CA2368934A1 - Metered dose inhaler for fluticasone propionate - Google Patents

Abstract

An inhalation pharmaceutical preparation comprises an inhalation drug formulation comprising fluticasone propionate or a physiologically acceptable solvate thereof and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients, in a metered dose inhaler having part or all of its internal surfaces coated with a polymer blend comprising one or more fluorocarbon polymers in combination with one or more non-fluorocarbon polymers.

Description

this Application is a Division of Canadian Patent Application S:N:

2,227,948, filed Apri1 10, 1996:
BACKGROUND OF THE INV'ENTtON
Drugs for treating respiratory and nasal disorders are frequently administered in aerosol formulations through the mouth or nose.. One widely used method for dispensing such aerosol drug formulations involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. The suspension is stored in a seated container capable of withstanding the pressure required to maintain the propellant as a liquid. The suspension is dispersed by activation of a dose metering valve affixed to the container.
A metering valve may be designed to consistently release a fixed, predetermined mass of the drug formulation upon each activation. As the suspension is forced from the container through the dose metering valve by the high vapor pressure of the propellant, the propellant Papidiy vaporizes leaving a fast moving cloud of very fine particles of the drug formulation. This cloud of particles is directed into the nose or mouth of the patient by a channelling device such as a cylinder or open-ended cone. Concurrently with the activation of the aerosol dose metering valve, the patient inhales the drug particles into the lungs or nasal cavity. Systems of dispensing drugs in this way are known as "metered dose inhalers"(MDI's). See Peter Byron, Respiratory Drug Delivery, CRC Press, Boca Raton, FL (1990) for a genera( background on this form of therapy.
Patients often rely on medication delivered by MDI's for rapid treatment of respiratory disorders which are debilitating and in some cases, even life threatening. Therefore, it is essential that the prescribed dose of aerosol medication delivered to the patient consistently meet the specifications claimed by the manufacturer and comply with the requirements of the FDA and other regulatory authorities. That is, every dose in the can must be the same within close tolerances.

Some aerosol drugs tend to adhere to the inner surfaces, i.e., watts of the can, valves, and caps, of the MDI. This can lead to the patient getting significantly less than the prescribed amount of drug upon each activation of the MDI. The problem is particutarfy acute with hydroftuoroalkane (also known as simply "ftuorocarbon'~ propellant systems, e.g., P134a and P227, under development in recent years to replace chloroftuorocarbons such as P11, P114 and P12.
We have found that coating the interior can surfaces of MDt's with a fluorocarbon polymer significantly reduces or essentially eliminates the prabtem of adhesion or deposition of fluticasone propionate on the can watts and thus ensures consistent delivery of medication in aerosol from the MDt.
SUMMARY OF THE lNVENTfON
In one aspect of the invention there is provided an inhalation pharmaceutical preparation comprising an inhalation drug formulation which comprises fluicasone propionate or a physiologically acceptable solvate thereof and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients, in a metered dose inhaler having part or all of its internal surfaces coated with a polymer blend comprising one or more fluorocarbon pol~,lmers in combination with one or more non-fluorocarbon polymers.

In another aspect of the invention there is provided use of an inhalation drug formulation comprising fluticasone propionate or a physiologically acceptable solvate thereof and a fluorocarhon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients, for the treatment of respiratory and nasal disorders, the formulation being dispensed in a metered dose inhaler having part or all of its internal surfaces coated with a polymer blend comprising one or more fluorocarbon polymers in combination with one or more non-fluorocarbon polymers.
DETAILED DESCRIPTION OF TEIE tNVENTiON
The term "metered dose inhaler" or 'MDi' means a unit comprising a can, a crimped cap covering the mouth of, the can, and a drug metering valve situated in the cap , while the term 'MDl system' also includes a suitable channelling device.
The terms 'MDl can" means the container without the cap and valve. The term 'drug metering valve" or 'MDI valve" refers to a valve and its associated mechanisms which delivers a predetermined amount of drug formulation from an MDI upon each activation. The channelling device may comprise; for example, an actuating device for the valve and a cylindrical or cone-(ike passage tt-~rough which medicament may be delivered from the filled MDl can via the MDI valve to the nose or mouth of a patient, e.g. a mouthpiece actuator. The relation of the parts of a typical MDi is ihustrated in US Patent 5,261,538:
The temp "fluorocarbon polymers" means a polymer in which one or more of the hydrogen atoms of the hydrocarbon chain have been replaced by fluorine atoms.
Thus, "fluorocarbon polymers" include perfiuorocarbon, hydrofiuorocarbon, chlorofiuorocarbon, hydro-chioroffuorocarbon polymers or other halogen substituted derivatives thereof. The "fluorocarbon polymers" may be branched, homo-polymers or co-polymers.
U.S. Patent No. 4,335,121, teaches an antiinflammatory steroid compound known by the chemical name [(6a, 11b, 16a, i7a)-6, 9-difiuoro-11-hydroxy-16=methyl-3-oxo-1~-(1-oxopropoxy}- androsta-1, 4-diene-17-carbothioic acid, S-fiuoromethyi ester and the generic name 'fluticasone propionate'. Fiuticasone propionate in aerosol form, has been accepted by the medical community as useful in the treatment of asthma and is marketed under the. trademarks 'Flovent ' and "Flonase'. Fiuticasone propionate may also be used in the form of a physiologically acceptable solvate.
The term 'drug formulation' means fiuticasone propionate (or a physiologically acceptable solvate thereof) optionally in combination with one or more other pharmacologically active agents such as other antiinf(ammatory agents, analgesic agents oc other respiratory drugs and optionally containing one or more excipients, and a fluorocarbon propellant. The term "exc(pients" as used herein means chemical agents having little or no pharmacological activity (for the quantities used) but which enhance the drug formulation or the performance of the MDl system. For example, excipients include but ace not (invited to surfactants, preservatives, flavorings, antioxidants, antiaggregating agents, and cosoivents, e.g., ethanol and diethyl ether.

Suitable surfactants are generally known in the art, for example, those surfactants disclosed in EP 0327777, published 16.08.89. The amount of surfactant employed is desirably in the range of 0.0001% to 50% weight to weight ratio relative to the drug, in particular 0.05 to 5% weight to a weight ratio. A

A~
particularly useful surfactant is 1,2-di[7-(F-hexyl) hexanoytj-glycero-3-phospho-N,N,N-trimethylethanolamine also knovsm as 3, ~, 9-trioxa-4-phosphadocosan-1-aminium, 17, i 7, 18, 18, 19, 19, 20, 20, 21, 21, 22, 22, 22-tridecaftuoro-7-[(8, 8, 9, 9, 10, 10, 11, 11, 12, 12, 13, 13; 13-tridecafluoro-1-oxotridecyl)oxyj-4-hydroxy-N, N,N-trimethyl-10-oxo-, inner salt, 4-oxide.
A polar cosolvent such as Cz~ aliphatic alcohots and polyols e.g. ethanol, isopropanol and propylene glycol, preferably ethanol, may be included in the drug formulation in the desired amount, either as the only excipient or in addition to other excipients such as surfactants. Suitably, the drug formulation may contain 0:01 to 5% w/w based on the propellant of a polar cosolvent e.g. ethanol, preferably 0.1 to 5% w/w e.g. about 0.1 to 1 % w/Hr.
tt will be appreciated by those skilled in the art that the drug formulation for use in 18 the invention may, if desired, contain fluticasone propionate (or a physiologically acceptable solvate thereof) in combination with one or more other pharmacologically active agents. Such medicaments may be selected from any suitable drug useful in inhalation therapy. Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dlhydromo~phine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diitiazem;
antiatlergics, e.g. cromoglycate, ketotifen or nedocromil; antiinfectives e.g.
cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories; e.g.
bectomethasone (e.g. the dipropionate), flunisollide, budesonide, tipredane or 2~ triamcinolone acetonide; antitussives, e.g. noscapine; bronchodtlators, e.g.
salbutamot, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutatine, isoetharine, tulobuterol, orc;iprenaline, or (-)-4-amino-3,5-d i c h 1 o ro- cc -jj(6-[2-(2-pyridinyl)ethoxyjhexyljaminojmethyljbenzenemethanol; .
diuretics, e.g. amiloride; anticholinergics e.g. iprat:ropium, atropine or oxitropium;
hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthine~ e.g. .
aminophyltine, choline theophyltinate, lysine theophyllinate or theophylfine;
and therapeutic proteins acid 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 s 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 medicament in the propellant.
Particularly preferred drug formulations contain fluticasone propionate (or a physiologically acceptable solvate thereof) in combination with a bronchodilator such as salbutamol (e.g. as the free base or the sulphate salt) or salmeterol {e.g.
as the xinafoate salt).
A particularly preferred drug combination is fiuticasone propionate and salmeterol xinafoate.
'Propellants' used herein mean pharmacologically inert liquids with boiling points from about room temperature (25°C) to about -25°C which singly or in combination exert a high vapor pressure at room temperature. Upon activation of the MDI system, the high vapor pressure of the propellant in the MDI forces a metered amount of drug fomnulation out through the metering valve then the propellant very rapidly vaporizes dispersing the drug particles. The propellants used in the present invention are low boiling fluorocarbons; in particular, y,1,1,2-tetrafluoroethane also known as "propellant 134x" or "P 134a" and 1,1,1,2,3,3,3-heptafluoro-n-propane also known as "propellant 227" or "P 227".
Drug formulations for use in the invention may be free or substantially free of formulation excipients e.g. surfactants and cosoivents etc. Such drug formulations are advantageous since they may be substantially taste and odour free, less irritant and less toxic than excipient-containing formulations.
Thus, a preferred drug formulation consists essentially of fluticasone propionate, or a physiciologically acceptable solvate thereof, optionally in combination with one or more other pharmacologically active agents particularly salmeterol (e.g. in the form of the xinafoate salt), and a fluorocarbon propellant. Preferred propellants: and 1,1,i,2-tetrafluoroethane, 1, l,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof, and especially 1,1,1,2-tetrafluoroethane.

Further drug formulations for use in the invention may be free or substantially free of surfactant. Thus, a further preferred drug formulation comprises or consists essentially of albuterol (or aphysiciologically acceptable solvate thereof), optionally in combination with one or more other pharmacologically active agents a fluorocarbon propellant and 0.01 to 5% w/w based on the propellant of a polar cosolvent, which formulation is substantially free of surfactant. Preferred propellants and 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or mixtures thereof, and especially 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoro-n-propane:
Most often the MDI can and cap are made of alurninurn or an alloy of aluminum, although other metals not affected by the drug formulation, such as stainless steel, an alloy of copper or tin plate, may be used. An MDI can may also be fabricated from glass or plastic. Preferably, however, the MDI cans employed in the present invention are made of aluminium or an alloy thereof.
Advantageously, strengthened aluminium or aluminum alloy MDl cans may be employed. Such strengthened MDl cans are capable of withstanding particularly stressful coating and curing conditions, e.g. particularly high temperatures, which may be required for certain fluorocarbon polymers. Strengthened MDI cans which have a reduced tendency to malform under' high temperatures include MDl cans comprising side walls and a base of increased thickness and MDi cans comprising a substantially ellipsoidal base (which increases the angle between the side walls and the base of the can), rather than the hemispherical base of v standard MDl cans. MDi cans having an ellipsoidal base offer the further advantage of facilitating the coating process.
The drug metering valve consists of parts usually made of stainless steel, a pharmacologically inert and propellant resistant polymer, such as acetal, polyamide (e.g., Nylon~), poiycarbonate, polyester, fluorocarbon polymer (e.g., Teflon~) or a combination of these materials. Additionally, seals and "O"
rings of various materiats (e.g., nitrite rubbers, polyurethane, acetyl resin, fluorocarbon polymers), or other elastomeric materials are employed in and around the valve.

Fluorocarbon polymers for use in the invention include fluorocarbon polymers which are made of multiples of one or more of the following monomeric units:
tetrafluoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane (PFA), ethylene tetrafluoroethylene (ETFE), vinytdienefiuoride (PVDF), and chlorinated ethylene tetrafluoroethylene.
Fluorinated polymers which have a relatively high ratio of #luorine to carbon, such as perftuorocarbon polymers e.g. PTFE, PFA, and FEP, are preferred.
The fluorinated polymer may be blended with non-#luorinated polymers such as . 70 polyamides, polyimides, polyethersulfones; poiyphenylene sulfides and amine-formaldehyde thermosetting resins. These added polymers improve adhesion of the polymer coating to the can walls. Preferred polymer blends are PTFE/FEP/polyamideimide, PTFElpolyethersulphone (PES) and FEP-benzoguanam ine.
Particularly preferred coatings are pure PFA, FEP and blends of PTFE and polyethersulphone (PES).
Fluorocarbon polymers are marketed under trademarks such as Teflon, Tefzel~, Halar~ , Hostaflon~ Potyflon~ and Neoflon~. Grades of polymer include FEP
DuPont 856-200, PFA DuPont 857.-200, PTFE-PES DuPont 3200-100, PTFE-FEP-polyamideimide DuPont 856P23485, FEP powder DuPont 532, and PFA
Hoechst 6900n. The coating thickness is in the range of. about 1 dun to about mm. Suitably the coating thickness is in the range of about 1 Eam to about 100 um, e.g. 1 Fun to 25 Vim. Coatings may be applied in one or more coats.
Preferably the fluorocarbon polymers for use in the invention are coated onto MDI
cans made of metal, especially MDI cans made ~of aluminium or an alloy thereof.
The particle size of the particular (e.g., micronised) drug should be such as to permit inhalation of substantially all the drug into the lungs upon adrninistrntion of the aerosol formulation and will thus be less ,than 100 microns, desirably less than 20 microns, and, in particular, in the range of 1-10 microns, e.g., t-5 microns.

The final drug formulation desirably contains 0.005-10% weight to weight ratio, in particular 0.005-5% weight to weight ratio, especially 0.01-1.0% weight to weight ratio, of drug relative to the total weight of the formulation.
A further aspect of the present invention is a metered dose inhaler having part or all of its internal metallic surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, for dispersing an inhalation drug formulation cornprising fluticasone propionate y0 and a fluorocarbon propellant optionally in combination with one or more other pharmacologically active agents and one or more excipients.
A particular aspect of the present invention is an A~1D1 having part or essentially all of its internal metallic surfaces coated with PFA or FEP, or blended fluoropolymer resin systems such as PTFE-PES with or without a primer coat of a polyamideimide or poiyethersulfone for dispensing a drug formulation as defined hereinabove. Preferred drug formulations for use in this MDl consist essentially of ffuticasone propionate (or a physiologically acceptable solvate, thereof), optionally in combination with one or more other pharmacoiogically active agents particularly salmeterol (e.g. in the form of the xinafoate salt), and a fluorocarbon propellant, particularly 1,1,1,2-tetrafluoroethane; 1,1,1,2,3,3,3 . heptafluoropropane or mixtures thereof, and especially 1,1,1,2-tetrafiuoroethane.
Preferably the MDI can is made of aluminium or an alloy thereof.
The MDf can may be coated by the means known in the art of metal coating. For example, a metal, such as aluminum or stainless steel, may be precoated as coil stock and cured before being stamped or drawn into the can shape. This method is well suited to high volume production for two rE~asons. First, the art of coating coil stock is well developed and several manufacturers can custom coat metal coil stock to high standards of uniformity and in a wide range of thicknesses.
Second, the precoated stock can be stamped or drawn at high speeds and precision by essentially the same methods used to draw or stamp uncoated stock.

Other techniques for obtaining coated cans is by electrostatic dry powder coating or by spraying preformed MDI cans inside with formulations of the coating fluorinated polymerlpolymer blend and then curing. The preformed MDI cans may also be dipped in the fluorocarbon p~oiymerlpolymer blend coating formulation and cured, thus becoming coated on the inside and out. The fluorocarbon polymerlpolymer blend formulation may also be poured inside the MDI cans then drained out leaving the insides with the polymer coat.
Conveniently, for ease of manufacture, preformed MDl cans are spray-coated with the fluoririated polymer/polymer blend.
The fluorocarbon polymer/polymer blend may also be formed in situ at the can walls using plasma polymerization of the fluorocarbon monomers. Fluorocarbon polymer film may be blown inside the MDI cans to form bags. A variety of fluorocarbon polymers such as ETFE, FEP, and PTFE are available as film stack.
The appropriate curing temperature is dependent on the fluorocarbon polymerlpolymer blend chosen for the coating and the coating method employed.
However, for coif coating and spray coating temp~aratures in excess of the rnetting point of the polymer are typically required, for example, about 50°C
above the 2D melting point, for up to about 20 minutes such as about 5 to 10 minutes e.g.
about 8 minutes or as required. For the above named preferred and particularly preferred fluorocarbon poiymer/polymer blends curing temperatures in the range of about 300°C to about 400°C, e.g. about 350°C to 380°C are suitable for plasma pofymeri2ation typically temperatures in the range of about 20°C
to about 100°C may be employed.
The MDl's taught herein may be prepared by methods of the art (e.g., see Byron, above and U.S. patent 5,345,980} substituting conventional cans for those coated with a fluorinated polymer/polymer blend. That is, fluticasone propionate and other components of the formulation are filled ini;o an aerosol can coated with a fluorinated polymerlpolymer blend. The can is fitted with a cap assembly waich is crimped in place. The suspension of the drug in the fluorocarbon propellant in liquid form may be introduced through the metering valve as taught in U.S.
5,345,980 .

~1 The MDI's with fluorocarbon polymer/polymer blend coated interiors; taught herein may be used in medical practice in a similar manner as non-coated MDI's now in clinical use. However the MDI's taught herein are p~articulariy useful for containing and dispensing inhaled drug formulations with hydrofluoroalkaneftuorocarbon propellants such as 134a with little, or essentially no, excipient and which tend to deposit or cling to the interior walls and parts of the MDI system. In certain cases it is advantageous to dispense an inhalation drug) with essentially no excipient, e.g., where the patient may be allergic to an excip~ient or the drug reacts with an i0 excipient.
MDI's containing the formulations described hereinabove, MDI systems and the use of such MDl systems for the treatment of respiratory disorders e.g. asthma comprise further aspects of the present invention.

1t will be apparent to those skilled in the art that modifications to the invention described herein can readily be made without departing from the spirit of the invention: Protection is sought for all the subject matter described herein including any such modifications.
The following non-iimitative Examples serve to iltustrate the invention.
EXAMPLES
Example ~
Standard 12.5 ml MDI cans (Presspart Lnc., Cary, NC) were spray-coated (Livingstone Coatings, Charlotte, NC) with primer (DuPont 85i-204) and cured to the vendor's standard procedure, then further spray-coated with either FEP or PFA (DuPont 856-200 and 857-200, respectively) and cured according to the vendor's standard procedure. The thickness of the coating is approximately 10 ~.m to 50 Ir.m. These cans are then purged of air {see PCT application number W094122722 (PCT/EP94/00921 )); the valves crimped in place, and a suspension of about 20 mg fluticasone propionate in about 12 gm P134a is filled through the valve.
~xars Standard 0.46 mm thick aluminum sheet (United Aluminum) was spray-coated (DuPont, Wilmington, DE) with FEP {DuPont 856-200) and cured. This sheet was then deep-drawn into cans (Presspart Inc., Cary, NC). The thickness of the coating is approximately 10 um to 50 u.m. These cans are then purged of air, the valves crimped in place, and a suspension of about 40 mg fituticasone propionate in about 12 gm P134A is filled through the valve.
Standard 12.5 ml MDI cans {Presspart inc., Cary NC) are spray-coated with PTFE-PES blend (DuPont) as a single coat and cured according to the vendor's standard procedure. The thickness of the coating is between approximately 1 Eun and approximately 20 um. These cans are then purged of air, the valves crimped in place, and a suspension of about 41.0 mg, 21.0 mg, 8.8 mg or 4.4 mg micronised fluticasone propionate in about 12 g P134a is filled through the valve.
Exasn~ lp a 4 Standard 12.5 mi MDf cans (Presspart Inc., Cary NC) are spray-coated with PTFE-FEP-polyamideimide blend (DuPont) and cured according to the vendor's standard procedure. The thickness of the coating is between approximately 1 dun and approximately 20 p.m. These cans are then purged of air the valves crimped in place, and a suspension of about 41.0 mg, 21.0 mg, 8.8 mg or 4.4 mg ' micronised fluticasone propionate in about 12 g P134a is filled through the valve.
' ~camr~te 5 Standard 12.5 mi MDi cans (Presspart Inc., Cary NC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating is between approximately 1 Nm and appro;~cimately 20 ~.m. These cans are then purged of air, the valves crimped in place, and a suspension of about , 41.0 mg. 21.0 mg, 8.8 mg or 4.4 mg micronised ftuticasone propionate in about 12 g P134a was filled through the valve.
Standard 0.46 mm thick aluminium sheet is spray coated with FEP-Benzoguanamine and cured. This heel is then deep-drawn into cans. These cans are then purged of air, the valves crimped in place, and a suspension of about 41.0 mg, 21.0 mg, 8.8 mg, or 4.4 mg micronised ftuticasone propionate in about 12 g P134a is filled through the valve.
Standard 12.5 ml MDI cans (Presspart inc., Cary NC) are spray-coated with an aqueous dispersion ~of PFA (Hoechst PFA-6900n) and cured. The thickness of the coating is between approximatefy~ 1 iun and approximately 20 Vim. These cans are then purged of air, the valves crimped in place, and ~a suspension of about 4i.0 mg, 21.0 mg, 8.8 mg, or 4:4 mg micronised fluticasone propionate in about 12 g P134a is filled through the valve.
Standard 12.5 mI MDI cans (Presspart Inc., Cary NC) are spray-coated with PTFE-PES blend (DuPont) as a single coat and cured according to the vendor's standard procedure. The thickness of the coating is between approximately ~
irm and approximately 20 ~.m. These cans are then purged of air, the valves crimped in place, and a suspension of about 8.8 mg, 22 mg or 44 mg of micronised fluticasone propionate with about 6.4 mg micronised satmeterol xinafoate in about 12 g P134a is filled through the valve.

~.4 Standard 12.5 ml MDl cans (Presspart Inc., Cary NC) are spray-coated with PTFE-FEP-polyamideimide blend (DuPont) and cured according to the vendor's standard procedure. The thickness of the coating is between approximately 1 Nm and approximately 20 u.m. These cans are then purged of air the valves crimped in place, and a suspension of about 8.8 mg, 22 mg or 44 mg of micronised fluticasone propionate with about 6.4 mg micronised salmeterol xinafoate in about 12 g P134a is filled through the valve.
Example 10 Standard 12.5 ml MDl cans (Presspart Inc., Cary NC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating is between approximately 1 l.im and approximately 20 um. These cans are then purged of air, the valves crimped in place, and a suspension of about 8.8 mg; 22 mg or 44 mg of micronised fluticasone propionate with about 6.4 mg micronised saimeterol xinafoate in about 12 g P134a is filled through the valve.
Example 11 Standard 0.46 mm thick aluminium sheet is ~ spray coated with FEP-Benzoguanamine and cured. This sheet is then deep-drawn into cans. These cans are then purged of air, the valves crimped in place, and a suspension of about 8.8 mg, 22 mg or 44 mg of micronised fluticasone propioriate with about 6.4 mg micronised salmeterol xinafoate in about 12 g P134a is filled through the valve.
.. exam fp a 12 3a ' Standard 12.5 ml MDt cans (Presspart inc., Cary NC) are spray-coated with an aqueous dispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of the coating is between approximately 1 ~.~m and approximately 20 ~.m. These cans are then purged of air, the valves crimped in place, and a suspension of about 8.8 mg, 22 mg or 44 mg of n'~icronised fluticasone propionate with about 6.4 mg micronised salmeterol xinafoate in about i2 g P134a is filled through the valve.
5 Example 13 Standard 12.5 ml MDI cans (Presspart Inc., Caiy NC) are spray-coated with PTFE-PES blend (DuPont) as a single coat and cured according to the vendor's standard procedure. The thickness of the coating is between approximately 1 Izm 10 and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg micronised fluticasone propionate with about 4 mg micronised salmeterol xinafoate in about 8 g P134a is filled through the valve.
15 Exam Ire 14 Standard 12.5 ml MDI cans (Presspart~ Inc., Cary NC) are spray-coated with PTFE-FEP-poiyamideimide blend (DuPont} and cured according to the vendor's standard procedure. The thickness of the coating is between approximately 1 um and approximately 20 ~.m. These cans are then purged of air the valves crimped in place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg micronised fluticasone propionate with about 4 mg micronised saimeterot xinafoate in about 8 g P134a is filled through the valve.
Exam Ip a 15 Standard 12.5 ml MDI cans (Presspart Inc., Cary INC) are spray-coated with FEP
powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating is between approximately i lam and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg micronised fluticasone propionate with abou~ 4 mg micronised salmeterol xinafoate in about 8 g P134a is filled through the valve.

, CA 02368934 2002-02-07 Standard 0.46 mm thick aluminium sheet is spray coated with FEP-Benzoguanamine and cured. This sheet is then deep-drawn into cans. These cans are then purged of air, the valves crimped in place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg micronised fiuticasone propionate with about mg micronised salmeterol xinafoate in about 8 g I'134a is filled through the valve.
Example 17 Standard 12.5 ml MDI cans (Presspart lnc., Cary NC) are spray-coated with an aqueous dispersion of PFA (Hoechst PFA-6900n) and cured. The thickness of the coating is between approximately 1 Nm and approximately 20 p.m. These cans are then purged of air, the valves crimped in place, and a suspension of about 5.5 mg, 13.8 mg or 27.5 mg micronised fluticasone propionate with about mg micronised saimeterol xinafoate in about 8 g P134a is filled through the valve.
Examples 3 to 7 are repeated except that a suspension of about 13.3 mg micronised fluticasone proprionate in about 21.4 g P227 is filled through the valve.
,ExamQles 23-27 Examples 3 to 7 are repeated except that 66 mg, or 6.6 mg micronised fiuticasone proprionate in about 182 mg ethanol and about 18.2 g P134a is fitted through the valve.
ExamQles 28-52 Examples 3 to 27 are repeated except that modified 72.5 m! MDl cans having a substantially ellipsoidal base (Presspart (nc., Cary fJC) were used.

r Dose delivery from the MDIs tested under simulated use conditions is found to be constant, compared to control MDts filled into uncoated cans which exhibit a significant decrease in dose delivered through use.

Claims (39)

1. An inhalation pharmaceutical preparation comprising an inhalation drug formulation which comprises fluticasone propionate or a physiologically acceptable solvate thereof and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients, in a metered dose inhaler having part or all of its internal surfaces coated with a polymer blend comprising one or more fluorocarbon polymers in combination with one or more non-fluorocarbon polymers.

2. A preparation according to claim 1, wherein said drug formulation further comprises a surfactant.

3. A preparation according to claim 1 or 2, wherein said drug formulation further comprises a polar cosolvent.

4. A preparation according to claim 1, wherein said drug formulation further comprises 0.01 to 5% w/w based upon propellant of a polar cosolvent, which formulation is substantially free of surfactant.

5. A preparation according to claim 1, 2, 3 or 4, wherein said drug formulation comprises fluticasone propionate or a physiologically acceptable solvate thereof in combination with a bronchodilator or an antiallergic.

6. A preparation according to claim 5, wherein said drug formulation comprises fluticasone propionate in combination with salmeterol xinafoate.

7. A preparation according to claim 1, wherein said drug formulation consists essentially of fluticasone propionate or a physiologically acceptable solvate thereof, optionally in combination with one or more other pharmacologically active agents, and a fluorocarbon propellant.

8. A preparation according to claim 7, wherein said drug formulation consists essentially of fluticasone propionate or a physiologically acceptable solvate thereof in combination with a bronchodilator or an antiallergic and a fluorocarbon propellant.

9. A preparation according to claim 8, wherein said drug formulation consists essentially of fluticasone propionate or a physiologically acceptable solvate thereof in combination with salmeterol or a physiologically acceptable salt thereof, and a fluorocarbon propellant.

10. A preparation according to claim 9, wherein said drug formulation consists essentially of fluticasone propionate in combination with salmeterol xinafoate and a fluorocarbon propellant.

11. A preparation according to claim 1, wherein said drug formulation consists of fluticasone propionate or a physiologically acceptable solvate thereof and a fluorocarbon propellant.

12. A preparation according to any one of claims 1 to 11, wherein the fluorocarbon propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-hepta-fluoro-n-propane or mixtures thereof.

13. A preparation according to claim 12, wherein the fluorocarbon propellant is 1,1,1,2-tetrafluoroethane.

14. A preparation according to any one of claims 1 to 13, wherein said inhaler comprises a can, a crimped cap covering the mouth of the can, and a drug metering valve situated in the cap, the can being made of metal and part of all of the internal surfaces being coated.

15. A preparation according to claim 14, wherein the metal is aluminium or an alloy thereof.

16. A preparation according to any one of claims 1 to 15, wherein said fluorocarbon polymer is a perfluorocarbon polymer.

17. A preparation according to claim 16, wherein said fluorocarbon polymer is selected from polytetrafluoroethylene (PTFE), perfluoroalkoxy-alkane (PFA), fluorinated ethylene propylene (FEP) and mixtures thereof.

18. A preparation according to any one of claims 1 to 17, wherein the fluorocarbon polymer is in combination with a non-fluorocarbon polymer selected from polyamide, polyimide, polyamideimide, polyethersulfone, polyphenylene sulfide and amine-formaldehyde thermosetting resins:

19. A preparation according to any one of claims 1 to 18, wherein said fluorocarbon polymer is in combination with a non-fluorocarbon polymer selected from polyamideimide and polyethersulphone.

20. A preparation according to any one of claims 1 to 19, wherein said polymer blend comprises polytetrafluoroethylene (PTFE) and polyethersulfone.

21 21. A preparation according to any one of claims 1 to 20, wherein said inhaler is a metered dose inhaler and is in combination with a channelling device for oral or nasal inhalation of the drug formulation.

22. Use of an inhalation drug formulation comprising fluticasone propionate or a physiologically acceptable solvate thereof and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients, for the treatment of respiratory and nasal disorders, the formulation being dispensed in a metered dose inhaler having part or all of its internal surfaces coated with a polymer blend comprising one or more fluorocarbon polymers in combination with one or more non-fluorocarbon polymers.

23. Use according to claim 22, wherein said drug formulation further comprises a surfactant.

24. Use according to claim 22 or 23, wherein said drug formulation further comprises a polar cosolvent.

25. Use according to claim 22, wherein said drug formulation further comprises 0.01 to 5% w/w based upon propellant of a polar cosolvent, which formulation is substantially free of surfactant.

26. Use according to claim 22, 23, 24 or 25, wherein said drug formulation comprises fluticasone propionate or a physiologically acceptable solvate thereof in combination with a bronchodilator or an antiallergic.

27. Use according to claim 26, wherein said drug formulation comprises fluticasone propionate in combination with salmeterol xinafoate.

28. Use according to claim 22, wherein said drug formulation consists essentially of fluticasone propionate or a physiologically acceptable solvate thereof, optionally in combination with one or more other pharmacologically active agents, and a fluorocarbon propellant.

29. Use according to claim 28, wherein said drug formulation consists essentially of fluticasone propionate or a physiologically acceptable solvate thereof in combination with a bronchodilator or an antiallergic, and a fluorocarbon propellant.

30. Use according to claim 29, wherein said drug formulation consists essentially of fluticasone propionate or a physiologically acceptable solvate thereof in combination with salmeterol or a physiologically acceptable salt thereof, and a fluorocarbon propellant.

31. Use according to claim 30, wherein said drug formulation consists essentially of fluticasone propionate in combination with salmeterol xinafoate, and a fluorocarbon propellant.

32. Use according to claim 22, wherein said drug formulation consists of fluticasone propionate or a physiologically acceptable solvate thereof and a fluorocarbon propellant.

33. Use-according to any one of claims 22 to 32, wherein the fluorocarbon propellant is 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-hepta-fluoro-n-propane or mixtures thereof.

34. Use according to claim 33, wherein the fluorocarbon propellant is 1,1,1,2-tetrafluoroethane.

35. Use according to any one of claims 22 to 34, wherein said fluorocarbon polymer is a prefluorocarbon polymer.

36. Use according to claim 35, wherein said fluorocarbon polymer is selected from polytetrafluoroethylene (PTFE), perfluoroalkoxyalkane (PFA), fluorinated ethylene propylene (FEP) and mixtures thereof.

37. Use according to any one of claims 22 to 36, wherein the fluorocarbon polymer is in combination with a non-fluorocarbon polymer selected from polyamide, polyimide, polyamideimide, polyethersulfone, polyphenylene sulfide and amine-formaldehyde thermosetting resins.

38. Use according to any one of claims 22 to 37, wherein said fluorocarbon polymer is in combination with a non-fluorocarbon polymer selected from polyamideimide and polyethersulphone.

39. Use according to any one of claims 22 to 38, wherein said polymer blend comprises polytetrafluoroethylene (PTFE) and polyethersulfone.