AEROSOL CONTAINING MEDICAMENTS

Abstract: Aerosol formulations comprising: (A) a medicament selected from the group comprising salmeterol, fluticasone esters, 4-amino-3,5-dichloro- alpha -[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl] benzenemethanol and physiologically acceptable salts and solvates thereof in particulate form and having a surface coating of a surfactant; and (B) a hydrogen-containing fluorocarbon or chlorofluorocarbon propellant; and methods for their preparation.

Description: - l - ^ Aerosol containing medicaments. This invention relates to aerosol formulations of use in 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 Freon 11 (CCI3F) in admixture with Freon 12 (CCI2F2) and Freon 114 (CF2CI.C 2CI) . 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 hydrogen-containing chlorofluorocarbons and f luorocarbons; medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP 0372777. 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-tetraf luoroethane) 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". We have now surprisingly found that, in contradistinction to this teaching, it is in fact possible to obtain stable dispersions -* of certain finely-powdered medicaments together with certain surfactants in hydrogen- cont a i n ing fluorocarbon or chlorofluorocarbon propellants such as 1, 1,1, 2-tetraf luoroethane if the surfactant is present as a dry coating on the particles of medicament. More particularly, such stable dispersions may be formed where the medicament is selected from salmeterol, fluticasone esters, 4-amino-3, 5-dichloro-α- [ [ [ 6- [2- (2-pyridinyl) ethoxy] hexyl] amino]methyl]benzenemethanol, and physiologically acceptable salts and solvates thereof. This is in contrast to the procedure of EP 0372777, where the medicament and surfactant are simultaneously homogenised, e.g. in ethanol, prior to addition of the propellant. There is thus provided an aerosol formulation comprising (A) a medicament selected from the group comprising salmeterol, fluticasone esters, 4-amino-3 , 5-dichloro-α- [ [ [ 6- [ 2- (2 - pyridinyl) ethoxy] hexyl] amino] methyl] benzenemethanol, and physiologically acceptable salts and solvates thereof in particulate form and having a surf ce-coating of a surfactant; and (B) a hydrogen-containing fluorocarbon or chlorofluorocarbon propellant. The propellants for use in the invention may be any hydrogen- containing fluorocarbon or chlorofluorocarbon or mixtures thereof having a sufficient vapour pressure to render them effective as propellants. Such propellants include for example C 1 _ 4 hydrogen- containing f luorocarbons and chlorofluorocarbons such as CH2CIF, CC1F 2 -CHC1F, CF3-CHCIF, CHF 2 -CC1F 2 , CHC1F-CHF 2 , CF 3 -CH 2 C1, CHF 2 - CHF 2 , CF 3 -CH 2 F, CC1F 2 -CH 3 , CHF 2 -CH 3 and CF3CHFCF3. Where mixtures of the hydrogen-containing f luorocarbons or chlorofluorocarbons are employed they may be mixtures of the above identified compounds or mixtures, preferably binary mixtures, with other hydrogen-containing fluorocarbons or chlorofluorocarbons for example CHC1F 2 , CH 2 F 2 and CF3CH3. The propellant may additionally contain a volatile saturated hydrocarbon for example n-butane, isobutane, pentane and isopentane. Preferably a single hydrogen-containing fluorocarbon or chlorofluorocarbon is employed as the propellant. Preferably the propellant will be a non-solvent for the medicament. Particularly preferred as propellants are 1, 1, 1, 2-tetraf luoroethane (C .CH2 ) and 1, 1,1,2,3,3, 3-heptafluoro-n-propane (CF3.CHF.CF3) . 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 CCI3F, CC1 F 2 and CF3CCI3. It is further desirable that the formulations of the invention are substantially free of liquid components of higher polarity than the propellant employed. In particular formulations which are free of alcohols such as ethanol are preferable. Polarity may be determined for example, by the method described in European Patent Application Publication No. 0327777. As used herein "substantially free" means less than 1% w/w based upon the hydrogen-containing fluorocarbon or chlorofluorocarbon, in particular less than 0.5% for example 0.1% or less. 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) to optimise the activity and/or stability of the medicament and/or to minimise the * solubility of the medicament in the propellant. Fo r use in the f o rmulat ions o f the present invent ion , salmeterol will preferably be in the form of its l-hydroxy-2- naphthoate salt , the fluticasone ester will preferably be the propionate, and 4-amino-3, 5-dichloro-α- [ [ [6- [2- (2-pyridinyl) ethoxy] hexyl] amino] methyl] benzenemethanol will preferably be in the form of the (R) enantiomer . The surfactants for use in the invention will have no affinity for the propellant (that is to say they will contain no groups which have affinity with the propellant) . The surfactants must be physiologically acceptable upon administration by inhalation . Surfactants within this category include materials such as benzalkonium chloride, lecithin, oleic acid and sorbitan trioleate (Span R 85) . The use of substantially non-ionic surfactants which have rea sonable solubility in substantia lly non-polar solvents is " » f requently advantageous s ince it f ac i lit ates coat ing of the medicament particles using solutions of surfactant in non-polar ^ solvents in which the medicament has limited or minimal solubility. Thus according to a further aspect of the invent ion the s urf act ant-coated medicament may be prepared by s lurrying part iculate (e . g . micronised) medicament with a solution of a surfactant such as lecithin in a substantially non-polar solvent (e. g. a lower alkane such as isopentane or a chlorofluorocarbon such as trichlorof luoromethane) , optionally homogenising the slurry (e .g. by sonication) , removing the solvent and if necessary simultaneously and/or subsequently breaking up the resulting solid cake . The thus- obtained surfactant-coated particulate medicaments are novel and form a further feature of the invention . The formulations of the invention may be prepared by dispersing the surface-coated medicament , obtained as described above, in the chosen propellant in an appropriate aerosol container, e . g . with the aid of sonication . The particle size of the finely-powdered medicament should be such as to permit inhalation of substantially all of the medicament int o the bronchial system upon administ ration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and preferably in the range 2-10 microns, e .g. 2-5 microns . The amount of surfactant employed in coating the particulate medicament is desirably in the range 0 . 01 - 10 . 0% w/w, preferably 0 .05 - 5. 0% w/w, relative to the medicament, and may advantageously be chosen such that a substantially monomolecular coating of surfactant is formed . The final aerosol formulation desirably contains 0 . 005 - 5 . 0% w/w, preferably 0 . 01 - 1 . 0% w/w, of coated medicament relative to the total weight of the formulation . The following non-limitative Examples serve to illustrate the invention . EXAMPLE 1 (A) Preparation of Lecithin-coated Salmeterol Hvdroxynaphthoate (a) Lecithin (Epikuron 145V - 3 . 65mg) was dissolved in a small amount of isopentane and the resulting solut ion wa s added to micronised salmeterol hydroxynaphthoate (0.5g) . Further isopentane (7 .0g total) was added to form a slurry, which was sonicated for 3 minutes . The resulting suspension was dried by evaporating the isopentane at ambient temperature in a fume cupboard, whereafter the resulting dried plug was roughly broken up and then dried further in a vacuum oven . The thus-obtained product was further broken up using a mortar and pestle to yield lecithin-coated salmeterol hydroxynaphthoate containing 0 .73% w/w of lecithin relative to the salmeterol hydroxynaphthoate . (b) The above procedure was repeated except that 6.10mg of lecithin was employed, whereby a coated product containing 1 .22 % w/w of lecithin relative to the salmeterol hydroxynaphthoate was obtained. (c) The above procedure was again repeated except that 7 . 80mg of lecithin was employed, thereby yielding a coated product containing 1 .56% w/w of lecithin relative to the salmeterol hydroxynaphthoate . (B) Formulation of Lecithin-coated Salmeterol Hydroxynaphthoate in 1, 1, 1, 2-Tetraf luoroethane Samples of each of the products of Example IA (a) - (c) (9. 1mg) were weighed into aerosol cans . 1, 1, 1, 2-Tetraf luoroethane (18 .2g - 99.5% w/w of total fill weight) was added to each can, whereafter suitable metering valves were crimped onto the cans , which were then each s onicated f or 5 minutes . The resulting aeroso ls contained salmeterol in an amount equivalent to 240 actuations at 25yg per actuation. Example 2 (A) Preparation of lecithin-coated fluticasone propionate Lecithin (Epikuron 145V - 2.5mg) was dissolved in a small amount of isopentane and the resulting solution was added to micronised fluticasone propionate (0 .5g) . Further isopentane (20ml) was added to form a slurry, which was sonicated for 3 minutes . The resulting suspension was dried by evaporat ing the isopentane at ambient temperature in a fume cupboard, whereafter the resulting dried plug was roughly broken up and then dried further in a vacuum oven . The thus-obtained product was further broken up using a mortar and pestle to yield lecithin-coated fluticasone propionate containing 0 .5% w / w of lecithin relative to the fluticasone propionate . (B) Formulation of lecithin-coated fluticasone propionate in 1,1,1,2-tetrafluoroethane A sample of the product of Example 2(A) (9.1mg) was weighed into aerosol cans, 1,1,1,2-Tetrafluoroethane (18.2g - 99.5% w/w 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 fluticasone propionate in an amount equivalent to 240 actuations at 25μg per actuation. Example 3 (A) Preparation of Oleic Acid-coated Salmeterol Hydroxynaphthoate Oleic acid (lOmg) was dissolved in a small amount of isopentane and the resulting solution was added to micronised salmeterol hydroxynaphthoate (l.Og) . Further isopentane (25ml total) was added to form a slurry, which was sonicated for 3 minutes. The resulting suspension was dried by evaporating the isopentane at ambient temperature in a fume cupboard, whereafter the resulting dried plug was roughly broken up and then dried further in a vacuum oven. The thus-obtained product was further broken up using a mortar and pestle to yield oleic acid-coated salmeterol hydroxynaphthoate containing 1.0% w/w of oleic acid relative to the salmeterol hydroxynaphthoate. (B) Formulation of Oleic acid-coated Salmeterol Hydroxynaphthoate in 1,1,1,2-Tetrafluoroethane Samples of the product of Example 3A (9.1mg) were weighed into aerosol cans. 1,1,1,2-Tetrafluoroethane (18.2g - 99.5% w/w 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 240 actuations at 25μg per actuation. Example 4 (A) Preparation of Sorbitan Trioleate-coated Salmeterol Hydroxynaphthoate Sorbitan trioleate (Span 85-10mg) was dissolved in a small amount of isopentane and the resulting solution was added to micronised salmeterol hydroxynaphthoate (l.Og) . Further isopentane (25ml total) was added to form a slurry, which was sonicated for 3 minutes. The resulting suspension was dried by evaporating the isopentane at ambient temperature in a fume cupboard, whereafter the resulting dried plug was roughly broken up and then dried further in a vacuum oven. The thus-obtained product was further broken up using a mortar and pestle to yield sorbitan trioleate-coated salmeterol hydroxynaphthoate containing 1.0% w/w of sorbitan trioleate relative to the salmeterol hydroxynaphthoate . (B) Formulation of Sorbitan Trioleate-coated Salmeterol Hydroxynaphthoate in 1, 1, 1,2-Tetraf luoroethane Samples of the product of Example 4A (9.1mg) were weighed into aerosol cans. 1, 1, 1,2-Tetraf luoroethane (18.2g - 99.5% w/w 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 240 actuations at 25μg per actuation.

Claims: Claims 1. An aerosol formulation comprising : (A) a medicament selected from the group comprisin salmeterol, fluticasone esters, 4-amino-3, 5-dichloro-α [ [ [6- [2- (2-pyridinyl) ethoxy] hexyl ] amino ] methyl] benzenemethanol and physiologically acceptable salts an solvates thereof in particulate form and having a surfac coating of a surfactant; and (B) a hydrogen-containing fluorocarbon or chlorofluorocarbo propellant . 2. A formulation as claimed in Claim 1 wherein the propellan comprises 1, 1, 1,2-tetrafluoroethane or 1, 1, 1,2, 3, 3, 3-heptafluoro propane . 3. A formulation as claimed in Claim 1 wherein the propellan comprises 1, 1, 1, 2-tetraf luoroethane. 4. A formulation as claimed in any one of Claims 1 to 3 which i substantially free of chlorofluorocarbons. 5. A formulation as claimed in any one of Claims 1 to 4 which i substantially free of liquid components of higher polarity than th propellant . 6. A formulation as claimed in any one of Claims 1 to 5 wherei the coated medicament has a particle size of less than 100 microns. 7. A formulation as claimed in any one of Claims 1 to 6 wherei the surfactant is present in an amount of from 0.01 to 10% w/w base on the medicament. 8. A formulation as claimed in any one of Claims 1 to 7 wherein the surfactant is selected from benzalkonium chloride, lecithin, oleic acid and sorbitan trioleate. 9. A formulation as claimed in- any one of Claims 1 to 8 wherein the surfactant-coated medicament is present in an amount of 0.005-5% w/w based upon the total weight of the medicament. 10. A formulation as claimed in any one of Claims 1 to 9 wherein the medicament is salmeterol in the form of its l-hydroxy-2- naphthoate salt. 11. A formulation as claimed in any one of Claims 1 to 9 wherein the medicament is fluticasone propionate. 12. A formulation as claimed in any one of Claims 1 to 9 wherein the medicament is the (R) enantiomer of 4-amino-3,5-dichloro-α-[ [ [6- [2-(2-pyridinyl)ethoxy]hexyl]amino] methyl]benzenemethanol. 13. A method for the preparation of an aerosol formulation comprising dispersing a surface-coated medicament selected f om the group comprising salmeterol, fluticasone esters, 4-amino-3,5- dichloro-α-[ [ [6-[2- (2-pyridinyl) ethoxy] hexyl] amino]methyl] benzenemethanol and physiologically acceptable salts and solvates thereof in a hydrogen-containing fluorocarbon or chlorofluorocarbon propellant in an aerosol container. 14. A method as claimed in Claim 13 wherein the surface-coated medicament is obtained by slurrying particulate medicament with a solution of a surfactant in a substantially non-polar solvent and then removing the solven .

Inventors: BURNELL PATRICIA KWONG PHIEU, TAYLOR ANTHONY JAMES, BURNELL, PATRICIA, KWONG, PHIEU, TAYLOR, ANTHONY, JAMES
Applicants: GLAXO GROUP LTD, GLAXO GROUP LIMITED
Application year: 1991
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K47, A61P29