CA2447510C - Fluorocarbon aerosol medicaments - Google Patents

Fluorocarbon aerosol medicaments Download PDF

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Publication number
CA2447510C
CA2447510C CA002447510A CA2447510A CA2447510C CA 2447510 C CA2447510 C CA 2447510C CA 002447510 A CA002447510 A CA 002447510A CA 2447510 A CA2447510 A CA 2447510A CA 2447510 C CA2447510 C CA 2447510C
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Prior art keywords
medicament
formulation
process according
propellant
canister
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CA002447510A
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French (fr)
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CA2447510A1 (en
Inventor
Rachel Ann Akehurst
Anthony James Taylor
David Andrew Wyatt
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Glaxo Group Ltd
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Glaxo Group Ltd
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Priority claimed from GB919126405A external-priority patent/GB9126405D0/en
Priority claimed from GB919126378A external-priority patent/GB9126378D0/en
Priority claimed from GB929202522A external-priority patent/GB9202522D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to CA002586146A priority Critical patent/CA2586146C/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
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    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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    • 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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    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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    • 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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    • A61K31/335—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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    • A61K31/44—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
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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
    • A61K31/4523—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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    • A61K31/4738—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
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    • 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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    • 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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    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61K9/0012—Galenical forms characterised by the site of application
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    • A61K9/124—Aerosols; Foams characterised by the propellant
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    • A61P11/08—Bronchodilators

Abstract

A pharmaceutical aerosol formulation for use for the administration of medicaments by inhalation comprises particulate fluticasone propionate as medicament and 1,1,1,2-tetrafluoroethane as propellant, and the formulation contains no significant amounts of surfactant; a canister suitable for delivering the pharmaceutical aerosol formulation comprises a container capable of withstanding the vapour pressure of the propellant used which container is closed with a metering valve and contains the pharmaceutical aerosol formulation. There is also provided a process for preparing a filled pharmaceutical aerosol canister which comprises: preparing a formulation of the invention and filling the formulation into an aluminium can which is closed with a metering valve. The formulation may be used for the manufacture of a medicament for administration by inhalation for the treatment of respiratory disorders such as asthma. >

Description

FLUOROCARBON AEROSOL MEDICAMENTS

This invention relates to aerosol formulations of use for the administration of medicaments by inhalation.
This application is a division of Canadian Application 2, 402, 300, 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 chlorofluorocarbon propellants and either a surfactant or a solvent, such as ethanol. The most commonly used aerosol propellants for medicaments have been propellant 1I (CC13F) and/or propeilant 114 (CFZClCFZCi) with propellant 12 (CC~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"
propeIlants.
A class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional chlorofluorocarbons comprise fluorocarbons and hydrogen-containing chlorofluorocarbons, 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 medic.aments- and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stability associated with the pharmaceutical fonnulations 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 surfactants, carboxylic acids, polyethoxylates etc) and even conventional chlorofluorocarbon propellants in small amounts intended to minimise potential ozone damage.
Thus, for exampie EP 0372777 requires the use of 1,1,1,2-tetrafluoroethane in combination wAth both a cosolvent having greater polarity than 1, 1, 1,2-tetrafluoroethane (e.g. an atlcohol or a lower alkane) and a surfactant in . order to achieve a stable formulation vf.a medicament powder. In particular it is. noted in the specification at 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 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 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-tetrafluorethane.
It has now surprisingly been found that, in contradistinction to these teachings, it is in fact possible to obtain satisfactory dispersions of certain medicaments in fluorocarbon or hydrogen-containing chlorofluorocarbon propellants such as 1,1,1,2-tetrafluorethane 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. More particularly, satisfactory dispersions may be formed where the medicament is selected from salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof.
In accordance with one aspect of the invention, there is provided a pharmaceutical aerosol formulation for use for the administration of medicaments by inhalation characterised in that it comprises particulate fluticasone propionate as medicament and 1,1,1,2-tetrafluoroethane as propellant, which formulation contains less than 0.0001%
w/w surfactant based on weight of the medicament.
In accordance with 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 formulation of the invention as described hereinbefore.
In another aspect of the invention, there is provided a process for preparation of a formulation of the invention as described hereinbefore, which comprises dispersing the medicament in the propellant.
In yet another aspect of the invention, there is provided a process for preparing a filled pharmaceutical aerosol canister which comprises:

(a) preparing a formulation of the invention as described hereinbefore; and (b) filling the formulation into an aluminium can which is closed with a metering valve.
In another aspect of the invention, there is provided a filled pharmaceutical aerosol canister obtained by the filling process of the invention.
In still another aspect of the invention, there is provided a process for preparing a metered dose inhaler which comprises fitting a filled canister of the invention into a channelling device.
There is also disclosed herein a pharmaceutical aerosol formulation which comprises particulate medicament selected from the group consisting of salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates (for example, hydrates) thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which formulation is substantially free of surfactant. 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.
Suitable pharmaceutically acceptable salts of the medicaments of use in the formulations described herein include acid addition salts such as, for example, sulphates, hydrochlorides and xinafoates (1-hydroxy-2-naphthoate), amine salts or alkali metal salts (e.g., sodium). Salmeterol will preferably be in the form of its xinafoate salt and salbutamol will preferably be in the form of its sulphate salt.
The final aerosol formulation desirably contains 0.005-10% w/w, preperably 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 formulation described herein may be any fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof having a sufficient vapour pressure to render them effective as propellants. Preferably the propel-lant will be a non-solvent for the medicament. Suitable propellants include, for example, C,,,hydrogen-containing chlorofluorocarbons such as CH2CIF, CCIF2CHC1F, CF,CHCIF, CHF2CCIF2, CHCIFCHF3, CF3CH2CI and CCIF2CH3; C,.4hydrogen-cantaining fluorocarbons iuch as CHF2CHF2, CF3CH=F, . CHF2CH1 and CF,CHFCF3; and perfluorooarbons such as CF3CF3 and CF~CFzCF,.
Where mixtures of the fluorocarbons or hydrogen-containing chlorofluorocarbons are employed they may be mixtures of the above identified compounds or mixtures, preferably binary mixtures, with other fluorocarbons or hydrogen-containing chloro-ftuorocarbons for example CHCIF2, CHZF2 and CF,CH3. Preferably a single fluorocarbon or hydrQgen-containing chlorofluorncarbon is employed as the propellant.
Particularly preferred as propellants are C,.,hydrogen-containing fluorocarbons such as 1,1,1,2-tetrafluolroethane(CF,CH2F) and= 1,1,1,2,3,3,3-heptafluoro-n-propane (CF3CHFCF,).

It is desirable 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 chtorofluorocarbons such as CC13F, CCkF2 and CF,CCI,.
The propellant may additionaUy contain a volatite adjuvant such as a saturated hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyt ether. In general, up to 50% w/w of the propellant may comprise a volatile hydrocarbon, for example 1 to 30% w/w. However, formulations which are substantially fnee of volatile adjuvants are preferred.

4a It is further desirable that the fonmulations of the invention are substantially free of liquid components of higher polarity than the poopellant employed. Polarity may be determined for example, by the method descnbed in European Patent Application Publication No. 0327777_ In particular formulations which are substantially free of alcohols such as ethanol are preferable. As used herein "substantially free"
means less than 1% w/w based upon the fluorocarbon or hydrogen-containing chlorofluorocarbon, in particular less than 0.5% for example 0.1% or less.

A particularly preferred embodiment of the invention provides a pharmaceutical aerosol formulation consisting essentially of fluticasone propionate and one or more particulate medicaments selected from the group consisting of salmeterol or a physiologically acceptable salt or solvate thereof, and the 1,1,1,2-tetrafluoroethane propellant.

It will be appreciated by those skilled in the art that the aerosol formulations according to the invention may, , if desired, contain a combinafion of two or more active ingredients. Aerosol compositions containing two active ingredients ('m 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. or may be selected from any other suitable drug useful in inhalation therapy and which may be presented in a form which is substantially 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;
antiinfectives e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines 5 and pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives, e.g.
noscapine;
bronchadilators, e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rinuterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-10. a-[[[6-[Z-(2=pyridinyl)ethoxyJhexyllaminoJmethyl)benzenemethanol;.
diuretics, e.g.
amiloride=, anticholinergics e.g. ipratropium, atropi-ne 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 sotvates (e.g. hydrates) to optitnise the activity . and/or stability of the medicament and/or to mininuse the solubility of the medicarnent in the propellant.
Particularly preferred aerosol formulations contain salbutamol (e.g. as the free base or the sulphate salt) or salmeterol (e.g. as the xinafoate salt)=-in combination with an antiinflam.matory steroid such as a beclomethasone ester (e.g. the diproprionate) or a fluticasone ester (e.g. the propionate) or an'antiallergic such as cromoglycate (e.g. the sodium salt). Combinations of salmeterol- and fluticasone propionate or beclomethasone dipropionate, or salbutamol and #luticasone propionate or beclomethasone dipropionate are preferred, especially salmeterol. xinafoate and fluticasone propionate or salbutamol and beolomethasone dipropionate.
The formulations of the invention may be prepared by dispersal of the medicament in the selected propeilant in an appropriate -container, e.g. with the aid of sonication. The process is desirably carried out under anhydrous conditions to obviate any adverse effects ofmoisture 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 exceUent delivery characteristics suitable for use in pressurised inhalers, even after prolonged storage. .liitinimising 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 acceptabiGty of the aerosol fonmulations according to the invention may be determined by techniques well known to those skiIled in the art. Thus, for example, the chemical stabitity 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 distnbution of the aerosol formulations according to the invention is particularly impressive and may be measured by conventionaI techniques; for example by cascade impaction or by the "Twin Impinger" analytical process. As used herein reference to the "Twin Impinger" assay means "Detennination 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 impingement 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, preferabiy 25 to 70%, for example 30 to 60%..
Optionaily, 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 formulation is substantially free of surfactant. By "surface-modified rnedicament" =
is meant particles of medicament selected from the group consisting of salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof which= have been surface-modified by admixture with a substantially non-polar non-solvent liquid, followed by removal of the liquid. 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 rea~y 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 respect.
The medicament is desirably slurried 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 example by evaporation or by filtration followed by evaporation, provided that following treatment the medicasnent is substantially free of the tiquid. 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 filled into canisters suitable for delivering pharmaceutical aerosol formulations. Canisters 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, lacquer-coated and/or plastic-coated, which container is closed with a metering valve. The metering valves are designed to deliver a metered 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, clilorobutyi, black and white butadiene-acrylonitnle rubbers, butyl rubber and neoprene. Suitable valves are commercially available from manufacturers wett known in the aerosol industry, for example, from Valois, Fiance (e.g. DFIO, DF30, I)F60) , Bespak plc, UK (e.g.
BK300, BK356) and 3M-Neotechnic Ltd, UK (e.g. SpraycniseO'').
Conventional bulk manufacturing methods and machinery we11 known to those skilled=
in the art of pharmaceutical aerosol manufacture=may be employed for the preparation of large scale batches fbr the commercial production of filled canisters.. Thus, for example, in one bulk manufacturing method a metering valve is crimped onto an aluminium can to form an empty canister. The particulate medicament is:, added to a charge vessel and liquified propeIlant is pressure filted 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 flled canister is convenientiy. 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 channeIling devices comprise for example a valve actuator and a cylindricai or cone-like passage. through which medicament may -be delivered from the filled canister via the metering valve to the nose or mouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or "puff", for example in the range of t0 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 puffs each time.
Suitable daily doses, may be, for example in the range 50 to 200 microgram of salmeterol, I00. to 1000 microgram of salbutamol, 50 to 2000 microgram of fluticasone propionate or 100 to 2000- microgram of beclomethasone dipropionate, depending on the severity of the disease.
Thus, for example, each valve actuation may deliver 25 microgram salmeterol, microgram salbutamol, 25, 50, 125 or 250 microgram fluticasone propionate or 50, 100, 200 or 250 microgram beclomethasone dipropionate. Typically each filled canister for I 5 use in a metered dose inhaler contains 100, 160 or 240 metered = doses or puffs of medicament.
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 foranulation as herein described.
The following non-linutative Examples serve to illustrate the invention.
Example 1 Mioronised salmeterol xinafoate (24mg) was weighed into a clean, dry, plastic-coated glass bottle and 1,1,.1,2-tetrafluoroethane (18.2g) was added from a vacuum flask. The bottle was quickfy sealed with a blank aluminium ferrule. The resulting aerosol contained 0.132% salmeterol xinafoate.

Exam lpe2 1-~I'icronised salmeterol xinafoate (38.28g) and 1,1,I,2-tetrafluoroethane (36.36kg) were added to a pressure vessel and mixed with a high shear mixer for 20 minutes.
Aliquots (18.2g) of the suspension were filled into aluminium cans closed with a metering 5 valve, filling under pressure through the valve using conventional filling equiprnent_ The resulting inhalers contained 9.57mg salmeterol xinafoate and delivered 25 microgram salmeterol (39.9 microgram salt) per actuation_ xam e 3 10 Micronised fluticasone propionate (24mg) was weighed into a clean, tiry, plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (18.2g) was added from a vacuum flask. The bottle was quicldy sealed with a blank aluminium ferrule.
The resulting aerosol contained 0.132% '/,, fluticasone propionate.

Examples 4 and 5 Micronised fluticasone propionate (66mg or 6.6mg) was weighed d'Lrectly into each of 100 open aluminium cans and a metering v.alve was then crimped into place on each can. 1,1,1,2-TetratIuoroethane (18.2g) was then added to each canister under pressure, through'the valve, and each fllled canister shaken to disperse the drug. The resulting inhalers contained 66 or 6.6mg fluticasone propionate and delivered 250 -or 25 microgram fluticasone propionate per actuation (Examples 4 and 5 respectively).

x i 6 Ivficronised salbutamol (24mg) was weighed.into a clean, dry, plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (18.2g) was added from a vacuum flask.
The bottle was quickly sealed with a blank aluminium ferrule. The resulting aerosol contained 0.I32% "'/ salbutamol.

Examples 7 and 8 Micronised salbutamol (24mg or 48mg) was weighed directly into each of 3 open aluminium cans. 1, 1, 1,2-Tetrafluoroethane (I 8.2g) was added to each can from a vacuum flask and a metering valve was then crimped into place. l;'ach filled canister was then shaken- in an ultrasonic bath for 8 minutes. The resulting inhalers contained 24mg or 48mg salbutamol and . delivered 100 or 200 microgram salbutamol per actuation (Examples 7 and 8 respectively).

uam le 9 Micronised salbutamol sulphate (31.7mg) was weighed into a clean, dry,-plastic-coated glass bottle and .1,1,1,2-tetrafluoroethane (18.2g) was added from a vacuum flask. The bottle was quickly sealed with a blank aluminium ferrule.
The resulting aerosol contained 0.174%'"/,. salbutamol sulphate.

Example 10 Micronised salbutamol sulphate (31.7mg) was weighed directly into each of 4 open aluminium cans. 1,1,1,2-Tetrafluoroeth4ne (18.2g) was added to each can from a vacuum flask and a metering valve was then crimped- into place. Each filled canister was then shaken in an ultrasonic bath for 5 minutes. The resulting inhalers contained 31.7mg .20 salbutamol sulphate and delivered 100 microgram salbutamol per actuation.

ExampleIt Isopentane (25m1) was added to micronised salmeterol xinafoate (0.5g) to form a slurry, which was sonicated for 3 minutes. The result"ing suspension was dried by evaporating the isopentane at ambient temperature to yield surface-modified salmeterol .xinafoate. Samples of this product (11.6mg) were weighed into aluminium aerosol cans and 1,1, I,2-tetrafluoroethane ( I8.2g - 99.95% wlw of total fill weight) was added to each can, whereafter suitable metering valves were crimped onto the cans, which were then each sonicated for 5 minutes. The resulting aerosols contained salmeterol in an amount equivalent to 240actuations at 25 microgram per actuation.

Exa~tple 12 11rFcronised beclomethasone dipropionate monohydrate (68 mg) was weighed into a clean, dry, plastic-coated glass bottle and 1, 1, 1,2-tetrafluoroethane (to 18.2g) was added from a vacuum flask. The bottle was quickly sealed with a metering valve. The resulting aerosol dispensed 250 microgram beclomethasone dipropionate (as the monohydrate) per 75.8mg actuation.

Exam,pIe 13 Micronised salmeterol xinafoate (9.57mg) 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 filled canister sonica.ted-for five-minutes. The aerosol delivers 25 microgram salmeterol per actuation_ Examnle 14 Nl.icronised fluticasone propionate (13.3mg) 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 filled canister sonicated for five niinutes. The aerosol delivers 50 microgram fluticasone propionate per actuation.
Ex~e15 1lticronised salbutamol sulphate (29mg) was weighed directly into an aluminium can and 1,I,1,2,3,3,3-heptafluoro-n propane (to 21.4g) added from a vacuum flask.
A
metering valve was crimped into place and the filled canister sonicated for five minutes.
-The aerosol delivered 100 microgram salbutamol per actuation.

Example 16 Micronised beclomethasone diproprionate monohydrate (62mg) was 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 was crimped into place and the filled canister sonicated for five minutes. The aerosol delivered 250 microgram beclomethasone diproprionate per actuation.

Example 17 Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25 micrcigram Fluticasone propionate 0.066 50 microgram 1,111,2-Tetrafluoroethane to 100 to 75.8mg 1Wlieronised medicaments were weighed into an aluminium can, 1,.1;1,2-tetrafluoroethane (18.2g) was added from a vacuum flask and a.metering valve was crimped into place.
F.,xample 18 Per Inhaler % w/w Per Actuation .Satmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate 0.165 125 microgram 1,1,1,2 Tetrafluoroethane to 100 to 75.8mg Mieronised medicaments were weighed into an aluminium can, 1, 1, 1,2-tetrafluoroethane (18.2g) was added from a vacuum flask and a metering valve was crimped into place.

Exaxn l~e 19 Per Inhaler % w/w Per Actuation Satmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate. 0.132 100 microgram 1,1,1,2-Tetrafluoroethane to 100 to 75.8mg Exampjg 20 Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate 0.330 250 microgram .30 I,1,1,,2=Tetrafluoroethane to 100 to 75.8mg Bxample 21 Per Inhaler % w/w Per Actuation Salbutamol * 0.132 100 microgram Fluticasone propionate 0_ 132 100 microgram 1,1,1,2 Tetraltuoroethane to 100 to 75.8mg * as free base or an equivalent weight of salt e.g. sulphate Ex snnle22 Per Inhater % w/w Per Actuation Salbutamol * 0.264 200 microgram Fluticasone propionate 0.330 250 microgram 1,1,1,2 Tetrafluoroethane to 100 to 75.8mg * as free base or an equivalent weight of salt e.g. sulphate Exam-ple 23 Per Inhaler % w/w Per Actuation Salmeterbl xinafoate 0.048 36.25 microgram Beclomethasone dipropionate 0.066 50 microgram 1, 1, 1,2-Tetrafluoroethane to 100 to 75.8mg Exarpg 24 Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate 0.264 200 microgram 1,1,1,2-TetraSuoroethane to 100 to 75.8mg Example 25 Per Inhaler % w/w Per Actuation Salbutamol * 0.132 100 microgram Beclomethasone dipropionate 0.066 50 microgram 5 1,1,1,2-Tetrafluoroethane to 100 to 75.8mg * as free base or an equivalent weight of salt e.g. sulphate Example 26 Per Inhaler % w/w Per Actuation 10 Salbutamol * 0.264 200 microgram Beciomethasone dipropionate 0.264 200 microgram 1, 1, 1,2-Tetrafluoroethane to 100 to 75.8mg as free base or an equivalent weight of salt e.g. sulphate 15 In Examples 19 to 26 micronised medicaments are weighed into aluminium cans, 1, I,1;2 tetra$uoroethane (18.2g) is -added from a vacuum flask, and metering valves are crimped into place.

Claims (13)

CLAIMS:
1. A process for preparing a filled pharmaceutical aerosol canister which comprises:
(a) preparing a pharmaceutical aerosol formulation for use in the administration of a medicament by inhalation characterised in that it comprises particulate fluticasone propionate optionally in combination with salmeterol or a physiologically acceptable salt thereof as medicament having a particle size of less than 100 microns and 1,1,1,2-tetrafluoroethane as propellant, which formulation contains less than 0.0001% w/w surfactant based on weight of the medicament; and (b) filling the formulation into an aluminium can which is closed with a metering valve.
2. A process according to claim 1, wherein said medicament comprises said fluticasone propionate in combination with said salmeterol or a physiologically acceptable salt thereof.
3. A process according to claim 1 or 2, wherein step (a) the formulation is prepared by dispersing the medicament in the propellant.
4. A process according to claim 1, 2 or 3, wherein step (b) the metering valve is crimped onto the aluminium can to form an empty canister and an aliquot of the formulation is filled through the metering valve into the canister.
5. A process according to claim 1 which comprises:
(c) crimping a metering valve onto an aluminium can to form an empty canister;
(d) adding particulate medicament to a charge vessel and pressure filling liquefied propellant through the charge vessel into a manufacturing vessel to form a drug suspension;
(e) mixing the drug suspension before recirculation to a filling machine;
and (f) filling an aliquot of the drug suspension through the metering valve into the canister.
6. A process according to any one of claims 1 to 5, wherein the formulation consists essentially of particulate fluticasone propionate as medicament and 1, 1, 1,2-tetrafluoroethane as propellant.
7. A process according to any one of claims 1 to 5, wherein the formulation consists essentially of particulate salmeterol or a physiologically acceptable salt thereof in combination with particulate fluticasone propionate as medicament and 1,1,1,2-tetrafluoroethane as propellant.
8. A process according to any one of claims 1 to 5, wherein the formulation consists essentially of particulate salmeterol xinafoate in combination with particulate fluticasone propionate as medicament and 1,1,1,2-tetrafluoroethane as propellant.
9. A process according to any one of claims 1 to 8, wherein the aluminium can is anodised, lacquer coated and/or plastic coated.
10. A filled pharmaceutical aerosol canister obtained by the process according to any one of claims 1 to 9.
11. A process for preparing a metered dose inhaler which comprises fitting a canister according to claim 10 into a suitable channelling device.
12. A process according to claim 11, wherein the channelling device comprises a valve actuator.
13. A metered dose inhaler obtained by the process of claim 11 or 12.
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