US20030089369A1 - Pressurised metered dose inhalers (MDI) - Google Patents
Pressurised metered dose inhalers (MDI) Download PDFInfo
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- US20030089369A1 US20030089369A1 US10/290,225 US29022502A US2003089369A1 US 20030089369 A1 US20030089369 A1 US 20030089369A1 US 29022502 A US29022502 A US 29022502A US 2003089369 A1 US2003089369 A1 US 2003089369A1
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- metered dose
- dose inhalers
- epoxy
- ethanol
- hfa
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
Definitions
- the invention relates to the use of pressurised metered dose inhalers (MDIs) having part or all of their internal surfaces consisting of stainless steel, anodised aluminium or lined with an inert organic coating.
- MDIs pressurised metered dose inhalers
- the invention also relates to compositions to be delivered with said MDIs.
- Pressurised metered dose 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 uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol.
- the preferred propellants used in aerosols for pharmaceutical use have been a group of 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).
- CFCs 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).
- 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 have been disclosed.
- HFAs are used as propellant
- adjuvants including compounds acting as co-solvents, surface active agents including fluorinated and non-fluorinated surfactants, dispersing agents including alkylpolyethoxylates and stabilizers.
- compositions for aerosol administration via MDIs can be solutions or suspensions.
- Solution compositions offer several advantages: they are convenient to manufacture being completely dissolved in the propellant vehicle and obviate physical stability problems associated with suspension compositions.
- WO94/13262 proposes the use of acids as stabilisers preventing the chemical degradation of the active ingredient in aerosol solution formulations comprising HFAs.
- ipratropium bromide is comprised, for which many composition examples are supplied, in which the active ingredient is in combination with an organic or inorganic acid.
- WO96/32099, WO96/32150, WO96/32151 and WO96/32345 disclose metered dose inhalers for the administration of different active ingredients in suspension in the propellant, wherein the internal surfaces of the inhaler are partially or completely coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers.
- Said applications do not however address the technical problem of the chemical stability of the active ingredient but they rather concern a different problem, namely that of the adhesion of micronized particles of the suspended active ingredient to the internal surfaces of the inhaler, such as the can walls, valves and sealings. It is also known from Eur. J. Pharm. Biopharm. 1997, 44, 195 that suspensions of drugs in HFA propellant are frequently subjected to absorption of the drug particles on the valves and on the internal walls of the inhaler. The properties of an epoxy phenol resin coating of the aerosol cans have been studied to circumvent this problem.
- WO95/17195 describes aerosol compositions comprising flunisolide, ethanol and HFA propellants. It is stated in the document that conventional aerosol canisters can be used to contain the composition and that certain containers enhance its chemical and physical stability. It is suggested that the composition can be preferably contained in vials coated with resins such as epoxy resins (e.g. epoxy-phenolic resins and epoxy-urea-formaldehyde resins).
- resins such as epoxy resins (e.g. epoxy-phenolic resins and epoxy-urea-formaldehyde resins).
- the preferred material for the aerosol cans is anodised aluminium.
- epoxy resins in can coatings are produced by the reaction of epichlorohydrin and bisphenol A (DGEBPA). Variations in the molecular weight and in the polymerisation degree result in resins of different properties.
- Phenoxy resins are other commercially important thermoplastic polymers derived from bisphenols and epichlorohydrin, characterized in that their molecular weights (MWs) are higher, ie, ca 45000, than those of conventional epoxy resins, ie, 8000 and lack terminal epoxide functionality.
- epoxy-phenol-novolac and epoxy-cresol-novolac resins obtained by glycidylation of the phenol-formaldehyde (novolac) or of the o-cresol-formaldehyde (o-cresol novolac) condensates respectively.
- the inhalers according to the invention effectively prevent the chemical degradation of the active ingredient.
- Pressurised metered dose inhalers for dispensing solution of an active ingredient in a hydrofluorocarbon propellant, a co-solvent and optionally a low-volatility component characterized in that part or all of the internal surfaces of said inhalers consist of stainless steel, anodised aluminium or are lined with an inert organic coating.
- Pressurised metered dose inhalers are known devices, usually consisting of a main body or can, acting as a reservoir for the aerosol formulation, a cap sealing the main body and a metering valve fitted in the cap.
- MDIs are usually made of a conventional material such as aluminium, tin plate, glass, plastic and the like.
- part or all of the internal surfaces of the inhalers consists of stainless steel, anodised aluminium or is lined with an inert organic coating.
- One of the preferred coating consists of epoxy-phenol resin. Any kind of stainless steel may be used. Suitable epoxy-phenol resins are commercially available.
- Active ingredients which may be used in the aerosol compositions to be dispensed with the inhalers of the invention are any ingredient which can be administered by inhalation and which meets problems of chemical stability in solution in HFA propellants giving rise to a decomposition when stored in conventional materials cans and in particular in aluminium cans.
- the hydrofluorocarbon propellant is preferably selected from the group of HFA 134a, HFA 227 and mixtures thereof.
- the co-solvent is usually an alcohol, preferably ethanol.
- the low volatility component when present, is selected from the group of glycols, particularly 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, 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; saccharine, ascorbic acid, cyclamic acid, amino acids, or aspartame, esters for example ascorbyl palmitate, isopropyl myristate and tocopherol esters; alkanes for example dodecane and octadecane; terpenes for
- the aerosols compositions to be delivered with the pressurised MDIs of the invention may contain from 0.2 to 2% by weight of said low volatility component.
- Propylene glycol, polyethylene glycol, isopropyl myristate and glycerol are particularly preferred low-volatility components.
- the function of the low volatility component is to modulate the MMAD of the aerosol particles. Being used at very low concentrations, it does not substantially affect the chemical stability of the compositions.
- active ingredients include: anticholinergics such as ipratropium bromide, oxitropium bromide, tiotropium bromide; acetal corticosteroids such as budesonide, ciclesonide, rofleponide; ginal corticosteroids such as flunisolide, triamcinolone acetonide; other corticosteroids such as fluticasone propionate, mometasone furoate; short or long acting beta-adrenergic agonists such as salbutamol, formoterol, salmeterol, TA 2005 and their combinations.
- anticholinergics such as ipratropium bromide, oxitropium bromide, tiotropium bromide
- acetal corticosteroids such as budesonide, ciclesonide, rofleponide
- chetal corticosteroids such as flunisolide, triamcinolone acetonide
- WO 94/13262 teaches that problems of chemical stability of medicaments and in particular of ipratropium bromide in aerosol solution compositions can be solved adding an acid, either an inorganic acid or an organic acid, to the HFA propellant/cosolvent system.
- compositions containing ipratropium bromide in HFA 134a/ethanol systems further containing an inorganic acid such as hydrochloric, nitric, phosphoric or sulfuric acid or an organic acid such as ascorbic or citric acid are provided.
- compositions comprising ipratropium bromide, a propellant containing a hydrofluoroalkane, a cosolvent and further comprising a low volatility component:
- ipratropium bromide with or without acids is stable in stainless steel, anodised aluminium or in some types of epoxy phenol resin lined cans;
- Another preferred active ingredient for the preparation of solution compositions in a HFA/cosolvent system to be dispensed by MDIs according to the present invention is budesonide.
- Previously HFA/budesonide compositions have been described, in which budesonide is present in suspension in the propellant system and the composition further comprises additional ingredients such as particular kinds of surfactants (EP 504112, WO 93/05765, WO 93/18746, WO 94/21229).
- compositions containing a mixture of HFA propellants to match the density of the propellant mixture to be substantially identical to the density of budesonide, up to 3% of an adjuvant such as ethanol and small amounts of surfactant.
- budesonide is chemically and physically stable.
- aerosol compositions of the invention distributed in inhalers having the internal surfaces consisting of stainless steel, anodised aluminium or coated with an inert material and preferably with epoxy-phenol resin are stable for long periods and do not undergo chemical degradation.
- the low volatility component may also act as a co-solvent, thus increasing the solubility of the drug in the formulation and increasing the physical stability and/or allowing the possibility to decrease the quantity of co-solvent required.
- a composition containing 4.8 mg of ipratropium bromide (20 ⁇ g/dose), 13% (w/w) ethanol, 1.0% (w/w) glycerol and HFA 134a to 12 ml/can was distributed in stainless steel, anodised aluminium, standard aluminium cans or in cans having different internal coatings and were stored at various conditions.
- the percent drug remaining in the composition shows that stainless steel and anodised aluminium cans as well as epoxy-phenol resins (1), (2) and (4) coated cans are effective in preventing the chemical degradation of ipratropium bromide, differently from glass cans or other tested coatings.
- Citric, ascorbic and hydrochloric acids were added to the formulations in the amounts reported in Table 3.
- compositions were tested after 1, 2 and 5 months storage at 40° C. in epoxy-phenol resin (4) coated cans.
- compositions containing 12 mg of budesonide (50 ⁇ g/dose), 13% or 15% (w/w) ethanol, 1.3% (w/w) glycerol in HFA 134a to 12 ml/can were distributed in stainless steel, anodised aluminium, standard aluminium, glass cans or in cans having different internal coatings and were stored at various conditions.
- compositions containing 7.2, 12, 16.8 mg of dexbudesonide (corresponding to 30, 50 and 70 ⁇ g/dose respectively), ethanol, 0.9 (w/w) PEG 400 or isopropyl myristate (IPM) in HFA 227 to 12 ml can was distributed in aluminium anodised cans and was stored 70 days at 50° C. The results are reported in Table 6.
- the FPD gives a direct measure of the mass of particles within the specified size range and is closely related to the efficacy of the product.
- a composition containing 60 mg of flunisolide (250 ⁇ g/dose), 15% (w/w) ethanol, 1% (w/w) glycerol in HFA 134a to 12 ml/can was distributed in anodised aluminium, glass cans or in cans having different internal coatings and were stored for 41 days at 50° C.
- the percent drug remaining in the composition shows the favourable effect of anodised aluminium and inert coating with epoxy-phenol resins on the chemical stability of the active ingredient in respect to glass cans.
- micronized budesonide in ethanol is 31.756 mg/g.
- Epoxy phenol resin 99 89 88.5 93.5 (1) (90) (89.5) (94.5) Epoxy phenol resin 97.5 90 88.5 89 (2) (92) (90.5) (91) Epoxy phenol resin 98.5 56.5 46 52.5 (3) (57.5) (47) (53.5) Anodised aluminum 94 89 87 90.5 (95) (92.5) (96.5) Glass type III* — 48.5 41.5 47 ( ⁇ ) ( ⁇ ) ( ⁇ )
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Abstract
The invention relates to the use of pressurised metered dose inhalers (MDIs) having part or all of their internal surfaces consisting of stainless steel, anodised aluminium or lined with an inert organic coating; and to compositions to be delivered with said MDIs.
Description
- The invention relates to the use of pressurised metered dose inhalers (MDIs) having part or all of their internal surfaces consisting of stainless steel, anodised aluminium or lined with an inert organic coating. The invention also relates to compositions to be delivered with said MDIs.
- Pressurised metered dose 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.
- MDI uses a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol.
- 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).
- 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 have been disclosed.
- Many of these applications, in which HFAs are used as propellant, propose the addition of one or more of adjuvants including compounds acting as co-solvents, surface active agents including fluorinated and non-fluorinated surfactants, dispersing agents including alkylpolyethoxylates and stabilizers.
- In the international application No. PCT/EP98/03533 filed on Oct. 06, 1998 the applicant described solution compositions for use in an aerosol inhaler, comprising an active material, a propellant containing a hydrofluoroalkane (HFA), a cosolvent and further comprising a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler.
- Compositions for aerosol administration via MDIs can be solutions or suspensions. Solution compositions offer several advantages: they are convenient to manufacture being completely dissolved in the propellant vehicle and obviate physical stability problems associated with suspension compositions.
- The widespread use of these formulations is limited by their chemical instability, causing the formation of degradation products.
- WO94/13262 proposes the use of acids as stabilisers preventing the chemical degradation of the active ingredient in aerosol solution formulations comprising HFAs. Among the selected medicaments ipratropium bromide is comprised, for which many composition examples are supplied, in which the active ingredient is in combination with an organic or inorganic acid.
- WO96/32099, WO96/32150, WO96/32151 and WO96/32345 disclose metered dose inhalers for the administration of different active ingredients in suspension in the propellant, wherein the internal surfaces of the inhaler are partially or completely coated with one or more fluorocarbon polymers optionally in combination with one or more non-fluorocarbon polymers.
- Said applications do not however address the technical problem of the chemical stability of the active ingredient but they rather concern a different problem, namely that of the adhesion of micronized particles of the suspended active ingredient to the internal surfaces of the inhaler, such as the can walls, valves and sealings. It is also known from Eur. J. Pharm. Biopharm. 1997, 44, 195 that suspensions of drugs in HFA propellant are frequently subjected to absorption of the drug particles on the valves and on the internal walls of the inhaler. The properties of an epoxy phenol resin coating of the aerosol cans have been studied to circumvent this problem.
- WO95/17195 describes aerosol compositions comprising flunisolide, ethanol and HFA propellants. It is stated in the document that conventional aerosol canisters can be used to contain the composition and that certain containers enhance its chemical and physical stability. It is suggested that the composition can be preferably contained in vials coated with resins such as epoxy resins (e.g. epoxy-phenolic resins and epoxy-urea-formaldehyde resins).
- Actually the results reported in Tables 5, 6 and 8 respectively on pages 16 and 19 of the cited application demonstrate that flunisolide decomposes only in plastic cans (Table 8), and that the percent drug recovery in compositions stored in aluminium, glass or epoxy-phenol formaldehyde resin coated vials is practically the same (Table 8). In other words there is no difference between aluminium, glass type III or epoxy/phenol-formaldehyde resin coated aluminium vials coated by Cebal. No data are reported for other types of epoxy resins.
- It has now been found that the chemical stability problems of active ingredients in solution in HFA propellants can be eliminated by storing and delivering said composition employing metered-dose inhalers having part or all of their internal metallic surfaces consisting of stainless steel, anodised aluminium or lined with an inert organic coating.
- The preferred material for the aerosol cans is anodised aluminium.
- In the case of epoxy-phenol resin coating the choice of the suitable coating will be opportunely made on the basis of the characteristics of the active ingredient.
- The most widely used epoxy resins in can coatings are produced by the reaction of epichlorohydrin and bisphenol A (DGEBPA). Variations in the molecular weight and in the polymerisation degree result in resins of different properties.
- Phenoxy resins are other commercially important thermoplastic polymers derived from bisphenols and epichlorohydrin, characterized in that their molecular weights (MWs) are higher, ie, ca 45000, than those of conventional epoxy resins, ie, 8000 and lack terminal epoxide functionality.
- Other multifunctional resins are epoxy-phenol-novolac and epoxy-cresol-novolac resins obtained by glycidylation of the phenol-formaldehyde (novolac) or of the o-cresol-formaldehyde (o-cresol novolac) condensates respectively.
- The inhalers according to the invention effectively prevent the chemical degradation of the active ingredient.
- Surprisingly and contrary to what reported in the prior art with regard to flunisolide, we found a considerable degradation of the tested active ingredients when their formulations were stored in glass containers type III.
- Pressurised metered dose inhalers for dispensing solution of an active ingredient in a hydrofluorocarbon propellant, a co-solvent and optionally a low-volatility component characterized in that part or all of the internal surfaces of said inhalers consist of stainless steel, anodised aluminium or are lined with an inert organic coating.
- Pressurised metered dose inhalers are known devices, usually consisting of a main body or can, acting as a reservoir for the aerosol formulation, a cap sealing the main body and a metering valve fitted in the cap.
- MDIs are usually made of a conventional material such as aluminium, tin plate, glass, plastic and the like.
- According to the invention, part or all of the internal surfaces of the inhalers consists of stainless steel, anodised aluminium or is lined with an inert organic coating. One of the preferred coating consists of epoxy-phenol resin. Any kind of stainless steel may be used. Suitable epoxy-phenol resins are commercially available.
- Active ingredients which may be used in the aerosol compositions to be dispensed with the inhalers of the invention are any ingredient which can be administered by inhalation and which meets problems of chemical stability in solution in HFA propellants giving rise to a decomposition when stored in conventional materials cans and in particular in aluminium cans.
- In the compositions to be delivered with the MDIs of the invention the hydrofluorocarbon propellant is preferably selected from the group of HFA 134a, HFA 227 and mixtures thereof.
- The co-solvent is usually an alcohol, preferably ethanol. The low volatility component, when present, is selected from the group of glycols, particularly 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, 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; saccharine, ascorbic acid, cyclamic acid, amino acids, or aspartame, esters for example ascorbyl palmitate, isopropyl myristate and tocopherol esters; 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 pyrrolidone; amines for example ethanolamine, diethanolamine, triethanolamine; steroids for example cholesterol, cholesterol esters. The low-volatility component has a vapour pressure at 25° C. lower than 0.1 kPa, preferably lower than 0.05 kPa.
- The aerosols compositions to be delivered with the pressurised MDIs of the invention may contain from 0.2 to 2% by weight of said low volatility component.
- Propylene glycol, polyethylene glycol, isopropyl myristate and glycerol are particularly preferred low-volatility components.
- The function of the low volatility component is to modulate the MMAD of the aerosol particles. Being used at very low concentrations, it does not substantially affect the chemical stability of the compositions.
- Examples of active ingredients include: anticholinergics such as ipratropium bromide, oxitropium bromide, tiotropium bromide; acetal corticosteroids such as budesonide, ciclesonide, rofleponide; chetal corticosteroids such as flunisolide, triamcinolone acetonide; other corticosteroids such as fluticasone propionate, mometasone furoate; short or long acting beta-adrenergic agonists such as salbutamol, formoterol, salmeterol, TA 2005 and their combinations. The active ingredients when possible may be present in racemic mixtures or in form of a single enantiomer or epimer.
- As said before, WO 94/13262 teaches that problems of chemical stability of medicaments and in particular of ipratropium bromide in aerosol solution compositions can be solved adding an acid, either an inorganic acid or an organic acid, to the HFA propellant/cosolvent system.
- Examples of compositions containing ipratropium bromide in HFA 134a/ethanol systems further containing an inorganic acid such as hydrochloric, nitric, phosphoric or sulfuric acid or an organic acid such as ascorbic or citric acid are provided.
- We found that in solution compositions comprising ipratropium bromide, a propellant containing a hydrofluoroalkane, a cosolvent and further comprising a low volatility component:
- a) different decomposition rates occur with different acids: for example we found that ipratropium bromide (20 μg/dose) in a composition of 13% (w/w) ethanol, 1.0% (w/w) glycerol, 20 μl/can of 1N hydrochloric acid and HFA 134a to 12 ml/can rapidly decomposes and after 3 months storage at 40° C. gives 85.0% average of drug remaining;
- b) ipratropium bromide with or without acids is stable in stainless steel, anodised aluminium or in some types of epoxy phenol resin lined cans;
- c) surprisingly certain kinds of materials, such as glass, coatings proposed in the prior-art to overcome the physical absorption phenomenon of the active ingredient, such as perfluoroalkoxyalkanes and fluorinated-ethylene-propylene polyether sulfone resins, or certain kinds of epoxy phenol coatings turned out to be completely unsatisfactory and ineffective in preventing its chemical degradation.
- Another preferred active ingredient for the preparation of solution compositions in a HFA/cosolvent system to be dispensed by MDIs according to the present invention is budesonide.
- Previously HFA/budesonide compositions have been described, in which budesonide is present in suspension in the propellant system and the composition further comprises additional ingredients such as particular kinds of surfactants (EP 504112, WO 93/05765, WO 93/18746, WO 94/21229).
- In WO 98/13031 it is reported that suspension formulations of budesonide have a propensity to rapidly form coarse flocs upon dispersion and redispersion which may deleteriously affect dosage reproducibility. There is also a tendency for budesonide to deposit from suspension onto the walls of the container.
- To achieve stable suspensions of particulate budesonide it is employed in the prior art a composition containing a mixture of HFA propellants to match the density of the propellant mixture to be substantially identical to the density of budesonide, up to 3% of an adjuvant such as ethanol and small amounts of surfactant.
- It is stated in the document that the levels of the adjuvants are low to avoid significant solubilization of drug, leading to a problem of chemical degradation and particle size increase on storage.
- In the solution compositions of the present invention budesonide is chemically and physically stable.
- The aerosol compositions of the invention distributed in inhalers having the internal surfaces consisting of stainless steel, anodised aluminium or coated with an inert material and preferably with epoxy-phenol resin are stable for long periods and do not undergo chemical degradation.
- Also in this case a considerable degradation of the active ingredient was noticed when glass containers were used.
- Analogously flunisolide and dexbudesonide (the 22R-epimer of budesonide) solutions in HFA propellant containing ethanol and a low-volatility component are stable when stored in inhalers having the internal surfaces consisting of anodised aluminium or coated with epoxy-phenol resin. Evident degradation of flunisolide was noticed when glass containers were used.
- It has been also found that the low volatility component may also act as a co-solvent, thus increasing the solubility of the drug in the formulation and increasing the physical stability and/or allowing the possibility to decrease the quantity of co-solvent required.
- The following examples further illustrate the invention. In the examples and tables the different types of epoxy phenol resins are indicated with numbers in brackets corresponding to:
- (1) Epoxy-phenol lacquered aluminium vials coated by Cebal
- (2) Epoxy-phenol lacquered aluminium vials coated by Presspart
- (3) Epoxy-phenol lacquered aluminium vials coated by Nussbaum & Guhl
- (4) Epoxy-phenol lacquered aluminium vials coated by Presspart, other than (2)
- A composition containing 4.8 mg of ipratropium bromide (20 μg/dose), 13% (w/w) ethanol, 1.0% (w/w) glycerol and HFA 134a to 12 ml/can was distributed in stainless steel, anodised aluminium, standard aluminium cans or in cans having different internal coatings and were stored at various conditions.
- The results are reported in Table 1 and Table 2.
- The percent drug remaining in the composition, measured by HPLC, shows that stainless steel and anodised aluminium cans as well as epoxy-phenol resins (1), (2) and (4) coated cans are effective in preventing the chemical degradation of ipratropium bromide, differently from glass cans or other tested coatings.
- The effect of different acids on the chemical stability of the composition of Example 1 was studied.
- Citric, ascorbic and hydrochloric acids were added to the formulations in the amounts reported in Table 3.
- The stability of the compositions was tested after 1, 2 and 5 months storage at 40° C. in epoxy-phenol resin (4) coated cans.
- Compositions containing 12 mg of budesonide (50 μg/dose), 13% or 15% (w/w) ethanol, 1.3% (w/w) glycerol in HFA 134a to 12 ml/can were distributed in stainless steel, anodised aluminium, standard aluminium, glass cans or in cans having different internal coatings and were stored at various conditions.
- The results are reported in Table 4 and 5.
- The percent drug remaining in the compositions, measured by HPLC, shows the favourable effect of stainless steel, anodised aluminium and inert coating on the chemical stability of the active ingredient in respect to standard aluminium or glass cans. The best results have been obtained with stainless steel, anodised aluminium cans and with epoxy-phenol or perfluoroalkoxyalkane coatings.
- EXAMPLE 4
- A composition containing 48 mg of dexbudesonide (200 μg/dose), 15% (w/w) ethanol, 1.3% (w/w) glycerol in HFA 134a to 12 ml can was distributed in epoxy-phenol lacquered aluminium cans and was stored at 40° C.
- The percent drug remaining in the composition after 8 months, measured by HPLC, was 95.4% (average value referred to two tests).
- The control of the epimeric distribution showed that there is no transfer from the 22R to the 22S epimer.
- Compositions containing 7.2, 12, 16.8 mg of dexbudesonide (corresponding to 30, 50 and 70 μg/dose respectively), ethanol, 0.9 (w/w) PEG 400 or isopropyl myristate (IPM) in HFA 227 to 12 ml can was distributed in aluminium anodised cans and was stored 70 days at 50° C. The results are reported in Table 6.
- The percent drug remaining in the composition measured by HPLC shows the favourable effect of anodised aluminium cans on the chemical stability of the active ingredient. The control of the epimeric distribution showed that there is no transfer from the 22R to the 22S epimer.
- The fine particle dose (FPD: weight of particles having an aerodynamic diameter lower than 4.7 μm) of dexbudesonide solution compositions in HFA 134a or HFA 227, prepared following the examples 4 and 5, was determined.
- The experiments were performed using the Andersen Cascade Impactor and the data obtained are average values from 10 shots.
- The results, reported in Table 7 and 8 show that dexbudesonide formulations of the invention are characterized by a very low dose and a very high fine particle dose.
- The FPD gives a direct measure of the mass of particles within the specified size range and is closely related to the efficacy of the product.
- A composition containing 60 mg of flunisolide (250 μg/dose), 15% (w/w) ethanol, 1% (w/w) glycerol in HFA 134a to 12 ml/can was distributed in anodised aluminium, glass cans or in cans having different internal coatings and were stored for 41 days at 50° C.
- The results are reported in Table 9.
- The percent drug remaining in the composition, measured by HPLC, shows the favourable effect of anodised aluminium and inert coating with epoxy-phenol resins on the chemical stability of the active ingredient in respect to glass cans.
- The solubility of ipratropium bromide and micronized budesonide in ethanol, glycerol and their mixtures has been investigated.
- The tests were carried out at room temperature.
- a) Solubility in Ethanol.
- About 8.5 g of absolute ethanol were weighed into a flask. The active ingredient (Ipratropium Bromide or Budesonide) was added in small amounts, under magnetic stirrer, until no further dissolution occurred (i.e.: a saturated solution was obtained). The flask was stirred for about 40 minutes, and left to settle overnight prior to analysis, to let the system equilibrate. The flask was kept sealed, to avoid evaporation.
- The solution obtained was then filtered and tested for the amount of active ingredient, according to the conventional analytical procedure.
- b) Solubility in Ethanol/Glycerol Mixtures.
- The required amounts of ethanol and glycerol were weighted into a flask, and mixed by a magnetic stirrer until a homogeneous phase was obtained.
- The solubility of ipratropium bromide in ethanol is 42.48 mg/g.
- The solubility data of ipratropium bromide in ethanol/glycerol mixtures are listed in Table 10.
- The solubility of micronized budesonide in ethanol is 31.756 mg/g.
- Solubility data of micronized budesonide in ethanol/glycerol mixtures are listed in Table 11.
- The data show that both the tested active ingredients are rather soluble in ethanol, and that their solubility increases even when small percentages of glycerol are added.
- The increase in solubility is maintained also in presence of HFA propellants.
TABLE 1 Percent ipratropium bromide (IPBr) recovered after storing the composition of Example 1 for 8 months at 40° C. in cans of different types CAN TYPE % RESIDUAL IPBr Epoxy-phenol resin (4) 96 Perfluoroalkoxyalkane 57 Fluorinated-ethylene-propylene/ 78 polyether sulphone (Xylan 8840(R)) Stainless steel 96 Standard aluminium 46 -
TABLE 2 Percent ipratropium bromide (IPBr) recovered after storing the composition of Example 1 for 30 and 60 days at 50° C., or for 96 days at 40° C. in cans of different types (average values referred to two tests). % RESIDUAL IPBr (% RESIDUAL IPBr RELATIVE TO t = 0) t = 30 days t = 60 days t = 96 days CAN TYPE t = 0 at 50° C. at 50° C. at 40° C. Epoxy phenol resin 99 89 88.5 93.5 (1) (90) (89.5) (94.5) Epoxy phenol resin 97.5 90 88.5 89 (2) (92) (90.5) (91) Epoxy phenol resin 98.5 56.5 46 52.5 (3) (57.5) (47) (53.5) Anodised aluminum 94 89 87 90.5 (95) (92.5) (96.5) Glass type III* — 48.5 41.5 47 (−) (−) (−) -
TABLE 3 Percent ipratropium bromide (IPBr) recovered after storing the compositions of Example 1, with different acids added, in epoxy-phenol (4) coated cans (average values referred to two tests) % RESIDUAL IPBr (% RESIDUAL IPBr RELATIVE TO t = 0) t = 1 month t = 2 months t = 5 months Acid t = 0 at 40° C. at 40° C. at 40° C. Citric (0.6% w/w) 98 98 99 94 (100) (101) (96) (0.3% w/w) 99 99 100 97 (100) (101) (98) (0.07% w/w) 99 98 99 96 (99) (100) (97) Ascorbic 119 113 112 110 (95) (94) (92) Hydrochloric (4 μl-1N) 101 100 104 96 (99) (102) (95) (10 μl-1N) 101 98 98 97 (97) (97) (96) (20 μl-1N) 100 95 98 97 (95) (98) (97) None 97 97 98 95 (100) (101) (98) -
TABLE 4 Percent budesonide recovered after storing the composition of Example 3 (13% ethanol) for 7 months at 40° C. in cans of different types CAN TYPE % RESIDUAL BUDESONIDE Epoxy-phenol resin (4) 100 Fluorinated-ethylene-propylene/ 93.5 polyether sulphone (Xylan 8840(R)) Stainless steel 97 Aluminium 68 Perfluoroalkoxyalkane 100 -
TABLE 5 Percent budesonide recovered after storing the composition of Example 3 (15% ethanol) for 33 and 73 days at 50° C. in cans of different types (average values referred to two tests). % RESIDUAL BUDESONIDE (% RESIDUAL BUDESONIDE RELATIVE TO t = 0) CAN TYPE t = 0 T = 33 days t = 73 days Epoxy phenol 99.3 97.0 95.4 resin (1) (97.7) (96.1) Epoxy phenol 99.5 96.6 95.6 resin (2) (97.0) (96.1) Epoxy phenol 99.3 96.6 95.9 resin (3) (97.2) (96.5) Anodised 99.9 99.2 97.7 aluminium (99.3) (97.8) Glass type III* — 86.15 80.4 (−) (−) -
TABLE 6 Percent dexbudesonide recovered after storing the compositions of Example 5 for 70 days at 50° C. in anodised aluminium cans (average values referred to two tests). % Residual dexbudesonide Metered (% residual dexbudesonide dose Ethanol Low vol. comp. relative to t = 0) (μg) % (w/w) 0.9% (w/w) t = 0 days t = 70 days 30 5 PEG 400 95.8 95.8 (100) IPM 98.1 96.8 (98.7) 50 8 PEG 400 99.0 98.0 (98.9) IPM 98.0 99.4 (101) 70 7 PEG 400 95.7 93.75 (98.0) IPM 100.4 96.3 (96.0) -
TABLE 7 Fine particle dose (FPD) values of dexbudesonide solution formulation in HFA 134a containing: dexbudesonide 14.4 mg/can (60 μg/shot) ethanol 8% (w/w) low volatility compound 0.9% (w/w) HFA 134a to 12 ml can (valve chamber volume = 63 μl) MMAD = 2.0 μm Low volatility FPD FPF Metered dose Delivered dose Compound (μg) (%) (μg) (μg) IPM 39.9 73.6 57.9 54.2 IPM 39.4 77.4 53.2 50.9 -
TABLE 8 Fine particle dose (FPD) values of dexbudesonide solution formulation in HFA 227 containing: dexbudesonide 15.12 mg/can (63 μg/shot) ethanol 7% (w/w) low volatility compound 0.9% (w/w) HFA 227 to 12 ml can (valve chamber volume = 63 μl) MMAD = 2.0 μm Low volatility FPD FPF Metered dose Delivered dose Compound (μg) (%) (μg) (μg) IPM 45.0 75.5 63.9 59.7 PEG 400 48.5 78.9 65.5 61.5 -
TABLE 9 Percent flunisolide recovered after storing the composition of Example 7 for 41 days at 50° C. in cans of different types (average values referred to two tests) % RESIDUAL FLUNISOLIDE (% RESIDUAL FLUNISOLIDE RELATIVE TO t = 0) CAN TYPE t = 0 t = 41 days t = 93 days Epoxy phenol 98.4 99.2 101.4 resin (1) (101) (103) Epoxy phenol 101.9 99.7 101.9 resin (2) (97.8) (100) Epoxy phenol 101.7 99.2 101.2 resin (3) (97.5) (99.6) Anodised 101.6 100.4 100.7 aluminium (98.8) (99.1) Glass type III* — — 97.5 (−) -
TABLE 10 Solubility of Ipratropium Bromide in ethanol/glycerol mixtures Ipratropium Bromide Ethanol (%) Glycerol (%) solubility (mg/g) 100 0 42.8 92.6 7.4 74.0 91.9 8.1 74.7 91.3 8.7 90.5 88.4 11.6 98.0 82.6 17.4 115.6 71.4 28.6 196.7 60 40 271.6 40 60 307.2 21.1 78.9 265.7 0 100 73.4 -
TABLE 11 Solubility of micronized Budesonide in ethanol/glycerol mixtures Budesonide solubility Ethanol (%) Glycerol (%) (mg/g) 100 0 31.756 92.5 7.5 36.264 91.9 8.1 36.277 91.3 8.7 37.328 87.7 12.3 38.364 83.3 16.7 37.209 71.4 28.6 35.768 60 40 28.962 39.9 60.1 14.840 21.1 78.9 3.990 0 100 0.214
Claims (11)
1. Pressurised metered dose inhalers containing a solution of an active ingredient in a hydrofluorocarbon propellant, a co-solvent and optionally a low-volatility component characterised in that part or all of the internal surfaces of said inhalers consist of stainless steel, anodised aluminium or are lined with an inert organic coating.
2. Pressurized metered dose inhalers according to claim 1 , wherein the active ingredients are selected from β2 agonists, steroids or anti-cholinergic agents and their combinations.
3. Pressurized metered dose inhalers according to claim 2 , wherein the active ingredient is ipratropium bromide, oxitropium bromide, tiotropium bromide, flunisolide, triamcinolone acetonide, fluticasone propionate, mometasone furoate, budesonide, ciclesonide, rofleponide and epimers thereof.
4. Pressurized metered dose inhalers according to any of claims from 1 to 3, containing a low-volatility component selected from glycerol, polyethylene glycol and isopropyl myristate.
5. Pressurized metered dose inhalers according to any of claims from 1 to 4, wherein the co-solvent is ethanol.
6. Pressurized metered dose inhalers according to any of claims from 1 to 5, wherein the propellant is selected from HFA 227, HFA 134a and their mixtures.
7. Pressurised metered dose inhalers according to any of claims 1 to 6 wherein the inert organic coating is perfluoroalkoxyalkane, epoxy-phenol resin or fluorinated-ethylene-propylene polyether sulfone.
8. Pressurised metered dose inhalers according to any of claims 1 to 7 wherein part or all of the internal surfaces are coated with an epoxy phenol resin.
9. Pressurised metered dose inhalers according to any of claims 1 to 6 wherein part or all of the internal surfaces consist of anodised aluminium.
10. Stabilized aerosol solution formulation consisting of an active ingredient in a hydrofluorocarbon propellant, a co-solvent and optionally a low-volatility component for use in a pressurised metered dose inhaler as claimed in any of claims 1 to 9 .
11. Aerosol solution formulation of dexbudesonide in a hydrofluorocarbon propellant and ethanol as a co-solvent, further comprising a low volatility compound selected from glycerol, isopropylmyristate and polyethylene glicol.
Priority Applications (2)
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US10/290,225 US20030089369A1 (en) | 1998-11-25 | 2002-11-08 | Pressurised metered dose inhalers (MDI) |
US11/060,564 US20050142071A1 (en) | 1998-11-25 | 2005-02-18 | Pressurised metered dose inhalers (MDI) |
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ITMI982559 IT1303789B1 (en) | 1998-11-25 | 1998-11-25 | New pressured metered dose inhalers (MDI) in which all the internal surfaces of the inhalers are stainless steel, anodised aluminum or are lined with an inert organic coating are new |
ITMI98A002559 | 1998-11-25 | ||
IT99MI001712 IT1313582B1 (en) | 1999-07-30 | 1999-07-30 | New pressured metered dose inhalers (MDI) in which all the internal surfaces of the inhalers are stainless steel, anodised aluminum or are lined with an inert organic coating are new |
ITMI99A001712 | 1999-07-30 | ||
US83188801A | 2001-07-19 | 2001-07-19 | |
US10/290,225 US20030089369A1 (en) | 1998-11-25 | 2002-11-08 | Pressurised metered dose inhalers (MDI) |
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US09/831,888 Continuation US7347199B1 (en) | 1998-11-25 | 1999-11-23 | Pressurised metered dose inhalers (MDI) |
PCT/EP1999/009002 Continuation WO2000030608A1 (en) | 1998-11-25 | 1999-11-23 | Pressurised metered dose inhalers (mdi) |
US83188801A Continuation | 1998-11-25 | 2001-07-19 |
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US10/244,519 Expired - Fee Related US7223381B2 (en) | 1998-11-25 | 2002-09-17 | Pressurised metered dose inhalers (MDI) |
US10/290,225 Abandoned US20030089369A1 (en) | 1998-11-25 | 2002-11-08 | Pressurised metered dose inhalers (MDI) |
US10/612,072 Expired - Fee Related US7740463B2 (en) | 1998-11-25 | 2003-07-03 | Pressurised metered dose inhalers (MDI) |
US11/060,564 Abandoned US20050142071A1 (en) | 1998-11-25 | 2005-02-18 | Pressurised metered dose inhalers (MDI) |
US12/023,315 Expired - Fee Related US8142763B2 (en) | 1998-11-25 | 2008-01-31 | 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 |
US12/132,852 Abandoned US20080247965A1 (en) | 1998-11-25 | 2008-06-04 | Pressurised metered dose inhalers (mdi) |
US13/004,204 Abandoned US20110100361A1 (en) | 1998-11-25 | 2011-01-11 | Pressurised metered dose inhalers (mdi) |
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US09/831,888 Expired - Fee Related US7347199B1 (en) | 1998-11-25 | 1999-11-23 | Pressurised metered dose inhalers (MDI) |
US10/244,519 Expired - Fee Related US7223381B2 (en) | 1998-11-25 | 2002-09-17 | Pressurised metered dose inhalers (MDI) |
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US11/060,564 Abandoned US20050142071A1 (en) | 1998-11-25 | 2005-02-18 | Pressurised metered dose inhalers (MDI) |
US12/023,315 Expired - Fee Related US8142763B2 (en) | 1998-11-25 | 2008-01-31 | 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 |
US12/132,852 Abandoned US20080247965A1 (en) | 1998-11-25 | 2008-06-04 | Pressurised metered dose inhalers (mdi) |
US13/004,204 Abandoned US20110100361A1 (en) | 1998-11-25 | 2011-01-11 | Pressurised metered dose inhalers (mdi) |
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GB201200525D0 (en) | 2011-12-19 | 2012-02-29 | Teva Branded Pharmaceutical Prod R & D Inc | An inhalable medicament |
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KR101313993B1 (en) * | 2012-07-24 | 2013-10-01 | 한국화학연구원 | Nebulizer |
DE102013214601B3 (en) | 2013-07-25 | 2014-05-22 | Aptar Radolfzell Gmbh | Housing for container unit of inhalation device e.g. metered-dose inhaler, for oral administration of pharmaceutical medium, has membrane reversibly deformed based on pressure in pressure chamber and acting together with pushbutton |
US10034866B2 (en) | 2014-06-19 | 2018-07-31 | Teva Branded Pharmaceutical Products R&D, Inc. | Inhalable medicament comprising tiotropium |
WO2015200049A1 (en) * | 2014-06-26 | 2015-12-30 | Island Breeze Systems Ca, Llc | Mdi related products and methods of use |
CA3180239A1 (en) * | 2014-09-08 | 2016-03-17 | Becton, Dickinson And Company | Enhanced platen for pharmaceutical compounding |
CN106620976B (en) * | 2016-12-28 | 2020-01-07 | 四川普锐特医药科技有限责任公司 | Fluticasone propionate quantitative inhalation aerosol |
US10231948B2 (en) | 2017-02-27 | 2019-03-19 | Jason Ty Nguyen | Metered dose inhaler compositions, systems, and methods |
US20210244896A1 (en) * | 2018-06-13 | 2021-08-12 | Puff-Ah Pty Ltd | Apparatus for use in delivering respiratory drugs |
Citations (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2868691A (en) * | 1956-03-21 | 1959-01-13 | Riker Laboratories Inc | Self-propelling compositions for inhalation therapy containing a salt of isoproterenol or epinephrine |
US4185100A (en) * | 1976-05-13 | 1980-01-22 | Johnson & Johnson | Topical anti-inflammatory drug therapy |
US4499108A (en) * | 1983-06-08 | 1985-02-12 | Schering Corporation | Stable pleasant-tasting albuterol sulfate pharmaceutical formulations |
US4835145A (en) * | 1984-06-11 | 1989-05-30 | Sicor Societa' Italiana Corticosteroidi S.P.A. | 16,17 acetals of pregnane derivatives and pharmaceutical compositions containing them |
US5192528A (en) * | 1985-05-22 | 1993-03-09 | Liposome Technology, Inc. | Corticosteroid inhalation treatment method |
US5891419A (en) * | 1997-04-21 | 1999-04-06 | Aeropharm Technology Limited | Environmentally safe flunisolide aerosol formulations for oral inhalation |
US5955058A (en) * | 1992-12-09 | 1999-09-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Stabilized medicinal aerosol solution formulations containing ipratropium bromide |
US6045784A (en) * | 1998-05-07 | 2000-04-04 | The Procter & Gamble Company | Aerosol package compositions containing fluorinated hydrocarbon propellants |
US6131565A (en) * | 1996-12-20 | 2000-10-17 | Stanwell Corporation Limited | Solar energy collector system |
US6143277A (en) * | 1995-04-14 | 2000-11-07 | Glaxo Wellcome Inc. | Metered dose inhaler for salmeterol |
US6150418A (en) * | 1998-10-17 | 2000-11-21 | Boehringer Ingelheim Pharma Kg | Active substance concentrate with formoterol, suitable for storage |
US6253762B1 (en) * | 1995-04-14 | 2001-07-03 | Glaxo Wellcome Inc. | Metered dose inhaler for fluticasone propionate |
US20010031244A1 (en) * | 1997-06-13 | 2001-10-18 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
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 |
US20030066525A1 (en) * | 1998-11-25 | 2003-04-10 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
US20030190289A1 (en) * | 2000-05-12 | 2003-10-09 | David Lewis | Formulations containing a glucocorticoid drug for the treatment of bronchopulmonary diseases |
US20040047809A1 (en) * | 2000-05-22 | 2004-03-11 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
US6713047B1 (en) * | 1998-11-25 | 2004-03-30 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
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 |
US20050220718A1 (en) * | 2004-02-27 | 2005-10-06 | 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 |
US20060120966A1 (en) * | 2002-10-23 | 2006-06-08 | Chiesi Farmaceutici S.P.A. | Salmeterol superfine formulation |
Family Cites Families (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US220718A (en) * | 1879-10-21 | Improvement in street-car warmers | ||
US154013A (en) * | 1874-08-11 | Improvement in carriage-lamps | ||
US3361306A (en) * | 1966-03-31 | 1968-01-02 | Merck & Co Inc | Aerosol unit dispensing uniform amounts of a medically active ingredient |
CA882187A (en) | 1968-03-13 | 1971-09-28 | Farbenfabriken Bayer Aktiengesellschaft | Thermoplastic-elastic moulding compounds |
US3622053A (en) * | 1969-12-10 | 1971-11-23 | Schering Corp | Aerosol inhaler with flip-up nozzle |
MX3864E (en) | 1975-05-27 | 1981-08-26 | Syntex Corp | A PROCESS TO PREPARE THE CRYSTALLINE COMPOUND 6-FLUIRO-11B 21-DIHIROXI-16 17-ISOPROPILIDENDIOXIPREGNA-1 4-DIEN-3 20-DIONA |
GB8334494D0 (en) * | 1983-12-24 | 1984-02-01 | Tanabe Seiyaku Co | Carbostyril derivatives |
US4584320A (en) * | 1985-01-03 | 1986-04-22 | David Rubin | Anti-asthmatic composition and method using 8,11,14,17-eicosatetraenoic acid |
GB8828477D0 (en) | 1988-12-06 | 1989-01-05 | Riker Laboratories Inc | Medical aerosol formulations |
US5225183A (en) * | 1988-12-06 | 1993-07-06 | Riker Laboratories, Inc. | Medicinal aerosol formulations |
IE67185B1 (en) | 1990-02-02 | 1996-03-06 | Fisons Plc | Propellant compositions |
DE59104030D1 (en) | 1990-02-14 | 1995-02-09 | Systec Ausbausysteme Gmbh | TRANSPORT TROLLEY WITH COIN LOCK. |
IT1244441B (en) * | 1990-09-13 | 1994-07-15 | Chiesi Farma Spa | MOUTH INHALATION DEVICE FOR AEROSOL DRUGS |
WO1992011236A1 (en) * | 1990-12-19 | 1992-07-09 | Smithkline Beecham Corporation | Aerosol formulations |
US6006745A (en) * | 1990-12-21 | 1999-12-28 | Minnesota Mining And Manufacturing Company | Device for delivering an aerosol |
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 |
EP0504112A3 (en) | 1991-03-14 | 1993-04-21 | Ciba-Geigy Ag | Pharmaceutical aerosol formulations |
KR100229975B1 (en) | 1991-05-21 | 1999-11-15 | 스티븐 에프. 웨인스톡 | Aerosol inhalation device |
DE59209686D1 (en) * | 1991-08-29 | 1999-06-02 | Broncho Air Medizintechnik Ag | MEDICAL DEVICE FOR INHALING DOSING AEROSOLS |
IL103238A (en) | 1991-09-25 | 1995-07-31 | Fisons Plc | Pressurised aerosol compositions |
US5219882A (en) | 1991-10-24 | 1993-06-15 | Emil Bisaccia | Treatment methods for lymes disease and associated debilitating conditions |
IL104068A (en) | 1991-12-12 | 1998-10-30 | Glaxo Group Ltd | Surfactant-free pharmaceutical aerosol formulation comprising 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n- propane as propellant |
ES2099415T3 (en) | 1991-12-18 | 1997-05-16 | Minnesota Mining & Mfg | SUSPENSION AEROSOL FORMULATIONS. |
DE4230876A1 (en) | 1992-03-17 | 1993-09-23 | Asta Medica Ag | COMPRESSED GAS PACKS USING POLYOXYETHYLENE GLYCERYL OLEATES |
SE9203743D0 (en) | 1992-12-11 | 1992-12-11 | Astra Ab | EFFICIENT USE |
WO1994014490A1 (en) | 1992-12-23 | 1994-07-07 | Bernhard Hugemann | Compacted drug body for use in the mechanical generation of inhalable active-substance particles |
EP0689423B1 (en) | 1993-03-17 | 1997-09-17 | Minnesota Mining And Manufacturing Company | Aerosol formulation containing a diol-diacid derived dispersing aid |
US5569450A (en) | 1993-03-17 | 1996-10-29 | Minnesota Mining And Manufacturing Company | Aerosol formulation containing an ester-, amide-, or mercaptoester-derived dispersing aid |
US5899201A (en) * | 1993-05-26 | 1999-05-04 | Minnesota Mining And Manufacturing Company | Aerosol actuator |
US6596260B1 (en) | 1993-08-27 | 2003-07-22 | Novartis Corporation | Aerosol container and a method for storage and administration of a predetermined amount of a pharmaceutically active aerosol |
DK0735884T3 (en) * | 1993-12-20 | 2000-10-09 | Minnesota Mining & Mfg | Flunisolide aerosol formulations |
US5508269A (en) * | 1994-10-19 | 1996-04-16 | Pathogenesis Corporation | Aminoglycoside formulation for aerosolization |
GB9425160D0 (en) | 1994-12-10 | 1995-02-08 | Glaxo Group Ltd | Medicaments |
MX9704550A (en) | 1994-12-22 | 1997-10-31 | Astra Ab | Aerosol drug formulations. |
GB9426252D0 (en) | 1994-12-24 | 1995-02-22 | Glaxo Group Ltd | Pharmaceutical composition |
DE4446891A1 (en) | 1994-12-27 | 1996-07-04 | Falk Pharma Gmbh | Stable aqueous budesonide solution |
US5653961A (en) | 1995-03-31 | 1997-08-05 | Minnesota Mining And Manufacturing Company | Butixocort aerosol formulations in hydrofluorocarbon propellant |
NZ306281A (en) * | 1995-04-14 | 1999-07-29 | Glaxo Wellcome Inc | Metered dose inhaler with part or all internal surfaces coated with fluorocarbon polymers for dispensing beclomethasone dipropionate |
TR199701167T1 (en) * | 1995-04-14 | 1998-03-21 | Glaxo Wellcome Inc. | Metered dose inhaler for albuterol. |
US5637505A (en) * | 1995-05-19 | 1997-06-10 | Chiron Diagnostics Corporation | Method to prepare dye-based reference material |
GB9526392D0 (en) * | 1995-12-22 | 1996-02-21 | Glaxo Group Ltd | Medicaments |
GB9612297D0 (en) | 1996-06-11 | 1996-08-14 | Minnesota Mining & Mfg | Medicinal aerosol formulations |
JP2000514085A (en) | 1996-07-08 | 2000-10-24 | ローヌ―プーラン・ロウラー・リミテッド | Pharmaceutical cyclosporin A aerosol solution formulation |
AU3811897A (en) | 1996-07-24 | 1998-02-10 | Oglios Therapeutics, Inc. | Antisense oligonucleotides as antibacterial agents |
GB9616237D0 (en) | 1996-08-01 | 1996-09-11 | Norton Healthcare Ltd | Aerosol formulations |
GB9620187D0 (en) | 1996-09-27 | 1996-11-13 | Minnesota Mining & Mfg | Medicinal aerosol formulations |
ATE301991T1 (en) | 1996-12-04 | 2005-09-15 | Link Products Ltd | MEDICINAL COMPOSITIONS AND DEVICES FOR ADMINISTRATION THEREOF |
US6413496B1 (en) | 1996-12-04 | 2002-07-02 | Biogland Ireland (R&D) Limited | Pharmaceutical compositions and devices for their administration |
DK1014943T3 (en) | 1997-02-05 | 2002-10-14 | Jago Res Ag | Medical aerosol formulations |
US6126919A (en) | 1997-02-07 | 2000-10-03 | 3M Innovative Properties Company | Biocompatible compounds for pharmaceutical drug delivery systems |
US6129905A (en) * | 1997-04-21 | 2000-10-10 | Aeropharm Technology, Inc. | Aerosol formulations containing a sugar as a dispersant |
ES2163873T3 (en) | 1997-06-12 | 2002-02-01 | Pac Holding Sa | PROCEDURE FOR THE ELIMINATION OF HALOGENED WASTE AND / OR CONTAINING HYDROCARBONS. |
GB2326334A (en) * | 1997-06-13 | 1998-12-23 | Chiesi Farma Spa | Pharmaceutical aerosol compositions |
BR7702049U (en) | 1997-09-05 | 1999-09-14 | Chiesi Farma Spa | Spray nozzle for use in an oral inhaler for aerosol medicines |
NZ504021A (en) * | 1997-10-17 | 2003-04-29 | Systemic Pulmonary Delivery Lt | Method and apparatus for delivering aerosolized medication having air discharged through air tube directly into plume of aerosolized medication |
SE9802073D0 (en) | 1998-06-11 | 1998-06-11 | Astra Ab | New use |
NZ509418A (en) | 1998-06-18 | 2003-06-30 | Boehringer Ingelheim Pharma | Pharmaceutical formulations for aerosols with two or more active substances |
US6451285B2 (en) | 1998-06-19 | 2002-09-17 | Baker Norton Pharmaceuticals, Inc. | Suspension aerosol formulations containing formoterol fumarate and a fluoroalkane propellant |
US6241969B1 (en) | 1998-06-26 | 2001-06-05 | Elan Corporation Plc | Aqueous compositions containing corticosteroids for nasal and pulmonary delivery |
ATE283033T1 (en) | 1998-07-24 | 2004-12-15 | Jago Res Ag | MEDICAL AEROSOL FORMULATIONS |
EP1102579B1 (en) | 1998-08-04 | 2003-03-19 | Jago Research Ag | Medicinal aerosol formulations |
CA2343123C (en) | 1998-10-17 | 2008-03-25 | Boehringer Ingelheim Pharma Kg | Active substance concentrate with formoterol, suitable for storage |
US6086379A (en) * | 1998-10-20 | 2000-07-11 | Research Foundation Of State University Of New York | System and method for training a swimmer |
PT1283036E (en) | 1998-11-13 | 2008-03-06 | Jagotec Ag | Multidosis dry powder inhaler with powder reservoir |
US6290930B1 (en) | 1998-12-18 | 2001-09-18 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes and budesonide |
US6004537A (en) | 1998-12-18 | 1999-12-21 | Baker Norton Pharmaceuticals, Inc. | Pharmaceutical solution aerosol formulations containing fluoroalkanes, budesonide and formoterol |
TR200102567T2 (en) | 1999-03-05 | 2002-01-21 | Chiesi Farmaceutici S.P.A. | Pharmaceutical compositions developed for inhalation |
ES2238334T3 (en) | 1999-12-24 | 2005-09-01 | Glaxo Group Limited | PHARMACEUTICAL FORMULATION IN SALMETEROL AEROSOL AND FLUTICASONA PROPIONATE. |
ES2222294T3 (en) * | 2001-07-02 | 2005-02-01 | Chiesi Farmaceutici S.P.A. | OPTIMIZED FORMULATION OF TOBRAMYCIN FOR ADMINISTRATION IN THE FORM OF AEROSOL. |
US6808684B2 (en) | 2002-04-05 | 2004-10-26 | International Flavors & Fragrance Inc. | Fragrance material |
-
1999
- 1999-11-22 DZ DZ990247A patent/DZ2947A1/en active
- 1999-11-23 JP JP2000583492A patent/JP2002530156A/en active Pending
- 1999-11-23 EP EP99958110A patent/EP1131051B1/en not_active Expired - Lifetime
- 1999-11-23 EE EEP200100276A patent/EE04259B1/en unknown
- 1999-11-23 TR TR2001/01441T patent/TR200101441T2/en unknown
- 1999-11-23 EA EA200100468A patent/EA004132B1/en not_active IP Right Cessation
- 1999-11-23 DE DE69942896T patent/DE69942896D1/en not_active Expired - Lifetime
- 1999-11-23 GE GEAP19995909A patent/GEP20033129B/en unknown
- 1999-11-23 EP EP06004955A patent/EP1666029A1/en not_active Withdrawn
- 1999-11-23 AT AT99958110T patent/ATE314838T1/en active
- 1999-11-23 EP EP05001105A patent/EP1523975B1/en not_active Expired - Lifetime
- 1999-11-23 CZ CZ20011834A patent/CZ301305B6/en not_active IP Right Cessation
- 1999-11-23 PL PL348717A patent/PL200658B1/en not_active IP Right Cessation
- 1999-11-23 WO PCT/EP1999/009002 patent/WO2000030608A1/en active Application Filing
- 1999-11-23 HU HU0104411A patent/HU226735B1/en unknown
- 1999-11-23 CA CA2352484A patent/CA2352484C/en not_active Expired - Fee Related
- 1999-11-23 PL PL383028A patent/PL204572B1/en unknown
- 1999-11-23 TR TR2007/04956T patent/TR200704956T2/en unknown
- 1999-11-23 DE DE29923839U patent/DE29923839U1/en not_active Ceased
- 1999-11-23 US US09/831,888 patent/US7347199B1/en not_active Expired - Fee Related
- 1999-11-23 DE DE69929358T patent/DE69929358T2/en not_active Expired - Lifetime
- 1999-11-23 DK DK99958110T patent/DK1131051T3/en active
- 1999-11-23 CN CNB99813743XA patent/CN1200690C/en not_active Expired - Lifetime
- 1999-11-23 IL IL14329499A patent/IL143294A0/en active IP Right Grant
- 1999-11-23 CA CA2698376A patent/CA2698376A1/en not_active Abandoned
- 1999-11-23 AT AT05001105T patent/ATE485812T1/en not_active IP Right Cessation
- 1999-11-23 SI SI9930867T patent/SI1131051T1/en unknown
- 1999-11-23 EP EP06004954A patent/EP1674079A3/en not_active Withdrawn
- 1999-11-23 NZ NZ511926A patent/NZ511926A/en not_active IP Right Cessation
- 1999-11-23 SK SK704-2001A patent/SK285246B6/en not_active IP Right Cessation
- 1999-11-23 KR KR1020017006460A patent/KR100696746B1/en not_active IP Right Cessation
- 1999-11-23 AU AU15563/00A patent/AU764696C/en not_active Ceased
- 1999-11-23 BR BRPI9916868-5A patent/BR9916868B1/en not_active IP Right Cessation
- 1999-11-23 ES ES99958110T patent/ES2255767T3/en not_active Expired - Lifetime
- 1999-11-23 NZ NZ527190A patent/NZ527190A/en not_active IP Right Cessation
- 1999-11-24 TN TNTNSN99220A patent/TNSN99220A1/en unknown
- 1999-11-24 EG EG149899A patent/EG25278A/en active
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- 1999-11-24 AR ARP990105991A patent/AR021391A1/en not_active Application Discontinuation
- 1999-11-24 CO CO99074044A patent/CO5170487A1/en not_active Application Discontinuation
- 1999-12-13 SA SA99200825A patent/SA99200825B1/en unknown
-
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- 2001-05-22 IL IL143294A patent/IL143294A/en not_active IP Right Cessation
- 2001-05-22 NO NO20012516A patent/NO330194B1/en not_active IP Right Cessation
- 2001-05-22 BG BG105532A patent/BG65596B1/en unknown
- 2001-05-22 MA MA26204A patent/MA26764A1/en unknown
-
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- 2002-11-08 US US10/290,225 patent/US20030089369A1/en not_active Abandoned
-
2003
- 2003-07-03 US US10/612,072 patent/US7740463B2/en not_active Expired - Fee Related
-
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- 2005-02-18 US US11/060,564 patent/US20050142071A1/en not_active Abandoned
-
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- 2006-02-07 CY CY20061100154T patent/CY1105356T1/en unknown
- 2006-11-22 IL IL179491A patent/IL179491A0/en unknown
-
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- 2008-01-31 US US12/023,315 patent/US8142763B2/en not_active Expired - Fee Related
- 2008-06-04 US US12/132,852 patent/US20080247965A1/en not_active Abandoned
-
2011
- 2011-01-11 US US13/004,204 patent/US20110100361A1/en not_active Abandoned
Patent Citations (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2868691A (en) * | 1956-03-21 | 1959-01-13 | Riker Laboratories Inc | Self-propelling compositions for inhalation therapy containing a salt of isoproterenol or epinephrine |
US4185100A (en) * | 1976-05-13 | 1980-01-22 | Johnson & Johnson | Topical anti-inflammatory drug therapy |
US4499108A (en) * | 1983-06-08 | 1985-02-12 | Schering Corporation | Stable pleasant-tasting albuterol sulfate pharmaceutical formulations |
US4835145A (en) * | 1984-06-11 | 1989-05-30 | Sicor Societa' Italiana Corticosteroidi S.P.A. | 16,17 acetals of pregnane derivatives and pharmaceutical compositions containing them |
US5192528A (en) * | 1985-05-22 | 1993-03-09 | Liposome Technology, Inc. | Corticosteroid inhalation treatment method |
US5955058A (en) * | 1992-12-09 | 1999-09-21 | Boehringer Ingelheim Pharmaceuticals, Inc. | Stabilized medicinal aerosol solution formulations containing ipratropium bromide |
US6143277A (en) * | 1995-04-14 | 2000-11-07 | Glaxo Wellcome Inc. | Metered dose inhaler for salmeterol |
US6253762B1 (en) * | 1995-04-14 | 2001-07-03 | Glaxo Wellcome Inc. | Metered dose inhaler for fluticasone propionate |
US6131565A (en) * | 1996-12-20 | 2000-10-17 | Stanwell Corporation Limited | Solar energy collector system |
US5891419A (en) * | 1997-04-21 | 1999-04-06 | Aeropharm Technology Limited | Environmentally safe flunisolide aerosol formulations for oral inhalation |
US20030206870A1 (en) * | 1997-06-13 | 2003-11-06 | Chiesi Farmaceutici S.P.A. | Pharaceutical aerosol composition |
US20010031244A1 (en) * | 1997-06-13 | 2001-10-18 | 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 |
US6045784A (en) * | 1998-05-07 | 2000-04-04 | The Procter & Gamble Company | Aerosol package compositions containing fluorinated hydrocarbon propellants |
US6150418A (en) * | 1998-10-17 | 2000-11-21 | Boehringer Ingelheim Pharma Kg | Active substance concentrate with formoterol, suitable for storage |
US20050142071A1 (en) * | 1998-11-25 | 2005-06-30 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
US6713047B1 (en) * | 1998-11-25 | 2004-03-30 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition containing HFA 227 and HFA 134a |
US20030066525A1 (en) * | 1998-11-25 | 2003-04-10 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
US20040096399A1 (en) * | 1998-11-25 | 2004-05-20 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
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 |
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 |
US20030190289A1 (en) * | 2000-05-12 | 2003-10-09 | David Lewis | Formulations containing a glucocorticoid drug for the treatment of bronchopulmonary diseases |
US20040047809A1 (en) * | 2000-05-22 | 2004-03-11 | 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 |
US20060083693A1 (en) * | 2000-05-22 | 2006-04-20 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
US7018618B2 (en) * | 2000-05-22 | 2006-03-28 | 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 |
US20050154013A1 (en) * | 2002-03-01 | 2005-07-14 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers containing solutions of beta-2 agonists |
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 |
US20050220718A1 (en) * | 2004-02-27 | 2005-10-06 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
Cited By (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7601336B2 (en) * | 1997-06-13 | 2009-10-13 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
US20030190287A1 (en) * | 1997-06-13 | 2003-10-09 | Chiesi Farmaceutici S.P.A. | Pharaceutical aerosol composition |
US20030206870A1 (en) * | 1997-06-13 | 2003-11-06 | Chiesi Farmaceutici S.P.A. | Pharaceutical aerosol composition |
US20090311196A1 (en) * | 1997-06-13 | 2009-12-17 | Chiesi Farmaceutici S.P.A | Pharmaceutical aerosol composition |
US20040062720A1 (en) * | 1997-06-13 | 2004-04-01 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
US8420058B2 (en) | 1997-06-13 | 2013-04-16 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
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 |
US20080115782A1 (en) * | 1998-11-25 | 2008-05-22 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (mdi) |
US20080247965A1 (en) * | 1998-11-25 | 2008-10-09 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (mdi) |
US20050142071A1 (en) * | 1998-11-25 | 2005-06-30 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
US6983743B2 (en) | 1999-05-26 | 2006-01-10 | Boehringer Ingelheim Pharma Kg | Stainless steel canister for propellant-driven metering aerosols |
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 |
US20060083693A1 (en) * | 2000-05-22 | 2006-04-20 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
US20060257324A1 (en) * | 2000-05-22 | 2006-11-16 | Chiesi Farmaceutici S.P.A. | Pharmaceutical solution formulations for pressurised metered dose inhalers |
US8168598B2 (en) | 2001-07-02 | 2012-05-01 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
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 |
US20100098642A1 (en) * | 2001-07-02 | 2010-04-22 | 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 |
US20110212912A1 (en) * | 2001-07-02 | 2011-09-01 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US20050152846A1 (en) * | 2002-03-01 | 2005-07-14 | Chiesi Farmaceutici S.P.A. | Formoterol superfine formulation |
US20090263488A1 (en) * | 2002-03-01 | 2009-10-22 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers containing solutions of beta-2 agonists |
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 |
US20110061651A1 (en) * | 2002-03-01 | 2011-03-17 | Chiesi Farmaceutici S.P.A. | Formoterol superfine formulation |
US20050154013A1 (en) * | 2002-03-01 | 2005-07-14 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers containing solutions of beta-2 agonists |
US20040126325A1 (en) * | 2002-03-12 | 2004-07-01 | David Lewis | Medicinal aerosol solution formulation products with improved chemical stability |
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 |
EP1915985A1 (en) | 2003-03-20 | 2008-04-30 | Boehringer Ingelheim Pharmaceuticals Inc. | Formulation for a Metered Dose Inhaler Using Hydro-Fluoro-Alkanes as Propellants |
US7914770B2 (en) | 2003-03-20 | 2011-03-29 | Boehringer Ingelheim Pharmaceuticals, Inc. | Formulation for a metered dose inhaler using hydro-fluoro-alkanes as propellants |
US20060099149A1 (en) * | 2003-05-21 | 2006-05-11 | Karib Kemi-Pharm Limited | Metered dose inhaler product |
US7273603B2 (en) * | 2003-07-11 | 2007-09-25 | Boehringer Ingelheim International Gmbh | HFC solution formulations containing an anticholinergic |
US20050008578A1 (en) * | 2003-07-11 | 2005-01-13 | Boehringer Ingelheim International Gmbh | HFC solution formulations containing an anticholinergic |
US20050101625A1 (en) * | 2003-09-26 | 2005-05-12 | Boehringer Ingelheim International Gmbh | Aerosol formulation for inhalation comprising an anticholinergic |
US7579358B2 (en) * | 2003-09-26 | 2009-08-25 | Boehringer Ingelheim International Gmbh | Aerosol formulation for inhalation comprising an anticholinergic |
US20050136009A1 (en) * | 2003-10-20 | 2005-06-23 | Schering Corporation | Pharmaceutical compositions |
US20080064674A1 (en) * | 2003-10-20 | 2008-03-13 | Schering Corporation | Pharmaceutical Compositions |
WO2005084640A1 (en) * | 2004-02-27 | 2005-09-15 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
US20070025920A1 (en) * | 2004-02-27 | 2007-02-01 | David Lewis | Stable Pharmaceutical Solution Formulations for Pressurized Metered Dose Inhalers |
CN100457087C (en) * | 2004-02-27 | 2009-02-04 | 奇斯药制品公司 | Stable pharmaceutical solution formulation for pressurized metered dose inhalers |
EA010311B1 (en) * | 2004-02-27 | 2008-08-29 | КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. | Aerosol solution formulations, pressurized metered dose inhalers and method for filling thereof |
US7381402B2 (en) | 2004-02-27 | 2008-06-03 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
EP1595531A1 (en) * | 2004-05-13 | 2005-11-16 | CHIESI FARMACEUTICI S.p.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
US8357352B2 (en) | 2004-07-02 | 2013-01-22 | Boehringer Ingelheim International Gmbh | Aerosol suspension formulations containing TG 227 ea or TG 134 a as propellant |
US20060002863A1 (en) * | 2004-07-02 | 2006-01-05 | Boehringer Ingelheim International Gmbh | Aerosol suspension formulations containing TG 227 ea or TG 134 a as propellant |
US20090298802A1 (en) * | 2005-03-30 | 2009-12-03 | Sequeira Joel A | Pharmaceutical Compositions |
US20090092559A1 (en) * | 2006-04-11 | 2009-04-09 | Boehringer Ingelheim Pharma Gbmh Co. Kg | Aerosol suspension formulations with TG 227 ea or TG 134 a as propellant |
US8518377B2 (en) | 2006-04-11 | 2013-08-27 | Boehringer Ingelheim Pharma Gbmh Co. Kg | Aerosol suspension formulations with TG 227 ea or TG 134 a as propellant |
US8227027B2 (en) | 2007-12-07 | 2012-07-24 | Presspart Gmbh & Co. Kg | Method for applying a polymer coating to an internal surface of a container |
US20090145427A1 (en) * | 2007-12-07 | 2009-06-11 | Groeger Joseph H | Method for Applying a Polymer Coating to an Internal Surface of a Container |
US8703306B2 (en) | 2007-12-07 | 2014-04-22 | Presspart Gmbh & Co. Kg | Method for applying a polymer coating to an internal surface of a container |
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