AP979A - Metered dose imhaler for salmeterol. - Google Patents

Metered dose imhaler for salmeterol. Download PDF

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Publication number
AP979A
AP979A APAP/P/1997/001113A AP9701113A AP979A AP 979 A AP979 A AP 979A AP 9701113 A AP9701113 A AP 9701113A AP 979 A AP979 A AP 979A
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Prior art keywords
inhaler according
fluorocarbon
drug formulation
combination
physiologically acceptable
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APAP/P/1997/001113A
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AP9701113A0 (en
Inventor
Ignatius Loy Britto
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Glaxo Wellcome Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00—Containers or packages with special means for dispensing contents
    • B65D83/14—Containers for dispensing liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant
    • B65D83/44—Valves specially adapted for the discharge of contents; Regulating devices
    • B65D83/52—Metering valves; Metering devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0222—Materials for reducing friction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/02—General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0233—Conductive materials, e.g. antistatic coatings for spark prevention

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Mechanical Engineering (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Containers And Packaging Bodies Having A Special Means To Remove Contents (AREA)
  • Steroid Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A metered dose Inhaler having part or all of its internal surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers, for dispensing an inhalation drug formulation comprising salmeterol, or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients.

Description

METERED DOSE INHALER FOR SALMETEROL
BACKGROUND OF THE INVENTION
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 sealed 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.
Ά 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 rapidly vaporizes leaving a fast moving cloud of very
----------------fine particles of the drug formulation. This cioud of particles is directed into' the nose or mouth of the patient by a channelling device such as a cylinder or open20 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 general 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.
Ap/P/ 9 7/01 113
AP 00979
I
Some aerosol drugs tend to adhere to the inner surfaces, i.e., walls 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 particularly acute with hydrofluoroalkane (also known as simply “fluorocarbon”) propellant systems, e.g., P134a and P227, under development in recent years to replace chlorofluorocarbons such as P11, P114 and P12.
We have found that coating the interior can surfaces of MDl's with a fluorocarbon polymer significantly reduces or essentially eliminates the problem of adhesion or ? 10 deposition of saimeterol on the can walls and thus ensures consistent delivery of medication in aerosol from the MDI.
SUMMARY OF THE INVENTION
A metered dose inhaler having part or all of its internal surfaces coated with one or more fluorocarbon polymers, optionally in combination with one or more nonfluorocarbon polymers, for dispensing an inhalation drug formulation comprising salmetecQl, or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients.
DETAILED DESCRIPTION OF THE INVENTION
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 MDI system also includes a suitable channelling device. The terms MDI 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-like passage through which medicament may be delivered from the filled MDI can via the MDI valve to the nose or mouth of a patient, e.g. a mouthpiece actuator. The relation of the parts
Ap/F/ 9 7 ' 0 1 113
AP 00979 of a typical MDI is illustrated in US Patent 5,261,538 incorporated herein by reference.
The term “fluorocarbon polymers” means a polymer in which one or more of the 5 hydrogen atoms of the hydrocarbon chain have been replaced by fluorine atoms.
Thus, “fluorocarbon polymers” include perfluorocarbon, hydrofluorocarbon, chlorofiuorocarbon, hydro-chlorofluorocarbon polymers or other halogen substituted derivatives thereof. The “fluorocarbon polymers” may be branched, homo-polymers or co-polymers.
,10
U.S. Patent No.4,992,474, incorporated herein by reference, teaches a bronchodilating compound particularly useful in the treatment of asthma and other respiratory diseases know by the chemical name 4-hydroxy-oc1-[[[6-(4phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol and the generic name salmeterol. Salmeterol as the tree base and as acid addition salts (particularly as the 1-hydroxy-2-naphthalenecarboxylic acid salt also known as hydroxynaphthoate or xinafoate salt), especially, in aerosol form, has been __________apcepted_by-4h.ajnedicatu^mmunity-as~a.-usef-ui-4Fe-at-men4--eT-a-slhm-a--and--is marketed under the trademark Serevent
The term “drug formulation*’ means salmeterol or a physiologically acceptable salt
J thereof (particularly the hydroxynaphthoate salt) optionally in combination with one or more other pharmacologically active agents such as antiinflammatory agents, analgesic agents or other respiratory drugs and optionally containing one or more excipients. The term “excipients” as used herein mean chemical agents having little or no pharmacological activity (tor the quantities used) but which enhance the drug formulation or the performance of the MDI system. For example, excipients include but are not limited to surfactants, preservatives, flavorings, antioxidants, antiaggregating agents, and cosolvents, e.g., ethanol and diethyl ether.
Salmeterol or salt thereof may be used in the form ot its R-isomer.
ro rx
Oi
Suitable surfactants are generally known in the art, tor example, those surfactants disclosed in European Patent Application No. 0327777. The amount ot surfactant
AP 00979 employed is desirable in the range of 0.0001% to 50% weight to weight ratio relative to the drug, in particular, 0.05 to 5% weight to weight ratio. A particularly useful surfactant is 1,2-di[7-(F-hexyl) hexanoyl]- glycero-3-phospho-N,N,Ntrimethylethanolamine also know as 3, 5, 9-trioxa-4-phosphadocosan-1-aminium, 17, 17, 18, 18, 19, 19, 20, 20, 21, 21, 22, 22, 22-tridecafiuoro-7-[(8, 8, 9, 9, 10, 10, 11, 11, 12,. 12, 13, 13, 13-tridecafluoro-1 -oxotridecyl)oxy]-4-hydroxy-N, Ν, Ntrimethyl-10-οχο-, inner salt, 4-oxide.
A polar cosolvent such as C aliphatic alcohols 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/w.
It will be appreciated by those skilled in the art that the drug formulation for use in o>
the invention may, if desired, contain salmeterol or a salt thereof in combination 77 [u II* wiiLQ^9LfE9Le--QlLeipharmacQLo_giGaliy-active^er4e.^S4j.cU-m^dicament-s-4nay----------— be selected from any suitable drug useful in inhalation therapy. 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 and pentamidine; antihistamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone (e.g. the dipropionate), flunisolide, budesonide, tipredane or triamcinolone acetonide; antitussives, e.g. noscapine; bronchodilators, e.g. salbutamol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, orciprenaline, or (-)-4-amino-3,5dichloro- ' a -[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol; diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropine or oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone; xanthines e.g. aminophyiline, choline theophyllinate, lysine theophyllinate or theophylline; and
AP 00979 therapeutic proteins and peptides, e.g. insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts (e.g. as alkali metal or amine salts or as acid addition salts) or as esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) to optimise the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant.
Particularly preferred drug formulations contain salmeterol or a physiologically acceptable salt thereof in combination with an anti-inflammatory steroid such as fluticasone propionate, beciomethasone dipropionate or physiologically acceptable solvates thereof.
A particularly preferred drug combination is salmeterol xinafoate and fluticasone propionate.
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 formulation 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, 1,1,1,2tetrafluoroethane also known as propellant 134a or P 134a and 1,1,1,2,3,3,3heptafluoro-n-propane also known as propellant 227“ or “P 227.
Drug formulations for use in the invention may be tree or substantially free of formulation excipients e.g. surfactants and cosolvents 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 salmeterol or a physiologically acceptable salt thereof, e.g. the xinafoate salt, optionally in combination with one or more other pharmacologically active agents particularly fluticasone propionate (or a physiologically acceptable solvate thereof), and a fluorocarbon propellant.
AP/P/ 9 7/01113
AP 00979
Preferred propellants are 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-npropane 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 a physiologically acceptable salt thereof), optionally in combination with one or more other pharmacologically active agents, a fluorocarbon propellant and 0.01 to 5% w/w based upon propellant of a polar .· cosolvent, which formulation is substantially free of surfactant. Preferred J 10 propellants are 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 1,1,1,2,3,3,3heptafluoro-n-propane.
Most often the MDI can and cap are made of aluminum or an ailoy 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 MDI cans may be employed. Such strengthened MDI cans are capable of withstanding particularly stressful coating -j 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 MD! 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 standard MDI 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®), polycarbonate, polyester,.fluorocarbon polymer (e.g., Teflon®) or a combination of these materials. Additionally, seals and Ό” rings of
Ap/P/ 9 7/01113
AP 00979 various materials (e.g., nitrile 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: tetrafiuoroethylene (PTFE), fluorinated ethylene propylene (FEP), perfluoroalkoxyalkane (PFA), ethylene tetrafiuoroethylene (ETFE), vinyldienefluoride (PVDF), and chlorinated ethylene tetrafiuoroethylene. Fluorinated polymers which have a relatively high ratio of fluorine to carbon, such ) 10 as perfiuorocarbon polymers e.g. PTFE, PFA, and FEP, are preferred.
The fluorinated polymer may be blended with non-fiuorinated polymers such as polyamides, polyimides, polyethersulfones, polyphenylene sulfides and amineformaldehyde thermosetting resins. These added polymers improve adhesion of the polymer coating to the can walls. Preferred poiymer blends are PTFE/FEP/polyamideimide, 'PTFE/polyethersulphone (PES) and FEPbenzoguanamine.
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®, Polyflon® and Neoflon®. Grades of polymer include FEP DuPont 856-200, PFA DuPont 857-200, PTFE-PES DuPont 3200-100, PTFE25 FEP-polyamideimide DuPont 856P23485, FEP powder DuPont 532, and PFA Hoechst 6900n. The coating thickness is in the range of about 1pm to about 1mm. Suitably the coating thickness is in the range of about 1pm to about 100pm, e.g. 1pm to 25pm. Coatings may be applied in one or more coats.
Preferably the fluorocarbon polymers for use in the invention are coated on to MDI cans made of metal, especially MDI cans made of aluminium or an alloy thereof.
AP/P/ 9 7/01113
AP 00979
8'
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 administration of the aerosol formulation and will thus be less than 100 microns, desirably less than 20 microns, and preferably in the range of 1-10 microns, e.g., 1-5 microns.
The final aerosol 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 comprising salmeterol or a salt thereof 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 MDI 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 polyethersulfone for dispensing a drug formulation as defined hereinabove. Preferred drug formulations for use in this MDI consist essentially of salmeterol (or a salt thereof, e.g. the xinafoate salt), optionally in combination with one or more other pharmacologically active agents particularly fluticasone propionate or a physiologically acceptable solvate thereof and a fluorocarbon propellant, particularly 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-npropane or mixtures thereof, and especially 1,1,1,2-tetrafluoroethane. Preferably the MDI can is made of aluminium or an alloy thereof.
The MDI 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 reasons. First, the art of coating coil stock is well developed and several manufacturers can custom coat metal coil
AR/P/ 9 7/01113
AP 00979 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 powdered coating or by spraying preformed MDI cans inside with formulations of the coating fluorinated polymer/poiymer biend and then curing. The preformed MDI cans may also be dipped in the fluorocarbon polymer/poiymer blend coating formulation and cured, thus becoming coated on the inside and out. The fluorocarbon polymer/poiymer 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 MD! cans are spray-coated with the fluorinated polymer/poiymer blend.
The fluorocarbon polymer/poiymer 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
--------------iiyofocardorvpOfymers^elras-ETFErFEPrand’PTFE-are’avaitable asTilm stock.
The appropriate curing temperature is dependent on the fluorocarbon polymer/poiymer blend chosen for the coating and the coating method employed. However, for coil coating and spray coating temperatures in excess of the melting point of the polymer are typically required, for example, about 50°C above the 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 polymer/poiymer 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 polymerization typically temperatures in the range of about 20°C to about 100°C may be employed.
The MDI'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/poiymer blend. That is, salmeterol or a salt thereof and
AP/F/ 9 7/01113
AP 00979 other components of the formulation are filled into an aerosol can coated with a fluorinated polymer/polymer blend. The can is fitted with a cap assembly which 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 incorporated herein by reference.
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 particularly useful for containing j 10 and dispensing inhaled drug formulations with hydrofluoroalkane fluorocarbon 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 excipient or the drug reacts with an 15 excipient.
MDI’s containing the formulations described hereinabove, MDI systems and the ________:_________________use of such MDI systems for the treatment of respiratory disorders e.g. asthma_______________ comprise further aspects of the present invention.
it will be apparent to those skilled in the art that modifications to the invention _. J 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-limitative Examples serve to illustrate the invention.
EXAMPLES ' Example 1
Standard 12.5 ml MDI cans (Presspart Inc., Cary, NC) were spray-coated (Livingstone Coatings, Charlotte, NC) with primer (DuPont 851-204) and cured to.
AP/P/ 9 7/01113
AP 00979 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 mm to 50 mm. These cans are then purged of air (see PCT application number
WO94/22722 (PCT/EP94/00921)), the valves crimped in place, and a suspension of about 4 mg salmeterol xinafoate (hydroxynaphthoate) in about 12 gm P134a is filled through the valve.
; Example 2 )10
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). These cans were then purged of air, the valves crimped in place, and a suspension of about 2.5 mg salmeterol xinafoate (hydroxynaphthoate) in about 7.5 gm P134A was filled through the valve.
__________,,.._____________-______________________________________________________________________Example 3 .....—----------------------------------------------20 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 .-J standard procedure. The thickness of the coating is between approximately 1 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 6.1 mg of micronised salmeterol xinafoate in about 12 g P134a is filled through the valve.
Example 4
Standard 12.5 ml MDI 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 pm and approximately 20 pm. These cans are then purged of air the valves crimped in
AP/P/ 9 7/01113 place, and a suspension of about 6.1 mg of micronised salmeterol xinafoate in about 12 g P134a is filled through the valve.
Example 5
Standard 12.5 ml 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 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 6.1 mg of micronised salmeterol xinafoate in about 12 g P134a is filled through the valve. Example 6
Standard 0.46 mm thick aluminium sheet (United Aluminium) 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 6.1 mg of micronised salmeterol xinafoate in about 12 g P134a is filled
—.........through th e valve. -------------------------------------------------------------------------- ----------------------------------- ------- ------20 Example 7
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 approximately 1 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 6.1 mg of micronised salmeterol xinafoate in about 12 g respectively P134a is filled through the valve.
Example 8
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 pm
AP,'' 9 7/01113
AP 00979 and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 4.25 mg of micronised salmeterol xinafoate in about 8 g P134a is filled through the valve.
Example 9
Standard 12.5 ml MDI 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 pm ‘ 10 and approximately 20 pm. These cans are then purged of air the valves crimped in place, and a suspension of about 4.25 mg of micronised salmeterol xinafoate in about 8 g P134a is filled through the valve. .
Example 10
Standard 12.5 ml MDI cans (Presspart Inc., Cary, NC) are spray-coated with FEP powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating ,- befween approximately 1 pm and approximately 20 pm. These cans are then purged of air, the vaives crimped in place, and a suspension of about 4.25 mg of micronised salmeterol xinafoate in about 8 g P134a is filled through the valve.
Example 11
Standard 0.46 mm thick aluminium sheet (United Aluminium) 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 4.25 mg of micronised salmeterol xinafoate in about 8 g P134a is filled through the valve.
Example 12
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
AP/P/ 9 7 / 0 1 1 1 3
AP 00979 coating is between approximately 1 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 4.25 mg of micronised salmeteroi xinafoate in about 8 g P134a is filled through the valve.
Example 13
Standard 12.5 ml MDI cans (Presspart Inc., Cary, NC) are spray-coated with ' PTFE-PES biend (DuPont) as a single coat and cured according to the vendor’s J10 standard procedure. The thickness of the coating is between approximately 1 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 6.4 mg micronised salmeteroi xinafoate with about 8.8 mg, 22 mg or 44 mg micronised fluticasone propionate in about 12 g
P134a is filled through the valve.
Example 14 gtancjarcj ^2.5 ml MDI 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 pm j and approximately 20 pm. These cans are then purged of air the valves crimped in place, and a suspension of about 6.4 mg micronised salmeteroi xinafoate with about 8.8 mg, 22 mg or 44 mg micronised fluticasone propionate in about 12 g
P134a is filled through the valve.
Example 15
Standard 12.5 ml 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 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 6.4 mg micronised salmeteroi xinafoate with about 8.8 mg, 22 mg or 44 mg micronised fluticasone propionate in about 12 g P134a is filled through the valve.
AP/P/ 9 7/01113
AP 00979
Example 16
Standard 0.46 mm thick aluminium sheet (United Aluminium) 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 6.4 mg micronised salmeterol xinafoate with about 8.8 mg, 22 mg or 44 mg micronised fluticasone propionate in about 12 g P134a is filled through the
I valve.
Example 17
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 approximately 1 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 6.4 mg micronised salmeterol xinafoate with about 8.8 mg, 22 mg or 44 mg micronised
--ftutfcascrreqjropiorTateTrrFrtront-TS^^TMadsrTittedWonglvthe vatve. ......
Example 18
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 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 4 mg micronised salmeterol xinafoate with about 5.5 mg, 13.8 mg or 27.5 mg fluticasone propionate in about 8 g P134a is filled through the valve.
Example 19
Standard 12.5 ml MDI cans (Presspart Inc., Cary, NC) are spray-coated with
PTFE-FEP-polyamideimide blend (DuPont) and cured according to the vendor’s
AFt/F/ 9 7/01113
AP 00979 standard procedure. The thickness of the coating is between approximately 1 pm and approximately 20 pm. These cans are then purged of air the valves crimped in place, and a suspension of about 4 mg micronised salmeterol xinafoate with about 5.5 mg, 13.8 mg or 27.5 mg fluticasone propionate in about 8 g P134a is filled through the valve.
Example 20
Standard 12.5 ml MDI cans (Presspart Inc., Cary, NC) are spray-coated with FEP 10 powder (DuPont FEP 532) using an electrostatic gun. The thickness of the coating is between approximately 1 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 4 mg micronised salmeterol xinafoate with about 5.5 mg, 13.8 mg or 27.5 mg fluticasone propionate in about 8 g P134a is filled through the valve.
Example 21 to o
r* en
--------Standard 0.46 mm thick aluminium sheet (United Aluminium) 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 4 mg micronised salmeterol xinafoate with about 5.5 mg, 13.8 mg or 27.5 mg fluticasone propionate in about 8 g P134a is filled through the valve.
fcAP/
Example 22 25
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 approximately 1 pm and approximately 20 pm. These cans are then purged of air, the valves crimped in place, and a suspension of about 4 mg micronised salmeterol xinafoate with about 5.5 mg, 13.8 mg or 27.5 mg fluticasone propionate in about 8 g P134a is filled through the valve.
AP 00979
Examples 23-28
Examples 3 to 7 are repeated except that a suspension of about 9.6 mg micronised salmeterol xinafoate in about 21.4 g P227 is filled through the valve.
Examples 29-33
Examples 3 to 7 are repeated except that about 9.6 mg micronised salmeterol ; xinafoate in about 182 mg ethanol and about 18.2 g P134a is filled through the j10 valve.
Examples 34 - 64
Examples 3 to 33 are repeated except that modified 12.5 ml MDI cans (Presspart 15 Inc. Cary, NC) with an ellipsoid base are used.
Dose delivery from the MDls tested under simulated use conditions is found to be significant decrease in dose delivered through use.

Claims (20)

We claim:
1. 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, for dispensing an inhalation drug formulation comprising salmeterol, or a physiologically acceptable salt thereof, and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents or one or more excipients.
2. An inhaler according to Claim 1 containing said drug formulation.
3. An inhaler according to Claim 2, wherein said drug formulation further comprises a surfactant.
4. An inhaler according to Claim 2 or Claim 3, wherein said drug formulation further comprises a polar cosolvent.
.
5.___AninhaieraccordingtoClaimZwhereinsaiddrugTormtiiationcomprises^ ~
0.01 to 5% w/w based upon propellant of a polar cosolvent, which formulation is substantially free of surfactant.
6. An inhaler according to any one of Claims 2 to 5, wherein said drug formulation comprises salmeterol or a physiologically acceptable salt thereof in combination with an anti-inflammatory steroid or an antiallergic.
7. An inhaler according to Claim 6, wherein said drug formulation comprises salmeterol xinafoate in combination with fluticasone propionate.
8. An inhaler according to Claim 2, wherein said drug formulation consists essentially of salmeterol or a physiologically acceptable salt thereof, optionally in combination with one or more other pharmacologically active agents, and a fluorocarbon propellant.
AP 0 0 9 7 9
9. An inhaler according to Claim 8, wherein said drug formulation consists essentially of saimeterol or a physiologically acceptable salt thereof in combination with an anti-inflammatory steroid or an antiallergic.
10. An inhaler according to Claim 9, wherein said drug formulation consists essentially of saimeterol or a physiologically acceptable solvate thereof in combination with fluticasone propionate or a physiologically acceptable solvate thereof.
11. An inhaler according to Claim 2, wherein said drug formulation consists of saimeterol or a physiologically acceptable salt thereof and a fluorocarbon propellant.
12. An inhaler according to any one of Claims 2 to 11 wherein the saimeterol is in the form of the xinafoate salt.
13. An inhaler according to any one of Claims 2 to 12, wherein the fluorocarbon propellant is 1,1,1,2- tetrafluoroethane or 1,1.1.2,3,3,3-heptafluoron-propane or mixtures thereof.
14. An inhaler according to Claim 13, wherein the fluorocarbon propellant is 1,1,1,2- tetrafluoroethane.
15 '
23. A metered dose inhaler system comprising a metered dose inhaler according to any one of Claim 1 to 22 fitted into suitable channelling device for oral or nasal inhalation of the drug formulation.
15. An inhaler according to any of Claims 1 to 14 wherein the can is made of metal and part or all of the internal metallic surfaces are coated.
16. An inhaler according to Claim 15 wherein the metal is aluminium or an alloy thereof.
17. An inhaler according to any one of Claims 1 to 16 wherein said fluorocarbon polymer is a perfluorocarbon polymer.
18. An inhaler according to Claim 17 wherein said fluorocarbon polymer is selected from PTFE, PFA, FEP and mixtures thereof.
AP 00979 io
19. An inhaler according to any one of Claims 1 to 18, 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.
20. An inhaler according to any one of Claims 1 to 19, wherein said fluorocarbon polymer is in combination with a non-fluorocarbon polymer selected from polyamideimide and polyethersulphone.
10
21. An inhaler according to any one of Claims 1 to 20, wherein said polymer blend comprises PTFE and polyethersulfone.
22. An inhaler according to any one of Claims 1 to 21 comprising a substantially ellipsoidal base.
20 24. Use of a metered dose inhaler system according to claim 23 for the treatment of respiratory disorders.
APAP/P/1997/001113A 1995-04-14 1996-04-10 Metered dose imhaler for salmeterol. AP979A (en)

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US58333296A 1996-01-05 1996-01-05
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