MX2011004730A - Pharmaceutical aerosol composition. - Google Patents
Pharmaceutical aerosol composition.Info
- Publication number
- MX2011004730A MX2011004730A MX2011004730A MX2011004730A MX2011004730A MX 2011004730 A MX2011004730 A MX 2011004730A MX 2011004730 A MX2011004730 A MX 2011004730A MX 2011004730 A MX2011004730 A MX 2011004730A MX 2011004730 A MX2011004730 A MX 2011004730A
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- Prior art keywords
- pharmaceutical composition
- aerosol
- composition according
- adjuvant
- aerosol pharmaceutical
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Classifications
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
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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
-
- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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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
- A61K31/33—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
- 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]
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Abstract
A pharmaceutical aerosol composition comprising at least one hydrofluoroalkane propellant; at least one active agent complexed with an adjuvant; and, optionally, at least one pharmaceutically acceptable excipient.
Description
PHARMACEUTICAL COMPOSITION IN AEROSOL
Field of the Invention
The present invention relates to an aerosol pharmaceutical composition. In particular, the present invention relates to a stable aerosol pharmaceutical composition, its manufacturing process and its use for the treatment of respiratory disorders.
Background of the Invention
The metered dose inhalers (MDIs) are, at present, the most efficient and best accepted means to supply exactly drugs in small doses to the human respiratory tract. Therapeutic agents commonly provided by the inhalation route include bronchodilators (2-β and anticholinergic agonists), corticosteroids, and anti-allergics. Inhalation may also be a viable route for anti-ineffective, vaccination, systemically acting and diagnostic agents, as well as anti-leukotrienes and anti-proteases.
The MDIs comprise a pressure resistant container typically filled with a product such as a drug dissolved in a liquefied propellant or micronized particles suspended in a liquefied propellant where the container is fitted with a metering valve. The actuation of the metering valve allows a small portion of the
REF .: 219948
The atomized product is released by means of which the pressure of the liquefied propellant carries the micronized or dissolved drug particles out of the container to the patient. The valve actuator is used to direct the aerosol atomizer in the patient's oropharynx.
Chlorofluorocarbons (CFCs) have been used extensively as propellants in drug formulations that are delivered to patients via a metered dose inhaler (MDI). However, recent scientific evidence suggests that CFCs damage the Earth's ozone layer. It is believed that ozone blocks harmful ultraviolet rays and that the depletion of the ozone layer will result in the incidence of skin cancer. As a result, CFCs are now being gradually replaced by hydrofluorocarbons or HFAs (names will be used interchangeably herein), (e.g., HFA 134a and HFA 227) as the preferred MDI propellants.
The HFA 134a propellants, or 1,1,1,2-tetrafluoroethane (the names will be used interchangeably herein), are non-flammable, have low toxicity and have adequate vapor pressure for use in aerosols.
However, HFA 134a is a very poor solvent that does not adequately dissolve or disperse commonly used surfactants such as sorbitan trioleate,
sorbitan monooleate, lecithins and oleic acid in useful concentrations without the aid of a co-solvent.
Similarly, the HFA 227 propellant, or 1, 1, 1, 2, 3, 3, 3 -heptafluropropane (the names will be used interchangeably herein) is non-flammable, has low toxicity and has a vapor pressure suitable for use in aerosols. However, the polarity and solubility of HFA 227 differs from those of commonly used CFC propellants, and many commonly used surfactants are not soluble or sparingly dispersible in HFA 227.
US5182097 relates to aerosol formulations consisting of 1,1,1,2-tetrafluoroethane, a drug and oleic acid as a surfactant to aid in the dispersion of the drug in the propellant.
US5612053 relates to respirable dry powder formulations comprising controlled release particles of a cohesive compound of a drug and a carrier, wherein the carrier is a natural polysaccharide gum added as a reillifier.
EP0384371 discloses aerosols in which 1, 1, 1, 2, 3, 3, 3 -heptafluoropropane or its mixture with propane, butane, isobutane, dimethyl ether, or 1,1, difluoroethane serves as the propellant. The application does not disclose, however, suspension aerosols or aerosol pharmaceutical formulation.
W093 / 11747 discloses a suspension pharmaceutical formulation suitable for aerosol administration, consisting essentially of a therapeutically effective amount of a drug and a propellant selected from the group consisting of HFA 134a, HFA 227, and a mixture thereof. The application specifically discloses formulations of Formoterol Fumarate in HFA 134a, HFA 227 and 1: 1 mixtures of HFA 134a and HFA 227. The formulations do not contain surfactants or ethanol. It is stated that mixtures of HFA 134a and HFA 227 can be adjusted for density equalization with the drug.
W093 / 11745 discloses aerosol pharmaceutical formulations, substantially free of surfactants containing chlorofluorocarbon propellants containing hydrogen or fluorocarbon and up to 5% of a polar co-solvent. Preferred propellants are HFA 134a and HFA 227 which are preferably used alone. The preferred polar co-solvent is ethanol and it is stated that in general, only small amounts for example, 0.05 to 3.0% w / w polar co-solvent are required to improve dispersion and the use of amounts in excess of 5% p / p can be disadvantageously tending to dissolve the medicament.
A number of aerosol medicinal formulations using HFA propellant systems are described in, for example, EP0372777, W091 / 11173, and W091 / 14422.
These applications are all well related to the preparation of pressurized aerosols for the administration of medicines. All applications propose the addition of one or more adjuvants such as alcohols, alénes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfactants, carboxylic acids, polyethoxylates, etc.) and even conventional chlorofluorocarbon propellants in small amounts proposed to minimize the potential ozone damage, but have not been able to establish any unexpected advantage.
US6303103 discloses a pharmaceutical aerosol formulation which comprises salbutamol particles and an anticholinergic medicament or physiologically acceptable salts and solvates thereof, a chlorofluorocarbon propellant containing hydrogen or fluorocarbon and substantially free of, or containing less than 0.0001% of surfactant by weight of the drug. However, to support the claimed invention, there is no explicit demonstration by means of examples or some data from stability studies.
Attempts have been made to coat drugs with only surfactants or preferably, but the results have not been very satisfactory.
WO91 / 04011 discloses a self-propelling powder aerosol composition containing drug
pre-micronized, finely divided solid, coated with a single non-perfluorinated surface active dispersing agent suspended in an aerosol propellant in which the dispersing agent is substantially insoluble.
PCT / GB2008 / 002029 disclose a formulation comprising tiotropium bromide coated with polyvinylpyrrolidone. This coating process suffers from the disadvantage that it requires multiple processing steps and can cause increasing difficulties due to excessive atomization and lack of uniformity.
The description of all these patents and patent applications is incorporated herein by reference.
The majority of the prior art suggests the use of surfactants. However, the use of surfactants may not be feasible for all drugs because considerable difficulties have been encountered in finding suitable suspending agents or surfactants which are soluble in hydrofluoroalkanes and capable of stabilizing drug suspensions. Also, with the additional incorporation of excipients together with the surfactants, the formulation can be destabilized.
Since HFAs are more polar and more hygroscopic than CFCs, water ingress is more significantly found in HFA MDIs, and which
they are also worsened by the use of water miscible cosolvents, polar, such as alcohol. The above phenomenon could also be influenced by the nature of the drug substance or other excipients present in the formulation. The environmental humidity diffuses in MDIs through the valve packages and adversely affects the physical stability of the MDI formulation promoting the growth and aggregation of the drug particle. The aggregation of drug particles can clog the valve orifice of the aerosol container by providing the inoperative dispensing device, or if a metering valve is employed, it can be to provide the inaccurate dosage which, in the case of highly potent drugs, can lead to undesirable results. In addition to increasing the particle size and obstruction holes, agglomeration can make the suspension physically unstable, an obviously undesirable result particularly in the case of aerosolized formulations.
Therefore, a need remains to provide a way to solve the problem of fine particle aggregation of drug and to provide a stable aerosol composition using hydrofluorocarbon propellants.
Brief Description of the Invention
The object of the present invention is to provide
a stable aerosol pharmaceutical composition.
Another object of the present invention is to provide a pharmaceutical aerosol composition wherein the fine particles of drug are not added during storage.
Still another object of the present invention is to provide a simple process for manufacturing the aerosol pharmaceutical composition according to the present invention.
Yet another object of the present invention is to provide an aerosol pharmaceutical composition with dose uniformity over the life of the can.
A further object of the present invention is to provide a pharmaceutical aerosol composition for use in the treatment of mild, moderate or severe chronic or acute symptoms or for prophylactic treatment of respiratory disorders.
In accordance with a first aspect of the present invention; A stable aerosol pharmaceutical composition comprising one or more HFA propellants and at least one active complex with an adjuvant is provided; and, optionally, one or more pharmaceutically acceptable excipients.
In accordance with a second aspect of the present invention; a composition is provided
stable aerosol pharmaceutical comprising at least one active complex with an adjuvant; one or more HFA propellants; and at least one other pharmaceutically acceptable excipient, such as at least one bulking agent and / or co-solvent.
In accordance with a third aspect of the present invention; A process for manufacturing the stable aerosol pharmaceutical composition is provided.
In accordance with a fourth aspect of the present invention; A pharmaceutical aerosol composition is provided for use in the treatment of mild, moderate or severe chronic or acute symptoms, or for the prophylactic treatment of respiratory disorders such as asthma.
Detailed description of the invention
As discussed above, there is a need to provide a new way to solve the problem of aggregation of fine particles of drug of aerosol composition and which remains stable during storage.
Surprisingly, the inventors have found that when the drug-adjuvant complex is used in the manufacture of the aerosol composition, the aggregation of fine particles of drug is significantly reduced which provides the composition stable during the storage period.
The inventors further note that the dispersion of surfactant in the pharmaceutical composition in aerosol with
Other pharmaceutically acceptable excipients provide the composition unstable during storage. In particular it was observed that the mass of fine particles does not remain the same or is reduced in a timely manner during storage. But, it was surprisingly found that when the drug was complexed with an adjuvant such as PVP K25, PVP K17 or PVP K30 etc., together with the addition of propellant (s) or optionally with one or more volume agents and / or co-solvent (s), the aggregation of fine particles of drug was significantly reduced and therefore keeps the composition stable during the storage period. It was also found that the composition continues to exhibit uniform delivered dose characteristics throughout the life of the MDI.
The present invention provides a pharmaceutical composition in aerosol. More specifically, the aerosol pharmaceutical composition comprises at least one complex of active pharmaceutical agent with an adjuvant, at least one hydrofluoroalkane (HFA) propellant and optionally other suitable excipients such as one or more bulking agent (s) and / or -solvent (s).
In a particularly advantageous embodiment, the adjuvant is a polymer, preferably a polyvinylpyrrolidone (PVP and other commercially available grades such as PVP K12, PVP K15, PVP K17, PVP K25,
PVP K30, PVP K60, PVP K90), preferably having a molecular weight ranging from PVP 2500 to PVP 1,200,000, preferably PVP 2500 to PVP 1,000,000. It has been found that when such polymers are complexed with drugs, they provide good quality aerosol pharmaceutical suspensions.
The term "adjuvant" is used throughout the description in a broad sense to include not only polyvinylpyrrolidone (PVP) and its other commercially available grades such as PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, but also suitable water-soluble and water-insoluble polymers or mixtures thereof, cyclodextrins, polyethylene glycols (for example, PEG 4000 and PEG 6000) and surfactants such as sorbitan trioleate, sorbitan monooleate, polysorbate, for example, polysorbate 20, 40, 60, 80, 120, lipids, lecithin, oleic acid, citric acid and polyoxyethylene lauryl ether (for example, Brij 30).
Water-soluble polymers that can be used as an adjuvant, in accordance with the present invention, comprise homopolymers and co-polymers of N-vinyl lactams, especially homopolymers and co-polymers of N-vinyl pyrrolidone for example, polyvinylpyrrolidone (PVP ), PVP and vinyl acetate copolymers, co-polymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, dextrins
such as maltodextrin grades, cellulose ethers and cellulose ethers, high molecular weight polyalkylene oxides such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide and propylene oxide and the like.
Water-insoluble polymers that can be used as an adjuvant, in accordance with the present invention, comprise acrylic copolymers for example, Eudragit E100 or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL30D, Eudragit RS30D, Eudragit NE30D, Acryl-Eze; polyvinyl acetate, for example, Kollicoat SR 30D; cellulose derivatives such as ethyl cellulose, cellulose acetate and the like.
In accordance with the present invention, the amount of adjuvant in the drug-adjuvant complex ranges from 0.5% to 500% by weight of the drug, preferably from 0.5% to 100% by weight of the drug. Suitable amounts of the adjuvant are 0.5%, 1%, 2%, 10%, 50% and 100% by weight of the drug.
The adjuvant drug is in particles (micronized form). Preferably the particle size is such as to allow substantially all particles to be potentially available for inhalation in the lungs after administration of the aerosol composition. Thus, for example, it is preferred that at least 90%, more preferably at least 95% by weight of the particles have
a diameter of less than 15 micrometers, preferably from 0.5 to 15 micrometers, more preferably from 0.5 to 10 micrometers, and most preferably from 0.5 to 5 micrometers. Most preferably at least 95% by weight of the particles have a diameter from 0.5 to 5 microns.
In accordance with the invention, drugs which can be complexed in aerosol compositions include any drug useful in inhalation therapy known to a person skilled in the art, which comprises one or more of the following for example, analgesics, example, codeine, dihydromorphine, ergotamine, fentanyl or morphine; preparations for angina, for example, diltiazem; antiallergics, for example, cromoglycate, ketotifen or nedocromil; anti-infectives for example, cephalosporins, penicillins, streptomycin, sulfonamides, tetracyclines and pentamidine; antihistamines, for example, metapyrylene; anti-inflammatory, for example, beclomethasone, flunisolide, budesonide, tipredane, triamcinolone acetonide, or fluticasone, - corticosteroids for example, budesonide, ciclesonide, fluticasone, betamethasone, beclomethasone, thixocortol, formocortol, rimexolone, prednisolone, methylprednisolone, deflazacort, prednisone, cortisone, dexamethasone, hrocortisone; antitussives, for example, noscapine; bronchodilators, for example, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline,
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metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutaline, isoetarin, tulobuterol, orciprenaline, or (-) 4-amino-3, 5-dichloro- .alpha. - [[[6- [2- (2-pyridinyl) ethoxy] hexyl] amino] methyl] benzenemethanol; diuretics, for example, amiloride; anticholinergics for example, tiotropium, ipratropium, aclidinium, atropine or oxitropium; hormones, for example, cortisone, hydrocortisone or prednisolone; xanthines for example, aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides, for example, insulin or glucagon or pharmaceutically acceptable salts thereof.
It will be appreciated by a person skilled in the art that the drugs may be used in the form of their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs, prodrugs of the same pharmaceutically acceptable to optimize the activity and / or stability of the composition.
Particularly preferred drugs for complex formation in aerosol composition, according to the invention, include antiallergics, anticholinergics, bronchodilators and corticosteroids for example salbutamol,
Beclomethasone, ipratropium, formoterol, tiotropium, aclidinium, salmeterol, fluticasone, budesonide, fenoterol, ciclesonide, mometasone, or their pharmaceutically acceptable salts are especially preferred.
The terms "bronchodilators" or
"corticosteroids" and the like are used broadly to include not only the beta-agonist or anticholinergic agents or corticosteroids per se, but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable enantiomers, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs.
Where appropriate, the following salts of the drugs mentioned above can be used; acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisilate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate diphosphate,
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polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, and triethiodide.
Useful betamimetic agents in the composition of the present invention include, but are not limited to, salbutamol, formoterol, levalbuterol, carmoterol, pirbuterol and salmeterol. Suitable pharmaceutically acceptable salts of the betamimetics include, but are not limited to, the hydrochloride, sulfate, maleate, tartrate and citrate salts. Preferably, the betamimetic agent is selected from salbutamol, salbutamol sulfate, levosalbutamol, levosalbutamol sulfate or levosalbutamol tartrate.
Anticholinergic agents useful in the composition of the present invention include, but are not limited to, oxitropium, ipratropium, aclidinium and tiotropium. Suitable pharmaceutically acceptable salts of the anticholinergic agents include, but are not limited to, the halide salts such as bromide, chloride or iodide. Preferably, the anticholinergic agent is tiotropium or tiotropium bromide or tiotropium bromide monohydrate.
A preferred aerosol pharmaceutical composition according to the present invention comprises: (a) an effective amount of at least one drug formed in complex with an adjuvant; (b) at least one hydrofluorocarbon propellant; and (c) optionally, at least one pharmaceutically acceptable excipient that includes one or more
volume agent (s) and / or co-solvent (s).
In a particularly preferred embodiment of the present invention, there is provided a stable aerosol pharmaceutical composition comprising: (a) an effective amount of at least one active pharmaceutical selected from tiotropium, aclidinium, ipratropium, levosalbutamol or a pharmaceutically acceptable salt thereof formed in complex with PVP K17 or PVP K30; (b) at least one hydrofluorocarbon propellant and (c) optionally at least one bulking agent (s) such as lactose and / or co-solvent (s) such as polyethylene glycol 400 (PEG 400) with other pharmaceutically acceptable excipients.
It will be appreciated by those skilled in the art that the aerosol composition according to the present invention can, if desired, comprise a combination of two or more drugs. Accordingly, the present invention further provides an aerosol composition comprising two or more drugs, wherein at least one drug is complexed with the adjuvant together with one or more optional pharmaceutically acceptable excipients.
Preferably, the aerosol pharmaceutical composition comprises bronchodilators such as tiotropium (e.g., as the bromide salt), salbutamol (e.g., as the free base or as the sulfate salt), levosalbutamol (e.g., as the sulfate salt) ), salmeterol (for
example, as the xinafoate salt), aclidinium, isoprenaline or its pharmaceutically acceptable salts or bronchodilator (s) in combination with one or more corticosteroid (s) such as a beclomethasone ester (eg, diproprionate), budesonide or an ester of fluticasone (e.g., propionate) or its other pharmaceutically acceptable salts, wherein at least one drug is complexed with the adjuvant.
Alternatively, the aerosol compositions may comprise a bronchodilator in combination with an antiallergic such as cromoglycate (eg, the sodium salt). Examples of such combinations include isoprenaline and sodium cromoglycate; salmeterol and fluticasone propionate; or salbutamol and beclomethasone dipropionate and the like.
In accordance with another aspect of the invention there is provided a pharmaceutical aerosol dispenser comprising a can having a chamber containing an aerosol pharmaceutical composition in accordance with the present invention; an outlet for delivering the aerosolized pharmaceutical composition to a patient in need thereof; and a valve for controlling the flow of the aerosolized pharmaceutical composition from the chamber to the outlet. Preferably the can is made of metal, glass or plastic materials such as polysulfone plastics
for example polysulfone (PSU) and polyethersulfone (PES). Preferably the pharmaceutical aerosol device is an MDI.
The present invention further provides a process for manufacturing a pharmaceutical aerosol dispenser for delivering the aerosol pharmaceutical formulation to a patient in need thereof, comprising:
(a) weigh the drug particles formed in complex in a suitable metal can,
(b) optionally mixing the drug particles formed in complex with one or more suitable excipients selected from co-solvents, bulking agents, antioxidants, lubricants and optionally with one or more surfactants or with other drugs similarly formed in complex or not formed in complex,
(c) crimping the can with a suitable valve and loading it with HFA propellant.
In another aspect, the present invention provides a process for manufacturing a complex of an active agent and an adjuvant comprising:
(a) mixing the active agent in an organic solvent (eg, acetone),
(b) heating the mixture of step (a) to a suitable temperature and adding water to form a clear solution;
(c) adding the adjuvant to the previous solution of step (b);
(d) concentrating the clear solution under reduced pressure, preferably under vacuum, to form a residue;
(e), washing the residue with the same solvent used in step (a); Y
(f) drying (for example at suitable temperature, or preferably at 50 ° C) the washed residue from step (e) to form a drug-adjuvant complex.
The solvent used in the above process can be selected from acetonitrile, methanol, water, dimethyl formamide, acetone, tetrahydrofuran, dimethyl sulfoxide. The most preferable solvent is acetone. .
Alternatively, the complex of an active agent and an adjuvant can be isolated by lyophilization or by flash evaporation of the solvent using suitable techniques known in the art such as spray drying. The technique of instantaneous evaporation with respect to the present invention means removal of the solvent by applying heat and vacuum.
The active agent used in the process for preparing the complex with an adjuvant according to the present invention may be in amorphous, crystalline, monohydrate or anhydrous form or a derivative or a polymorph or a
prodrug of it.
The aerosol pharmaceutical composition according to the present invention may optionally contain one or more excipients or carriers conventionally used in the pharmaceutical aerosol formulation technique. Such optional excipients include, but are not limited to, flavor masking agents, buffers, antioxidants, water and chemical stabilizers.
Examples of suitable bulking agents include, but are not limited to, one or more of saccharides such as monosaccharides, disaccharides, polysaccharides and sugar alcohols such as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches. , dextran or mannitol. The bulking agent can be present in a concentration of 0.005-500%, more preferably in a range of 0.005-300% by weight of the complex. The preferred volume agent is Lactose.
Examples of cosolvents include, but are not limited to, one or more of polyethylene glycol ("PEG"), propylene glycol, isopropyl myristate or glycerol. Suitably, the cosolvent is PEG, such as PEG 200 or PEG 400. The cosolvent may be present in a range of about 0.05% to about 15% by weight of the composition. Suitably, the cosolvent is present in a range of from about 0.05% up to about 1% or
about 0.05% to about 0.3% by weight of the composition.
The present invention may optionally comprise antioxidants such as citric acid, benzalkonium chloride.
As discussed above, aerosol compositions traditionally contain CFC propellants. Due to environmental concerns, HFA propellants are now preferred over CFC propellants. As will be understood by those skilled in the art, HFA propellants suitable 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). Optionally, mixtures of two or more such halogen-substituted hydrocarbons can also be used.
The invention is particularly useful in that it makes it possible to achieve stable pharmaceutically acceptable dispersions using HFA propellants such as the aerosol propellant. The aerosol compositions of the invention can be prepared with HFA propellant alone or a mixture of HFA propellant and another miscible adjuvant having a polarity equal to or less than the polarity of the HFA propellant.
In a further aspect, the present invention provides an aerosolized pharmaceutical composition of
according to the present invention for use in the treatment of mild, moderate or severe chronic or acute symptoms, or for the prophylactic treatment, of a respiratory disorder, such as asthma.
In a preferred embodiment, the present invention provides the use of the aerosolized pharmaceutical composition according to the present invention in the manufacture of a medicament for the treatment of mild, moderate or severe chronic or acute symptoms, or for the prophylactic treatment of a respiratory disorder, such as asthma.
In another preferred embodiment, there is provided a method of treating mild, moderate or severe chronic or acute symptoms, or for the prophylactic treatment, of a respiratory disorder, such as asthma, which comprises administering a therapeutically effective amount of an aerosol pharmaceutical composition. in accordance with the present invention to a patient in need thereof.
The following examples are for purposes of illustration of the invention only and are not proposed in any way to limit the scope of the present invention. Eg emplos:
Process to prepare the complex of tiotropium bromide-PVP
1) 5 g of tiotropium bromide were introduced into a reaction vessel. Acetone was added. The mixture of
The reaction was heated to a temperature of 50-55 ° C. Additional water (15 ml) was added to the reaction mixture to give a clear solution. To this solution was added 2.5 g of PVP-K-17. The solution was concentrated under vacuum to give a residue. The residue was washed with acetone (15 ml) and dried under vacuum at 50 ° C to give the title compound (6 g).
2) 5 g of tiotropium bromide were introduced into a reaction vessel. Water (15 ml) was added to the reaction mixture to give a clear solution. To this solution was added 2.5 g of PVP-K-17. The solution was concentrated under vacuum to give a residue. The residue was washed with acetone (15 ml) and dried under vacuum at 50 ° C to give the title complex (6 g).
3) tiotropium bromide-PVP complex formed by lyophilization
5 g of tiotropium bromide and 2.5 g of polyvinylpyrrolidone (PVP) were stirred in 50 ml of water at 25-30 ° C until dissolved. The solution was quickly frozen in a dry ice bath. The solution was lyophilized at a condenser temperature of about 0 ° C in the presence of high vacuum. The resulting title complex was obtained in the form of a solid (5.8 g).
4) Tiotropium Bromide-PVP Evaporated Formation Complex
2. 5 g of tiotropium bromide and 1.25 g of
Polyvinylpyrrolidone (PVP) were stirred in 10 ml of ethanol at 25-30 ° C until dissolved. The solution was poured into a polyethylene tray and the ethanol was evaporated in a vacuum oven in the presence of a stream of nitrogen. The product was isolated from the resulting dry solid title (2.5 g).
5) tiotropium bromide-PVP Complex formed by spray drying
2. 5 g of tiotropium bromide were dissolved in 25 ml of methanol. 1.25 g of PVP were dissolved in methanol (15 ml). Both solutions were mixed and spray dried. The parameters used for the manufacture of the drug-adjuvant complex are as follows:
Instrument - Labultima LU-222 ADVANCE SPRAY DRYER Temperature - 50-55 ° C
Vacuum - 40mm WC
Pressure of N2 -1-2 kg
Feed speed - 3ml / min.
The solid product was collected in a collector (2.0
9) ·
Examples of Aerosol Pharmaceutical Composition:
Composition 1: Aerosol pharmaceutical composition containing Tiotropium-PVP Complex (0.5%), co-solvent and HFA propellant.
2
Process:
(a) The active ingredient was added to the can.
(b) The can was crimped with the metering valve and loaded with the propellant and PEG solution.
Composition 2: Aerosol pharmaceutical composition containing Tiotropium-PVP Complex (100%), co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the can.
(b) The can was crimped with the metering valve and loaded with the propellant and PEG solution.
Composition 3: Pharmaceutical composition in aerosol containing Tiotropium-PVP Complex (0.5%) and propellant of
HFA
Ingredients Amount / can
1.8 mg Monohydrate Complex
tiotropium or PVP-anhydrous (0.5%)
HFA-227 C.S.
Process:
(a) The active ingredient was added to the can.
(b) The can was crimped with the metering valve.
(c) The can was loaded with HFA227.
Composition 4: Aerosol pharmaceutical composition containing ipratropium-PVP Bromide Complex (0.5%) and HFA propellant.
Process:
(a) The active ingredient was added to the can.
(b) The can was crimped with the dosing valve. (c) The can was loaded with HFA227.
Composition 5: Aerosol pharmaceutical composition containing Tiotropium-PVP Complex (100%) and HFA propellant.
Process:
(a) The active ingredient was added to the can.
(b) The can was crimped with the metering valve. (c) The can was loaded with HFA227.
Composition 6: Aerosol pharmaceutical composition containing Tiotropium-PVP Complex (0.5%), volume agent, co-solvent and HFA propellant.
Process:
(a) The active ingredient to the can.
(b) Lactose was added to (a).
(c) The can was crimped with the metering valve and loaded with propellant.
Composition 7: Aerosol pharmaceutical composition containing levosalbutamol Sulphate-PVP Complex (0.5%), volume agent and HFA propellant.
Process:
(a) The active ingredient to the can.
(b) Lactose was added to (a).
(c) The can was crimped with the metering valve and loaded with propellant.
Composition 8: Pharmaceutical composition in aerosol
containing Levosalbutamol Tartrate Complex -PVP (0.5%), volume agent and HFA propellant.
Process:
(a) The active ingredient to the can.
(b) Lactose was added to (a).
(c) The can was crimped with the metering valve and loaded with propellant.
Composition 9: Aerosol pharmaceutical composition containing Tiotropium-PVP Complex (0.5%), volume agent, co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the can.
(b) Lactose was added to (a).
(c) The can was crimped with the metering valve and loaded with the propellant and PEG solution.
Composition 10: Pharmaceutical composition in aerosol containing Tiotropium-PVP Complex (0.5%), agent of
volume, co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the can.
(b) Lactose was added to (a).
(c) The can was crimped with the metering valve and loaded with the propellant solution and
PEG.
Composition 11: Aerosol pharmaceutical composition containing Tiotropium-PVP Complex (0.5%), volume agent, co-solvent and HFA propellant.
Process:
(a) The active ingredient was added to the can.
(b) Lactose was added to (a).
(c) The can was crimped with the metering valve and loaded with the propellant and PEG solution.
Composition 12:
Process:
(a) The active ingredients were added to the can.
(b) The can was crimped with the metering valve. (c) The can was loaded with HFA227.
Composition 13:
Process:
(a) The active ingredient is added to the can.
(b) The can was crimped with the metering valve.
(c) The can was loaded with HFA227.
Composition 14:
Process:
(a) The active ingredients were added to the can.
(b) The can was crimped with the dosing valve. (c) The can was loaded with HFA227.
Composition 15:
Process:
(a) The active ingredients were added to the can.
(b) The can was crimped with the dosing valve.
(c) The can was loaded with HFA227.
Composition 16:
Process:
(a) The active ingredients were added to the can.
(b) The can was crimped with the metering valve and the can was loaded with the propellant and PEG solution.
Stability study data of aerosol pharmaceutical composition comprising drug-adjuvant complex and
HFA:
An accelerated stability study was carried out comparing the following three different series of compositions (1) drug and HFA propellant; (2) drug-adjuvant complex and HFA propellant; and (3) drug, co-solvent, surfactant, bulking agent and HFA propellant.
Composition Ingredients Cnt / Tin Results Mass No. (mg) Particle
Fine (meg)
6 months,
40 ° C 4.1
Complex of
3 monohydrate 1.8 Initial 4.0
of bromide
tiotropium- PVP-K-25
(0.5%)
HFA 227 C.S. 3 months,
40 ° C 4.2
6 months, 4.1
40 ° C
Initial Monohydrate
Bromide 4, 1.8 3.9
tiotropium
PEG 400 0.3% 3 months,
40 ° C 3.9
PVP-K-25 0.001% 6 months,
HFA 227 C.S. 40 ° C 4.5
It was found that the aerosol composition containing the drug-adjuvant complex exhibits consistent fine particle size during the study when stored at accelerated stability conditions.
It will be readily apparent to one skilled in the art that various substitutions and modifications may be made to the invention described herein without departing from the scope of the invention. Thus, it should be understood that although the present invention has been specifically described by the preferred embodiments and optional features, the modification and variation of
5
the concepts described herein can be restored by those skilled in the art, and such modifications and variations are considered to fall within the scope of the invention.
It should be understood that the phraseology and terminology used here is for the purpose of description and should not be considered as limiting. The use of "including," "comprising," or "having" and variations therein means encompassing the items listed after those and their equivalents as well as additional items.
It should be noted that, as used in this specification and appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a propeller" includes a single propeller as well as two or more different propellers; the reference to a "cosolvent" refers to a single cosolvent or combinations of two or more cosolvents, and the like.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (25)
1. A pharmaceutical aerosol composition characterized in that it comprises at least one hydrofluoroalkane (HFA) propellant; at least one active agent formed in complex with an adjuvant; and, optionally, one or more pharmaceutically acceptable excipients.
2. An aerosol pharmaceutical composition according to claim 1, characterized in that the adjuvant is selected from polymer; cyclodextrins, polyethylene glycols, lipids, citric acid, and surfactants such as sorbitan trioleate, sorbitan monooleate, polysorbates, lecithin, oleic acid, polyoxyethylene lauryl ether, or mixtures thereof.
3. An aerosol pharmaceutical composition according to claim 2, characterized in that the adjuvant is a polymer.
4. An aerosol pharmaceutical composition according to claim 3, characterized in that the polymer is a water soluble polymer, a water insoluble polymer; or a mixture of them.
5. An aerosol pharmaceutical composition according to claim 4, characterized in that the Water soluble polymer comprises polyvinylpyrrolidone, homopolymers and co-polymers of N-vinyl lactams such as homopolymers and co-polymers of N-vinyl pyrrolidone, co-polymers of polyvinyl pyrrolidone and vinyl acetate, co-polymers of N-vinyl pyrrolidone and vinyl acetate or vinyl propionate, dextrins such as maltodextrin grades, cellulose esters and cellulose ethers, polyalkylene oxides of high molecular weight such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide and propylene oxide.
6. An aerosol pharmaceutical composition according to claim 4, characterized in that the water-insoluble polymer comprises acrylic copolymers; polyvinyl acetate; cellulose derivatives such as ethyl cellulose, cellulose acetate.
7. An aerosol pharmaceutical composition according to claim 1 to 5, characterized in that the adjuvant is a polyvinylpyrrolidone.
8. An aerosol pharmaceutical composition according to claim 7, characterized in that the polyvinylpyrrolidone is a polyvinylpyrrolidone having a molecular weight ranging from 2500 to 1,200,000.
9. An aerosol pharmaceutical composition according to any preceding claim, characterized in that the amount of adjuvant in the complex of the active agent and adjuvant ranges from 0.5% to 500% by weight of the active agent.
10. An aerosol pharmaceutical composition according to any preceding claim, characterized in that the complex of the active agent and the adjuvant is particulate and has a size distribution such that at least 90% of the particles have a diameter of less than or equal to 15. micrometers
11. An aerosol pharmaceutical composition according to any preceding claim, characterized in that the active agent is an antiallergic, an anticholinergic or a bronchodilator.
12. An aerosol pharmaceutical composition according to claim 11, characterized in that the active agent is selected from tiotropium, salbutamol, beclomethasone, ipratropium, formoterol, aclidinium, salmeterol, fluticasone, budesonide, fenoterol, ciclesonide, mometasone, or a salt thereof pharmaceutically acceptable.
13. An aerosol pharmaceutical composition according to claim 12, characterized in that the active agent is salbutamol, salbutamol sulfate, levosalbutamol, salbutamol levosulfate, levosalbutamol tartrate, ipratropium, ipratropium bromide, tiotropium, tiotropium bromide or monohydrate tiotropium bromide .
14. an aerosol pharmaceutical composition of according to any preceding claim, characterized in that the pharmaceutically acceptable excipients include a bulking agent, a cosolvent or both.
15. An aerosol pharmaceutical composition according to claim 14, characterized in that the pharmaceutically acceptable excipients also include a taste masking agent, a buffer, an antioxidant, water and a chemical stabilizer.
16. An aerosol pharmaceutical composition according to claim 14 or 15, characterized in that the bulking agent includes one or more saccharides and / or one or more sugar alcohols.
17. An aerosol pharmaceutical composition according to claim 14, 15 or 16, characterized in that the cosolvent includes one or more of polyethylene glycol, propylene glycol, isopropyl myristate and glycerol.
18. An aerosol pharmaceutical composition according to any preceding claim, characterized in that the HFA propellant is 1,1,1,2-tetrafluoroethane (HFA-134a), 1, 1, 2, 3, 3, 3-heptafluoropropane ( HFA-227) or a mixture thereof.
19. A pharmaceutical aerosol composition according to any preceding claim, characterized in that it is used in the treatment of symptoms chronic or mild, moderate or severe acute, or for the prophylactic treatment, of a respiratory disorder, such as asthma.
20. Use of an aerosol pharmaceutical composition according to any of claims 1 to 18 in the manufacture of a medicament for the treatment of mild, moderate or severe chronic or acute symptoms, or for the prophylactic treatment of a respiratory disorder, such as asthma.
21. A method of treating mild, moderate or severe chronic or acute symptoms, or for the prophylactic treatment, of a respiratory disorder, such as asthma, characterized in that it comprises administering a therapeutically effective amount of an aerosol pharmaceutical composition in accordance with any of the claims 1 to 18 to a patient in need thereof.
22. A pharmaceutical aerosol dispenser characterized in that it comprises a can having a chamber containing an aerosol pharmaceutical composition according to any preceding claim; an outlet for delivering the aerosolized pharmaceutical composition to a patient in need thereof and a valve for controlling the flow of the aerosolized pharmaceutical composition from the chamber to the outlet.
23. A process to manufacture a dispenser aerosol pharmaceutical for supplying a pharmaceutical composition according to any of claims 1 to 18, characterized in that it comprises: (a) placing a predetermined amount of the complex of the active agent and the adjuvant in a suitable can, (b) optionally mixing the complex with one or more pharmaceutically acceptable excipients; (c) crimping the can with a suitable valve and loading it with the HFA propellant.
24. A process for manufacturing a complex of an active agent and an adjuvant, characterized in that it comprises: (a) mixing the active agent in an organic solvent; (b) heating the mixture of step (a) to a suitable temperature and adding water to form a clear solution; (c) adding the adjuvant to the solution of step (c); (d) concentrating the solution of step (d) under reduced pressure to form a residue; (e) washing the residue of step (d) with the same solvent used in step (a); Y (f) drying the washed residue from step (e) to form a drug-adjuvant complex.
25. A pharmaceutical aerosol composition characterized in that it is substantially as described with reference to the examples.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN2351MU2008 | 2008-11-04 | ||
IN2402MU2008 | 2008-11-14 | ||
PCT/GB2009/002575 WO2010052450A1 (en) | 2008-11-04 | 2009-10-29 | Tiotropium bromide having a low degree of crystallinity |
PCT/GB2009/002617 WO2010052466A2 (en) | 2008-11-04 | 2009-11-04 | Pharmaceutical aerosol composition |
Publications (1)
Publication Number | Publication Date |
---|---|
MX2011004730A true MX2011004730A (en) | 2011-05-30 |
Family
ID=41630445
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX2011004730A MX2011004730A (en) | 2008-11-04 | 2009-11-04 | Pharmaceutical aerosol composition. |
Country Status (12)
Country | Link |
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EP (1) | EP2362766A2 (en) |
JP (1) | JP2012507574A (en) |
KR (1) | KR20110096538A (en) |
CN (1) | CN102238939B (en) |
AU (1) | AU2009312598A1 (en) |
BR (1) | BRPI0916047A2 (en) |
CA (1) | CA2742718A1 (en) |
MX (1) | MX2011004730A (en) |
NZ (1) | NZ592861A (en) |
RU (1) | RU2565438C2 (en) |
WO (1) | WO2010052466A2 (en) |
ZA (1) | ZA201103347B (en) |
Families Citing this family (8)
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RU2493827C1 (en) * | 2012-10-03 | 2013-09-27 | Шолекс Девелопмент Гмбх | Stable combined solution of fenoterol hydrobromide and ipratropium bromide |
KR20150096371A (en) * | 2012-10-23 | 2015-08-24 | 시플라 리미티드 | Pharmaceutical composition |
GB201306984D0 (en) * | 2013-04-17 | 2013-05-29 | Mexichem Amanco Holding Sa | Composition |
KR101484481B1 (en) * | 2014-08-07 | 2015-01-20 | 주식회사 다림바이오텍 | Manufacturing method of subligual spray composition comprising PDE-5 inhibitor, and subligual spray composition manufactured by the same |
CN107320464A (en) * | 2017-04-28 | 2017-11-07 | 北京北朋科技有限公司 | The preparation method of the budesonide suspension of high pH value |
GB2573297A (en) * | 2018-04-30 | 2019-11-06 | Mexichem Fluor Sa De Cv | Pharmaceutical composition |
WO2020070620A2 (en) * | 2018-10-01 | 2020-04-09 | 3M Innovative Properties Company | Formulation and aerosol canisters, inhalers, and the like containing the formulation |
CN114796166A (en) * | 2021-01-29 | 2022-07-29 | 北京远大九和药业有限公司 | Aerosol containing terpene volatile oil and preparation method thereof |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4684698A (en) * | 1986-05-02 | 1987-08-04 | Gaf Corporation | Water soluble multicomplex of chlorothiazide, furosemide and poly(N-vinyl-2-pyrrolidone) |
IL103238A (en) * | 1991-09-25 | 1995-07-31 | Fisons Plc | Pressurised aerosol compositions |
EP0655237A1 (en) * | 1993-11-27 | 1995-05-31 | Hoechst Aktiengesellschaft | Medicinal aerosol formulation |
US6361760B1 (en) * | 1995-09-19 | 2002-03-26 | Fujisawa Pharmaceutical Co., Ltd. | Aerosol compositions |
EP1019021B2 (en) * | 1997-09-29 | 2012-12-26 | Novartis AG | Stabilized preparations for use in metered dose inhalers |
DE10214031A1 (en) * | 2002-03-27 | 2004-02-19 | Pharmatech Gmbh | Process for the production and application of micro- and nanoparticles by micronization |
SI1682542T1 (en) * | 2003-11-03 | 2010-04-30 | Boehringer Ingelheim Int | Novel crystalline anhydride with anticholinergic effect |
SI1881980T1 (en) * | 2005-05-02 | 2012-12-31 | Boehringer Ingelheim International Gmbh | Novel crystalline forms of tiotropium bromide |
ES2384486T3 (en) * | 2005-12-19 | 2012-07-05 | Sicor, Inc. | New form of tiotropium bromide and procedure for its preparation |
EP2327403A3 (en) * | 2007-02-19 | 2011-08-31 | Cipla Limited | Pharmaceutical combinations of at least two bronchodilators |
GB0801876D0 (en) * | 2008-02-01 | 2008-03-12 | Vectura Group Plc | Suspension formulations |
-
2009
- 2009-11-04 BR BRPI0916047A patent/BRPI0916047A2/en not_active IP Right Cessation
- 2009-11-04 MX MX2011004730A patent/MX2011004730A/en not_active Application Discontinuation
- 2009-11-04 KR KR1020117012589A patent/KR20110096538A/en not_active Application Discontinuation
- 2009-11-04 CN CN200980148430.5A patent/CN102238939B/en not_active Expired - Fee Related
- 2009-11-04 NZ NZ592861A patent/NZ592861A/en not_active IP Right Cessation
- 2009-11-04 CA CA2742718A patent/CA2742718A1/en not_active Abandoned
- 2009-11-04 JP JP2011535158A patent/JP2012507574A/en active Pending
- 2009-11-04 AU AU2009312598A patent/AU2009312598A1/en not_active Abandoned
- 2009-11-04 RU RU2011122652/15A patent/RU2565438C2/en not_active IP Right Cessation
- 2009-11-04 EP EP09753178A patent/EP2362766A2/en not_active Withdrawn
- 2009-11-04 WO PCT/GB2009/002617 patent/WO2010052466A2/en active Application Filing
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2011
- 2011-05-09 ZA ZA2011/03347A patent/ZA201103347B/en unknown
Also Published As
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AU2009312598A1 (en) | 2010-05-14 |
ZA201103347B (en) | 2012-01-25 |
BRPI0916047A2 (en) | 2015-11-10 |
NZ592861A (en) | 2013-01-25 |
CA2742718A1 (en) | 2010-05-14 |
RU2011122652A (en) | 2012-12-20 |
RU2565438C2 (en) | 2015-10-20 |
JP2012507574A (en) | 2012-03-29 |
KR20110096538A (en) | 2011-08-30 |
EP2362766A2 (en) | 2011-09-07 |
WO2010052466A8 (en) | 2011-11-24 |
CN102238939B (en) | 2015-05-20 |
CN102238939A (en) | 2011-11-09 |
WO2010052466A3 (en) | 2010-11-04 |
WO2010052466A2 (en) | 2010-05-14 |
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