CA2455115C - Pharmaceutical aerosol formulation - Google Patents
Pharmaceutical aerosol formulation Download PDFInfo
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- CA2455115C CA2455115C CA002455115A CA2455115A CA2455115C CA 2455115 C CA2455115 C CA 2455115C CA 002455115 A CA002455115 A CA 002455115A CA 2455115 A CA2455115 A CA 2455115A CA 2455115 C CA2455115 C CA 2455115C
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- medicament
- formulation
- propellant
- canister
- tetrafluoroethane
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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]
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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
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- A—HUMAN NECESSITIES
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- 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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- 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
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
- A61K9/124—Aerosols; Foams characterised by the propellant
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A61P11/00—Drugs for disorders of the respiratory system
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Abstract
A pharmaceutical formulation for use in the administration of medicaments by inhalation comprising particulate medicament which is an anticholinergic medicament selected from ipratropium, atropine and oxitropium or a salt thereof and 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof as propellant, which formulation contains no significant amount of surfactant, is free of chlorofluorocarbons and is free of alcohols.
Description
PHARMACEUTICAL AEROSOL FORMULATION
This invention relates to aerosol formulations of use for the administration of S medicaments by inhalation.
This Application is a Division of Canadian Patent Application Serial No. 2, 421, 976, filed December 4, 1992.
The use of aerosols to administer medicaments has been known for several decades.
Such aerosols generally comprise the medicament, one or more chiorofluorocarbon propellants and either a surfactant or a solvent, such as ethanol. The most commonly used aerosol propellants for medicaments have been propellant I1 (CCI3F) and/or propellant 114 (CF,CICF~CI) with propellant 12 (CCI:F_). However these propellants are now believed to provoke the degradation of stratospheric ozone and there is, thus a need to provide aerosol formulations for medicaments which employ so called "ozone-friendly"
propellants.
A class of propellants which are believed to have minimal ozone-depteting effects in '! 5 comparison to conventional chlorofluorocarbons comprise fluorocarbons and hydrogen-containing chiorofluorocarbons, and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP
0372777.
W091/0401 1, W091/11173, W091/11495 and W091/14422. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stabilityassociated with the pharmaceutical formulations 'prepared. The applications all propose the. addition of one or more of adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfaetants, carboxylic acids, polyethoxylates etc) and even conventional chiorofluorocarbon propeliants in small amounts intended to minimise potential ozone damage.
Thus, for example EP 0372777 requires the use of 1,1,1,2-tetrafluoroethane in combination with both a cosolverit having greater-polarity than 1,1,1,2-tetrafluoroethane (e.g. an alcohol or a lower alkane) and a surfactant in order to achieve :
astable formulation of a medicament powder: In particular it is.noted in the specification au page 3, line 7 that "it has been found that the use of propellant 134a (1,1,1,2-tetrafluoroethane) and drug as a binary mixture or in combination with a conventional surfactant such as sorbitan trioleate does not provide formulations having suitable properties for use with pressurised inhalers". Surfactants are s generally recognised by those skilled in the art to be essential components of aerosol formulations, required not only to reduce aggregation of the medicament but also to lubricate the valve employed, thereby ensuring consistent reproducibility of valve actuation and accuracy of dose dispensed. Whilst WO 91/11173, WO 91/11495 and WO 91/14422 are concerned with formulations io comprising an admixture of drug and surfactant, WO 91/04011 discloses medicinal aerosol formulations in which the particulate medicaments are pre-coated with surfactant prior to dispersal in 1, 1, 1,2-tetrafluoroethane.
It has now surprisingly been found that, in contradistinction to these teachings, it is in fact possible to obtain satisfactory dispersions of medicaments in 15 fluorocarbon or hydrogen-containing chlorofluorocarbon propellants such as 1, 1, 1,2-tetrafluoroethane without recourse to the use of any surfactant or cosolvent in the composition, or the necessity to pre-treat the medicament prior to dispersal in the propellant.
In accordance with one aspect of the invention, there is provided a 20 pharmaceutical formulation for use in the administration of medicaments by inhalation comprising particulate medicament which is an anticholinergic medicament selected from ipratropium, atropine and oxitropium or a salt thereof and 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof as propellant, which formulation contains no significant amount of 25 surfactant, is free of chlorofluorocarbons and is free of alcohols.
In another aspect of the invention, there is provided a canister suitable for delivering a pharmaceutical aerosol formulation which comprises a container capable of withstanding the vapour pressure of the propellant used, which container is closed with a metering valve, and contains a pharmaceutical aerosol 30 formulation of the invention.
In a further aspect of the invention, there is provided a metered dose inhaler which comprises a canister of the invention fitted into a suitable channeling device.
In still another aspect of the invention, there is provided use of a formulation of the invention in the manufacture of a medicament for the treatment of asthma by inhalation thereapy.
In yet another aspect of the invention, there is provided a process for preparing a formulation of the invention which comprises dispersing the medicament in the propellant.
This disclosure also provides a pharmaceutical aerosol formulation which comprises particulate medicament and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which formulation is substantially free of surfactant and with the proviso that said medicament is other than salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or a physiologically acceptable sale or solvate thereof. By "substantially free of surfactant" is meant formulations which contain no significant amounts of surfactant, for example, less than 0.0001 % by weight of the medicament.
The particle size of the particulate (e.g. micronised) medicament should be such as to permit inhalation of substantially all of the medicament into the lungs upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and preferably in the range 1-10 microns, e.g. 1-5 microns.
Medicaments which may be administered in aerosol formulations according to the invention include any drug useful in inhalation therapy which may be presented in a form whicit is sttbstantially completely insoluble in the selected propellant.
Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine. fentanyl or morphine; anginal preparations, e.g.
diltiazem;
antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti-infectives, e.g.
cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine;
antihistamines, e.g. methapyritene; anti-inflammatories, e.g, flunisolide, budesonide, tipredane or triamciaolone acatonide; antitussives, e.g. noscapine;
bronchodi:lators. e.g.
ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol..
phenylephrine, phenyipropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-a-[[[6-[2-(2-pyridinyl) ethoxy) hexyl]amino]methyl]benzenemethanol; diuretics, e.g. amiloride;
anticholinergics e.g.
ipratropium, atropine or oxitropium; hormones, e.g. cortisone. hydrocortisone or prednisolone, xanthines e.g, aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides. e.g. insulin or glucagon.
It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament andlor to minimise the solubility of the medicanient in the propellant.
Particularly preferred medicaments for administration using aerosol formulations in accordance with the invention include anti-allergics, bronchodilators and anti-inflammatory steroids of use in the treatment of respiratory disorders such as asthma by inhalation therapy, for example cromoglycate. (e.g. the sodium salt), terbutaline (e.g.
the sulphate salt), reproterol (e.g. the hydrochloride salt) or (-)-4-amino-3,5-dichloro-a-[[[6-[2-(2-pyridinyl)-ethoxy]hexyl]amino]methyl]benzenemethanol.
It will be appreciated by those skilled in the art that the aerosol formulations according to the invention may, if desired, contain a combination of two or more active ingredients. Aerosol compositions containing two active ingredients (in a conventional propellant system) are known, for example, for the treatment of respiratory disorders such as asthma. Accordingly the present invention further provides aerosol formulations in accordance with the invention which contain two or more particulate medicaments_ Medicaments may be selected from suitable combinations of the medicaments mentioned hereinbefore. Thus, suitable combinations of bronchodilatory agents include ephedrine 5 and theophylline, fenoterol and ipratropium, and isoetharine and phenylephrine aerosol fonmulations.
Preferred aerosol formulations in accordance with the invention comprise (a) an effective amount of a particulate bronchodilatory medicament (b) an effective amount of a particulate antiinflatnmatory, preferably a steroidal antiinflammatory medicament and (c) a fluorocarbon or hydrogen - containing chlorofluorocarbon propeflant with the proviso that said medicaments are other than salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or a physiologically acceptable salt or solvate thereof.
Alternatively aerosol formulations may contain a bronchodilator such as isoprenaline in combination with an antiallergic such as cromoglycate (e.g. the sodium salt).
Combinations of isoprenaline and sodium cromoglycate are especially preferred.
The final aerosol formulation desirably contains 0.005-10% w/w, preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.
The propellants =for use in the invention may be any fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof having a sufficient vapour pressure to render them effective as propellants. Preferably the propellant will be a non-solvent for the medicament. Suitable propellants include, for example, C,,,,hydrogen-containing chlorofluorocarbons such as CH,CIF, CCiF,CHCIF, CF3CHCIF, CHF,CCIF_, CfICIFCHF,, CFCH:CI and . CCIF:CH,; C,.hydrogen-containing fluorocarbons such as CHF_CHFõ CF3CI-H_F, CHF,CH3 and CF3CHFCF and perfluorocarbons such as CF,CF, and CF3CF,CF3.
Where mixtures of the fluorocarbons or hydrogen-containing chlorofluorocarbons are etnployed they may be mixtures of the above identified compounds or mixtures, preferably binary mixtures, with other fluorocarbons or hydrogen-containing chiorofluorocarbons for example CHCtFõ CI-l-F_ and CF1CH,. Preferably a single fluorocarbon or hydrogen-containing chlorofluoroearbon is employed as the propellant.
Particularly preferred as propellants are C,,,hydrogen-containing fluorocarbons such as 1,1,1,2-tetrafluoroethane (CF3CH,F) and 1,1,1,2,3,3,3-heptafluoro-n-propane (CF3 CHFCF3).
S It is desirabte that the formulations of the invention contain no components which may provoke the degradation of stratospheric ozone. in particular it is desirable that the formulations are substantially free of chlorofluorocarbons such as CCI3F, CCIA
and CF3CCI,.
The propellant may additionally contain a voiatile adjuvant such as a saturated l0 hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyl ether. In general, up to 50% w/w of the propellant may comprise a volatile hydrocarbon, for example I to 30% w/w. However, fonmulations which are substantially free of volatile adjuvants are preferred.
It is further desirable that the formulations of the invention are substantially free of 15 liquid components of higher polarity than the propellant employed. Polarity may be determined for example, by the method described in Eiiropean Patent Application Publication No. 0327777. In particular formulations which are substantially free of alcohols such as ethanol are preferable. As used herein "substantially free"
meansiess than 1% w/w based upon the fluorocarbon or hydrogen-containing chlorofluorocarbon, in 20 particular less than 0.5% for exatitple 0. t% or less.
A particularly preferred embodiment the invention provides a pharmaceutical aerosol formulation consisting essentially of one more particulate medicament and one or more fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, with the proviso that said rnedicament is other than salmeterot, salbutamol, fluticasone ipropionate, 25 beclomethasone dipropionate or a physiologically acceptable salt or solvate thereof.
The formulations of the invention may be prepared by dispersal of the rttedicament in the selected propellant in an appropriate container, e.g. with the aid of sonication: The process is desirably carried out under anhydrous conditons to obviate any adverse effects of moisture, on suspension stability.
This invention relates to aerosol formulations of use for the administration of S medicaments by inhalation.
This Application is a Division of Canadian Patent Application Serial No. 2, 421, 976, filed December 4, 1992.
The use of aerosols to administer medicaments has been known for several decades.
Such aerosols generally comprise the medicament, one or more chiorofluorocarbon propellants and either a surfactant or a solvent, such as ethanol. The most commonly used aerosol propellants for medicaments have been propellant I1 (CCI3F) and/or propellant 114 (CF,CICF~CI) with propellant 12 (CCI:F_). However these propellants are now believed to provoke the degradation of stratospheric ozone and there is, thus a need to provide aerosol formulations for medicaments which employ so called "ozone-friendly"
propellants.
A class of propellants which are believed to have minimal ozone-depteting effects in '! 5 comparison to conventional chlorofluorocarbons comprise fluorocarbons and hydrogen-containing chiorofluorocarbons, and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP
0372777.
W091/0401 1, W091/11173, W091/11495 and W091/14422. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stabilityassociated with the pharmaceutical formulations 'prepared. The applications all propose the. addition of one or more of adjuvants such as alcohols, alkanes, dimethyl ether, surfactants (including fluorinated and non-fluorinated surfaetants, carboxylic acids, polyethoxylates etc) and even conventional chiorofluorocarbon propeliants in small amounts intended to minimise potential ozone damage.
Thus, for example EP 0372777 requires the use of 1,1,1,2-tetrafluoroethane in combination with both a cosolverit having greater-polarity than 1,1,1,2-tetrafluoroethane (e.g. an alcohol or a lower alkane) and a surfactant in order to achieve :
astable formulation of a medicament powder: In particular it is.noted in the specification au page 3, line 7 that "it has been found that the use of propellant 134a (1,1,1,2-tetrafluoroethane) and drug as a binary mixture or in combination with a conventional surfactant such as sorbitan trioleate does not provide formulations having suitable properties for use with pressurised inhalers". Surfactants are s generally recognised by those skilled in the art to be essential components of aerosol formulations, required not only to reduce aggregation of the medicament but also to lubricate the valve employed, thereby ensuring consistent reproducibility of valve actuation and accuracy of dose dispensed. Whilst WO 91/11173, WO 91/11495 and WO 91/14422 are concerned with formulations io comprising an admixture of drug and surfactant, WO 91/04011 discloses medicinal aerosol formulations in which the particulate medicaments are pre-coated with surfactant prior to dispersal in 1, 1, 1,2-tetrafluoroethane.
It has now surprisingly been found that, in contradistinction to these teachings, it is in fact possible to obtain satisfactory dispersions of medicaments in 15 fluorocarbon or hydrogen-containing chlorofluorocarbon propellants such as 1, 1, 1,2-tetrafluoroethane without recourse to the use of any surfactant or cosolvent in the composition, or the necessity to pre-treat the medicament prior to dispersal in the propellant.
In accordance with one aspect of the invention, there is provided a 20 pharmaceutical formulation for use in the administration of medicaments by inhalation comprising particulate medicament which is an anticholinergic medicament selected from ipratropium, atropine and oxitropium or a salt thereof and 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof as propellant, which formulation contains no significant amount of 25 surfactant, is free of chlorofluorocarbons and is free of alcohols.
In another aspect of the invention, there is provided a canister suitable for delivering a pharmaceutical aerosol formulation which comprises a container capable of withstanding the vapour pressure of the propellant used, which container is closed with a metering valve, and contains a pharmaceutical aerosol 30 formulation of the invention.
In a further aspect of the invention, there is provided a metered dose inhaler which comprises a canister of the invention fitted into a suitable channeling device.
In still another aspect of the invention, there is provided use of a formulation of the invention in the manufacture of a medicament for the treatment of asthma by inhalation thereapy.
In yet another aspect of the invention, there is provided a process for preparing a formulation of the invention which comprises dispersing the medicament in the propellant.
This disclosure also provides a pharmaceutical aerosol formulation which comprises particulate medicament and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which formulation is substantially free of surfactant and with the proviso that said medicament is other than salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or a physiologically acceptable sale or solvate thereof. By "substantially free of surfactant" is meant formulations which contain no significant amounts of surfactant, for example, less than 0.0001 % by weight of the medicament.
The particle size of the particulate (e.g. micronised) medicament should be such as to permit inhalation of substantially all of the medicament into the lungs upon administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and preferably in the range 1-10 microns, e.g. 1-5 microns.
Medicaments which may be administered in aerosol formulations according to the invention include any drug useful in inhalation therapy which may be presented in a form whicit is sttbstantially completely insoluble in the selected propellant.
Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine. fentanyl or morphine; anginal preparations, e.g.
diltiazem;
antiallergics, e.g. cromoglycate, ketotifen or nedocromil; anti-infectives, e.g.
cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine;
antihistamines, e.g. methapyritene; anti-inflammatories, e.g, flunisolide, budesonide, tipredane or triamciaolone acatonide; antitussives, e.g. noscapine;
bronchodi:lators. e.g.
ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol..
phenylephrine, phenyipropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-a-[[[6-[2-(2-pyridinyl) ethoxy) hexyl]amino]methyl]benzenemethanol; diuretics, e.g. amiloride;
anticholinergics e.g.
ipratropium, atropine or oxitropium; hormones, e.g. cortisone. hydrocortisone or prednisolone, xanthines e.g, aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; and therapeutic proteins and peptides. e.g. insulin or glucagon.
It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament andlor to minimise the solubility of the medicanient in the propellant.
Particularly preferred medicaments for administration using aerosol formulations in accordance with the invention include anti-allergics, bronchodilators and anti-inflammatory steroids of use in the treatment of respiratory disorders such as asthma by inhalation therapy, for example cromoglycate. (e.g. the sodium salt), terbutaline (e.g.
the sulphate salt), reproterol (e.g. the hydrochloride salt) or (-)-4-amino-3,5-dichloro-a-[[[6-[2-(2-pyridinyl)-ethoxy]hexyl]amino]methyl]benzenemethanol.
It will be appreciated by those skilled in the art that the aerosol formulations according to the invention may, if desired, contain a combination of two or more active ingredients. Aerosol compositions containing two active ingredients (in a conventional propellant system) are known, for example, for the treatment of respiratory disorders such as asthma. Accordingly the present invention further provides aerosol formulations in accordance with the invention which contain two or more particulate medicaments_ Medicaments may be selected from suitable combinations of the medicaments mentioned hereinbefore. Thus, suitable combinations of bronchodilatory agents include ephedrine 5 and theophylline, fenoterol and ipratropium, and isoetharine and phenylephrine aerosol fonmulations.
Preferred aerosol formulations in accordance with the invention comprise (a) an effective amount of a particulate bronchodilatory medicament (b) an effective amount of a particulate antiinflatnmatory, preferably a steroidal antiinflammatory medicament and (c) a fluorocarbon or hydrogen - containing chlorofluorocarbon propeflant with the proviso that said medicaments are other than salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or a physiologically acceptable salt or solvate thereof.
Alternatively aerosol formulations may contain a bronchodilator such as isoprenaline in combination with an antiallergic such as cromoglycate (e.g. the sodium salt).
Combinations of isoprenaline and sodium cromoglycate are especially preferred.
The final aerosol formulation desirably contains 0.005-10% w/w, preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.
The propellants =for use in the invention may be any fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof having a sufficient vapour pressure to render them effective as propellants. Preferably the propellant will be a non-solvent for the medicament. Suitable propellants include, for example, C,,,,hydrogen-containing chlorofluorocarbons such as CH,CIF, CCiF,CHCIF, CF3CHCIF, CHF,CCIF_, CfICIFCHF,, CFCH:CI and . CCIF:CH,; C,.hydrogen-containing fluorocarbons such as CHF_CHFõ CF3CI-H_F, CHF,CH3 and CF3CHFCF and perfluorocarbons such as CF,CF, and CF3CF,CF3.
Where mixtures of the fluorocarbons or hydrogen-containing chlorofluorocarbons are etnployed they may be mixtures of the above identified compounds or mixtures, preferably binary mixtures, with other fluorocarbons or hydrogen-containing chiorofluorocarbons for example CHCtFõ CI-l-F_ and CF1CH,. Preferably a single fluorocarbon or hydrogen-containing chlorofluoroearbon is employed as the propellant.
Particularly preferred as propellants are C,,,hydrogen-containing fluorocarbons such as 1,1,1,2-tetrafluoroethane (CF3CH,F) and 1,1,1,2,3,3,3-heptafluoro-n-propane (CF3 CHFCF3).
S It is desirabte that the formulations of the invention contain no components which may provoke the degradation of stratospheric ozone. in particular it is desirable that the formulations are substantially free of chlorofluorocarbons such as CCI3F, CCIA
and CF3CCI,.
The propellant may additionally contain a voiatile adjuvant such as a saturated l0 hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyl ether. In general, up to 50% w/w of the propellant may comprise a volatile hydrocarbon, for example I to 30% w/w. However, fonmulations which are substantially free of volatile adjuvants are preferred.
It is further desirable that the formulations of the invention are substantially free of 15 liquid components of higher polarity than the propellant employed. Polarity may be determined for example, by the method described in Eiiropean Patent Application Publication No. 0327777. In particular formulations which are substantially free of alcohols such as ethanol are preferable. As used herein "substantially free"
meansiess than 1% w/w based upon the fluorocarbon or hydrogen-containing chlorofluorocarbon, in 20 particular less than 0.5% for exatitple 0. t% or less.
A particularly preferred embodiment the invention provides a pharmaceutical aerosol formulation consisting essentially of one more particulate medicament and one or more fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, with the proviso that said rnedicament is other than salmeterot, salbutamol, fluticasone ipropionate, 25 beclomethasone dipropionate or a physiologically acceptable salt or solvate thereof.
The formulations of the invention may be prepared by dispersal of the rttedicament in the selected propellant in an appropriate container, e.g. with the aid of sonication: The process is desirably carried out under anhydrous conditons to obviate any adverse effects of moisture, on suspension stability.
The formulations according to the invention form weakly flocculated suspensions on standing but, surprisingly, these suspensions have been found to be easily redispersed by mild agitation to provide suspensions with excellent delivery characteristics suitable for use in pressurised inhalers, even after prolonged storage. Minimising and preferably avoiding the use of formulation excipients e.g. surfactants, cosolvents etc in the aerosol formulations according to the invention is also advantageous since the formulations may be substantially taste and odour free, less irritant and less toxic than conventional formulations.
The chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well knowrr to those skilled in the art. Thus, for example, the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product. Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.
The particle size distribution of the aerosol formulations according to the invention is particularly impressive and may be measured by conventional techniques, for example by cascade impaction or by the "Twin Impinger" analytical process. As used herein reference to the "Twin Impinger" assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A" as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated. As used herein reference to "respirable fraction" means the amount of active ingredient. collected in the.lower iFnpingeranent chamber per. actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above. The formulations according to the invention have been found to have a respirable fraction of 20% or more by weight of the -medicament, preferably 25 to 70%, for example-30 to 60%.
The chemical and physical stability and the pharmaceutical acceptability of the aerosol formulations according to the invention may be determined by techniques well knowrr to those skilled in the art. Thus, for example, the chemical stability of the components may be determined by HPLC assay, for example, after prolonged storage of the product. Physical stability data may be gained from other conventional analytical techniques such as, for example, by leak testing, by valve delivery assay (average shot weights per actuation), by dose reproducibility assay (active ingredient per actuation) and spray distribution analysis.
The particle size distribution of the aerosol formulations according to the invention is particularly impressive and may be measured by conventional techniques, for example by cascade impaction or by the "Twin Impinger" analytical process. As used herein reference to the "Twin Impinger" assay means "Determination of the deposition of the emitted dose in pressurised inhalations using apparatus A" as defined in British Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Such techniques enable the "respirable fraction" of the aerosol formulations to be calculated. As used herein reference to "respirable fraction" means the amount of active ingredient. collected in the.lower iFnpingeranent chamber per. actuation expressed as a percentage of the total amount of active ingredient delivered per actuation using the twin impinger method described above. The formulations according to the invention have been found to have a respirable fraction of 20% or more by weight of the -medicament, preferably 25 to 70%, for example-30 to 60%.
Optionally, the medicament may be surface-modified prior to its dispersion in the propellant by treatment with a substantially non-polar liquid medium which is a non-solvent for the medicament. There is thus provided in a further aspect of the invention an aerosol formulation comprising particulate, surface-modified medicament, as defined herein, and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which fotmulation is substantially free of surfactant. By "surface-modified medicament"
is meant particles of inedicament, which have been surface-modif'ied by admixture with a substantially non-polar non-solvent liquid, followed by removal of the liquid, with the proviso that said medicament is other than salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or a physiologically acceptable salt or solvate thereof. The substantially non-polar non-solvent liquid medium is conveniently an aliphatic hydrocarbon, e.g. a lower alkane, which is sufficiently volatile to permit its ready evaporation, e.g. at ambient temperature and pressure, after slurrying with the medicament. The use of isopentane as liquid medium is particularly advantageous in this ! 5 respect.
The medicament is desirably siurried with- the liquid medium under anhydrous conditions to obviate any adverse effects of moisture on suspension stability.
The slurry may advantageously be sonicated to maximise the surface-modifying effect of the treatment. The liquid may be removed by any convenient means for - exampie by evaporation or by filtration followed by evaporation, provided that following treatment the medicament is substantially free of the liquid. The formulations of the invention will be substantially free of the non-solvent non-polar liquid. Surface-modified medicament prepared by the above described process comprises a further aspect of the present invention.
The formulations according to the invention may be fdled into canisters suitable for delivering pharmaceutical aerosol formulations. Canii;ters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example.an aluminium can which may optionally be anodised, laequer-coated and/or plastic-coated, which container is closed with a metering valve. The metering valves are designed to deliver a metered CA 02455115 2004-02-11 .
is meant particles of inedicament, which have been surface-modif'ied by admixture with a substantially non-polar non-solvent liquid, followed by removal of the liquid, with the proviso that said medicament is other than salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or a physiologically acceptable salt or solvate thereof. The substantially non-polar non-solvent liquid medium is conveniently an aliphatic hydrocarbon, e.g. a lower alkane, which is sufficiently volatile to permit its ready evaporation, e.g. at ambient temperature and pressure, after slurrying with the medicament. The use of isopentane as liquid medium is particularly advantageous in this ! 5 respect.
The medicament is desirably siurried with- the liquid medium under anhydrous conditions to obviate any adverse effects of moisture on suspension stability.
The slurry may advantageously be sonicated to maximise the surface-modifying effect of the treatment. The liquid may be removed by any convenient means for - exampie by evaporation or by filtration followed by evaporation, provided that following treatment the medicament is substantially free of the liquid. The formulations of the invention will be substantially free of the non-solvent non-polar liquid. Surface-modified medicament prepared by the above described process comprises a further aspect of the present invention.
The formulations according to the invention may be fdled into canisters suitable for delivering pharmaceutical aerosol formulations. Canii;ters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example.an aluminium can which may optionally be anodised, laequer-coated and/or plastic-coated, which container is closed with a metering valve. The metering valves are designed to deliver a metered CA 02455115 2004-02-11 .
amount of the formulation per actuation and incorporate a gasket to prevent leakage of propellant through the valve. The gasket may comprise any suitable elastomeric material such as for example low density polyethylene. chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK (e.g:
BK300, 8K356) and 3M-Neotechnic Ltd, UK (e.g. SpraymiseP'').
Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of largo scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aiuminium can to form an empty canister. The particulate medicament is added to a charge vessel and liqttified propellant is pressure filled through the charge vessel into a manufacturing vessel. The drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.
Typically, in batches prepared for pharmaceutical use, each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
Each filled canister is conveniently fitted into a suitable channelling device prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient. Suitable channelling devices comprise for example a valve actuator and a cylindrical or cone-like passage through which medicarnent may be delivered from the filled canister via the metering_valve to the nose or mouth of a patient e:g. a mouthpicce actuator. Metered dose inhalers are designed to.deliver o-fuced'unit dosage of medicament per actuation : or "pufl",. for example in; the range of 10 to 5000 microgram medicament per puff.
Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will.be appreciated that the precise dose administered will depend -on the age and condition of the patient; the particular particulate medicament used and the frequency of,administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example from I to 8 times per day, giving for example 1.2,3 or 4 5 puffs each time.
Thus, for example, each valve actuation may deliver 5mg sodium cromoglycate, microgram terbutaline sulphate or 500 microgram reproterol hydrochloride.
Typically each filled canister for use in a metered dose inhaler contains 100, 160 or 240 metered doses or puffs of medicament.
10 The filled canisters 'and metered dose inhalers described herein comprise further aspects of the present invention.
A still further aspect of the present invention comprises a method of treating respiratory disorders such as, for example, asthma, which comprises administration by inhalation of an effective amount of a formulation as herein described.
The following non-limitative Examples serve to illustrate the invention.
Example 1 Micronised sodium cromoglycate (1.2g) is weighed directly into an aluminium can and 1,1,1,2-tetrafluorethane (to 18.2g) added from a vacuum flask. A metering valve.is crimped into place and the sealed can sonicated for five minutes. The aerosol delivers 5mg sodium cromoglycate per actuation.
ESample 2 Micronised.terbutaline sulphate (60mg) is weighed directly into an aluminium.can-and 1,1,1,2-tetrafluorethane (to 18.2g) added from a vacuum flask. A metering valve is crimped into place and the sealed can sonicated for five minutes. The aerosol delivers 250 microgram terbutaline sulphate per actuation.
ZZ
Exa+1g 3 Micronised reproterol hydrochloride (120mg) is weighed directly into an aluminium can and 1,1,1,2-tetrafluorethane (to 18.2g) added from a vacuum flask. A
metering valve is crimped into place and the sealed can sonicated for five minutes. The aerosol delivers 500 microgram reproterol hydrochloride per actuation.
Example 4 Micronised terbutaline sulphate (60mg) is weighed directly into an aluminium can and 1,1,1,2,3,3;3-heptafluoro-n-propane (to 21.4g) added from a vacuum flask. A
metering valve is crimped into place and the sealed can sonicated for five minutes. The aerosol delivers 250 microgram terbutaline sulphate per actuation.
BK300, 8K356) and 3M-Neotechnic Ltd, UK (e.g. SpraymiseP'').
Conventional bulk manufacturing methods and machinery well known to those skilled in the art of pharmaceutical aerosol manufacture may be employed for the preparation of largo scale batches for the commercial production of filled canisters. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aiuminium can to form an empty canister. The particulate medicament is added to a charge vessel and liqttified propellant is pressure filled through the charge vessel into a manufacturing vessel. The drug suspension is mixed before recirculation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.
Typically, in batches prepared for pharmaceutical use, each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
Each filled canister is conveniently fitted into a suitable channelling device prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient. Suitable channelling devices comprise for example a valve actuator and a cylindrical or cone-like passage through which medicarnent may be delivered from the filled canister via the metering_valve to the nose or mouth of a patient e:g. a mouthpicce actuator. Metered dose inhalers are designed to.deliver o-fuced'unit dosage of medicament per actuation : or "pufl",. for example in; the range of 10 to 5000 microgram medicament per puff.
Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will.be appreciated that the precise dose administered will depend -on the age and condition of the patient; the particular particulate medicament used and the frequency of,administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example from I to 8 times per day, giving for example 1.2,3 or 4 5 puffs each time.
Thus, for example, each valve actuation may deliver 5mg sodium cromoglycate, microgram terbutaline sulphate or 500 microgram reproterol hydrochloride.
Typically each filled canister for use in a metered dose inhaler contains 100, 160 or 240 metered doses or puffs of medicament.
10 The filled canisters 'and metered dose inhalers described herein comprise further aspects of the present invention.
A still further aspect of the present invention comprises a method of treating respiratory disorders such as, for example, asthma, which comprises administration by inhalation of an effective amount of a formulation as herein described.
The following non-limitative Examples serve to illustrate the invention.
Example 1 Micronised sodium cromoglycate (1.2g) is weighed directly into an aluminium can and 1,1,1,2-tetrafluorethane (to 18.2g) added from a vacuum flask. A metering valve.is crimped into place and the sealed can sonicated for five minutes. The aerosol delivers 5mg sodium cromoglycate per actuation.
ESample 2 Micronised.terbutaline sulphate (60mg) is weighed directly into an aluminium.can-and 1,1,1,2-tetrafluorethane (to 18.2g) added from a vacuum flask. A metering valve is crimped into place and the sealed can sonicated for five minutes. The aerosol delivers 250 microgram terbutaline sulphate per actuation.
ZZ
Exa+1g 3 Micronised reproterol hydrochloride (120mg) is weighed directly into an aluminium can and 1,1,1,2-tetrafluorethane (to 18.2g) added from a vacuum flask. A
metering valve is crimped into place and the sealed can sonicated for five minutes. The aerosol delivers 500 microgram reproterol hydrochloride per actuation.
Example 4 Micronised terbutaline sulphate (60mg) is weighed directly into an aluminium can and 1,1,1,2,3,3;3-heptafluoro-n-propane (to 21.4g) added from a vacuum flask. A
metering valve is crimped into place and the sealed can sonicated for five minutes. The aerosol delivers 250 microgram terbutaline sulphate per actuation.
Claims (13)
1. A pharmaceutical formulation for use in the administration of medicaments by inhalation comprising particulate medicament which is an anticholinergic medicament selected from ipratropium, atropine and oxitropium or a salt thereof and 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof as propellant, which formulation is substantially free of surfactant, is free of chloroflurocarbons and is free of alcohols, and wherein the particulate medicament has a particle size of less than 100 microns.
2. A formulation according to claim 1, wherein the propellant is 1,1,1,2-tetrafluoroethane or 1, 1, 1,2,3,3,3-heptafluoroethane.
3. A formulation according to claim 2, wherein the propellant is 1,1,1,2-tetrafluoroethane.
4. A formulation according to any one of claims 1 to 3, wherein the medicament is present in an amount of 0.005 to 5% w/w based on the total weight of the formulation.
5. A formulation according to claim 4, wherein the medicament is present in an amount of 0.01 to 1% w/w based on the total weight of the formulation.
6. A formulation according to any one of claims 1 to 5, wherein the particulate medicament is ipratropium or a salt thereof.
7. A canister for delivering a pharmaceutical aerosol formulation which comprises a container withstanding the vapour pressure of the propellant used, which container is closed with a metering valve, and contains a pharmaceutical aerosol formulation as claimed in any one of claims 1 to 6.
8. A canister according to claim 7, wherein the container is a metal can.
9. A canister according to claim 8, wherein the metal can is aluminium.
10. A canister according to claim 8 or claim 9, wherein the metal can is plastics-coated, lacquer coated or anodised.
11. A metered dose inhaler which comprises a canister as claimed in any one of claims 7 to 10, fitted into a channelling device.
12. Use of a formulation according to any one of claims 1 to 6, in the manufacture of a medicament for the treatment of asthma by inhalation therapy.
13. A process for preparing a formulation according to any one of claims 1 to 6, which comprises dispersing the medicament in the propellant.
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GB929202522A GB9202522D0 (en) | 1992-02-06 | 1992-02-06 | Medicaments |
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CA002421976A CA2421976C (en) | 1991-12-12 | 1992-12-04 | Medicaments |
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CA002381329A Expired - Fee Related CA2381329C (en) | 1991-12-12 | 1992-12-04 | Medicaments |
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US (6) | US5922306A (en) |
EP (1) | EP0616524B1 (en) |
JP (1) | JP3026841B2 (en) |
AT (1) | ATE171865T1 (en) |
AU (1) | AU663905B2 (en) |
CA (4) | CA2125666C (en) |
DE (1) | DE69227257T2 (en) |
DK (1) | DK0616524T3 (en) |
ES (1) | ES2123576T3 (en) |
WO (1) | WO1993011744A1 (en) |
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-
1992
- 1992-12-04 CA CA002125666A patent/CA2125666C/en not_active Expired - Fee Related
- 1992-12-04 CA CA002455115A patent/CA2455115C/en not_active Expired - Fee Related
- 1992-12-04 JP JP5510574A patent/JP3026841B2/en not_active Expired - Lifetime
- 1992-12-04 WO PCT/EP1992/002809 patent/WO1993011744A1/en not_active Application Discontinuation
- 1992-12-04 DE DE69227257T patent/DE69227257T2/en not_active Revoked
- 1992-12-04 EP EP92924668A patent/EP0616524B1/en not_active Revoked
- 1992-12-04 ES ES92924668T patent/ES2123576T3/en not_active Expired - Lifetime
- 1992-12-04 CA CA002381329A patent/CA2381329C/en not_active Expired - Fee Related
- 1992-12-04 AT AT92924668T patent/ATE171865T1/en not_active IP Right Cessation
- 1992-12-04 DK DK92924668T patent/DK0616524T3/en active
- 1992-12-04 AU AU30851/92A patent/AU663905B2/en not_active Ceased
- 1992-12-04 CA CA002421976A patent/CA2421976C/en not_active Expired - Fee Related
-
1998
- 1998-04-15 US US09/060,110 patent/US5922306A/en not_active Expired - Lifetime
-
1999
- 1999-03-09 US US09/264,665 patent/US6200549B1/en not_active Expired - Fee Related
-
2000
- 2000-04-28 US US09/559,574 patent/US6306369B1/en not_active Expired - Fee Related
-
2001
- 2001-09-04 US US09/944,213 patent/US20020031479A1/en not_active Abandoned
-
2003
- 2003-03-31 US US10/401,722 patent/US6893628B2/en not_active Expired - Fee Related
-
2005
- 2005-05-09 US US11/124,086 patent/US20050207991A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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DE69227257T2 (en) | 1999-03-25 |
US6306369B1 (en) | 2001-10-23 |
ES2123576T3 (en) | 1999-01-16 |
CA2381329A1 (en) | 1993-06-24 |
DK0616524T3 (en) | 1999-06-21 |
US6893628B2 (en) | 2005-05-17 |
EP0616524A1 (en) | 1994-09-28 |
CA2421976C (en) | 2004-04-20 |
WO1993011744A1 (en) | 1993-06-24 |
US20020031479A1 (en) | 2002-03-14 |
US6200549B1 (en) | 2001-03-13 |
US20030165437A1 (en) | 2003-09-04 |
US20050207991A1 (en) | 2005-09-22 |
CA2381329C (en) | 2003-04-15 |
CA2125666C (en) | 2002-07-16 |
US5922306A (en) | 1999-07-13 |
CA2455115A1 (en) | 1993-06-24 |
CA2125666A1 (en) | 1993-06-24 |
JPH07502034A (en) | 1995-03-02 |
EP0616524B1 (en) | 1998-10-07 |
AU3085192A (en) | 1993-07-19 |
ATE171865T1 (en) | 1998-10-15 |
CA2421976A1 (en) | 1993-06-24 |
JP3026841B2 (en) | 2000-03-27 |
AU663905B2 (en) | 1995-10-26 |
DE69227257D1 (en) | 1998-11-12 |
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