CA2654041A1 - Stable aerosol pharmaceutical formulations - Google Patents
Stable aerosol pharmaceutical formulations Download PDFInfo
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- CA2654041A1 CA2654041A1 CA002654041A CA2654041A CA2654041A1 CA 2654041 A1 CA2654041 A1 CA 2654041A1 CA 002654041 A CA002654041 A CA 002654041A CA 2654041 A CA2654041 A CA 2654041A CA 2654041 A1 CA2654041 A1 CA 2654041A1
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- pharmaceutically acceptable
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
-
- 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
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P11/08—Bronchodilators
Abstract
The present invention provides a stable aerosol pharmaceutical formulation of a beta- agonist, an anticholinergic, or a combination thereof in combination with a cosolvent and optionally a surfactant. The invention also provides a method of making the stable aerosol pharmaceutical formulation and methods of treating bronchoconstriction, asthma and related conditions with the stable aerosol pharmaceutical formulation of the present invention.
Description
STABLE AEROSOL PHARMACEUTICAL FORMULATIONS
BACKGROUND
[0001] Asthma is chronic inflammatory disease affecting about 20 million to 35 million persons worldwide, in which the patient suffers episodes of reversible airway obstruction.
Asthma is generally treated by administration of anti-inflammatory drugs or bronchodilators.
Anti-inflammatory drugs useful for the treatment of asthma include corticosteroids, mast cell stabilizers, and leulcotriene inhibitors. Bronchodilators include beta-agonists, anticholinergics, and methylxanthines. Beta-agonists can be used to treat exercise-induced astluna. Beta-agonists can be combined with other classes of drugs like corticosteroids, anti-cholinergics and leulcotriene inhibitors. The combination of a beta-agonist, such as albuterol, and an anticholinergic, such as ipratropium, has proven to be highly effective because the drugs provide bronchodilation by different mechanism of action.
BACKGROUND
[0001] Asthma is chronic inflammatory disease affecting about 20 million to 35 million persons worldwide, in which the patient suffers episodes of reversible airway obstruction.
Asthma is generally treated by administration of anti-inflammatory drugs or bronchodilators.
Anti-inflammatory drugs useful for the treatment of asthma include corticosteroids, mast cell stabilizers, and leulcotriene inhibitors. Bronchodilators include beta-agonists, anticholinergics, and methylxanthines. Beta-agonists can be used to treat exercise-induced astluna. Beta-agonists can be combined with other classes of drugs like corticosteroids, anti-cholinergics and leulcotriene inhibitors. The combination of a beta-agonist, such as albuterol, and an anticholinergic, such as ipratropium, has proven to be highly effective because the drugs provide bronchodilation by different mechanism of action.
[0002] Many asthma drugs are administered through inhalation. Suitable inhalation devices include metered dose inhalers ("MDTs"), dry powder inhalers and nebulizers.
Metered dose inhalers conventionally contain one or more liquefied chlorofluorocarbons ("CFCs") as propellant. Such materials are suitable for use in such applications since they have the right vapor pressures (or can be mixed in the right proportions to achieve a vapor pressure in the right range) and are essentially taste and odor-free.
Metered dose inhalers conventionally contain one or more liquefied chlorofluorocarbons ("CFCs") as propellant. Such materials are suitable for use in such applications since they have the right vapor pressures (or can be mixed in the right proportions to achieve a vapor pressure in the right range) and are essentially taste and odor-free.
[0003] One such CFC-containing metered dose inhaler is CombiventOO Inhalation Aerosol which contains a microcrystalline suspension of ipratropium bromide and albuterol sulfate in a pressurized metered-dose aerosol unit for oral inhalation administration.
[0004] Due to environmental concerns, it is now desirable to use hydrofluoroalkane ("HFA") propellants instead of CFCs in metered dose inllalers containing asthma drugs. For example, US20040184994 relates to a formulation comprising water in an amount of about 0.13 to about 0.18 percent (w/w) of the product formulation, at least one HFA
as a propellant, one or more active ingredients and one or more excipients, wherein the preferred active ingredients are ipratropium and albuterol and the excipients are citric acid, ethanol and polyvinylpyrrolidone ("PVP").
as a propellant, one or more active ingredients and one or more excipients, wherein the preferred active ingredients are ipratropium and albuterol and the excipients are citric acid, ethanol and polyvinylpyrrolidone ("PVP").
(0005] US20050085445 relates to a metered-dose aerosol inhaler composition, which contains a) at least one pharmaceutical active ingredient, b) at least one propellant (preferred propellants being HFA 227 and HFA 134a), c) at least one native or modified cyclodextrin, d) at least one liydrophilic additive, and e) optionally ethanol.
[0006] US20050089478 relates to a formulation comprising fonnoterol and budesonide for use in the treatment of respiratory diseases. The composition further contains HFA-227 propellant, PVP and polyethylene glycol ("PEG"), preferably PVP K25 and PEG
1000.
1000.
[0007] However, MDI formulations containing HFA propellants do not have suspension characteristics as good as those formulations containing CFC Propellants. For example, an MDI formulation containing the beta-agonist albuterol sulfate and an anticholinergic agent, such as ipratropium bromide or tiotropium, with an HFA propellant is not a stable suspension and either quiclcly sediments or forms an emulsion.
[0008] For this reason, it is difficult to obtain a stable suspension using an HFA
propellant. As a result, cosolvents such as water and alcohols (ethanol) have been used in combination with beta-agonist agents and anticholinergic agents in formulations containing HFA propellants. Unfortunately, the use of these cosolvents also leads to stability problems and other issues, such as agglomeration/increased particle size of the active agents, which are also undesirable.
SUMMARY
propellant. As a result, cosolvents such as water and alcohols (ethanol) have been used in combination with beta-agonist agents and anticholinergic agents in formulations containing HFA propellants. Unfortunately, the use of these cosolvents also leads to stability problems and other issues, such as agglomeration/increased particle size of the active agents, which are also undesirable.
SUMMARY
[0009] According to a first aspect of the present invention, there is provided a pharmaceutical formulation comprising: an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof; a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof; a cosolvent; and a hydrofluoroalkane propellant. The anticholinergic agent may also be a pharmaceutically acceptable enantiomer, pharmaceuticatly acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof. The beta-agonist agent may also be a phaimaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodi-ug thereof.
[0010] In an embodiment, the cosolvent is selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and isopropyl myristrate.
[0011] The formulation may further comprise a surfactant. The surfactant may be selected from the group consisting of polyvinylpyrrolidone, sorbitan trioleate, oleic acid, citric acid, and polyoxyethylene(4)lauryl ether.
[0012] In an embodiment, the anticholinergic agent is selected from ipratropium or tiotropium or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable hydrates thereof. Alternatively, the anticholinergic agent is selected from ipratropium or tiotropium or pharmaceutically acceptable enantiomers, phannaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Suitably, the anticholinergic agent is ipratropium.
[0013] In an embodiment, the beta-agonist is selected from the group consisting of albuterol, formoterol, levalbuterol, pirbuterol and salmeterol, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable hydrates thereof.
Alternatively, the beta-agonist is selected from the group consisting of albuterol, formoterol, levalbuterol, pirbuterol and salmeterol, or pharmaceutically acceptable enantiomers, phannaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Suitably, the beta-agonist is albuterol.
Alternatively, the beta-agonist is selected from the group consisting of albuterol, formoterol, levalbuterol, pirbuterol and salmeterol, or pharmaceutically acceptable enantiomers, phannaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Suitably, the beta-agonist is albuterol.
[0014] In another embodiment, the anticholinergic agent is ipratropium or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof and the beta-agonist is albuterol or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
Alternatively, the anticholinergic agent is ipratropium or a pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or phannaceutically acceptable prodrug thereof. Alternatively, the beta-agonist is albuterol or a pharmaceutically acceptable enaltiomer, phaimaceutically acceptable derivative, pharinaceutically acceptable polylnozph or pharm.aceutically acceptable prodrug thereof.
Alternatively, the anticholinergic agent is ipratropium or a pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or phannaceutically acceptable prodrug thereof. Alternatively, the beta-agonist is albuterol or a pharmaceutically acceptable enaltiomer, phaimaceutically acceptable derivative, pharinaceutically acceptable polylnozph or pharm.aceutically acceptable prodrug thereof.
[0015] In an embodiinent, the cosolvent is present in an amount of about 0.05%
to about 15% of the total weight of the formulation.
to about 15% of the total weight of the formulation.
[0016] In another embodiment, the surfactant is present in an amount of about 0.00001%
to about 10% of the total weight of the formulation.
to about 10% of the total weight of the formulation.
[0017] Preferably, the forinulation is substantially free of alcohol.
[0018] Preferably, the formulation is substantially free of water.
[0019] Tn an embodiment, the formulation contains less than about 0.1 % water by weight of the formulation.
[0020] The formulation may comprise ipratropium bromide or its monohydrate, albuterol sulfate, about 0.05% to about 1% polyethylene glycol, about 0.00001% to about 0.1%
polyvinylpyrrolidone, and a hydrofluoroalkane propellant.
polyvinylpyrrolidone, and a hydrofluoroalkane propellant.
[0021] According to a second aspect of the present invention, there is provided a pharmaceutical formulation comprising: an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof; a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof;a polysorbate; and a hydrofluoroalkane propellant. The anticholinergic agent may also be a pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof. The beta-agonist agent may also be a pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or phannaceutically acceptable prodrug thereof.
[0022] The polysorbate may be selected from polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate and polyoxyethylene sorbitan monoisostearate.
Suitably, the polysorbate may be selected from polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyetllylene (40) sorbitan moilostearate (Tween 60), polyoxyethylene (20) sorbitan monooleate (Tween 80) and polyoxyethylene (20) sorbitan monoisostearate (Tween 120). Suitably, the polysorbate is polyoxyethylene sorbitan monolaurate, for example polyoxyethylene (20) sorbitan monolaurate.
Suitably, the polysorbate may be selected from polyoxyethylene (20) sorbitan monolaurate (Tween 20), polyoxyethylene (20) sorbitan monopalmitate (Tween 40), polyoxyetllylene (40) sorbitan moilostearate (Tween 60), polyoxyethylene (20) sorbitan monooleate (Tween 80) and polyoxyethylene (20) sorbitan monoisostearate (Tween 120). Suitably, the polysorbate is polyoxyethylene sorbitan monolaurate, for example polyoxyethylene (20) sorbitan monolaurate.
[0023] Tiz an embodiment, the polysorbate, for example polyoxyethylene sorbitan monolaurate, is present in an amount of about 0.05% by weight of the formulation.
[0024] In another embodiment, there is no cosolvent present in the formulation.
[0025] In an embodiment, the anticholinergic agent is selected from ipratropium or tiotropium or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable hydrates thereof. Alternatively, the anticholinergic agent is selected from ipratropium or tiotropium or pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Suitably, the anticholinergic agent is ipratropium.
[0026] In an embodiment, the beta-agonist is selected from the group consisting of albuterol, formoterol, levalbuterol, pirbuterol and salmeterol, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates or pharmaceutically acceptable hydrates thereof.
Alternatively, the beta-agonist is selected from the group consisting of albuterol, formoterol, levalbuterol, pirbuterol and salmeterol, or pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Suitably, the beta-agonist is albuterol.
Alternatively, the beta-agonist is selected from the group consisting of albuterol, formoterol, levalbuterol, pirbuterol and salmeterol, or pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof. Suitably, the beta-agonist is albuterol.
[0027] In another embodiment, the anticholinergic agent is ipratropium or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof and the beta-agonist is albuterol or a phannaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof.
Alteinatively, the anticholinergic agent is ipratropium or a phannaceutically acceptable enantiomer, pharmaceutically acceptable derivative, phannaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof. Alternatively, the beta-agonist is albuterol or a pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodnig thereof.
Alteinatively, the anticholinergic agent is ipratropium or a phannaceutically acceptable enantiomer, pharmaceutically acceptable derivative, phannaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof. Alternatively, the beta-agonist is albuterol or a pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodnig thereof.
[0028] Preferably, the formulation is substantially free of alcohol.
[0029] Preferably, the formulation is substantially free of water.
[0030] In an embodiment, the formulation contains less than about 0.1 % water by weight of the formulation.
[0031] According to a third aspect of the present invention, there is provided a method of making a pharmaceutical formulation comprising: (a) mixing a hydrofluoroallcane propellant with a cosolvent to forin a solution; (b) forming a first homogenized suspension of an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof; a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof; and a hydrofluoroalkane propellant; and (c) adding the first homogenized suspension to the solution to fonn a second homogeneous suspension. The anticholinergic agent may also be a phasmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof. The beta-agonist agent may also be a pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof.
[0032] Tn an embodiment, the cosolvent is selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and isopropyl myristrate.
[0033] The method may further comprise dissolving a surfactant in the cosolvent. The surfactant may be selected from the group consisting of polyvinylpyrrolidone, sorbitan trioleate, oleic acid, citric acid, and polyoxyethylene(4)lauryl ether.
[0034] The method may be for malcing the formulation described in the first two aspects of the invention.
[0035] According to a fourth aspect of the present invention, there is provided a method of malcing a phannaceutical formulation comprising: (a) dissolving polyoxyethylene sorbitan monolaurate in a hydrofluoroalkane propellant to fonn a solution; (b) forming a first homogenized suspension of an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or pharmaceutically acceptable hydrate thereof; a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or phaimaceutically acceptable hydrate thereof; and a hydrofluoroalkane propellant; and(c) adding the first homogenized suspension to the solution to form a second suspension. The anticholinergic agent may also be a pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, phannaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof. The beta-agonist agent may also be a pharmaceutically acceptable enantiomer, phannaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof.
[0036] The method may be for malcing the formulation described in the first two aspects of the invention.
[0037] According to a fifth aspect of the present invention, there is provided a metered dose inhaler comprising a formulation according to any one of claims 1 to 18, and a canister coated with a polymer. The polymer may be selected from the group consisting of a fluorocarbon polymer, an epoxy copolyiner, and an ethylene copolymer.
[0038] In an embodiment, the metered dose inhaler furtlier comprises a sealing gasket.
The sealing gasket may comprise a butyl elastomer.
[00391 According to a sixth aspect of the present invention, there is provided a method of treating bronchoconstriction, bronchospasm, asthma and related disorders comprising administering an effective amount of a formulation described above to patient in need thereof.
[0040] According to a seventh aspect of the present invention, there is provided the use of a formulation described above in medicine.
[0041] According to an eighth aspect of the present invention, there is provided the use of a formulation described above in the manufacture of a medicament for treating bronchoconstriction, bronchospasm, asthma and related disorders.
[0042] Thus, the present invention provides a stable metered dose inhaler ("MDI") formulation comprising a pharmaceutically active agent with an HFA propellant along with suitable excipients. Surprisingly, it was found that a combination of particular active ingredients with particular excipients provides a stable MDI foimulation. The active ingredients are an anticholinergic agent and a beta-agonist agent. The particular excipients are cosolvents other than alcohol, like polyethylene glycol ("PEG"), propylene glycol, isopropyl myristrate or glycerol, optionally in combination with a surfactant, and an HFA
propellant and other suitable excipients. The formulation of the present invention does not fonn agglomerates. The present invention also provides a process for manufacture of a metered dose iiihalation fonnulation. In an embodiment, the cosolvent is not an alcohol. In another embodiment, the cosolvent is not water.
[0043] It has also been surprisingly discovered that the use of polyoxyethylene sorbitan monolaurate and an HFA propellant and other suitable excipients, without an additional cosolvent, provides a stable formulation with the particular active ingredients.
[0044] The present invention also provides a method for the treatment of bronchoconstriction, bronchospasm, asthma and related disorders thereof, which method comprises adininistering to a patient in need thereof an effective amount of a metered dose inhalation formulation according to the present invention.
[0045] Other aspects of the invention will become apparent by consideration of the detailed description and examples.
DETAILED DESCRIPTION
[0046] The present invention provides a stable aerosol pharmaceutical formulation. More specifically, the stable aerosol pharmaceutical formulation contains a phannaceutically active agent in combination with a hydrofluoroalkane ("HFA") propellant and other suitable excipients.
[0047] As discussed earlier, aerosol formulations traditionally contained CFC
propellants.
Due to environmental concems, HFA propellants are now preferred over CFC
propellants. As will be understood by those skilled in the art, suitable HFA propellants for use in the present invention include, but are not limited to, 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA-227).
[0048] The foimulations of the present invention are suitable for use in MDIs.
MDIs are compact drug delivery systems that use a liquefied propellant to atomize a precisely metered volume of a pharmaceutical forinulation into particles, which are small enough to penetrate deep into the patient's lungs. MDIs allow for targeted delivery of the drug to the desired site of the tlierapeutic effect - the lung.
[0049] The fonnulation of the present invention also includes a cosolvent, such as polyethylene glycol ("PEG"), propylene glycol, isopropyl inyristrate or glycerol. Suitably, the cosolvent is PEG in liquid fonn, such as PEG 200 or PEG 400. The cosolvent can be present in a range of about 0.05% to about 15% by weight of the fonnulation:
Suitably, the cosolvent is present in a range of about 0.05% to about 1% or about 0.05% to about 0.3% by weight of the formulation.
[0050] Furtlier, it has been found that when an optional surfactant is used along with the cosolvent, the surfactant maintains the homogeneity of the suspension and also acts as a lubricant for the smooth functioning of the valve on the MDI. Suitable surfactants include, but are not limited to, polyvinylpyrrolidone ("PVP"), sorbitan trioleate, oleic acid, citric acid, and polyoxyethylene(4)lauryl ether (Brij 30 ). Suitably the surfactant is PVP, such as PVP
K25 or PVP K30 or PVP K17. The surfactant can be present in a range of about 0.00001% to about 10% by weight of the formulation. Suitably, the surfactant is present in a range of about 0.00001 % to about 0.1 % or about 0.0001 % to about 0.001 % by weight of the formulation.
[0051] Suitably, the formulations of the present invention are substantially free of water and alcohol. The term "substantially free of' means that the formulation contains less than about 5% water or alcohol by weight of the formulation. The formulations may contain less than about 3% water or alcohol. Preferably, the formulations contain less than about 1%, more preferably less than about 0.5%, still more preferably less than 0.1% or still more preferably less than about 0.05% water or alcohol. Most preferably, the formulations of the present invention contain no water or alcohol.
[0052] The present invention further provides a pharmaceutical formulation comprising an anticholinergic agent, a beta-agonist agent, polyoxyethylene sorbitan monolaurate, and a hydrofluoroalkane propellant. The polyoxyethylene sorbitan monolaurate can be present in a range of about 0.00001% to about 10% by weight of the formulation. Suitably, the polyoxyethylene sorbitan monolaurate is present in a range of about 0.00001 %
to about 0.1 %
or about 0.0001% to about 0.001% by weight of the formulation. More suitably, the polyoxyethylene sorbitan monolaurate is present in an amount of about 0.05% by weight of the formulation.
[0053] Pharmaceutically active agents usefiil in the formulations of the present invention include one or more of drugs selected .froin the class of beta-agonists agents and anticholinergic agents. The terms "beta-agonist agent" or "beta-agonist" or "anticholinergic agent" are used in a broad sense to include not only the beta-agonist or anticholinergic agent per se but also their phaimaceutically acceptable salts, pharmaceutically acceptable solvates and phaimaceutically acceptable hydrates. It will also be appreciated that the terms "beta-agonist agent" or "beta-agonist" or "anticholinergic agent" may also include pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, phannaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, etc.
[0054] Beta-agonist agents useful in the formulations of the present invention include, but are not limited to, albuterol, formoterol, levalbuterol, pirbuterol and salmeterol. The international name for albuterol is salbutaznol. Suitable pharmaceutically acceptable salts of the beta-agonists include, but are not limited to the hydrochloride, sulfate, maleate, tartrate, and citrate salts. Suitably, the beta-agonist is albuterol or albuterol sulfate.
[0055] Anticholinergic agents useful in the formulations of the present invention include, but are not limited to, ipratropium and tiotropium. Suitable pharmaceutically acceptable salts of the anticholinergic agents include, but are not limited to, the halide salts such as bromide, chloride and iodide. Suitably, the anticholinergic agent is ipratropium or ipratropium bromide or ipratropium bromide monohydrate.
[0056] Suitably, the beta-agonist in the formulations is albuterol and the anticholinergic agent is ipratropium or ipratropium bromide or ipratropium bromide monohydrate.
Alternatively, the beta-agonist in the formulations is albuterol sulfate and the anticholinergic agent is ipratropium or ipratropium bromide or ipratropium bromide monohydrate.
[0057] The present invention also provides a method of manufacturing a stable aerosol formulation according to the present invention. If used, the surfactaiit is dissolved in the cosolvent. The resulting solution is then mixed with an HFA propellant. If the surfactant is not used, the cosolvent is mixed with an HFA propellant. The pharmaceutically active agent is homogenized with additional HFA propellant to form a homogenized suspension. The homogenized suspension of active ingredients and solution of cosolvent and HFA
propellant are mixed to forin a second homogeneous suspension. The homogeneous second suspension is then placed in a precrimped canister or other container suitable for use as a metered dose inhaler.
[0058] For example, surfactant PVP IU5 is dissolved in cosolvent PEG200 or PEG400 to make a clear solution. A quantity of HFA-227 propellant is added to the clear solution. A
first homogenized suspension of ipratropiuin bromide and albuterol sulfate and additional HFA-227 propellant is prepared. The first homogenized suspension is added to the-solution of PVP K25, PEG200 or PEG400 and HFA-227 to form a second homogeneous suspension.
The resulting second suspension is then placed in a precrimped canister or other container suitable for use as a metered dose inhaler.
[0059] The present invention further provides a method for the treatment of bronchoconstriction, bronchospasm, asthma and related disorders thereof, coinprising administering to a patient in need thereof a stable aerosol formulation according to the present invention. Related disorders include, but are not limited to, clhronic obstructive puhnonary disease, chronic bronchitis and emphysema.
[0060] The formulation of the present invention may be administered one, two, three or four times per day with one or more activations, e.g. two, three or four activations, of the metering valve per administration to treat bronchoconstriction, astluna and related disorders thereof. Up to about twelve inhalations of the pharmaceutical formulation of the present invention may be administered per 24 hour period.
[0061] Suitably, each actuation of the metering valve delivers about 21 g of an anticholinergic agent, such as ipratropium bromide monohydrate and about 120 g of a beta-agonist agent, such as albuterol sulfate from the metered dose inhaler.
Suitably, each container or metered dose inhaler canister contains about 200 inhalations. As one skilled in the art is aware, the dose may be adjusted depending on the therapeutic objective of the use of the active agents and the age and condition of the patient.
[0062] We observed that some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each activation of the MDI. Coating the inner surface of the container with a suitable polynler can reduce this adhesion problem.
Suitable coatings iilclude, but are not limited to, fluorocarbon copolymers such as FEP-PES
(fluorinated ethylene propylene and polyethersulphone) and PFA-PES
(perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene.
[0063] Also, during storage, moisture can enter the MDI mainly tlu-ough the crimped area of the valve and through the stem by diffusion. To reduce the alnount of moisture entering the MDI, the metering valve is suitably comprised of a butyl elastomer.
[0064] It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without -departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
[0065] The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1 [0066] Formulations 1 to 18 listed below were prepared in the following manner.
[0067] The surfactant was dissolved in the cosolvent by sonication/homogenization for minutes. This solution was mixed for 10 - 25 minutes in a mixing vessel with approximately 10%-15% of the total amount of propellant required for the batch. If the surfactant was not used, only the cosolvent was mixed with the propellant.
[00681 The active agents were homogenized in a separate homogenizer with approximately 5-15% of the total amount of propellant required for the batch.
The homogenization speed and time ranged from 1000 - 1500 RPM for 15 to 30 minutes. The resulting homogenized suspension was transferred from the homogenizer to the mixing vessel through a double diaphragm pump. The remaining quantity of the propellant was then added to the mixing vessel.
[0069] The suspension was then mixed under constant stirring of 200 - 300 RPM
for not less than 20 minutes and kept under recirculation through the double diaphragm pump.
[0070] Forinulation 1 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Sorbitan Trioleate 0.00002% 0.00408 mg PEG 200 0.05% 10.2 mg HFA-227 20.4 gm [0071] Formulation 2 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Sorbitan Trioleate 0.00004% 0.00816 mg PEG 200 0.05% 10.2 mg HFA-227 20.4 gm [00721 Formulation 3 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Sorbitan Trioleate 0.05% 10.2 mg PEG 200 0.05% 10.2 mg HFA-227 20.4 gm [0073] Formulation 4 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.00001 % 0.00204 mg PEG 200 0.1 % 20.4 mg HFA-227 20.4 gm [0074] Formulation 5 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.00001% 0.00204 mg PEG 200 1% 204 mg HFA-227 20.2 gm [0075] Formulation 6 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.001% 0.204 mg PEG 200 0.3% 61.2 mg HFA-227 20.2 gm [0076] Fonnulation 7 Qtylcan Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 30 0.1% 20.41ng PEG 200 1% 204 mg HFA-227 20.2 gm [0077] Fonnulation 8 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVPK30 0.001% 0.204mg PEG2000.3% 61.2mg HFA-227 20.3 gm [0078] Formulation 9 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Oleic acid 0.001% 0.204 mg PEG200 1% 204 mg HFA-227 20.2 gm [0079] Formulation 10 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 ing Sorbitan Trioleate 0.00002% 0.00408 mg PEG 400 0.05% 10.2 mg HFA-227 20.4 gm [0080] Formulation 11 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuteol Sulfate 28.8 mg Sorbitan Trioleate 0.00004% 0.00816 mg PEG 400 0.05% 10.2 mg HFA-227 20.4 gm [0081] Formulation 12 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Sorbitan Trioleate 0.05% 10.2 mg PEG 400 0.05% 10.2 mg HFA-227 20.4 gm [0082] Fonnulation 13 Qty/can Ipratro ium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.00001 /a 0.00204 mg PEG 400 0.1 % 20.4 mg HFA-227 20.4 gm [0083] Formulation 14 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.00001% 0.00204 mg PEG 400 1% 204 mg HFA-227 20.2 gm [0084] Formulation 15 Qty/can Ipratro ium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.001% 0.204 mg PEG 400 0.3 % 61.2 mg HFA-227 20.2 gm [0085] Formulation 16 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K30 0.1% 20.4 mg PEG 400 1% 204 mg HFA-227 20.2 gm [0086] Formulation 17 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 30 0.001% 0.204 mg PEG 400 0.3 % 61.2 mg HFA-227 20.3 gm [0087] Formulation 18 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Oleic acid 0.001 % 0.204 mg PEG400 1% 204 mg HFA-227 20.2 gm Example 2 [0088] Formulation 19 listed below was prepared in the following manner.
[0089] Polyoxyethylene sorbitan monolaurate (Tween 20) was dissolved in HFA
propellant to form a solution. The active ingredients were homogenized with additional HFA
propellant. The solution was then mixed with the homogenized suspension of active ingredients and HFA to form a second homogeneous suspension. The second suspension was then placed in a precrimped canister or other container suitable for use as an MDI. The formulation showed good stability.
[0090] Fomlulation 19 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Tween 20 (0.05%) 10.2 mg HFA-227 20.4 gm Example 3 [0091] Formulations made according to the process described above in Example 1 were tested for stability. Stability was determined by analyzing the particle size of the active ingredients using microscopy. The results are shown below in Table 1.
[0092] Examples 1 to 4 exemplify prior art formulations. Exainples 5 to 7 exemplify the formulation of the present invention.
[0093] An increase in particle size in examples 1 to 4, indicated that the active ingredien.ts were not as stable in the prior art formulations compared to the stability of the active ingredients in the formulations of the present invention.
Table 1. Effect of different combinations of cosolvent and surfactant on the suspension characteristics and particle size of ipratropium bromide and albuterol sulfate.
Active Cosolvent Surfactant Propellant Suspension Particle size In redients characteristics observation 1 Ipratropium -- -- HFA Particles Agglomeration (5.04 mg) Propellant remain in Albuterol (P134a or homogeneous sulfate P227) suspension for (28.8 mg) less than 5 seconds.
2 lpratropium Alcohol -- HFA Particles 70% particles (5.04 mg) (1-5%) Propellant remain in between 10 to Albuterol (P134a or homogeneous 12.5 microns sulfate P227) suspension for (28.8 mg) about 10-15 seconds.
3 lpratropium Alcohol/ -- HFA Particles 85% particles (5.04 mg) Water Propellant remain in between 10 to Albuterol (1-5%) (P134a or homogeneous 12.5 microns sulfate P227) suspension for with (28.8 mg) about 10-15 agglomeration seconds.
4 lpratropium Alcohol Polyvinyl- HFA Particles 70% particles (5.04 mg) (1-5%) pyrrolidone Propellant remain in between 10 to Albuterol or sorbitan (P134a or homogeneous 12.5 microns sulfate trioleate or P227) suspension for (28.8 mg) oleic acid or about 10-15 citric acid or seconds.
polyoxy-ethylene(4) lauryl ether (0.02- 10%) lpratropium PEG200/ -- HFA Particles 90% particles (5.04 mg) 400 Propellant remain in below 2.5 Albuterol (0.05- (P134a or homogeneous microns &
sulfate 15%) P227) suspension for 10% between (28.8 mg) about 10-15 2.5 to 5 seconds. microns 6 Ipratropium PEG200/ Polyvinyl- HFA Particles 90% particles (5.04 mg) 400 pyrrolidone Propellant remain in below 2.5 Albuterol (0.05- or sorbitan (P134a or homogeneous microns &
sulfate 15%) trioleate or P227) suspension for 10% between (28.8 mg) oleic acid or about 10-15 2.5 to 5 citric acid or seconds. microns polyoxy-ethylene(4) lauryl ether (0.00001-10%) 7 lpratropium -- Polysorbate HFA Particles 90% pa.i-ticles (5.04 mg) 20 or Propellant remain in below 2.5 Albuterol Polysorbate (P134a or homogeneous microns &
sulfate 80 (0.01- P227) suspension for 10% between (28.8 mg) 0.05%) about 10-15 2.5 to 5 seconds. microns [0094] It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including,"
"comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
[0095] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a propellant" includes a single propellant as well as two or more different propellants, reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.
The sealing gasket may comprise a butyl elastomer.
[00391 According to a sixth aspect of the present invention, there is provided a method of treating bronchoconstriction, bronchospasm, asthma and related disorders comprising administering an effective amount of a formulation described above to patient in need thereof.
[0040] According to a seventh aspect of the present invention, there is provided the use of a formulation described above in medicine.
[0041] According to an eighth aspect of the present invention, there is provided the use of a formulation described above in the manufacture of a medicament for treating bronchoconstriction, bronchospasm, asthma and related disorders.
[0042] Thus, the present invention provides a stable metered dose inhaler ("MDI") formulation comprising a pharmaceutically active agent with an HFA propellant along with suitable excipients. Surprisingly, it was found that a combination of particular active ingredients with particular excipients provides a stable MDI foimulation. The active ingredients are an anticholinergic agent and a beta-agonist agent. The particular excipients are cosolvents other than alcohol, like polyethylene glycol ("PEG"), propylene glycol, isopropyl myristrate or glycerol, optionally in combination with a surfactant, and an HFA
propellant and other suitable excipients. The formulation of the present invention does not fonn agglomerates. The present invention also provides a process for manufacture of a metered dose iiihalation fonnulation. In an embodiment, the cosolvent is not an alcohol. In another embodiment, the cosolvent is not water.
[0043] It has also been surprisingly discovered that the use of polyoxyethylene sorbitan monolaurate and an HFA propellant and other suitable excipients, without an additional cosolvent, provides a stable formulation with the particular active ingredients.
[0044] The present invention also provides a method for the treatment of bronchoconstriction, bronchospasm, asthma and related disorders thereof, which method comprises adininistering to a patient in need thereof an effective amount of a metered dose inhalation formulation according to the present invention.
[0045] Other aspects of the invention will become apparent by consideration of the detailed description and examples.
DETAILED DESCRIPTION
[0046] The present invention provides a stable aerosol pharmaceutical formulation. More specifically, the stable aerosol pharmaceutical formulation contains a phannaceutically active agent in combination with a hydrofluoroalkane ("HFA") propellant and other suitable excipients.
[0047] As discussed earlier, aerosol formulations traditionally contained CFC
propellants.
Due to environmental concems, HFA propellants are now preferred over CFC
propellants. As will be understood by those skilled in the art, suitable HFA propellants for use in the present invention include, but are not limited to, 1,1,1,2-tetrafluoroethane (HFA-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA-227).
[0048] The foimulations of the present invention are suitable for use in MDIs.
MDIs are compact drug delivery systems that use a liquefied propellant to atomize a precisely metered volume of a pharmaceutical forinulation into particles, which are small enough to penetrate deep into the patient's lungs. MDIs allow for targeted delivery of the drug to the desired site of the tlierapeutic effect - the lung.
[0049] The fonnulation of the present invention also includes a cosolvent, such as polyethylene glycol ("PEG"), propylene glycol, isopropyl inyristrate or glycerol. Suitably, the cosolvent is PEG in liquid fonn, such as PEG 200 or PEG 400. The cosolvent can be present in a range of about 0.05% to about 15% by weight of the fonnulation:
Suitably, the cosolvent is present in a range of about 0.05% to about 1% or about 0.05% to about 0.3% by weight of the formulation.
[0050] Furtlier, it has been found that when an optional surfactant is used along with the cosolvent, the surfactant maintains the homogeneity of the suspension and also acts as a lubricant for the smooth functioning of the valve on the MDI. Suitable surfactants include, but are not limited to, polyvinylpyrrolidone ("PVP"), sorbitan trioleate, oleic acid, citric acid, and polyoxyethylene(4)lauryl ether (Brij 30 ). Suitably the surfactant is PVP, such as PVP
K25 or PVP K30 or PVP K17. The surfactant can be present in a range of about 0.00001% to about 10% by weight of the formulation. Suitably, the surfactant is present in a range of about 0.00001 % to about 0.1 % or about 0.0001 % to about 0.001 % by weight of the formulation.
[0051] Suitably, the formulations of the present invention are substantially free of water and alcohol. The term "substantially free of' means that the formulation contains less than about 5% water or alcohol by weight of the formulation. The formulations may contain less than about 3% water or alcohol. Preferably, the formulations contain less than about 1%, more preferably less than about 0.5%, still more preferably less than 0.1% or still more preferably less than about 0.05% water or alcohol. Most preferably, the formulations of the present invention contain no water or alcohol.
[0052] The present invention further provides a pharmaceutical formulation comprising an anticholinergic agent, a beta-agonist agent, polyoxyethylene sorbitan monolaurate, and a hydrofluoroalkane propellant. The polyoxyethylene sorbitan monolaurate can be present in a range of about 0.00001% to about 10% by weight of the formulation. Suitably, the polyoxyethylene sorbitan monolaurate is present in a range of about 0.00001 %
to about 0.1 %
or about 0.0001% to about 0.001% by weight of the formulation. More suitably, the polyoxyethylene sorbitan monolaurate is present in an amount of about 0.05% by weight of the formulation.
[0053] Pharmaceutically active agents usefiil in the formulations of the present invention include one or more of drugs selected .froin the class of beta-agonists agents and anticholinergic agents. The terms "beta-agonist agent" or "beta-agonist" or "anticholinergic agent" are used in a broad sense to include not only the beta-agonist or anticholinergic agent per se but also their phaimaceutically acceptable salts, pharmaceutically acceptable solvates and phaimaceutically acceptable hydrates. It will also be appreciated that the terms "beta-agonist agent" or "beta-agonist" or "anticholinergic agent" may also include pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, phannaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, etc.
[0054] Beta-agonist agents useful in the formulations of the present invention include, but are not limited to, albuterol, formoterol, levalbuterol, pirbuterol and salmeterol. The international name for albuterol is salbutaznol. Suitable pharmaceutically acceptable salts of the beta-agonists include, but are not limited to the hydrochloride, sulfate, maleate, tartrate, and citrate salts. Suitably, the beta-agonist is albuterol or albuterol sulfate.
[0055] Anticholinergic agents useful in the formulations of the present invention include, but are not limited to, ipratropium and tiotropium. Suitable pharmaceutically acceptable salts of the anticholinergic agents include, but are not limited to, the halide salts such as bromide, chloride and iodide. Suitably, the anticholinergic agent is ipratropium or ipratropium bromide or ipratropium bromide monohydrate.
[0056] Suitably, the beta-agonist in the formulations is albuterol and the anticholinergic agent is ipratropium or ipratropium bromide or ipratropium bromide monohydrate.
Alternatively, the beta-agonist in the formulations is albuterol sulfate and the anticholinergic agent is ipratropium or ipratropium bromide or ipratropium bromide monohydrate.
[0057] The present invention also provides a method of manufacturing a stable aerosol formulation according to the present invention. If used, the surfactaiit is dissolved in the cosolvent. The resulting solution is then mixed with an HFA propellant. If the surfactant is not used, the cosolvent is mixed with an HFA propellant. The pharmaceutically active agent is homogenized with additional HFA propellant to form a homogenized suspension. The homogenized suspension of active ingredients and solution of cosolvent and HFA
propellant are mixed to forin a second homogeneous suspension. The homogeneous second suspension is then placed in a precrimped canister or other container suitable for use as a metered dose inhaler.
[0058] For example, surfactant PVP IU5 is dissolved in cosolvent PEG200 or PEG400 to make a clear solution. A quantity of HFA-227 propellant is added to the clear solution. A
first homogenized suspension of ipratropiuin bromide and albuterol sulfate and additional HFA-227 propellant is prepared. The first homogenized suspension is added to the-solution of PVP K25, PEG200 or PEG400 and HFA-227 to form a second homogeneous suspension.
The resulting second suspension is then placed in a precrimped canister or other container suitable for use as a metered dose inhaler.
[0059] The present invention further provides a method for the treatment of bronchoconstriction, bronchospasm, asthma and related disorders thereof, coinprising administering to a patient in need thereof a stable aerosol formulation according to the present invention. Related disorders include, but are not limited to, clhronic obstructive puhnonary disease, chronic bronchitis and emphysema.
[0060] The formulation of the present invention may be administered one, two, three or four times per day with one or more activations, e.g. two, three or four activations, of the metering valve per administration to treat bronchoconstriction, astluna and related disorders thereof. Up to about twelve inhalations of the pharmaceutical formulation of the present invention may be administered per 24 hour period.
[0061] Suitably, each actuation of the metering valve delivers about 21 g of an anticholinergic agent, such as ipratropium bromide monohydrate and about 120 g of a beta-agonist agent, such as albuterol sulfate from the metered dose inhaler.
Suitably, each container or metered dose inhaler canister contains about 200 inhalations. As one skilled in the art is aware, the dose may be adjusted depending on the therapeutic objective of the use of the active agents and the age and condition of the patient.
[0062] We observed that some aerosol drugs tend to adhere to the inner surfaces, i.e., walls of the cans and valves, of the MDI. This can lead to the patient getting significantly less than the prescribed amount of the active agent upon each activation of the MDI. Coating the inner surface of the container with a suitable polynler can reduce this adhesion problem.
Suitable coatings iilclude, but are not limited to, fluorocarbon copolymers such as FEP-PES
(fluorinated ethylene propylene and polyethersulphone) and PFA-PES
(perfluoroalkoxyalkane and polyethersulphone), epoxy and ethylene.
[0063] Also, during storage, moisture can enter the MDI mainly tlu-ough the crimped area of the valve and through the stem by diffusion. To reduce the alnount of moisture entering the MDI, the metering valve is suitably comprised of a butyl elastomer.
[0064] It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without -departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
[0065] The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
Example 1 [0066] Formulations 1 to 18 listed below were prepared in the following manner.
[0067] The surfactant was dissolved in the cosolvent by sonication/homogenization for minutes. This solution was mixed for 10 - 25 minutes in a mixing vessel with approximately 10%-15% of the total amount of propellant required for the batch. If the surfactant was not used, only the cosolvent was mixed with the propellant.
[00681 The active agents were homogenized in a separate homogenizer with approximately 5-15% of the total amount of propellant required for the batch.
The homogenization speed and time ranged from 1000 - 1500 RPM for 15 to 30 minutes. The resulting homogenized suspension was transferred from the homogenizer to the mixing vessel through a double diaphragm pump. The remaining quantity of the propellant was then added to the mixing vessel.
[0069] The suspension was then mixed under constant stirring of 200 - 300 RPM
for not less than 20 minutes and kept under recirculation through the double diaphragm pump.
[0070] Forinulation 1 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Sorbitan Trioleate 0.00002% 0.00408 mg PEG 200 0.05% 10.2 mg HFA-227 20.4 gm [0071] Formulation 2 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Sorbitan Trioleate 0.00004% 0.00816 mg PEG 200 0.05% 10.2 mg HFA-227 20.4 gm [00721 Formulation 3 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Sorbitan Trioleate 0.05% 10.2 mg PEG 200 0.05% 10.2 mg HFA-227 20.4 gm [0073] Formulation 4 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.00001 % 0.00204 mg PEG 200 0.1 % 20.4 mg HFA-227 20.4 gm [0074] Formulation 5 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.00001% 0.00204 mg PEG 200 1% 204 mg HFA-227 20.2 gm [0075] Formulation 6 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.001% 0.204 mg PEG 200 0.3% 61.2 mg HFA-227 20.2 gm [0076] Fonnulation 7 Qtylcan Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 30 0.1% 20.41ng PEG 200 1% 204 mg HFA-227 20.2 gm [0077] Fonnulation 8 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVPK30 0.001% 0.204mg PEG2000.3% 61.2mg HFA-227 20.3 gm [0078] Formulation 9 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Oleic acid 0.001% 0.204 mg PEG200 1% 204 mg HFA-227 20.2 gm [0079] Formulation 10 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 ing Sorbitan Trioleate 0.00002% 0.00408 mg PEG 400 0.05% 10.2 mg HFA-227 20.4 gm [0080] Formulation 11 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuteol Sulfate 28.8 mg Sorbitan Trioleate 0.00004% 0.00816 mg PEG 400 0.05% 10.2 mg HFA-227 20.4 gm [0081] Formulation 12 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Sorbitan Trioleate 0.05% 10.2 mg PEG 400 0.05% 10.2 mg HFA-227 20.4 gm [0082] Fonnulation 13 Qty/can Ipratro ium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.00001 /a 0.00204 mg PEG 400 0.1 % 20.4 mg HFA-227 20.4 gm [0083] Formulation 14 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.00001% 0.00204 mg PEG 400 1% 204 mg HFA-227 20.2 gm [0084] Formulation 15 Qty/can Ipratro ium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 25 0.001% 0.204 mg PEG 400 0.3 % 61.2 mg HFA-227 20.2 gm [0085] Formulation 16 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K30 0.1% 20.4 mg PEG 400 1% 204 mg HFA-227 20.2 gm [0086] Formulation 17 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg PVP K 30 0.001% 0.204 mg PEG 400 0.3 % 61.2 mg HFA-227 20.3 gm [0087] Formulation 18 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Oleic acid 0.001 % 0.204 mg PEG400 1% 204 mg HFA-227 20.2 gm Example 2 [0088] Formulation 19 listed below was prepared in the following manner.
[0089] Polyoxyethylene sorbitan monolaurate (Tween 20) was dissolved in HFA
propellant to form a solution. The active ingredients were homogenized with additional HFA
propellant. The solution was then mixed with the homogenized suspension of active ingredients and HFA to form a second homogeneous suspension. The second suspension was then placed in a precrimped canister or other container suitable for use as an MDI. The formulation showed good stability.
[0090] Fomlulation 19 Qty/can Ipratropium Bromide monohydrate 5.04 mg Albuterol Sulfate 28.8 mg Tween 20 (0.05%) 10.2 mg HFA-227 20.4 gm Example 3 [0091] Formulations made according to the process described above in Example 1 were tested for stability. Stability was determined by analyzing the particle size of the active ingredients using microscopy. The results are shown below in Table 1.
[0092] Examples 1 to 4 exemplify prior art formulations. Exainples 5 to 7 exemplify the formulation of the present invention.
[0093] An increase in particle size in examples 1 to 4, indicated that the active ingredien.ts were not as stable in the prior art formulations compared to the stability of the active ingredients in the formulations of the present invention.
Table 1. Effect of different combinations of cosolvent and surfactant on the suspension characteristics and particle size of ipratropium bromide and albuterol sulfate.
Active Cosolvent Surfactant Propellant Suspension Particle size In redients characteristics observation 1 Ipratropium -- -- HFA Particles Agglomeration (5.04 mg) Propellant remain in Albuterol (P134a or homogeneous sulfate P227) suspension for (28.8 mg) less than 5 seconds.
2 lpratropium Alcohol -- HFA Particles 70% particles (5.04 mg) (1-5%) Propellant remain in between 10 to Albuterol (P134a or homogeneous 12.5 microns sulfate P227) suspension for (28.8 mg) about 10-15 seconds.
3 lpratropium Alcohol/ -- HFA Particles 85% particles (5.04 mg) Water Propellant remain in between 10 to Albuterol (1-5%) (P134a or homogeneous 12.5 microns sulfate P227) suspension for with (28.8 mg) about 10-15 agglomeration seconds.
4 lpratropium Alcohol Polyvinyl- HFA Particles 70% particles (5.04 mg) (1-5%) pyrrolidone Propellant remain in between 10 to Albuterol or sorbitan (P134a or homogeneous 12.5 microns sulfate trioleate or P227) suspension for (28.8 mg) oleic acid or about 10-15 citric acid or seconds.
polyoxy-ethylene(4) lauryl ether (0.02- 10%) lpratropium PEG200/ -- HFA Particles 90% particles (5.04 mg) 400 Propellant remain in below 2.5 Albuterol (0.05- (P134a or homogeneous microns &
sulfate 15%) P227) suspension for 10% between (28.8 mg) about 10-15 2.5 to 5 seconds. microns 6 Ipratropium PEG200/ Polyvinyl- HFA Particles 90% particles (5.04 mg) 400 pyrrolidone Propellant remain in below 2.5 Albuterol (0.05- or sorbitan (P134a or homogeneous microns &
sulfate 15%) trioleate or P227) suspension for 10% between (28.8 mg) oleic acid or about 10-15 2.5 to 5 citric acid or seconds. microns polyoxy-ethylene(4) lauryl ether (0.00001-10%) 7 lpratropium -- Polysorbate HFA Particles 90% pa.i-ticles (5.04 mg) 20 or Propellant remain in below 2.5 Albuterol Polysorbate (P134a or homogeneous microns &
sulfate 80 (0.01- P227) suspension for 10% between (28.8 mg) 0.05%) about 10-15 2.5 to 5 seconds. microns [0094] It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including,"
"comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
[0095] It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a propellant" includes a single propellant as well as two or more different propellants, reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.
Claims (32)
1. A pharmaceutical formulation comprising: an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof; a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof;
a cosolvent selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and isopropyl myristrate; and a hydrofluoroalkane propellant.
a cosolvent selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and isopropyl myristrate; and a hydrofluoroalkane propellant.
2. A formulation according to claim 1, wherein the formulation further comprises a surfactant.
3. A formulation according to claim 2, wherein the surfactant is selected from the group consisting of polyvinylpyrrolidone, sorbitan trioleate, oleic acid, citric acid, and polyoxyethylene(4)lauryl ether.
4. A formulation according to any preceding claim, wherein the anticholinergic agent is selected from ipratropium or tiotropium or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
5. A formulation according to claim 4, wherein the anticholinergic agent is ipratropium.
6. A formulation according to any preceding claim, wherein the beta-agonist is selected from the group consisting of albuterol, formoterol, levalbuterol, pirbuterol and salmeterol, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives; pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
7. A formulation according to claim 6, wherein the beta-agonist is albuterol.
8. A formulation according to any one of claims 1 to 3, wherein the anticholinergic agent, is ipratropium or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof and the beta-agonist is albuterol or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof.
9. A formulation according to any preceding claim, wherein the cosolvent is present in an amount of about 0.05% to about 15% of the total weight of the formulation.
10. A formulation according to claim 2, wherein the surfactant is present in an amount of about 0.00001% to about 10% of the total weight of the formulation.
11. A formulation according to any preceding claim, wherein the formulation is substantially free of alcohol.
12. A formulation according to any preceding claim, wherein the formulation is substantially free of water.
13. A formulation according to any one of claims 1 to 12, wherein the formulation contains less than about 0.1% water by weight of the formulation.
14. A formulation according to claim 1, comprising ipratropium bromide or its monohydrate, albuterol sulfate, about 0.05% to about 1% polyethylene glycol, about 0.00001% to about 0.1% polyvinylpyrrolidone, and a hydrofluoroalkane, propellant.
15. A pharmaceutical formulation comprising: an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof; a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof;
a polysorbate; and a hydrofluoroalkane propellant, wherein there is no cosolvent present in the formulation.
a polysorbate; and a hydrofluoroalkane propellant, wherein there is no cosolvent present in the formulation.
16. A formulation according to claim 15, wherein the polysorbate is selected from polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate; polyoxyethylene (20) sorbitan monooleate and polyoxyethylene (20) sorbitan monoisostearate.
17. A formulation according to claim 15 or 16, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate.
18. A formulation according to claim 15, 16 or 17, wherein the polysorbate is present in an amount of about 0.05% by weight of the formulation.
19. A method of making a pharmaceutical formulation comprising:
(a) mixing a hydrofluoroalkane propellant with a cosolvent to form a solution;
(b) forming a first homogenized suspension of an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof, a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative; pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof; and a hydrofluoroalkane propellant; and (c) adding the first homogenized suspension to the solution to form a second homogeneous suspension.
(a) mixing a hydrofluoroalkane propellant with a cosolvent to form a solution;
(b) forming a first homogenized suspension of an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof, a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative; pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof; and a hydrofluoroalkane propellant; and (c) adding the first homogenized suspension to the solution to form a second homogeneous suspension.
20. A method according to claim 19, wherein the cosolvent is selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and isopropyl myristrate.
21 21. A method according to claim 19 or 20, further comprising dissolving a surfactant in the cosolvent.
22. A method according to claim 21, wherein the surfactant is selected from the group consisting of polyvinylpyrrolidone, sorbitan trioleate, oleic acid, citric acid, and polyoxyethylene(4)lauryl ether.
23. A method of making a pharmaceutically formulation comprising:
(a) dissolving a polysorbate in a hydrofluoroalkane propellant to form a solution;
(b) forming a first homogenized suspension of an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof; a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof; and a hydrofluoroalkane propellant; and (c) adding the first homogenized suspension to the solution to form a second suspension.
(a) dissolving a polysorbate in a hydrofluoroalkane propellant to form a solution;
(b) forming a first homogenized suspension of an anticholinergic agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof; a beta-agonist agent or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph or pharmaceutically acceptable prodrug thereof; and a hydrofluoroalkane propellant; and (c) adding the first homogenized suspension to the solution to form a second suspension.
24. A method according to claim 23, wherein the polysorbate is selected from polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate and polyoxyethylene (20) sorbitan monoisostearate.
25. A method according to claim 23 or 24, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate
26. A metered dose inhaler comprising a formulation according to, any one of claims 1 to 18, and a canister coated with a polymer.
27. A metered dose inhaler according to claim 26, wherein the polymer is selected from the group consisting of a fluorocarbon polymer, an epoxy copolymer, and an ethylene copolymer.
28. A metered dose inhaler according to claim 26 or 27, further comprising a sealing gasket.
29. A metered dose inhaler according to claim 28, wherein the sealing gasket comprises a butyl elastomer.
30. A method of treating bronchoconstriction, bronchospasm, asthma and related disorders comprising administering an effective amount of a formulation according to any one of claims 1 to 18 to patient in need thereof.
31. Use of a formulation according to any one of claims 1 to 18 in medicine.
32. Use of a formulation according to any one of claims 1 to 18 in the manufacture of a medicament for treating bronchoconstriction, bronchospasm, asthma and related disorders.
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| ME00220B (en) * | 2000-05-22 | 2010-10-10 | Chiesi Farm Spa | Stable pharmaceutical solution formulations for pressurised metered dose inhalers |
| GB0106046D0 (en) * | 2001-03-12 | 2001-05-02 | Glaxo Group Ltd | Canister |
| US20030018019A1 (en) * | 2001-06-23 | 2003-01-23 | Boehringer Ingelheim Pharma Kg | Pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics |
| EP2319584A1 (en) * | 2002-08-29 | 2011-05-11 | Cipla Ltd. | Pharmaceutical products and compositions comprising salmeterol, ciclesonide and tiotropium |
| 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 |
| US20060079544A1 (en) * | 2004-08-13 | 2006-04-13 | Boehringer Ingelheim International Gmbh | Medicaments for the prevention or treatment of alveolar pneumonia comprising an anticholinergic |
| CA2580019A1 (en) * | 2004-09-09 | 2006-03-16 | Cipla Limited | Pharmaceutical composition comprising an isomer of a betamimetic agent and an anti-cholinergic agent |
-
2006
- 2006-09-21 US US11/533,857 patent/US20070286814A1/en not_active Abandoned
-
2007
- 2007-06-11 CL CL200701686A patent/CL2007001686A1/en unknown
- 2007-06-11 PE PE2007000733A patent/PE20080204A1/en not_active Application Discontinuation
- 2007-06-12 US US12/304,363 patent/US20090191134A1/en not_active Abandoned
- 2007-06-12 CA CA002654041A patent/CA2654041A1/en not_active Abandoned
- 2007-06-12 EP EP07733191A patent/EP2040670A1/en not_active Withdrawn
- 2007-06-12 KR KR1020097000418A patent/KR20090033355A/en not_active Application Discontinuation
- 2007-06-12 MX MX2008015589A patent/MX2008015589A/en not_active Application Discontinuation
- 2007-06-12 RU RU2009100156/15A patent/RU2009100156A/en not_active Application Discontinuation
- 2007-06-12 AU AU2007259064A patent/AU2007259064A1/en not_active Abandoned
- 2007-06-12 JP JP2009514892A patent/JP2009539958A/en active Pending
- 2007-06-12 ZA ZA200810142A patent/ZA200810142B/en unknown
- 2007-06-12 BR BRPI0711688-8A patent/BRPI0711688A2/en not_active IP Right Cessation
- 2007-06-12 WO PCT/GB2007/002183 patent/WO2007144604A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200810142B (en) | 2009-11-25 |
| KR20090033355A (en) | 2009-04-02 |
| AU2007259064A1 (en) | 2007-12-21 |
| EP2040670A1 (en) | 2009-04-01 |
| WO2007144604A1 (en) | 2007-12-21 |
| RU2009100156A (en) | 2010-07-20 |
| JP2009539958A (en) | 2009-11-19 |
| MX2008015589A (en) | 2009-03-20 |
| US20070286814A1 (en) | 2007-12-13 |
| BRPI0711688A2 (en) | 2012-01-17 |
| US20090191134A1 (en) | 2009-07-30 |
| CL2007001686A1 (en) | 2008-03-14 |
| PE20080204A1 (en) | 2008-04-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20130612 |