US20040184993A1 - Pharmaceutical aerosol composition containing HFA 227 and HFA 134a - Google Patents
Pharmaceutical aerosol composition containing HFA 227 and HFA 134a Download PDFInfo
- Publication number
- US20040184993A1 US20040184993A1 US10/766,857 US76685704A US2004184993A1 US 20040184993 A1 US20040184993 A1 US 20040184993A1 US 76685704 A US76685704 A US 76685704A US 2004184993 A1 US2004184993 A1 US 2004184993A1
- Authority
- US
- United States
- Prior art keywords
- hfa
- aerosol
- low volatility
- composition
- composition according
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
Definitions
- the invention relates to aerosol compositions for pharmaceutical use.
- this invention relates to aerosol compositions for use in pressurised metered dose inhalers (MDIs).
- MDIs pressurised metered dose inhalers
- the invention also relates to solution aerosol compositions, wherein the propellant comprises HFA 134a or HFA 227 or their mixtures.
- Another aspect of the invention relates to pressurised MDIs for dispensing said compositions.
- Inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation.
- Active materials commonly delivered by inhalation include bronchodilators such as ⁇ 2 agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergics and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
- bronchodilators such as ⁇ 2 agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergics and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
- MDI pressurised metered dose inhaler
- Formulations used in MDIs generally comprise the active material, one or more liquefied propellants and a surfactant or a solvent.
- chlorofluorocarbons which are commonly called Freons or CFCs, such as CCl 3 F (Freon 11 or CFC-11), CCl 2 F 2 (Freon 12 or CFC-12), and CClF 2 -CClF 2 (Freon 114 or CFC-114).
- Chlorofluorocarbons have properties particularly suitable for use in aerosols, including high vapour pressure which generates clouds of droplets of a suitable particle size from the inhaler.
- CFC chlorofluorocarbon
- Hydrofluoroalkanes (HFAs) known also as hydro-fluoro-carbons (HFCs)] contain no chlorine and are considered less destructive to ozone and these are proposed as substitutes for CFCs.
- HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of medicinal aerosol formulations using such HFA propellant systems are disclosed in several patent applications.
- HFAs are used as propellant, propose the addition of one or more of adjuvants including compounds acting as cosolvents, surface active agents including fluorinated and non-fluorinated surfactants, dispersing agents including alkylpolyethoxylates and stabilizers.
- Cosolvents which may be used in these formulations include alcohols such as ethanol and polyols such as propylene glycol.
- EP 0372777 requires the use of HFA 134a as a propellant in combination with both a surfactant and an adjuvant having higher polarity than the propellant.
- a surfactant is often added to improve the physical stability of the suspension.
- EP 0372777 states that the presence of surfactant assists in the preparation of stable, homogeneous suspensions and may also assist in the preparation of stable solution formulations.
- Surfactants also lubricate the valve components in the inhaler device.
- EP 504112 relates to a pharmaceutical aerosol formulation free from CFCs containing a propellant (hydrocarbon, HFA or a mixture), one or more pharmaceutical active ingredients, a non-ionic surfactant and optionally other conventional pharmaceutical auxiliaries suitable for aerosol formulations comprising solvents having a higher polarity than the propellant, other non-ionic surfactants as valve lubricants, vegetable oils, phospholipids, taste masking agents.
- a propellant hydrocarbon, HFA or a mixture
- non-ionic surfactant optionally other conventional pharmaceutical auxiliaries suitable for aerosol formulations comprising solvents having a higher polarity than the propellant, other non-ionic surfactants as valve lubricants, vegetable oils, phospholipids, taste masking agents.
- DE 4123663 describes a medical aerosol composition containing a dispersion or suspension of an active agent in association with a compound with surface-active or lipophilic properties, heptafluoropropane as propellant and an alcohol such as ethanol and/or propylene glycol.
- U.S. Pat. No. 5,502,076 concerns compositions used in inhalation aerosols comprising an HFA, leukotriene antagonists and dispersing agent comprising 3C-linked triesters, vitamin E acetate, glycerin, t-BuOH, or transesterified oil/polyethylene glycol.
- EP 384371 describes a propellant for an aerosol, comprising pressure-liquefied HFA 227 in a mixture with pressure-liquefied propane and/or n-butane and/or iso-butane and/or dimethyl ether and/or 1,1-difluoroethane.
- the document also discloses foam formulations (shaving and shower foams) containing glycerol as additive.
- an aerosol device for example an MDI
- the effectiveness of an aerosol device is a function of the dose deposited at the appropriate site in the lungs. Deposition is affected by several parameters, of which the most important are the Fine Particle Dose (FPD) and the aerodynamic particle size. Solid particles and/or droplets in an aerosol formulation can be characterized by their mass median aerodynamic diameter (MMAD, the diameter around which the mass aerodynamic diameters are distributed equally).
- FPD Fine Particle Dose
- MMAD mass median aerodynamic diameter
- the FPD gives a direct measure of the mass of particles within a specified size range and is closely related to the efficacy of the product.
- Particle deposition in the lung depends largely upon three physical mechanisms: (1) impaction, a function of particle inertia; (2) sedimentation due to gravity; and (3) diffusion resulting from Brownian motion of fine, submicrometer ( ⁇ 1 ⁇ m) particles. The mass of the particles determines which of the three main mechanisms predominates.
- the effective aerodynamic diameter is a function of the size, shape and density of the particles and will affect the magnitude of forces acting on them. For example, while inertial and gravitational effects increase with increasing particle size and particle density, the displacements produced by diffusion decrease. In practice, diffusion plays little part in deposition from pharmaceutical aerosols. Impaction and sedimentation can be assessed from a measurement of the mass median aerodynamic diameter (MMAD) which determines the displacement across streamlines under the influence of inertia and gravity, respectively.
- MMAD mass median aerodynamic diameter
- Aerosol particles of equivalent MMAD and GSD have similar deposition in the lung irrespective of their composition.
- the GSD is a measure of the variability of the aerodynamic particle diameters.
- the particles for inhalation have a diameter of about 0.8 to 5 ⁇ m.
- Particles which are larger than 5 ⁇ m in diameter are primarily deposited by inertial impaction in the oropharynx, particles 0.5 to 5 ⁇ m in diameter, influenced mainly by gravity, are ideal for deposition in the conducting airways, and particles 0.5 to 3 ⁇ m in diameter are desirable for aerosol delivery to the lung periphery. Particles smaller than 0.5 ⁇ m may be exhaled.
- Respirable particles are generally considered to be those with aerodynamic diameters less than 5 ⁇ m. These particles, particularly those with a diameter of about 3 ⁇ m, are efficiently deposited in the lower respiratory tract by sedimentation.
- the size of aerosol particles is important in respect to the side effects of the drugs.
- the oropharynx deposition of aerosol formulations of steroids can result in side effects such as candidiasis of mouth and throat.
- a higher systemic exposure to the aerosol particles due to deep lung penetration can enhance the undesired systemic effects of the drugs.
- the systemic exposure to steroids can produce side effects on bone metabolism and growth.
- HFA substitutes may not be pharmaceutically or clinically equivalent and adjustment of dose and regimen may be necessary, giving problems for doctor, pharmacist and patient.
- EP 0553298 describes an aerosol formulation comprising: a therapeutically effective amount of beclomethasone 17,21 dipropionate (BDP); a propellant comprising a hydrofluorocarbon selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof, and ethanol in an amount effective to solubilize the beclomethasone 17,21 dipropionate in the propellant.
- BDP beclomethasone 17,21 dipropionate
- a propellant comprising a hydrofluorocarbon selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof, and ethanol in an amount effective to solubilize the beclomethasone 17,21 dipropionate in the propellant.
- the formulation is further characterized in that substantially all of the beclomethasone 17,21 dipropionate is dissolved in the formulation and that the formulation contains no more than 0,0005% by weight of any surfactant.
- WO93/11747 discloses that in suspension aerosol compositions the density of the propellant may be changed by using HFA 134a and HFA 227 mixtures so as to bring it to approximately the same value of the density of the active ingredient, minimizing thereby the sedimentation of the drug particles.
- the low volatility component has a vapour pressure at 25° C. not more than 0.1 kPa, preferably not more than 0.05 kPa.
- the low vapour pressure of the low volatility component is to be contrasted with that of the cosolvent which preferably has a vapour pressure at 25° C. not less than 3 kPa, more preferably not less than 5 kPa.
- the cosolvent has advantageously a higher polarity than that of the propellant and the cosolvent is used to increase the solubility of the active material in the propellant.
- the cosolvent is an alcohol.
- the cosolvent is preferably ethanol.
- the cosolvent may include one or more materials.
- the low volatility component may be a single material or a mixture of two or more materials.
- the low volatility component can be any compound, safe and compatible with the propellant system of the invention capable to influence either the size or the density of the aerosol particle so affecting the MMAD.
- glycols are particularly suitable for use as the low volatility component, especially propylene glycol, polyethylene glycol and glycerol.
- alkanols such as decanol (decyl alcohol), sugar alcohols including sorbitol, mannitol, lactitol and maltitol, glycofural (tetrahydro-furfurylalcohol) and dipropylene glycol.
- alkanols such as decanol (decyl alcohol)
- sugar alcohols including sorbitol, mannitol, lactitol and maltitol
- glycofural tetrahydro-furfurylalcohol
- dipropylene glycol dipropylene glycol
- the low volatility component may include esters for example ascorbyl palmitate and tocopherol.
- esters for example ascorbyl palmitate and tocopherol.
- esters isopropyl myristate is particularly preferred.
- various other materials may be suitable for use as the low volatility component including vegetable oils, organic acids for example saturated carboxylic acids including lauric acid, myristic acid and stearic acid; unsaturated carboxylic acids including sorbic acid, and especially oleic acid, which has been previously used in aerosol formulations, in order to improve the physical stability of drug suspensions, as a dispersing agent useful in keeping the suspended particles from agglomerating; saccharine, ascorbic acid, cyclamic acid, amino acids or aspartame; alkanes for example dodecane and octadecane; terpenes for example menthol, eucalyptol, limonene; sugars for example lactose, glucose, sucrose; polysaccharides for example ethyl cellulose, dextran; antioxidants for example butylated hydroxytoluene, butylated hydroxyanisole; polymeric materials for example polyvinyl alcohol, polyvinyl alcohol, polyvinyl
- the amount of low volatility component in the composition depends to some extent upon its density and the amount of active material and cosolvent in the composition.
- the composition includes not more than 20% by weight of the low volatility component.
- the composition includes not more than 10% by weight of the low volatility component.
- the composition may contain at least 0.2%, preferably at least 1% by weight of the low volatility component.
- the composition may contain between 1% and 2% by weight.
- the influence on the MMAD of the particles is correlated to the ratio of the two HFA components (as well as to the amount and density of the low volatility component).
- the MMAD can be modulated by changing the ratio between HFA 134a and HFA 227; said ratio may range from 10:90 to 90:10.
- the composition is such that, on actuation of the aerosol inhaler in use, the MMAD of the aerosol particles is not less than 21m.
- the MMAD is preferably not less than 2.5 ⁇ m and for a few formulations, the preferred MMAD will be greater than 3 ⁇ m or even greater than 4 ⁇ m.
- a small quantity of water may be added to the composition to improve the solution of the active material and/or the low volatility component in the cosolvent.
- the active material may be one or more of any biologically active material which could be administered by inhalation.
- Active materials commonly administered in that way include ⁇ 2 agonists, for example salbutamol and its salts, steroids for example beclomethasone dipropionate or anti-cholinergics for example ipratropium bromide and combinations thereof.
- the aerosol particles advantageously have an MMAD of not less than 2 ⁇ m, for many formulations more preferably not less than 2.5 ⁇ m.
- the solution formulations with MMAD>2 may be obtained by using a metering chamber ⁇ 40 ⁇ l, preferably 25 ⁇ l: the fine particle delivery (Stage 3 to filter; ⁇ 4.7 ⁇ m) determined through a Andersen Cascade Impactor is increased by at least 10% in comparison with the same formulation packaged with a valve with a metering chamber of at least 50 ⁇ l and the same sump, as it will be shown hereinbelow.
- Also provided is a method of filling an aerosol inhaler with a composition comprising filling the following components into the inhaler
- HFA hydrofluoroalkane
- the aerosol compositions of the invention described below were prepared by the following method.
- the required components of a composition were added into a can in the following order: drug, non-volatile additive, absolute ethanol.
- the propellant was added through the valve.
- the weight gain of the can after each component was added was recorded to allow the percentage, by weight, of each component in the formulation to be calculated.
- the aerodynamic particle size distribution of each formulation was characterized using a Multistage Cascade Impactor according to the procedure described in the European Pharmacopoeia 2nd edition, 1995, part V.5.9.1. pages 15-17. In this specific case an Andersen Cascade Impactor (ACI) was used. Results represented were obtained from ten cumulative actuations of a formulation. Deposition of the drug on each ACI plate was determined by high pressure liquid chromatography. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were calculated from plots of the cumulative percentage undersize of drug collected on each ACI plate (probit scale), against the upper cut off diameter for each respective ACI plate (log10 scale). The fine particle dose of each formulation was determined from the mass of drug collected on Stages 3 through to Filter ( ⁇ 4.7 ⁇ m) divided by the number of actuations per experiment.
- ACI Andersen Cascade Impactor
- Table 1 shows the MMAD characteristics of aerosol formulations containing beclomethasone dipropionate (BDP) (active material), glycerol as low volatility component and different mixtures of HFA 134a and HFA 227.
- BDP beclomethasone dipropionate
- glycerol active material
- HFA 134a low volatility component
- HFA 227 HFA 227
- Table 2 shows the effects of valve chamber (also known as metering chamber) volumes at sump volume constant on the generation of aerosol clouds.
- compositions of the invention consisting of aerosol drug solution in a mixture of 134a and 227 HFA propellants, a cosolvent and optionally a low volatility component, added into an aerosol inhaler having a chamber volume ranging from 25 to 50 ⁇ l, constitute a delivery system which allow improvement of the delivery characteristics of drugs to the lung by modulating the aerodynamic particle size and size distribution so that the pattern of deposition gives the desired clinical effect.
- metered-dose inhalers having part or all of their internal metallic surfaces consisting of stainless steel, anodized aluminium or lined with an inert organic coating can be employed.
Abstract
In a solution composition for use in an aerosol inhaler which comprises an active material, a propellant containing a hydrofluoroalkane, a cosolvent and optionally a low volatility m compound the use of a mixture of HFA 134a and HFA 227 allows to modulate the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler to target specific regions of the respiratory tract. Moreover the fine particle dose (FPD) of the active ingredient in the composition increases by reducing the metering chamber volume.
Description
- The invention relates to aerosol compositions for pharmaceutical use. In particular, this invention relates to aerosol compositions for use in pressurised metered dose inhalers (MDIs). The invention also relates to solution aerosol compositions, wherein the propellant comprises HFA 134a or HFA 227 or their mixtures.
- Another aspect of the invention relates to pressurised MDIs for dispensing said compositions.
- Inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation.
- Active materials commonly delivered by inhalation include bronchodilators such as β2 agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergics and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
- There are a number of types of inhaler currently available. The most widely used type is a pressurised metered dose inhaler (MDI) which uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol. Formulations used in MDIs (aerosol formulations) generally comprise the active material, one or more liquefied propellants and a surfactant or a solvent.
- For many years the preferred propellants used in aerosols for pharmaceutical use have been a group of chlorofluorocarbons which are commonly called Freons or CFCs, such as CCl3F (Freon 11 or CFC-11), CCl2F2 (Freon 12 or CFC-12), and CClF2-CClF2 (Freon 114 or CFC-114). Chlorofluorocarbons have properties particularly suitable for use in aerosols, including high vapour pressure which generates clouds of droplets of a suitable particle size from the inhaler.
- Recently, the chlorofluorocarbon (CFC) propellants such as Freon 11 and Freon 12 have been implicated in the destruction of the ozone layer and their production is being phased out.
- Hydrofluoroalkanes [(HFAs) known also as hydro-fluoro-carbons (HFCs)] contain no chlorine and are considered less destructive to ozone and these are proposed as substitutes for CFCs.
- HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of medicinal aerosol formulations using such HFA propellant systems are disclosed in several patent applications.
- Many of these applications, in which. HFAs are used as propellant, propose the addition of one or more of adjuvants including compounds acting as cosolvents, surface active agents including fluorinated and non-fluorinated surfactants, dispersing agents including alkylpolyethoxylates and stabilizers.
- Cosolvents which may be used in these formulations include alcohols such as ethanol and polyols such as propylene glycol.
- Medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP 0372777. EP 0372777 requires the use of HFA 134a as a propellant in combination with both a surfactant and an adjuvant having higher polarity than the propellant.
- For aerosol suspension compositions, a surfactant is often added to improve the physical stability of the suspension. EP 0372777 states that the presence of surfactant assists in the preparation of stable, homogeneous suspensions and may also assist in the preparation of stable solution formulations.
- Surfactants also lubricate the valve components in the inhaler device.
- The use of propylene glycol as a solvent having a higher polarity than the propellant in HFA pressurised metered dose inhalers formulations has been mentioned in several other patent applications and for example in:
- EP 504112 relates to a pharmaceutical aerosol formulation free from CFCs containing a propellant (hydrocarbon, HFA or a mixture), one or more pharmaceutical active ingredients, a non-ionic surfactant and optionally other conventional pharmaceutical auxiliaries suitable for aerosol formulations comprising solvents having a higher polarity than the propellant, other non-ionic surfactants as valve lubricants, vegetable oils, phospholipids, taste masking agents.
- DE 4123663 describes a medical aerosol composition containing a dispersion or suspension of an active agent in association with a compound with surface-active or lipophilic properties, heptafluoropropane as propellant and an alcohol such as ethanol and/or propylene glycol.
- Other applications propose the addition of dispersing agents to the composition. U.S. Pat. No. 5,502,076 concerns compositions used in inhalation aerosols comprising an HFA, leukotriene antagonists and dispersing agent comprising 3C-linked triesters, vitamin E acetate, glycerin, t-BuOH, or transesterified oil/polyethylene glycol.
- EP 384371, describes a propellant for an aerosol, comprising pressure-liquefied HFA 227 in a mixture with pressure-liquefied propane and/or n-butane and/or iso-butane and/or dimethyl ether and/or 1,1-difluoroethane. The document also discloses foam formulations (shaving and shower foams) containing glycerol as additive.
- The effectiveness of an aerosol device, for example an MDI, is a function of the dose deposited at the appropriate site in the lungs. Deposition is affected by several parameters, of which the most important are the Fine Particle Dose (FPD) and the aerodynamic particle size. Solid particles and/or droplets in an aerosol formulation can be characterized by their mass median aerodynamic diameter (MMAD, the diameter around which the mass aerodynamic diameters are distributed equally).
- The FPD gives a direct measure of the mass of particles within a specified size range and is closely related to the efficacy of the product.
- Particle deposition in the lung depends largely upon three physical mechanisms: (1) impaction, a function of particle inertia; (2) sedimentation due to gravity; and (3) diffusion resulting from Brownian motion of fine, submicrometer (<1 μm) particles. The mass of the particles determines which of the three main mechanisms predominates.
- The effective aerodynamic diameter is a function of the size, shape and density of the particles and will affect the magnitude of forces acting on them. For example, while inertial and gravitational effects increase with increasing particle size and particle density, the displacements produced by diffusion decrease. In practice, diffusion plays little part in deposition from pharmaceutical aerosols. Impaction and sedimentation can be assessed from a measurement of the mass median aerodynamic diameter (MMAD) which determines the displacement across streamlines under the influence of inertia and gravity, respectively.
- Aerosol particles of equivalent MMAD and GSD (Geometric Standard Deviation) have similar deposition in the lung irrespective of their composition. The GSD is a measure of the variability of the aerodynamic particle diameters.
- For inhalation therapy there is a preference for aerosols in which the particles for inhalation have a diameter of about 0.8 to 5 μm. Particles which are larger than 5 μm in diameter are primarily deposited by inertial impaction in the oropharynx, particles 0.5 to 5 μm in diameter, influenced mainly by gravity, are ideal for deposition in the conducting airways, and particles 0.5 to 3 μm in diameter are desirable for aerosol delivery to the lung periphery. Particles smaller than 0.5 μm may be exhaled.
- Respirable particles are generally considered to be those with aerodynamic diameters less than 5 μm. These particles, particularly those with a diameter of about 3 μm, are efficiently deposited in the lower respiratory tract by sedimentation.
- Besides the therapeutic purposes, the size of aerosol particles is important in respect to the side effects of the drugs. For example, it is well known that the oropharynx deposition of aerosol formulations of steroids can result in side effects such as candidiasis of mouth and throat.
- On the other hand a higher systemic exposure to the aerosol particles due to deep lung penetration can enhance the undesired systemic effects of the drugs. For example, the systemic exposure to steroids can produce side effects on bone metabolism and growth.
- It has been reported that the particle size characteristics of HFA aerosol formulations of the state of the art are often very different from the products to be replaced.
- HFA substitutes may not be pharmaceutically or clinically equivalent and adjustment of dose and regimen may be necessary, giving problems for doctor, pharmacist and patient.
- An alternative is the seamless transition from the old to the new formulas which demands the same deposition of the drug in the lung. For any product, this can be inferred from the amount of drug and its particle size distribution in the aerosol cloud. Matching CFC and HFA formulations with suspension technology is practicable because the particle size of the aerosol cloud is dominated by the particle size of the suspended drug, defined by the milling or precipitation process.
- However, when, as commonly occurs, solution formulations are unavoidable, the volumetric contribution of suspended particles is absent and much finer clouds, largely defined by the concentration of the drug in the solution, are generated. In these circumstances, a co-solvent, such as alcohol, is often added to ensure satisfactory solubility. The fine clouds from such formulations give more extensive deposition in the lung periphery than their CFC counterparts.
- EP 0553298 describes an aerosol formulation comprising: a therapeutically effective amount of beclomethasone 17,21 dipropionate (BDP); a propellant comprising a hydrofluorocarbon selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof, and ethanol in an amount effective to solubilize the beclomethasone 17,21 dipropionate in the propellant. The formulation is further characterized in that substantially all of the beclomethasone 17,21 dipropionate is dissolved in the formulation and that the formulation contains no more than 0,0005% by weight of any surfactant.
- It has been reported in literature that these new formulations of beclomethasone dipropionate (BDP) as a solution in HFA 134a deliver a particle size distribution with a MMAD of 1.1 μm. This means that the peripheral pulmonary deposition of very small particles increases and submicronic particles can easily be directly absorbed from the alveoli into the bloodstream. The rate and extent of systemic absorption is significantly increased and as a consequence undesired effects for example certain side effects can increase. A relatively large fraction of the dose is exhaled. The implications of this for clinical efficacy and toxic effects are great. They arise because the principles of formulation using HFAs may modify the physical form of the respired cloud.
- It has now been surprisingly found that in solution formulations of the present application comprising an active material, a propellant containing a hydrofluoroalkane (HFA), a cosolvent and optionally a low volatility compound, the use of a mixture of HFA 134a and of HFA 227 allows the modulation of the MMAD of the aerosol particles on actuation of the inhaler to a value which is suited for the pulmonary administration.
- Mixtures of hydrofluoroalkanes have been previously used in suspension-based pMDI compositions to vary the density of the continuous phase in order to match the density of the suspended drug and maximize the physical stability of the pMDI suspension.
- Williams R. O. et al. in Drug Dev. Ind. Pharm. 24(8), 763-770, 1998 investigated the influence of propellant composition on the characteristics of suspension aerosol compositions. The results showed that as the density of the propellant blends approached the density of the suspended drug particles, the formulation became more physically stable.
- Analogously, WO93/11747 discloses that in suspension aerosol compositions the density of the propellant may be changed by using HFA 134a and HFA 227 mixtures so as to bring it to approximately the same value of the density of the active ingredient, minimizing thereby the sedimentation of the drug particles.
- Therefore the aerosol compositions using the new propellant systems disclosed in the known prior art seek to overcome problems of physical stability of the formulations.
- It has surprisingly been found that in solution compositions by using a mixture of HFA 134a and HFA 227 and optionally a low volatility component, the MMAD of the aerosol particles on actuation of the inhaler can be modulated and thus the compositions may be formulated so that the aerodynamic particle size characteristics are optimized.
- Advantageously, the low volatility component has a vapour pressure at 25° C. not more than 0.1 kPa, preferably not more than 0.05 kPa.
- The low vapour pressure of the low volatility component is to be contrasted with that of the cosolvent which preferably has a vapour pressure at 25° C. not less than 3 kPa, more preferably not less than 5 kPa.
- The cosolvent has advantageously a higher polarity than that of the propellant and the cosolvent is used to increase the solubility of the active material in the propellant.
- Advantageously the cosolvent is an alcohol. The cosolvent is preferably ethanol. The cosolvent may include one or more materials.
- The low volatility component may be a single material or a mixture of two or more materials.
- In general terms the low volatility component can be any compound, safe and compatible with the propellant system of the invention capable to influence either the size or the density of the aerosol particle so affecting the MMAD.
- We have found that glycols are particularly suitable for use as the low volatility component, especially propylene glycol, polyethylene glycol and glycerol.
- Other particularly suitable materials are thought to include other alcohols and glycols, for example alkanols such as decanol (decyl alcohol), sugar alcohols including sorbitol, mannitol, lactitol and maltitol, glycofural (tetrahydro-furfurylalcohol) and dipropylene glycol.
- The low volatility component may include esters for example ascorbyl palmitate and tocopherol. Among the esters isopropyl myristate is particularly preferred.
- It is also envisaged that various other materials may be suitable for use as the low volatility component including vegetable oils, organic acids for example saturated carboxylic acids including lauric acid, myristic acid and stearic acid; unsaturated carboxylic acids including sorbic acid, and especially oleic acid, which has been previously used in aerosol formulations, in order to improve the physical stability of drug suspensions, as a dispersing agent useful in keeping the suspended particles from agglomerating; saccharine, ascorbic acid, cyclamic acid, amino acids or aspartame; alkanes for example dodecane and octadecane; terpenes for example menthol, eucalyptol, limonene; sugars for example lactose, glucose, sucrose; polysaccharides for example ethyl cellulose, dextran; antioxidants for example butylated hydroxytoluene, butylated hydroxyanisole; polymeric materials for example polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrollidone; amines for example ethanolamine, diethanolamine, triethanolamine; steroids for example cholesterol, cholesterol esters.
- The amount of low volatility component in the composition depends to some extent upon its density and the amount of active material and cosolvent in the composition. Advantageously, the composition includes not more than 20% by weight of the low volatility component. Preferably the composition includes not more than 10% by weight of the low volatility component.
- On actuation of the inhaler, the propellant and the ethanol vaporise but because of the low vapour pressure of the low volatility component, that component generally will not.
- It is thought that it is preferable for the composition to contain at least 0.2%, preferably at least 1% by weight of the low volatility component. The composition may contain between 1% and 2% by weight.
- According to the present invention, as it can be noticed from the results reported in the tables, the influence on the MMAD of the particles is correlated to the ratio of the two HFA components (as well as to the amount and density of the low volatility component).
- The MMAD can be modulated by changing the ratio between HFA 134a and HFA 227; said ratio may range from 10:90 to 90:10.
- From the data reported in Table 1, it is clear that MMAD is increased by increasing the proportion of HFA 227 in the mixture.
- Most advantageously, the composition is such that, on actuation of the aerosol inhaler in use, the MMAD of the aerosol particles is not less than 21m. For some active materials the MMAD is preferably not less than 2.5 μm and for a few formulations, the preferred MMAD will be greater than 3 μm or even greater than 4 μm.
- In some cases a small quantity of water may be added to the composition to improve the solution of the active material and/or the low volatility component in the cosolvent.
- The active material may be one or more of any biologically active material which could be administered by inhalation. Active materials commonly administered in that way include β2 agonists, for example salbutamol and its salts, steroids for example beclomethasone dipropionate or anti-cholinergics for example ipratropium bromide and combinations thereof.
- As indicated above, on actuation of the inhaler, the aerosol particles advantageously have an MMAD of not less than 2 μm, for many formulations more preferably not less than 2.5 μm.
- It has also been found, and it is a further object of the invention, that it is possible to increase the “fine particle dose” or FPD of the active ingredients in the compositions of the invention, without affecting MMAD, by decreasing the metering chamber volume of the metered dose inhaler (increasing thereby the space above it named “sump”) and/or changing the ratio between the metering chamber and the space above by increasing the sump. In particular, by reducing the metering chamber volume from 50 μl to 25 μl at sump volume constant, it is possible to increase the fine particle delivery up to 40%.
- This result could be only obtained with solution compositions in which the MMAD of the particles is higher than 2 μm and it is particularly surprising since it is known from Williams R. O. et al. in Pharmaceutical Research 14(4), 438-443, 1997 that in suspension based PMDI containing HFA 134a the aerodynamic particle size distribution was not influenced as the metering chamber volume of the valve was increased.
- The solution formulations with MMAD>2 may be obtained by using a metering chamber <40 μl, preferably 25 μl: the fine particle delivery (Stage 3 to filter; <4.7 μm) determined through a Andersen Cascade Impactor is increased by at least 10% in comparison with the same formulation packaged with a valve with a metering chamber of at least 50 μl and the same sump, as it will be shown hereinbelow.
- Using a reduced metering chamber volume (e.g. about 40 μl or lower for a conventional inhaler), favourable results are obtained even with aerosol compositions wherein the propellant consists either in HFA 227 or in HFA 134a alone.
- Also provided is a method of filling an aerosol inhaler with a composition, the method comprising filling the following components into the inhaler
- (a) one or more active materials,
- (b) optionally one or more low volatility components,
- (c) one or more cosolvents
- followed by the addition of a propellant containing a hydrofluoroalkane (HFA) or a mixture of HFAs.
- Embodiments of the invention will now be described by way of example.
- The aerosol compositions of the invention described below were prepared by the following method. The required components of a composition were added into a can in the following order: drug, non-volatile additive, absolute ethanol. After crimping of the valve on to the can, the propellant was added through the valve. The weight gain of the can after each component was added was recorded to allow the percentage, by weight, of each component in the formulation to be calculated.
- The aerodynamic particle size distribution of each formulation was characterized using a Multistage Cascade Impactor according to the procedure described in the European Pharmacopoeia 2nd edition, 1995, part V.5.9.1. pages 15-17. In this specific case an Andersen Cascade Impactor (ACI) was used. Results represented were obtained from ten cumulative actuations of a formulation. Deposition of the drug on each ACI plate was determined by high pressure liquid chromatography. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were calculated from plots of the cumulative percentage undersize of drug collected on each ACI plate (probit scale), against the upper cut off diameter for each respective ACI plate (log10 scale). The fine particle dose of each formulation was determined from the mass of drug collected on Stages 3 through to Filter (<4.7 μm) divided by the number of actuations per experiment.
- Table 1 shows the MMAD characteristics of aerosol formulations containing beclomethasone dipropionate (BDP) (active material), glycerol as low volatility component and different mixtures of HFA 134a and HFA 227. As can be seen, the MMAD is substantially influenced by the ratio of the two fluorocarbons whereas FPD is substantially unaffected.
- The presence of the low volatility component contributes to the modulation of the MMAD: its percent content (w/w) can be properly adapted to obtain the desired MMAD.
- Table 2 shows the effects of valve chamber (also known as metering chamber) volumes at sump volume constant on the generation of aerosol clouds.
- In particular, the data shown in Table 2 show that FPD increases with decreasing valve chamber volume and that FPD can be increased by more that 40% by reducing the volume of a valve metering chamber. MMAD or GSD are not conversely affected by changing the volume of the valve-metering chamber.
- Therefore, the compositions of the invention consisting of aerosol drug solution in a mixture of 134a and 227 HFA propellants, a cosolvent and optionally a low volatility component, added into an aerosol inhaler having a chamber volume ranging from 25 to 50 μl, constitute a delivery system which allow improvement of the delivery characteristics of drugs to the lung by modulating the aerodynamic particle size and size distribution so that the pattern of deposition gives the desired clinical effect.
- To obviate possible chemical stability problems of active ingredients in solution in HFA propellants metered-dose inhalers having part or all of their internal metallic surfaces consisting of stainless steel, anodized aluminium or lined with an inert organic coating can be employed.
TABLE 1 Effect of HFA 134a/HFA 227 mixtures upon the MMAD of pMDI solution formulation BDP 250 μg/shot Ethanol 15% (w/w) Glycerol 1.3% (w/w) HFA to 12 ml Actuator = 0.30 mm HFA 227/ MMAD FPD FPD3 < 4.7 μm* HFA 134a (μm) (%) (μg) 100:0 4.2, 3.9, 3.8 20, 20, 24 47, 45, 50 75:25 3.7, 3.7 25, 25 56, 57 50:50 3.4, 3.7 25, 25 56, 56 25:75 3.3, 3.2 27, 28 60, 62 0:100 2.8, 2.8 27, 27 58, 59 -
TABLE 2 Effect of Valve Chamber Volume upon the FPD of pMDIs containing HFA 134a and HFA 227 Solutions Formulations BDP 50 μg/shot Ethanol 13% (w/w) Glycerol 1.3% (w/w) HFA to 12 ml Chamber Metered Volume FPD < 4.7 μm MMAD Dose (μl) Propellant (μg) (μm) GSD (μg) actuator orifice 0.30 mm 25 HFA 134a 19.2 2.6 2.0 57 50 13.9 2.8 2.1 49 100 11.7 2.7 2.2 51 25 HFA 227 16.4 3.6 2.1 58 50 13.1 3.5 2.2 51 100 12.6 3.5 2.2 49 actuator orifice 0.25 mm 25 HFA 134a 26.0 2.8 1.9 55
Claims (18)
1. A composition in form of solution for use in an aerosol inhaler, the composition comprising an active material, a propellant containing a hydrofluoroalkane (HFA), a cosolvent, optionally a low volatility component characterized in that the propellant consists of a mixture of HFA 227 and HFA 134a.
2. A composition according to claim 1 , wherein the ratio of HFA 227/HFA 134a ranges from 10:90 to 90:10.
3. A composition according to claim 1 or 2, wherein the low volatility component has a vapour pressure at 25° C. lower than 0.1 kPa.
4. A composition according to claim 3 , wherein the low volatility component has a vapour pressure at 25° C. lower than 0.05 kPa.
5. A composition according to any preceding claim, wherein the cosolvent has' a vapour pressure at 25° C. lower than 3 kPa.
6. A composition according to any preceding claim, wherein the cosolvent has a vapour pressure at 25° C. lower than 5 kPa.
7. A composition according to any preceding claim, wherein the cosolvent is an alcohol.
8. A composition according to any preceding claim, wherein the low volatility component includes a glycol, oleic acid or isopropyl myristate.
9. A composition according to any preceding claim, wherein the composition includes not more than 20% by weight of the low volatility component.
10. A composition according to any preceding claim, wherein the composition includes at least 0.2% by weight of the low volatility component.
11. A composition according to any preceding claim, the composition being such that, on actuation of the aerosol inhaler in use, the MMAD of the aerosol particles is not less than 2 μm.
12. An aerosol inhaler containing a solution composition comprising an active material, a propellant containing one or more hydrofluoroalkane, a cosolvent and optionally a low volatility component wherein the particle MMAD is greater than 2 μm and the fine particle dose (<4.7 μm) is >30%.
13. An aerosol inhaler according to claim 12 wherein the particle MMAD is greater than 2 μm and the fine particle dose (<4.7 μm) is >40%.
14. An aerosol inhaler according to claims 12 and 13 wherein the particle MMAD is greater than 0.2 μm and the fine particle dose. (<4.7 μm) is >50%.
15. An aerosol inhaler according to claims 12 to 14 having a chamber volume ranging from 25 to 50 μl yielding an increase of FPD compared to inhalers having chamber volumes larger than 50 μl.
16. An aerosol inhaler according to claims 12 to 15 containing the compositions of claims 1-11.
17. An aerosol inhaler according to claims 12 to 16 having part or all of the internal surfaces consisting of stainless steel, anodised aluminium or lined with an inert organic coating.
18. A delivery system for the administration of drugs to the lung consisting of aerosol drug solution in a mixture of 134a and 227 HFA propellants, a cosolvent and optionally a low volatility component, in an aerosol inhaler having a chamber volume ranging from 25 to 50 μl.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/766,857 US20040184993A1 (en) | 1998-11-25 | 2004-01-30 | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT1998MI002558A IT1303788B1 (en) | 1998-11-25 | 1998-11-25 | MEDICINAL AEROSOL FORMULATIONS. |
ITMI98A002558 | 1998-11-25 | ||
US09/831,886 US6713047B1 (en) | 1998-11-25 | 1999-11-22 | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
US10/766,857 US20040184993A1 (en) | 1998-11-25 | 2004-01-30 | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/831,886 Division US6713047B1 (en) | 1998-11-25 | 1999-11-22 | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
PCT/EP1999/008959 Division WO2000030607A1 (en) | 1998-11-25 | 1999-11-22 | PHARMACEUTICAL AEROSOL COMPOSITION CONTAINING HFA 227 AND HFA 134a |
Publications (1)
Publication Number | Publication Date |
---|---|
US20040184993A1 true US20040184993A1 (en) | 2004-09-23 |
Family
ID=11381136
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/831,886 Expired - Fee Related US6713047B1 (en) | 1998-11-25 | 1999-11-22 | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
US10/766,857 Abandoned US20040184993A1 (en) | 1998-11-25 | 2004-01-30 | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/831,886 Expired - Fee Related US6713047B1 (en) | 1998-11-25 | 1999-11-22 | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
Country Status (22)
Country | Link |
---|---|
US (2) | US6713047B1 (en) |
EP (1) | EP1133277B1 (en) |
JP (1) | JP2002530316A (en) |
KR (1) | KR100794060B1 (en) |
CN (1) | CN1177582C (en) |
AT (1) | ATE368450T1 (en) |
AU (1) | AU770529B2 (en) |
BR (1) | BR9916865A (en) |
CA (1) | CA2352483C (en) |
CY (1) | CY1106904T1 (en) |
DE (1) | DE69936730T2 (en) |
DK (1) | DK1133277T3 (en) |
ES (1) | ES2289832T3 (en) |
IL (1) | IL143293A0 (en) |
IT (1) | IT1303788B1 (en) |
MA (1) | MA26763A1 (en) |
NO (1) | NO330195B1 (en) |
NZ (1) | NZ511923A (en) |
PT (1) | PT1133277E (en) |
TR (1) | TR200101442T2 (en) |
WO (1) | WO2000030607A1 (en) |
ZA (1) | ZA200104220B (en) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030190287A1 (en) * | 1997-06-13 | 2003-10-09 | Chiesi Farmaceutici S.P.A. | Pharaceutical aerosol composition |
US20030190289A1 (en) * | 2000-05-12 | 2003-10-09 | David Lewis | Formulations containing a glucocorticoid drug for the treatment of bronchopulmonary diseases |
US20040033201A1 (en) * | 1999-06-18 | 2004-02-19 | 3M Innovative Properties Company | Process for making chemically stable C-17/21 OH 20-ketosteroid aerosol products |
US20050034720A1 (en) * | 2000-01-07 | 2005-02-17 | Gaetano Brambilla | Aerosol inhaler |
US20050129621A1 (en) * | 2002-03-01 | 2005-06-16 | Chiesi Farmaceutici S.P.A. | Aerosol formulations for pulmonary administration of medicaments to produce a systemic effect |
US20050142071A1 (en) * | 1998-11-25 | 2005-06-30 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
US20050152846A1 (en) * | 2002-03-01 | 2005-07-14 | Chiesi Farmaceutici S.P.A. | Formoterol superfine formulation |
US20050163722A1 (en) * | 2001-07-02 | 2005-07-28 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US6967017B1 (en) | 1999-07-23 | 2005-11-22 | Chiesi Farmaceutici S.P.A. | Formulations of steroid solutions for inhalatory administration |
US20060083693A1 (en) * | 2000-05-22 | 2006-04-20 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
US20060120966A1 (en) * | 2002-10-23 | 2006-06-08 | Chiesi Farmaceutici S.P.A. | Salmeterol superfine formulation |
US20060165603A1 (en) * | 2002-06-06 | 2006-07-27 | Chiesi Farmaceutici S.P.A. | Solubilisation of drugs in hfa propellant by means of emulsions |
US20060257324A1 (en) * | 2000-05-22 | 2006-11-16 | Chiesi Farmaceutici S.P.A. | Pharmaceutical solution formulations for pressurised metered dose inhalers |
US7381402B2 (en) | 2004-02-27 | 2008-06-03 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
EP2011534A1 (en) * | 2007-07-03 | 2009-01-07 | CHIESI FARMACEUTICI S.p.A. | Metered dose inhaler actuator |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1303788B1 (en) * | 1998-11-25 | 2001-02-23 | Chiesi Farma Spa | MEDICINAL AEROSOL FORMULATIONS. |
US6739333B1 (en) | 1999-05-26 | 2004-05-25 | Boehringer Ingelheim Pharma Kg | Stainless steel canister for propellant-driven metering aerosols |
DE60031504T2 (en) | 1999-09-11 | 2007-04-05 | Glaxo Group Ltd., Greenford | FLUTICASONPROPIONATE DRUG PREPARATION |
DE60019167T2 (en) * | 1999-12-24 | 2006-05-11 | Glaxo Group Ltd., Greenford | PHARMACEUTICAL AEROSOL FORMULATION CONTAINING SALMETEROL AND FLUTICASONE |
GB2367011A (en) * | 2000-08-26 | 2002-03-27 | Glaxo Group Ltd | Metered dose inhaler for salmeterol |
EP1340503A1 (en) * | 2002-03-01 | 2003-09-03 | CHIESI FARMACEUTICI S.p.A. | Solution aerosol formulation containing esters of 3, 17-dihydroxy oestratriene derivates for pulmonary delivery |
US7311894B2 (en) | 2002-03-28 | 2007-12-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | HFA suspension formulations containing an anticholinergic |
EP1452179A1 (en) * | 2003-02-27 | 2004-09-01 | CHIESI FARMACEUTICI S.p.A. | Novel medicament combination of a highly potent long-lasting beta2-agonist and a corticosteroid |
EP1915985A1 (en) | 2003-03-20 | 2008-04-30 | Boehringer Ingelheim Pharmaceuticals Inc. | Formulation for a Metered Dose Inhaler Using Hydro-Fluoro-Alkanes as Propellants |
KR101113003B1 (en) | 2003-03-20 | 2012-02-24 | 베링거 인겔하임 파마슈티칼즈, 인코포레이티드 | Formulation for a metered dose inhaler using hydro-fluoro-alkanes as propellants |
EP1663159A4 (en) * | 2003-09-10 | 2010-06-09 | Map Pharmaceuticals Inc | Aerosol formulations for delivery of dihydroergotamine to the systemic circulation via pulmonary inhalation |
AR041873A1 (en) * | 2003-10-30 | 2005-06-01 | Pablo Cassara Srl Lab | A PHARMACEUTICAL FORMULATION IN ADEQUATE AEROSOL FOR ORAL OR NASAL INHALATION CONTAINING GLUCOCORTICOIDS IN A STABLE SOLUTION TO STORAGE; A METHOD FOR STABILIZING FORMULATIONS AND USE OF A STABILIZING AGENT |
KR20070000476A (en) * | 2004-02-27 | 2007-01-02 | 키에시 파르마슈티시 엣스. 피. 에이. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
CN1583170A (en) * | 2004-06-10 | 2005-02-23 | 安米 | Medicine for human lysozyme against virus and drug-fast bacteria and its preparation |
JP5209963B2 (en) | 2004-07-02 | 2013-06-12 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Aerosol suspension formulation containing TG227EA or TG134A as propellant |
DE102006017320A1 (en) | 2006-04-11 | 2007-10-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aerosol suspension formulations with TG 227 ea or TG 134 a as propellant |
WO2011150441A1 (en) * | 2010-06-03 | 2011-12-08 | Wholesome Biopharm Pty Ltd | Medical aerosol formulation comprising ribavirin |
RU2578975C2 (en) * | 2010-08-03 | 2016-03-27 | КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. | Pharmaceutical preparation containing phosphodiesterase inhibitor |
WO2014205030A1 (en) * | 2013-06-19 | 2014-12-24 | Map Pharmaceuticals, Inc. | Pulmonary administration of rotigotine |
US20160310410A1 (en) | 2015-04-24 | 2016-10-27 | Glenmark Specialty S.A. | Pharmaceutical compositions comprising arformoterol and glycopyrronium |
CN114796166A (en) * | 2021-01-29 | 2022-07-29 | 北京远大九和药业有限公司 | Aerosol containing terpene volatile oil and preparation method thereof |
CN114522143A (en) * | 2022-02-22 | 2022-05-24 | 暨南大学 | Low-refrigeration-effect composite propellant for inhalation aerosol and preparation method and application thereof |
Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3095355A (en) * | 1961-10-12 | 1963-06-25 | Revlon | Aerosol composition |
US3860618A (en) * | 1967-08-08 | 1975-01-14 | Philip Saxton Hartley | Chromone |
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 |
US5192528A (en) * | 1985-05-22 | 1993-03-09 | Liposome Technology, Inc. | Corticosteroid inhalation treatment method |
US5653961A (en) * | 1995-03-31 | 1997-08-05 | Minnesota Mining And Manufacturing Company | Butixocort aerosol formulations in hydrofluorocarbon propellant |
US5776432A (en) * | 1990-10-18 | 1998-07-07 | Minnesota Mining And Manufacturing Company | Beclomethasone solution aerosol formulations |
US6004537A (en) * | 1998-12-18 | 1999-12-21 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes, budesonide and formoterol |
US6126919A (en) * | 1997-02-07 | 2000-10-03 | 3M Innovative Properties Company | Biocompatible compounds for pharmaceutical drug delivery systems |
US6461591B1 (en) * | 1997-02-05 | 2002-10-08 | Jago Research Ag | Medical aerosol formulations |
US6713047B1 (en) * | 1998-11-25 | 2004-03-30 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
US6716414B2 (en) * | 2000-05-22 | 2004-04-06 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
US20050129621A1 (en) * | 2002-03-01 | 2005-06-16 | Chiesi Farmaceutici S.P.A. | Aerosol formulations for pulmonary administration of medicaments to produce a systemic effect |
US20050152846A1 (en) * | 2002-03-01 | 2005-07-14 | Chiesi Farmaceutici S.P.A. | Formoterol superfine formulation |
US20060120966A1 (en) * | 2002-10-23 | 2006-06-08 | Chiesi Farmaceutici S.P.A. | Salmeterol superfine formulation |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH89518A (en) * | 1919-03-22 | 1921-06-01 | Croning Johannes | Housing for cylinder locks that can be adjusted according to the door thickness. |
GB8828477D0 (en) | 1988-12-06 | 1989-01-05 | Riker Laboratories Inc | Medical aerosol formulations |
DE69105212T2 (en) | 1990-10-18 | 1995-03-23 | Minnesota Mining & Mfg | AEROSOL PREPARATION CONTAINING BECLOMETASON 17.21 DIPROPIONATE. |
DK0820279T3 (en) * | 1995-04-14 | 2002-10-07 | Smithkline Beecham Corp | Dosing metered inhaler for Albuterol |
GB9612297D0 (en) * | 1996-06-11 | 1996-08-14 | Minnesota Mining & Mfg | Medicinal aerosol formulations |
EP0914143A1 (en) * | 1996-07-08 | 1999-05-12 | Rhone-Poulenc Rorer Limited | Medicinal cyclosporin-a aerosol solution formulation |
GB9620187D0 (en) * | 1996-09-27 | 1996-11-13 | Minnesota Mining & Mfg | Medicinal aerosol formulations |
GB2326334A (en) | 1997-06-13 | 1998-12-23 | Chiesi Farma Spa | Pharmaceutical aerosol compositions |
-
1998
- 1998-11-25 IT IT1998MI002558A patent/IT1303788B1/en active
-
1999
- 1999-11-22 EP EP99958096A patent/EP1133277B1/en not_active Expired - Lifetime
- 1999-11-22 KR KR1020017006520A patent/KR100794060B1/en not_active IP Right Cessation
- 1999-11-22 PT PT99958096T patent/PT1133277E/en unknown
- 1999-11-22 CA CA002352483A patent/CA2352483C/en not_active Expired - Fee Related
- 1999-11-22 AU AU15553/00A patent/AU770529B2/en not_active Ceased
- 1999-11-22 ES ES99958096T patent/ES2289832T3/en not_active Expired - Lifetime
- 1999-11-22 NZ NZ511923A patent/NZ511923A/en not_active IP Right Cessation
- 1999-11-22 WO PCT/EP1999/008959 patent/WO2000030607A1/en active IP Right Grant
- 1999-11-22 DK DK99958096T patent/DK1133277T3/en active
- 1999-11-22 BR BR9916865-0A patent/BR9916865A/en not_active Application Discontinuation
- 1999-11-22 US US09/831,886 patent/US6713047B1/en not_active Expired - Fee Related
- 1999-11-22 IL IL14329399A patent/IL143293A0/en not_active IP Right Cessation
- 1999-11-22 AT AT99958096T patent/ATE368450T1/en active
- 1999-11-22 JP JP2000583491A patent/JP2002530316A/en active Pending
- 1999-11-22 TR TR2001/01442T patent/TR200101442T2/en unknown
- 1999-11-22 DE DE69936730T patent/DE69936730T2/en not_active Expired - Lifetime
- 1999-11-22 CN CNB998148717A patent/CN1177582C/en not_active Expired - Fee Related
-
2001
- 2001-05-22 NO NO20012517A patent/NO330195B1/en not_active IP Right Cessation
- 2001-05-22 MA MA26203A patent/MA26763A1/en unknown
- 2001-05-23 ZA ZA200104220A patent/ZA200104220B/en unknown
-
2004
- 2004-01-30 US US10/766,857 patent/US20040184993A1/en not_active Abandoned
-
2007
- 2007-10-04 CY CY20071101264T patent/CY1106904T1/en unknown
Patent Citations (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3095355A (en) * | 1961-10-12 | 1963-06-25 | Revlon | Aerosol composition |
US3860618A (en) * | 1967-08-08 | 1975-01-14 | Philip Saxton Hartley | Chromone |
US5192528A (en) * | 1985-05-22 | 1993-03-09 | Liposome Technology, Inc. | Corticosteroid inhalation treatment method |
US5776432A (en) * | 1990-10-18 | 1998-07-07 | Minnesota Mining And Manufacturing Company | Beclomethasone solution aerosol 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 |
US5653961A (en) * | 1995-03-31 | 1997-08-05 | Minnesota Mining And Manufacturing Company | Butixocort aerosol formulations in hydrofluorocarbon propellant |
US6461591B1 (en) * | 1997-02-05 | 2002-10-08 | Jago Research Ag | Medical aerosol formulations |
US6126919A (en) * | 1997-02-07 | 2000-10-03 | 3M Innovative Properties Company | Biocompatible compounds for pharmaceutical drug delivery systems |
US6713047B1 (en) * | 1998-11-25 | 2004-03-30 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
US6004537A (en) * | 1998-12-18 | 1999-12-21 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes, budesonide and formoterol |
US6716414B2 (en) * | 2000-05-22 | 2004-04-06 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
US20060083693A1 (en) * | 2000-05-22 | 2006-04-20 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
US20050129621A1 (en) * | 2002-03-01 | 2005-06-16 | Chiesi Farmaceutici S.P.A. | Aerosol formulations for pulmonary administration of medicaments to produce a systemic effect |
US20050152846A1 (en) * | 2002-03-01 | 2005-07-14 | Chiesi Farmaceutici S.P.A. | Formoterol superfine formulation |
US20060120966A1 (en) * | 2002-10-23 | 2006-06-08 | Chiesi Farmaceutici S.P.A. | Salmeterol superfine formulation |
Cited By (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090311196A1 (en) * | 1997-06-13 | 2009-12-17 | Chiesi Farmaceutici S.P.A | Pharmaceutical aerosol composition |
US8420058B2 (en) | 1997-06-13 | 2013-04-16 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
US20030206870A1 (en) * | 1997-06-13 | 2003-11-06 | Chiesi Farmaceutici S.P.A. | Pharaceutical aerosol composition |
US7601336B2 (en) * | 1997-06-13 | 2009-10-13 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
US20040062720A1 (en) * | 1997-06-13 | 2004-04-01 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
US20030190287A1 (en) * | 1997-06-13 | 2003-10-09 | Chiesi Farmaceutici S.P.A. | Pharaceutical aerosol composition |
US20050142071A1 (en) * | 1998-11-25 | 2005-06-30 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
US20050220717A1 (en) * | 1999-06-18 | 2005-10-06 | 3M Innovative Properties Company | Steroid solution aerosol products with enhanced chemical stability |
US20040033201A1 (en) * | 1999-06-18 | 2004-02-19 | 3M Innovative Properties Company | Process for making chemically stable C-17/21 OH 20-ketosteroid aerosol products |
US6967017B1 (en) | 1999-07-23 | 2005-11-22 | Chiesi Farmaceutici S.P.A. | Formulations of steroid solutions for inhalatory administration |
US20050034720A1 (en) * | 2000-01-07 | 2005-02-17 | Gaetano Brambilla | Aerosol inhaler |
US20030190289A1 (en) * | 2000-05-12 | 2003-10-09 | David Lewis | Formulations containing a glucocorticoid drug for the treatment of bronchopulmonary diseases |
US20060257324A1 (en) * | 2000-05-22 | 2006-11-16 | Chiesi Farmaceutici S.P.A. | Pharmaceutical solution formulations for pressurised metered dose inhalers |
US20060083693A1 (en) * | 2000-05-22 | 2006-04-20 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
US7696178B2 (en) | 2001-07-02 | 2010-04-13 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US20050163722A1 (en) * | 2001-07-02 | 2005-07-28 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US8168598B2 (en) | 2001-07-02 | 2012-05-01 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US20110212912A1 (en) * | 2001-07-02 | 2011-09-01 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US7939502B2 (en) | 2001-07-02 | 2011-05-10 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US20100098642A1 (en) * | 2001-07-02 | 2010-04-22 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US20110061651A1 (en) * | 2002-03-01 | 2011-03-17 | Chiesi Farmaceutici S.P.A. | Formoterol superfine formulation |
US20050152846A1 (en) * | 2002-03-01 | 2005-07-14 | Chiesi Farmaceutici S.P.A. | Formoterol superfine formulation |
US8313732B2 (en) | 2002-03-01 | 2012-11-20 | Chiesi Farmaceutici S.P.A. | Formoterol superfine formulation |
US20050129621A1 (en) * | 2002-03-01 | 2005-06-16 | Chiesi Farmaceutici S.P.A. | Aerosol formulations for pulmonary administration of medicaments to produce a systemic effect |
US20060165603A1 (en) * | 2002-06-06 | 2006-07-27 | Chiesi Farmaceutici S.P.A. | Solubilisation of drugs in hfa propellant by means of emulsions |
US20060120966A1 (en) * | 2002-10-23 | 2006-06-08 | Chiesi Farmaceutici S.P.A. | Salmeterol superfine formulation |
US8088362B2 (en) | 2002-10-23 | 2012-01-03 | Chiesi Farmaceutici S.P.A. | Salmeterol superfine formulation |
US7381402B2 (en) | 2004-02-27 | 2008-06-03 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
WO2009003657A1 (en) * | 2007-07-03 | 2009-01-08 | Chiesi Farmaceutici S.P.A. | Metered dose inhaler actuator |
EP2011534A1 (en) * | 2007-07-03 | 2009-01-07 | CHIESI FARMACEUTICI S.p.A. | Metered dose inhaler actuator |
EA018547B1 (en) * | 2007-07-03 | 2013-08-30 | КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. | Metered dose inhaler actuator |
Also Published As
Publication number | Publication date |
---|---|
CA2352483C (en) | 2009-01-20 |
NO20012517L (en) | 2001-07-23 |
MA26763A1 (en) | 2004-12-20 |
IL143293A0 (en) | 2002-04-21 |
PT1133277E (en) | 2007-10-09 |
CA2352483A1 (en) | 2000-06-02 |
NZ511923A (en) | 2003-10-31 |
US6713047B1 (en) | 2004-03-30 |
ITMI982558A1 (en) | 2000-05-25 |
WO2000030607A1 (en) | 2000-06-02 |
AU770529B2 (en) | 2004-02-26 |
ES2289832T3 (en) | 2008-02-01 |
WO2000030607A8 (en) | 2001-03-22 |
NO330195B1 (en) | 2011-03-07 |
DE69936730D1 (en) | 2007-09-13 |
CN1331581A (en) | 2002-01-16 |
JP2002530316A (en) | 2002-09-17 |
KR20010080560A (en) | 2001-08-22 |
AU1555300A (en) | 2000-06-13 |
KR100794060B1 (en) | 2008-01-10 |
BR9916865A (en) | 2001-11-13 |
IT1303788B1 (en) | 2001-02-23 |
NO20012517D0 (en) | 2001-05-22 |
ATE368450T1 (en) | 2007-08-15 |
ZA200104220B (en) | 2002-05-23 |
EP1133277A1 (en) | 2001-09-19 |
EP1133277B1 (en) | 2007-08-01 |
TR200101442T2 (en) | 2002-05-21 |
DE69936730T2 (en) | 2008-04-30 |
CY1106904T1 (en) | 2012-05-23 |
DK1133277T3 (en) | 2007-12-27 |
CN1177582C (en) | 2004-12-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6713047B1 (en) | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a | |
US8420058B2 (en) | Pharmaceutical aerosol composition | |
EP0920302B1 (en) | Pharmaceutical aerosol composition | |
WO2011061498A2 (en) | Inhalation solutions | |
AU774250B2 (en) | Pharmaceutical aerosol composition |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |