about 13 minutes) were found. Thus, the formoterol suspension aerosol exhibited long term stability. Tablel

Abstract

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

Description

PRESSURIZED METERED DOSE INHALERS AND
PHARMACEUTICAL AEROSOL FORMULATIONS
1. Field of the Invention.
The invention relates to pressurized metered dose inhalers and aerosol formulations for inhalation therapy.
2. Background of the Invention.
Because of environmental considerations, chlorohydrocarbon and chlorofluorocarbon propeilants for aerosol formulations for medical uses have been largely replaced 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 metered dose inhalers.
Such medicinal aerosol formulations are generally of the solution or suspension type. Each type is composed of, at least, the medicament and the propellant. Some formulations also include one or more special purpose adjuvants such as a cosolvent or a surfactant (EP O 372777). Conventional aerosol solution formulations contain low concentrations of a cosolvent more polar than the propellant. Conventional aerosol suspension formulations contain a surfactant rather than a cosolvent on a theory that the surfactant would prevent agglomeration of the particles, their adhesion to the walls of the aerosol container, and provide for lubrication of the dispensing valve ("actuator"). (US 3,014,844).
Ethanol has been used as a cosolvent. However, previous teachings (see, e.g., EP 0 616525) have taught away from using concentrations of ethanol greater than 5% for solution aerosol formulations for β-agonists. Historically, ethanol concentrations greater than 5% have been used only for steroid-based formulations with hydrofluoroalkane propellants.
The β-agonist drug, formoterol ("eformoterol" in Europe) and its derivatives, have proven difficult to formulate in conventional aerosols. Such formulations have exhibited short shelf-lives and require refrigeration.
Refrigeration is undesirable because many patients are required to carry the aerosol canisters on their persons. There remains, therefore, an important need for aerosol formulations for β-agonist drugs such as formoterol and its derivatives that remain chemically and physically stable during storage at ambient conditions of temperature and humidity.
SUMMARY OF THE INVENTION
An objective of the present invention is to provide a pressurized metered dose inhaler that contains a stable formulation of a β-agonist drug, which does not require the use of refrigeration.
Another objective of he present invention is to provide a stable formulation of a β-agonist drug that is suitable for use as an aerosol, which does not require the use of refrigeration. The above objectives and other objectives are surprisingly achieved by the following. The present invention provides a novel pressurized metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition comprising: a β-agonist drug; at least one fluoroalkane propellant; and greater than 5% by weight, based on 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 metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition comprising: particles of a β-agonist drug; at least one fluoroalkane propellant; and a surfactant that is capable of forming a suspension of the particles of β-agonist drug.
The invention also provides a novel aerosol formulation adapted for use in a pressurized aerosol container, said aerosol formulation being formulated from a composition comprising: a β-agonist drug; at least one fluoroalkane propellant; and greater than 5% by weight, based on 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, said aerosol formulation being formulated from a composition comprising: particles of a β-agonist drug; at least one fluoroalkane propellant; and a surfactant that is capable of forming a suspension of the particles of β-agonist drug.
The aerosol formulations are surprisingly stable under conditions up to about 40°C and about 75% relative humidity for at least about four weeks. BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates a chromatogram of formoterol fumarate formulated as a suspension; and
Fig. 2 illustrates a chromatogram of the formoterol fumarate after storage for 28 days at 40°C and 75% relative humidity.
DETAILED DESCRIPTION OF THE INVENTION
It has been unexpectedly discovered that the stability of aerosol formulations of solutions of a β-agonist drug can be significantly improved by utilizing 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 suitable for application to the lungs or nasal passages of a human, such as base form or weak acid form. The present invention will be described with reference to the β-agonist drug formoterol. The term "formoterol" is hereinafter understood to mean the base form of formoterol as well as the weak acid form of formoterol, unless stated otherwise. A preferred weak acid form of formoterol is formoterol fumarate.
The amount of β-agonist drug utilized in the aerosol formulation will depend on the type of drug selected. For formoterol fumarate, the concentration utilized 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 suitable for inhalation and capable of solubilizing or dissolving the selected 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 one to six 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 usually present in an amount of 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. Based on the disclosure provided herein, one skilled in the art will recognize that lower concentrations of medicament usually require lower concentrations of solvent, and vice versa, in order to form a stable solution.
Any fluoroalkane propellant that is suitable for inhalation can 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 may be added to modify propellant characteristics as required. Preferably, the aerosol formulation is substantially free of chlorofluorocarbons. However, if desired chlorofluorocarbons can be utilized.
The propellant for solution formulations is usually present in an amount of from about 70% to about 94% by weight, based on the total weight of the aerosol formulation. A preferred aerosol formulation comprises HFA-134a in an amount 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 comprises about 85 % by weight of HFA-134a, about 15 % by weight of ethanol, and about 0.01 % by weight of formoterol fumarate.
Pressurized metered dose inhalers are now well known in the art. Any pressurized metered dose inhalerthat is suitable for application of drugs to the lungs or nose of a patient can be used. Pressurized metered dose inhalers usually are equipped with a metering valve having a spray orifice diameter of about 460μm. However, with the higher concentrations of solvent employed in the present invention, it may be desirable that the solvent evaporates as soon as possible after inhalation. This can be achieved by reducing the spray orifice diameter, for example, to 250μm, in combination with using solvent concentrations of about 10 to about 15% by weight. Based on the disclosure provided herein, one skilled in the art will be able to adjust the component composition to deliver a desired dose for the selected metered valve, without undue experimentation. For example, the composition may be altered to adjust the vapor pressure of the formulation. The aerosol formulation and metering valve are usually selected to provide a therapeutically effective amount of the β-agonist drug per activation. An example of a therapeutically effective amount of formoterol fumarate is about 12 μg per activation.
It has also been unexpectedly discovered that stable aerosol formulations of suspensions of particles of a β-agonist drug can be formed by utilizing the β-agonist drug in combination with a surfactant that is capable of forming a suspension of the β-agonist drug particles. The present invention will be described with reference to the β-agonist drug formoterol.
The propellant can be any of the propellants described herein with reference to solution aerosol formulations. However, the propellant in suspension aerosol formulations can be utilized in amounts up to about 99.9% by weight, based on the total weight of the aerosol formulation.
The amount of β-agonist drug utilized in the aerosol formulation will depend on the type of drug selected. For formoterol fumarate, the concentration utilized 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 suitable for inhalation into the nose or lung. Suitable average particle sizes are about 10Oμm and less, preferably about 20μm and less, and more preferably in the range of about 1 to about 10μm.
Any surfactant that is suitable for application to the lungs of a patient and which is capable of forming a suspension of particles of the β-agonist drug can be utilized. Examples of suitable surfactants include polyalcohols such as polyethylene glycol (PEG 300), diethylene glycol monoethyl ether (Transcutol), poiyoxyethylene(20) sorbitan monolaurate (Tween 20) or monooleate (Tween 80), propoxylated polyethylene glycol (Antarox 31 R1 ), polyoxyethylene 4-lauryi ether (Brij 30), and surfactants having similar HLBs. 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 comprises 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 comprises 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 canister comprises about 12.6 g/canister of HFA-134a, about
0.002 g/canister Brij 30, and about 0.002 g/canister of formoterol fumarate.
The following examples are presented merely to illustrate particular embodiments of the invention and not to limit the claims which are supported by the entire specification.
Examples I-3
Three suspension aerosols according the present invention were formulated by combining the components shown in Table 1 , using the following steps:
1. Weighing the solvent or surfactant into a plastic coated glass bottle or an aluminum canister. 2. Adding the weighed drug.
3. Crimping a valve upon the bottle or canister.
4. Adding a known amount of propellant through the valve into the bottle or canister.
5. Sonicating the formulation for about 5 minutes. A Presspart, 19 mL, aluminum metered dose inhaler canister with a
Bespak BK357, 63 μL metered valve was used, unless otherwise stated.
The properties of the Example aerosol formulations were tested using one or more of the following: appearance (no external signs of leaking or deformation should be present); leakage to meet United States Pharmacopeia 23 and National Formulary 18 standards; canister contents to be within 10% of the mean; drug per container to be within 25% of the mean; chemical assay to be within 90.0-110% of label claim; weight per metered dose; unit spray content and content uniformity to meet Pharmacopeial Forum, vol. 22, no. 6 standards; and aerodynamic size distribution and water determination. The test results 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 demonstrated that the Tween 20 formulation deposited a greater amount of drug on the actuator. Therefore, in order to minimize deposition on this type of actuator, Brij 30 was a more useful surfactant in these formulations than was Tween 20.
Examples 4-7 Four solution aerosols according to 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 solution aerosol formulations, Examples 6 and 7 were maintained for 1 month (28 days) at 40°C and 75% relative humidity, which are considered herein as accelerated conditions. 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 indicates that the dose delivered (by unit spray determination) after storage under accelerated conditions was lower than that obtained with the initial samples due to drug adsorption onto the valve gasket material. However, the solution aerosol formulations showed no signs of chemical deterioration.
Examples 8 and 9 Two solution aerosols according to 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 solution aerosol formulations, Example 9 was maintained for 1 month (28 days) at 40°C and 75% relative humidity, which are considered herein as accelerated conditions. 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 3.
The drug could not be recovered from the gasket materials during this study, which resulted in a loss of about 15% by weight. However, the solution aerosol formulations showed no signs of chemical deterioration.
Examples 10-13
Four suspension aerosols according to present invention were 5 formulated by combining the components shown 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 are considered herein as accelerated conditions. The suspension aerosol formulations were ,0 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 storage, the dose delivered (by unit spray determination) in Examples 12 and 13 was less than that obtained with the : 5 initial Examples 10 and 11 , but not reduced by the same degree as with the solution formulation examples.
Examples 14-17
Four suspension aerosols according to present invention were 0 formulated by combining the components shown 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 are considered herein as accelerated conditions. The suspension aerosol formulations were 25 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 demonstrates that there was about a 10% loss of drug after storage under accelerated conditions in Examples 16 and 17, relative to the initial Examples 14 and 15. This value is within acceptable limits and was in the area of 100% material balance (canister contents - drug per canister). In addition, the USP accepted method for determining particle size (Andersen impacter) was employed. The results showed that there was no chemical (as appearance of a known degradation product or loss of parent compound) or physical instability after storage including (1 ) as an increase in particle size (MMAD - mass median aerodynamic diameter), (2) change in the distribution (GSD - geometric standard deviation), (3) change in fine particle dose, or (4) change in fine particle fraction.
Examples 18 and 19
Two suspension aerosols according to present invention were formulated by combining the components shown 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 A suspension aerosol formulation was formed by combining 99.96 % by weight of HFA-134a, 0.02 % by weight formoterol fumarate, and 0.02 % by weight of 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 obtained as Figs. 1 and 2 respectively. In each Figure, only a single peak, representing the intact drug, was observed. No peaks representing breakdown products of the drug (expected to be at about 13 minutes) were found. Thus, the formoterol suspension aerosol exhibited long term stability. Tablel
Figure imgf000014_0001
Figure imgf000014_0003
Figure imgf000014_0002
T2 - Tween® 20
P3 - Polyethylene glycol 300
Figure imgf000015_0001
Table 3
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000017_0001
Table 5
Figure imgf000018_0001
Table 6
Figure imgf000019_0001
Figure imgf000020_0001
While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to those of ordinary skill in the art that various changes and modifications can be made to the claimed invention without departing from the spirit and scope thereof.

Claims

Claims:
1. A pressurized metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition comprising: a ╬▓-agonist drug; at least one fluoroalkane propellant; and greater than 5% by weight, based on total weight of said aerosol formulation, of a solvent that is capable of solubilizing or dissolving said ╬▓-agonist drug.
2. A pressurized metered dose inhaler according to claim 1 , wherein said metering valve is constructed and arranged to provide metered doses of said ╬▓-agonist drug in an amount that is thereapuetically effective.
3. A pressurized metered dose inhaler according to claim 1 , wherein said metering valve is constructed and arranged to provide metered doses of said ╬▓-agonist drug in an amount of about 12 ╬╝g per actuation of said meterering valve.
4. A pressurized metered dose inhaler according to claim 1 , wherein said fluoroalkane comprises 1 ,1 ,1 ,2-tetrafluoroethane.
5. A pressurized metered dose inhaler according to claim 1 , wherein said formulation is substantially free of chlorofluorocarbons.
6. A pressurized metered dose inhaler according to claim 1 , wherein said propellant is present in an amount of from about 70 to about 94% by weight.
7. A pressurized metered dose inhaler according to claim 1 , wherein said solvent is present in an amount of at least 10% by weight.
5
8. A pressurized metered dose inhaler according to claim 1 , wherein said solvent is present in an amount of at least 15% by weight.
9. A pressurized metered dose inhaler according to claim 1 , wherein o said solvent is present in an amount in the range of from greater than
5% to about 30% by weight, based on the total weight of said aerosol formulation.
10. A pressurized metered dose inhaler according to claim 1 , wherein5 said solvent is selected from the group consisting of ethers and alcohols.
11. A pressurized metered dose inhaler according to claim 1 , wherein said solvent comprises an aliphatic alcohol having from 1 to about 60 carbon atoms.
12. A pressurized metered dose inhaler according to claim 1 , wherein said solvent comprises ethanol. 5
13. A pressurized metered dose inhaler according to claim 1 , wherein said solvent is more polar than said propellant.
14. A pressurized metered dose inhaler according to claim 1 , wherein said ╬▓-agonist drug comprises formoterol.
15. A pressurized metered dose inhaler according to claim 14, wherein said formoterol is present in an amount of about 1 % by weight or less, based on the total weight of said aerosol formulation.
16. A pressurized metered dose inhaler according to claim 14, wherein said formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of said aerosol formulation.
17. A pressurized metered dose inhaler according to claim 14, wherein said formoterol comprises formoterol fumarate.
18. A pressurized metered dose inhaler according to claiml , wherein said aerosol formulation is substantially free of a surfactant.
19. A pressurized metered dose inhaler according to ciaim 14, wherein said formoterol comprises formoterol fumarate in an amount of up to about 1 % by weight, said solvent comprises ethanol in an amount of greater than 5% to about 30% by weight, and said propellant is present in an amount of from about 70% to about 94% by weight, all weights based on the total weight of said aerosol formulation.
20. A pressurized metered dose inhaler according to claim 1 , wherein said aerosol formulation is adapted to be stable under conditions up to about 40 ┬░C and about 75% relative humidity for at least about four weeks.
21. A pressurized metered dose inhaler comprising a container equipped with a metering valve and containing a pressurized aerosol formulation formulated from a composition comprising: particles of a ╬▓-agonist drug; at least one fluoroalkane propellant; and a surfactant that is capable of forming a suspension of said particles of ╬▓-agonist drug.
22. A pressurized metered dose inhaler according to ciaim 21 , wherein said metering valve is constructed and arranged to provide metered doses of said ╬▓-agonist drug in an amount that is therapeutically effective.
23. A pressurized metered dose inhaier according to claim 21 , wherein said metering valve is constructed and arranged to provide metered doses of said ╬▓-agonist drug in an amount of about 12 ╬╝g per actuation of said metering valve.
24. A pressurized metered dose inhaler according to ciaim 21 , wherein said fluoroalkane comprises 1 ,1 ,1 ,2-tetrafluoroethane.
25. A pressurized metered dose inhaler according to ciaim 21 , wherein said formulation is substantially free of chlorofluorocarbons.
26. A pressurized metered dose inhaler according to claim 21 , wherein said propellant is present in an amount up to about 99.9% by weight.
27. A pressurized metered dose inhaler according to claim 21 , wherein said ╬▓-agonist drug comprises formoterol.
28. A pressurized metered dose inhaler according to claim 27, wherein said formoterol has an average particle size of less than about 100 ╬╝m.
29. A pressurized metered dose inhaler according to claim 27, wherein said formoterol has an average particle size of less than about 20 ╬╝m.
30. A pressurized metered dose inhaler according to claim 27, wherein said formoterol has an average particle size of from about 1 ╬╝m to about 10 ╬╝m.
31. A pressurized metered dose inhaier according to claim 21 , wherein said aerosol formulation is substantially free of a solvent.
32. A pressurized metered dose inhaler according to ciaim 27, wherein said formoterol is present in an amount of about 1 % by weight or less, based on the total weight of said aerosol formulation.
33. A pressurized metered dose inhaler according to ciaim 27, wherein said formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of said aerosol formulation.
34. A pressurized metered dose inhaler according to claim 27, wherein said formoterol comprises formoterol fumarate.
35. A pressurized metered dose inhaler according to claim 21 , wherein said surfactant is present in an of at least about 0.002 % by weight, based on the total weight of said aerosol composition.
36. A pressurized metered dose inhaler according to ciaim 21 , wherein said surfactant is present in an of about 1 % by weight or less, based on the total weight of said aerosol composition.
37. A pressurized metered dose inhaler according to ciaim 21 , wherein said surfactant is at least one selected from the group consisting of polyalcohols.
38. A pressurized metered dose inhaier according to claim 21 , wherein said surfactant comprises at least one selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, polyoxyethylene(20) sorbital monolaurate or monooieate; and polyoxyethylene 4-lauryl ether.
39. A pressurized metered dose inhaler according to claim 21 , wherein said surfactant comprises polyoxyethylene 4-lauryl ether.
40. A pressurized metered dose inhaler according to ciaim 27, wherein said formoterol comprises formoterol fumarate in an amount of up to about 1 % by weight, said surfactant comprises polyoxyethylene 4- lauryl ether in an amount of about 1 % by weight or less, and said propellant is present in an amount 99.9% by weight, all weights based on the total weight of said aerosol formulation.
41. A pressurized metered dose inhaler according to claim 21 , wherein said aerosol formulation is adapted to be stable under conditions up to about 40┬░C and about 75% relative humidity for at least about four weeks.
42. An aerosol formulation adapted for use in a pressurized aerosol container, said aerosol formulation being formulated from a composition comprising: a ╬▓-agonist drug; at least one fluoroalkane propellant; and greater than 5% by weight, based on total weight of said aerosol formulation, of a solvent that is capable of solubilizing or dissolving said ╬▓-agonist drug.
43. An aerosol formulation according to ciaim 42, wherein said fluoroalkane comprises 1 ,1 ,1 ,2-tetrafluoroethane.
44. An aerosol formulation according to claim 42, wherein said formulation is substantially free of chlorofluorocarbons.
45. An aerosol formulation according to claim 42, wherein said propellant is present in an amount of from about 70 to about 94% by weight.
46. An aerosol formulation according to ciaim 42, wherein said solvent is present in an amount of at least 10% by weight.
47. An aerosol formulation according to claim 42, wherein said solvent is present in an amount of at least 15% by weight.
48. An aerosol formulation according to claim 42, wherein said solvent is present in an amount in the range of from greater than 5% to about
30% by weight, based on the total weight of said aerosol formulation.
49. An aerosol formulation according to claim 42, wherein said solvent is selected from the group consisting of ethers and alcohols.
50. An aerosol formulation according to claim 42, wherein said solvent comprises an aliphatic alcohol having from 1 to about 6 carbon atoms.
51. An aerosol formulation according to ciaim 42, wherein said solvent comprises ethanol.
52. An aerosol formulation according to claim 42, wherein said solvent is more polar than said propellant.
53. An aerosol formulation according to claim 42, wherein said ╬▓-agonist drug comprises formoterol.
54. An aerosol formulation according to claim 53, wherein said formoterol is present in an amount of about 1 % by weight or less, based on the total weight of said aerosol formulation.
55. An aerosol formulation according to ciaim 53, wherein said formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of said aerosol formulation.
56. An aerosol formulation according to ciaim 53, wherein said formoterol comprises formoterol fumarate.
57. An aerosol formulation according to claim 42, wherein said aerosol formulation is substantially free of a surfactant.
58. An aerosol formulation according to ciaim 53, wherein said formoterol comprises formoterol fumarate in an amount of up to about 1 % by weight, said solvent comprises ethanol in an amount of greater than 5% to about 30% by weight, and said propellant is present in an amount of from about 70% to about 94% by weight, all weights based on the total weight of said aerosol formulation.
59. An aerosol formulation according to claim 42, wherein said aerosol formulation is adapted to be stable under conditions 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, said aerosol formulation being formulated from a composition comprising: particles of a ╬▓-agonist drug; at least one fluoroalkane propellant; and a surfactant that is capable of forming a suspension of said particles of ╬▓-agonist drug.
61. An aerosol formulation according to claim 60, wherein said fluoroalkane comprises 1 ,1 ,1 ,2-tetrafluoroethane.
62. An aerosol formulation according to claim 60, wherein said formulation is substantially free of chlorofluorocarbons.
63. An aerosol formulation according to claim 60, wherein said propeliant is present in an amount up to about 99.9% by weight.
64. An aerosol formulation according to claim 60, wherein said ╬▓-agonist drug comprises formoterol.
65. An aerosol formulation according to claim 64, wherein said formoterol has an average particle size of less than about 100 ╬╝m.
66. An aerosol formulation according to claim 64, wherein said formoterol has an average particle size of less than about 20 ╬╝m.
67. An aerosol formulation according to ciaim 64, wherein said formoterol has an average particle size of from about 1 ╬╝m to about 10 ╬╝m.
68. An aerosol formulation according to claim 60, wherein said aerosol formulation is substantially free of a solvent.
69. An aerosol formulation according to claim 64, wherein said formoterol is present in an amount of about 1 % by weight or less, based on the total weight of said aerosol formulation.
70. An aerosol formulation according to claim 64, wherein said formoterol is present in an amount of about 0.01 to about 0.02% by weight, based on the total weight of said aerosol formulation.
71. An aerosol formulation according to claim 64, wherein said formoterol comprises formoterol fumarate.
72. An aerosol formulation according to claim 60, wherein said surfactant is present in an of at least about 0.002 % by weight, based on the total weight of said aerosol composition.
73. An aerosol formulation according to claim 60, wherein said surfactant is present in an of about 1 % by weight or less, based on the total weight of said aerosol composition.
74. An aerosol formulation according to claim 60, wherein said surfactant is at least one selected from the group consisting of polyalcohols.
75. An aerosol formulation according to claim 60, wherein said surfactant comprises 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 formulation according to claim 60, wherein said surfactant comprises polyoxyethylene 4-lauryl ether.
77. An aerosol formulation according to claim 64, wherein said formoterol comprises formoterol fumarate in an amount of up to about 1 % by weight, said surfactant comprises polyoxyethylene 4-lauryl ether in an amount of about 1 % by weight or less, and said propellant is present in an amount 99.9% by weight, all weights based on the total weight of said aerosol formulation.
78. An aerosol formulation according to ciaim 60, wherein said aerosol formulation is adapted to be stable under conditions up to about 40┬░C and about 75% relative humidity for at least about four weeks.
PCT/US1999/013863 1998-06-19 1999-06-18 Pressurized metered dose inhalers and pharmaceutical aerosol formulations comprising a beta-agonist WO1999065460A2 (en)

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AU48259/99A AU762927B2 (en) 1998-06-19 1999-06-18 Pressurized metered dose inhalers and pharmaceutical aerosol formulations
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003066031A1 (en) * 2002-02-07 2003-08-14 Pharmatech Gmbh Cyclodextrines for use as suspension stabilizers in pressure-liquefied propellants
WO2003086349A1 (en) * 2002-04-05 2003-10-23 3M Innovative Properties Company Formoterol and ciclesonide aerosol formulations
US6716414B2 (en) 2000-05-22 2004-04-06 Chiesi Farmaceutici S.P.A. Stable pharmaceutical solution formulations for pressurized metered dose inhalers
US6964759B2 (en) 2000-02-22 2005-11-15 Chiesi Farmaceutici S.P.A. Formulations containing an anticholinergic drug for the treatment of chronic obstructive pulmonary disease
US6967017B1 (en) 1999-07-23 2005-11-22 Chiesi Farmaceutici S.P.A. Formulations of steroid solutions for inhalatory administration
US7223381B2 (en) 1998-11-25 2007-05-29 Chiesi Farmaceutici S.P.A. Pressurised metered dose inhalers (MDI)
US7381402B2 (en) 2004-02-27 2008-06-03 Chiesi Farmaceutici S.P.A. Stable pharmaceutical solution formulations for pressurized metered dose inhalers
US7566445B1 (en) 1996-08-01 2009-07-28 Norton Healthcare Limited Medicinal aerosols and methods of delivery thereof
EP2201964A2 (en) 2002-03-01 2010-06-30 CHIESI FARMACEUTICI S.p.A. Formoterol superfine formulation
US9114164B2 (en) 2011-10-12 2015-08-25 Mexichem Amanco Holding S.A. De C.V. Compositions comprising salbutamol sulphate
US9517216B2 (en) 2011-10-12 2016-12-13 Mexichem Amanco Holding S.A. De C.V. Compositions comprising salbutamol sulphate
US10258568B2 (en) 2011-05-13 2019-04-16 Mexichem Amanco Holdings S.A. De C.V. Pharmaceutical compositions
US10525006B2 (en) 2006-04-21 2020-01-07 Chiesi Farmaceutici S.P.A. Pharmaceutical solution formulations for pressurised metered dose inhalers
US10792256B2 (en) 2016-09-19 2020-10-06 Mexichem Fluor S.A. De C.V. Pharmaceutical composition
US10888546B2 (en) 2016-09-19 2021-01-12 Mexichem Fluor S.A. De C.V. Pharmaceutical composition
US10959965B2 (en) 2013-04-17 2021-03-30 Mexichem Amanco Holding S.A. De C.V. Composition comprising salbutamol sulphate
US11260052B2 (en) 2016-09-19 2022-03-01 Mexichem Fluor S.A. De C.V. Pharmaceutical composition
US11559505B2 (en) 2015-12-04 2023-01-24 Mexichem Fluor S.A. De C.V. Pharmaceutical composition

Families Citing this family (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010031244A1 (en) * 1997-06-13 2001-10-18 Chiesi Farmaceutici S.P.A. Pharmaceutical aerosol composition
US6451285B2 (en) * 1998-06-19 2002-09-17 Baker Norton Pharmaceuticals, Inc. Suspension aerosol formulations containing formoterol fumarate and a fluoroalkane propellant
US6315985B1 (en) * 1999-06-18 2001-11-13 3M Innovative Properties Company C-17/21 OH 20-ketosteroid solution aerosol products with enhanced chemical stability
IT1317720B1 (en) * 2000-01-07 2003-07-15 Chiesi Farma Spa DEVICE FOR THE ADMINISTRATION OF AEROSOL DOSED PRESSURIZED INPROPELLENT HYDROFLUOROALKANS.
IT1318514B1 (en) * 2000-05-12 2003-08-27 Chiesi Farma Spa FORMULATIONS CONTAINING A GLUCOCORTICOSTEROID DRUG FOR THE TREATMENT OF BRONCOPOLMONARY DISEASES.
US20030072717A1 (en) * 2001-02-23 2003-04-17 Vapotronics, Inc. Inhalation device having an optimized air flow path
PT1372608E (en) * 2001-03-30 2008-01-04 Jagotec Ag Medical aerosol formulations
ES2222294T3 (en) * 2001-07-02 2005-02-01 Chiesi Farmaceutici S.P.A. OPTIMIZED FORMULATION OF TOBRAMYCIN FOR ADMINISTRATION IN THE FORM OF AEROSOL.
US20030178022A1 (en) * 2001-12-21 2003-09-25 Chiesi Farmaceutici S.P.A. Pressurized metered dose inhaler (PMDI) actuators and medicinal aerosol solution formulation products comprising therse actuators
GB0219511D0 (en) * 2002-08-21 2002-10-02 Norton Healthcare Ltd Method of preparing dry powder inhalation compositions
US20050158248A1 (en) * 2002-08-21 2005-07-21 Xian-Ming Zeng Method of preparing dry powder inhalation compositions
MXPA05001903A (en) * 2002-08-21 2005-04-28 Norton Healthcare Ltd Inhalation composition.
GB0323684D0 (en) * 2003-10-09 2003-11-12 Jagotec Ag Improvements in or relating to organic compounds
GB0323685D0 (en) * 2003-10-09 2003-11-12 Jagotec Ag Improvements in or relating to organic compounds
WO2007008427A2 (en) * 2005-07-08 2007-01-18 Xemplar Pharmaceuticals, Llc Aerosol compositions and methods
US8367734B1 (en) 2005-08-11 2013-02-05 Amphastar Pharmaceuticals Inc. Stable epinephrine suspension formulation with high inhalation delivery efficiency
US8815258B2 (en) 2009-05-29 2014-08-26 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
KR101976107B1 (en) * 2009-05-29 2019-05-09 펄 테라퓨틱스 인코포레이티드 Respiratory delivery of active agents
GB0918149D0 (en) 2009-10-16 2009-12-02 Jagotec Ag Improved medicinal aerosol formulation
US20120272951A1 (en) 2009-12-16 2012-11-01 3M Innovative Properties Company Formulations and methods for controlling mdi particle size delivery
RU2696582C2 (en) 2013-03-15 2019-08-05 Перл Терапьютикс, Инк. Methods and systems for conditioning disperse crystalline materials
CN109464429B (en) * 2018-12-13 2021-04-27 上海方予健康医药科技有限公司 Inhalation pressure quantitative aerosol pharmaceutical composition and preparation method thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3014844A (en) * 1957-01-31 1961-12-26 Riker Laboratories Inc Self-propelling powder dispensing compositions
WO1991011173A1 (en) * 1990-02-02 1991-08-08 Fisons Plc Propellant compositions
EP0504112A2 (en) * 1991-03-14 1992-09-16 Ciba-Geigy Ag Pharmaceutical aerosol formulations
WO1993011747A1 (en) * 1991-12-18 1993-06-24 Minnesota Mining And Manufacturing Company Suspension aerosol formulations
WO1996019198A1 (en) * 1994-12-22 1996-06-27 Astra Aktiebolag Aerosol drug formulations
WO1997047286A1 (en) * 1996-06-11 1997-12-18 Minnesota Mining And Manufacturing Company Medicinal aerosol formulations of formoterol

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL7708731A (en) 1976-08-13 1978-02-15 Montedison Spa PROCESS FOR THE PREPARATION OF NEW DRIVER COMPOSITIONS FOR AEROSOLS.
US5225183A (en) * 1988-12-06 1993-07-06 Riker Laboratories, Inc. Medicinal aerosol formulations
US5766573A (en) * 1988-12-06 1998-06-16 Riker Laboratories, Inc. Medicinal aerosol formulations
BR9106595A (en) 1990-06-29 1993-04-20 Fisons Plc PRESSURIZED AEROSOL COMPOSITION
ATE114112T1 (en) 1990-10-18 1994-12-15 Minnesota Mining & Mfg AEROSOL PREPARATION CONTAINING BECLOMETASONE 17,21-DIPROPIONATE.
MX9203481A (en) 1990-10-18 1992-07-01 Minnesota Mining & Mfg FORMULATIONS.
US5190029A (en) 1991-02-14 1993-03-02 Virginia Commonwealth University Formulation for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content
WO1992022286A1 (en) 1991-06-12 1992-12-23 Minnesota Mining And Manufacturing Company Albuterol sulfate suspension aerosol formulations
DE4123663A1 (en) 1991-07-17 1993-01-21 Schwabe Willmar Gmbh & Co Medicinal aerosol free from fluoro:chlorocarbon(s) - contains active agent in suspending or dispersing aid and alcohol with hepta:fluoro:propane as propellant
DK0616525T3 (en) * 1991-12-12 1996-01-08 Glaxo Group Ltd medications
US5736124A (en) * 1991-12-12 1998-04-07 Glaxo Group Limited Aerosol formulations containing P134a and particulate medicament
AU673660C (en) 1991-12-18 2002-07-25 Astrazeneca Ab New combination of formoterol and budesonide
ATE137666T1 (en) 1991-12-31 1996-05-15 Hoechst Ag MEDICAL AEROSOL FORMULATION
US5492688A (en) 1993-04-28 1996-02-20 The Center For Innovative Technology Metered dose inhaler fomulations which include the ozone-friendly propellant HFC 134a and a pharmaceutically acceptable suspending, solubilizing, wetting, emulsifying or lubricating agent
US5508023A (en) 1994-04-11 1996-04-16 The Center For Innovative Technology Pharmaceutically acceptable agents for solubilizing, wetting, emulsifying, or lubricating in metered dose inhaler formulations which use HFC-227 propellant
DE4446891A1 (en) * 1994-12-27 1996-07-04 Falk Pharma Gmbh Stable aqueous budesonide solution
GB9616237D0 (en) * 1996-08-01 1996-09-11 Norton Healthcare Ltd Aerosol formulations
US6039932A (en) * 1996-09-27 2000-03-21 3M Innovative Properties Company Medicinal inhalation aerosol formulations containing budesonide
SE9603669D0 (en) 1996-10-08 1996-10-08 Astra Ab New combination
ATE301991T1 (en) 1996-12-04 2005-09-15 Link Products Ltd MEDICINAL COMPOSITIONS AND DEVICES FOR ADMINISTRATION THEREOF
US6451285B2 (en) * 1998-06-19 2002-09-17 Baker Norton Pharmaceuticals, Inc. Suspension aerosol formulations containing formoterol fumarate and a fluoroalkane propellant
US6004537A (en) * 1998-12-18 1999-12-21 Baker Norton Pharmaceuticals, Inc. Pharmaceutical solution aerosol formulations containing fluoroalkanes, budesonide and formoterol

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3014844A (en) * 1957-01-31 1961-12-26 Riker Laboratories Inc Self-propelling powder dispensing compositions
WO1991011173A1 (en) * 1990-02-02 1991-08-08 Fisons Plc Propellant compositions
EP0504112A2 (en) * 1991-03-14 1992-09-16 Ciba-Geigy Ag Pharmaceutical aerosol formulations
WO1993011747A1 (en) * 1991-12-18 1993-06-24 Minnesota Mining And Manufacturing Company Suspension aerosol formulations
WO1996019198A1 (en) * 1994-12-22 1996-06-27 Astra Aktiebolag Aerosol drug formulations
WO1997047286A1 (en) * 1996-06-11 1997-12-18 Minnesota Mining And Manufacturing Company Medicinal aerosol formulations of formoterol

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8834849B2 (en) 1996-08-01 2014-09-16 Norton Healthcare Limited Medicinal aerosols and methods of delivery thereof
US9650203B2 (en) 1996-08-01 2017-05-16 Norton Healthcare Limited Medicinal aerosols and methods of delivery thereof
US7566445B1 (en) 1996-08-01 2009-07-28 Norton Healthcare Limited Medicinal aerosols and methods of delivery thereof
US7223381B2 (en) 1998-11-25 2007-05-29 Chiesi Farmaceutici S.P.A. Pressurised metered dose inhalers (MDI)
US7347199B1 (en) 1998-11-25 2008-03-25 Chiesi Farmaceutici S.P.A. Pressurised metered dose inhalers (MDI)
US8142763B2 (en) 1998-11-25 2012-03-27 Chiesi Farmaceutici S.P.A. Pressurized metered dose inhalers (MDI) containing a solution comprising ipratropium bromide, HFA propellant, and co-solvent and comprising a container with a specific internal surface composition and/or lining
US6967017B1 (en) 1999-07-23 2005-11-22 Chiesi Farmaceutici S.P.A. Formulations of steroid solutions for inhalatory administration
US6964759B2 (en) 2000-02-22 2005-11-15 Chiesi Farmaceutici S.P.A. Formulations containing an anticholinergic drug for the treatment of chronic obstructive pulmonary disease
US7018618B2 (en) 2000-05-22 2006-03-28 Chiesi Farmaceutici S.P.A. Stable pharmaceutical solution formulations for pressurized metered dose inhalers
HRP20021025B1 (en) * 2000-05-22 2013-11-22 Chiesi Farmaceutici S.P.A. Stable pharmaceutical solution formulations for pressurised metered dose inhalers
US6716414B2 (en) 2000-05-22 2004-04-06 Chiesi Farmaceutici S.P.A. Stable pharmaceutical solution formulations for pressurized metered dose inhalers
EP2223682A1 (en) 2000-05-22 2010-09-01 Chiesi Farmaceutici S.p.A. Stable pharmaceutical solution formulations for pressurised metered dose inhalers
WO2003066031A1 (en) * 2002-02-07 2003-08-14 Pharmatech Gmbh Cyclodextrines for use as suspension stabilizers in pressure-liquefied propellants
EP2201964A2 (en) 2002-03-01 2010-06-30 CHIESI FARMACEUTICI S.p.A. Formoterol superfine formulation
EP3536344A1 (en) 2002-03-01 2019-09-11 Chiesi Farmaceutici S.p.A. Formoterol superfine formulation
EP3494995A2 (en) 2002-03-01 2019-06-12 Chiesi Farmaceutici S.p.A. Formoterol superfine formulation
WO2003086349A1 (en) * 2002-04-05 2003-10-23 3M Innovative Properties Company Formoterol and ciclesonide aerosol formulations
US7381402B2 (en) 2004-02-27 2008-06-03 Chiesi Farmaceutici S.P.A. Stable pharmaceutical solution formulations for pressurized metered dose inhalers
US11213485B2 (en) 2006-04-21 2022-01-04 Chiesi Farmaceutici S.P.A. Pharmaceutical solution formulations for pressurized metered dose inhalers
US10525006B2 (en) 2006-04-21 2020-01-07 Chiesi Farmaceutici S.P.A. Pharmaceutical solution formulations for pressurised metered dose inhalers
US10258569B2 (en) 2011-05-13 2019-04-16 Mexichem Amanco Holdings S.A. De C.V. Pharmaceutical compositions
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US10039828B2 (en) 2011-10-12 2018-08-07 Mexichem Amanco Holding S.A. De C.V. Compositions comprising salbutamol sulphate
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