Aerosol compositions

Abstract: This invention relates to aerosol formulations of use for the administration of medicaments by inhalation, in particular a pharmaceutical aerosol formulation which comprises particulate medicament selected from the group comprising salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant, which formulation is substantially free of surfactant. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of a pharmaceutical aerosol formulation as defined is also described.

Description: This invention relates to aerosol formulations of use for the administration of medicaments by inhalation. 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 11 (CCl 3 F) and/or propellant 114 (CF 2 ClCF 2 Cl) with propellant 12 (CCl 2 F 2 ). 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-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 , WO91/04011 , WO91/11173 , WO91/11495 and WO91/14422 . 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 stability associated 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 surfactants, carboxylic acids, polyethoxylates etc) and even conventional chlorofluorocarbon propellants 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 cosolvent having greater polarity than 1,1,1,2-tetrafluoroethane (e.g. an alcohol or a lower alkane) and a surfactant in order to achieve a stable formulation of 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 WO91/11173 , WO91/11495 and WO91/14422 are concerned with formulations comprising an admixture of drug and surfactant, WO91/04011 discloses medicinal aerosol formulations in which the particulate medicaments are pre-coated with surfactant prior to dispersal in 1,1,1,2-tetrafluoroethane. WO92/08447 discloses formulations comprising a drug which is surface coated with a surfactant and a hydrofluorocarbon propellant. WO91/11496 discloses use of HFA227 as an alternative propellant optionally in admixture with another propellant gas. US3,320,125 discloses CFC-containing pharmaceutical aerosol formulations in which use of sorbitan trioleate is avoided by use of propellant 11 at a concentration of 5-50%. We have now surprisingly 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-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. There is thus provided in one aspect of the invention a pharmaceutical aerosol formulation for use in the administration of medicaments by inhalation characterised in that it consists essentially of particulate medicament which is salmeterol or a physiologically acceptable salt thereof and fluticasone propionate in combination and 1,1,1,2-tetrafluoroethane as propellant and that the formulation is free of surfactant, wherein said formulation contains medicament in an amount of 0.01% to 1% w/w relative to the total weight of the formulation. By 'free of surfactant' is meant formulations which contain no significant amounts of surfactant, for example less than 0.0001% by weight of the medicament. There is also provided a pharmaceutical aerosol formulation for use in the administration of medicaments by inhalation characterised in that it consists of particulate medicament which is salmeterol or a physiologically acceptable salt thereof and fluticasone propionate in combination and 1,1,1,2-tetrafluoroethane as propellant, wherein said formulation contains medicament in an amount of 0.01% to 1% w/w relative to the total weight of the formulation. As another aspect the present invention provides use of a pharmaceutical aerosol formulation as hereinbefore defined for the manufacture of a medicament for administration by inhalation for the treatment of respiratory disorders. 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 of the present invention 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. The propellant for use in the invention is 1,1,1,2-tetrafluoroethane which has a sufficient vapour pressure to render it effective as a propellant. 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 chlorofluorocarbons such as CCl 3 F, CCl 2 F 2 and CF 3 CCl 3 . Further, formulations which are substantially free of volatile adjuvants such as a saturated hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyl ether, are preferred. 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) to optimise the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant. Particularly preferred aerosol formulations contain a combination of salmeterol xinafoate and fluticasone propionate. The formulations of the invention may be prepared by dispersal of the medicament in the selected propellant 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 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. 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 known 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 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, preferably 25 to 70%, for example 30 to 60%. The formulations for use in 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 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 gasketto 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, BK356) and 3M-Neotechnic Ltd, UK (e.g. Spraymiser ™ ). 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 large scale batches for 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 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 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 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 1 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 and 50 to 2000 microgram of fluticasone propionate, depending on the severity of the disease. Thus, for example, each valve actuation may deliver 25 microgram salmeterol and 25, 50, 125 or 250 microgram fluticasone propionate. Typically each filled canister for use in a metered dose inhaler contains 100, 160 or 240 metered doses or puffs of medicament. Respiratory disorders such as, for example, asthma, can be treated by the 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 Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate 0.066 50 microgram 1,1,1,2-Tetrafluoroethane to 100 to 75.8mg Micronised 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. Example 2 Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate 0.165 125 microgram 1,1,1,2-Tetrafluoroethane to 100 to 75.8mg Micronised 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. Example 3 Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate 0.132 100 microgram 1,1,1,2-Tetrafluoroethane to 100 to 75.8mg Example 4 Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate 0.330 250 microgram 1,1,1,2-Tetrafluoroethane to 100 to 75.8mg Example 5 Per Inhaler % w/w Per Actuation Salmeterol xinafoate 0.048 36.25 microgram Fluticasone propionate 0.264 200 microgram 1,1,1,2-Tetrafluoroethane to 100 to 75.8mg In Examples 3 to 5 micronised medicaments are weighed into aluminium cans, 1,1,1,2-tetrafluoroethane (18.2g) is added from a vacuum flask, and metering valves are crimped into place.

Claims: A pharmaceutical aerosol formulation for use in the administration of medicaments by inhalation characterised in that it consists essentially of particulate medicament which is salmeterol or a physiologically acceptable salt thereof and fluticasone propionate in combination and 1,1,1,2-tetrafluoroethane as propellant, and that the formulation is free of surfactant, wherein said formulation contains medicament in an amount of 0.01 to 1% w/w relative to the total weight of the formulation. A pharmaceutical aerosol formulation for use in the administration of medicaments by inhalation characterised in that it consists of particulate medicament which is salmeterol or a physiologically acceptable salt thereof and fluticasone propionate in combination and 1,1,1,2-tetrafluoroethane as propellant, wherein said formulation contains medicament in an amount of 0.01 to 1% w/w relative to the total weight of the formulation. A formulation as claimed in claim 1 or claim 2 wherein salmeterol is present as the xinafoate salt. A pharmaceutical aerosol formulation according to claim 3 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.066% w/w. A pharmaceutical aerosol formulation according to claim 3 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.165% w/w. A pharmaceutical aerosol formulation according to claim 3 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.132% w/w. A pharmaceutical aerosol formulation according to claim 3 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.330% w/w. A pharmaceutical aerosol formulation according to claim 3 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.264% w/w. A pharmaceutical aerosol formulation according to any one of claims 1 to 8 wherein the use is use in the treatment of respiratory disorders. A pharmaceutical aerosol formulation according to claim 9 wherein the respiratory disorder is asthma. The use of a pharmaceutical aerosol formulation according to any one of claims 1 to 8 for the manufacture of a medicament for administration by inhalation for the treatment of respiratory disorders. The use of a pharmaceutical aerosol formulation according to claim 11 wherein said respiratory disorder is asthma. A canister comprising a container closed with a metering valve which contains a pharmaceutical aerosol formulation according to any one of claims 1 to 8. A canister according to claim 13 wherein the container is an aluminium can. A canister according to claim 14 wherein the aluminium can is anodised, lacquer coated and/or plastic coated. A metered dose inhaler which comprises a canister according to any of claims 13 to 15 fitted into a suitable channelling device. A process for the preparation of a pharmaceutical aerosol formulation for use in the administration of medicaments by inhalation characterised in that it consists essentially of particulate medicament which is salmeterol or a physiologically acceptable salt thereof and fluticasone propionate in combination and 1,1,1,2-tetrafluoroethane as propellant, and that the formulation is free of surfactant, wherein said formulation contains medicament in an amount of 0.01% to 1% w/w relative to the total weight of the formulation, which process comprises dispersing the medicament in the propellant. A process for the preparation of a pharmaceutical aerosol formulation for use in the administration of medicaments by inhalation characterised in that it consists of particulate medicament which is salmeterol or a physiologically acceptable salt thereof and fluticasone propionate in combination and 1,1,1,2-tetrafluoroethane as propellant, wherein said formulation contains medicament in an amount of 0.01% to 1% w/w relative to the total weight of the formulation, which process comprises dispersing the medicament in the propellant. A process as claimed in claim 17 or claim 18 wherein salmeterol is present as the xinafoate salt. A process according to claim 19 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.066% w/w. A process according to claim 19 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.165% w/w. A process according to claim 19 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.132% w/w. A process according to claim 19 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.330% w/w. A process according to claim 19 wherein salmeterol xinafoate is present in the formulation at a concentration of 0.048% w/w and fluticasone propionate is present in the formulation at a concentration of 0.264% w/w.

Inventors: MARRIOTT RACHEL ANN, TAYLOR ANTHONY JAMES, WYATT DAVID ANDREW, MARRIOTT, RACHEL ANN, TAYLOR, ANTHONY JAMES, WYATT, DAVID ANDREW
Applicants: GLAXO GROUP LTD, GLAXO GROUP LIMITED
Application year: 1992
Main classification: A61K9
IPC codes: A61K31, A61K9, A61P11, A61K45, A61K47, A61M15