EP1259276A2 - Aerosol-doseur - Google Patents

Aerosol-doseur

Info

Publication number
EP1259276A2
EP1259276A2 EP01917037A EP01917037A EP1259276A2 EP 1259276 A2 EP1259276 A2 EP 1259276A2 EP 01917037 A EP01917037 A EP 01917037A EP 01917037 A EP01917037 A EP 01917037A EP 1259276 A2 EP1259276 A2 EP 1259276A2
Authority
EP
European Patent Office
Prior art keywords
component
metered dose
accessory
dose inhaler
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01917037A
Other languages
German (de)
English (en)
Inventor
Mark Andrew c/o Glaxo Wellcome plc HAILEY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0004761A external-priority patent/GB0004761D0/en
Priority claimed from GB0018624A external-priority patent/GB0018624D0/en
Priority claimed from GB0018653A external-priority patent/GB0018653D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1259276A2 publication Critical patent/EP1259276A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • 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

Definitions

  • the present invention relates to metered dose inhalers. More especially, the invention relates to a metered dose inhaler for consistently dispensing a prescribed dose of medicament.
  • 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 formulating the drug as a suspension or a solution in a liquefied gas propellant.
  • the suspension/solution is stored in a sealed canister capable of withstanding the pressure required to maintain the propellant as a liquid.
  • the suspension/solution is dispersed by activation of a dose metering valve affixed to the canister.
  • a metering valve generally comprises a metering chamber which is of a set volume and is designed to administer per actuation an accurate predetermined dose of medicament.
  • the propellant rapidly 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 channeling device such as a cylinder or open-ended cone.
  • a channeling device such as a cylinder or open-ended cone.
  • 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.
  • a problem which can exist with drug delivery devices such as MDI's is the deposition of the medicament, or the solid component from a suspension of a particulate product in a liquid propellant, onto the internal surfaces of the device which occurs after a number of operation cycles and/or storage. This can lead to a reduction in the efficacy of the device and of the resulting treatment as the deposition of the product reduces the amount of active drug available to be dispensed to the patient and markedly reduces the uniformity of the dose dispensed during the lifetime of the device.
  • hydrofluoroalkane propellants for example, 1 ,1,1 ,2-tetrafluoroethane (HFA134a) and 1 , 1,1 ,2, 3,3,3-n- heptafluoropropane (HFA227) which have been developed as ozone friendly replacements of chlorofluorocarbons such as P11, P114 and P12.
  • UK patent application GB-A-2,328,932 discloses the use of a liner of a material such as fluoropolymer, ceramic or glass to line a portion of the wall of the metering chamber in a metering valve of an MDI. Although this alleviates the problem of deposition in these types of dispensers, it does require the re-design or modification of mouldings and mould tools for producing the valve members to allow for insertion of the liner.
  • Canadian patent application 2130867 describes a metered dose inhaler containing an aerosol formulation in which the internal walls of the canister are coated with a cross-linked plastics coating.
  • Polytetrafluoroethylene (PTFE) and perfluoroethylenepropylene (FEP) are specifically mentioned as suitable coating materials.
  • International patent application PCT/US96/05005 describes a metered dose inhaler in which part or all of the internal surfaces of the canister are coated with a cross-linked polymeric composition, particularly polymer blends comprising one or more fluorocarbon polymers in combination with one or more non-fluorocarbon polymers.
  • the aforementioned polymer coatings minimize deposition of the drug onto the walls of the canister or other MDI components
  • certain technical disadvantages are associated with this approach.
  • the component may deform as a result of being subject to the elevated temperatures, typically in excess of 300°C, required for the coating process. Therefore, components have to be formed from thicker sheets of material which increases costs and the quantity of waste material.
  • difficulties arise in ensuring adhesion of the polymer to the component walls and more particularly with uniformity of the coating over the component surface.
  • MDI's and components thereof so provided advantageously reduce drug deposition onto the walls of the components and afford greater dose uniformity over the lifetime of the device.
  • the invention provides a metered dose inhaler comprising an interfacial surface having the following properties:- (i) a contact angle of greater than 70 degrees; and (ii) a conductivity of greater than 2.4mS.
  • the invention provides a component or accessory for use in a metered dose inhaler comprising an interfacial surface having the following properties:- (i) a contact angle of greater than 70 degrees; and (ii) a conductivity of greater than 2.4mS.
  • interfacial surface defines all or part of any internal surface of the metered dose inhaler, component or accessory, that contacts or comes into contact, i.e. forms an interface with, a medicament during storage and/or dispensing thereof.
  • the term "metered dose inhaler” or “MDI” means a unit comprising a canister, a cap covering the mouth of the canister, a drug metering valve situated in the cap, a metering chamber and a suitable channeling device into which the canister is fitted.
  • 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 channeling 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 of a typical MDI is illustrated in US Patent 5,261 ,538 incorporated herein by reference.
  • the component or accessory may include a canister, and/or a metering valve, and/or a metering chamber, and/or a channeling device and/or an actuator for use in a metered dose inhaler.
  • the contact angle of the interfacial surface is greater than 90 degrees, e.g. greater than 110 degrees.
  • contact angle is identified as the angle between a liquid water droplet and a solid surface at the liquid/solid gas interface.
  • the conductivity of the interfacial surface is greater than 4.0mS. Typically, the conductivity is greater than 7.9mS.
  • conductivity is evaluated by applying a low voltage of 6.3V between the surface and a salt (e.g. 1 % sodium chloride) solution alongside the surface, using a WACOTM Enamel Rater II Balance, i.e. using the WACO Conductivity Test for the Determination of Coating Integrity of Metered Dose Inhalers. Therefore, measurements from products according to the invention according to this apparatus are greater than 15mA, typically greater than 25mA, e.g. greater than 50mA, which corresponds to a conductivity of greater than 2.4mS, 4.0mS and 7.9mS respectively.
  • a salt e.g. 1 % sodium chloride
  • the products according to the present invention reduce the variation in dosage with respect to a conventionally polymer coated metered dose inhaler.
  • the metered dose inhaler is suitable for consistently dispensing a dose of medicament ranging between 90 and 110% of a prescribed single dosage.
  • the metered dose inhaler is suitable for dispensing a dose of medicament ranging, for example, between 95 and 105% of a prescribed single dosage, e.g. between 97% and 103%, such as between 98% and 102%, of a prescribed single dosage.
  • Mean dose is calculated by taking ten metered dose inhalers. The beginning of use (BOU) dose and the end of use (EOU) dose is measured for each of the ten inhalers. The mean of the 20 measurements is then calculated. The dosing consistency is calculated by looking at the dose from BOU to EOU and quoting the mean result from each of the 10 determinations as a percentage of the overall mean.
  • Consistently dispensing defines the dose uniformity of the aerosol medication dispensed to the patient from the first dose through to the final dose dispensed from the drug canister in the MDI device.
  • the interfacial surface may have a linear, non-cross-linked polymeric compound disposed thereon.
  • the polymeric compound is disposed as a muiti-molecular layer thereon.
  • the polymeric compound is disposed as a mono-molecular layer thereon.
  • the polymeric compound is a fluorocarbon.
  • the fluorocarbon is highly fluorinated, e.g. has a high fluorine to carbon ratio.
  • polymeric compounds will generally be employed as mixtures, the nature of which may be varied as part of optimisation of the employment of the invention.
  • the polymeric compound comprises a functional grouping which is capable of anchoring the compound to the surface of the substrate (e.g. component).
  • the compound may be anorgano-phosphate such as a phosphate based perfluoroether derivative.
  • the compound is a phosphoric ester.
  • the interfacial surface has a compound disposed thereon having the general formula (I):
  • R 1 comprises a fluoro-alkyl functional group
  • x and y are such that the molecular weight of the compound is in the range 350-1000
  • R 2 comprises a phosphoric ester functional group
  • the interfacial surface has a compound disposed thereon having the general formula (II):
  • R 3 comprises -(OCH 2 -CH 2 ) z -OPO(OH) 2 ; x, y and z are such that the molecular weight of the compound is in the range 900-2100; and v and w independently represent 1 or 2.
  • v and w are both 1. In a second preferred embodiment v and w are both 2.
  • the compounds may be an organo-silane derivative such as a silane derivative of perfluoropolyoxyalkane, e.g. a silane derivative of perfluoropolyoxyalkane having a molecular weight in the range 1600-1750.
  • organo-silane derivative such as a silane derivative of perfluoropolyoxyalkane, e.g. a silane derivative of perfluoropolyoxyalkane having a molecular weight in the range 1600-1750.
  • the interfacial surface may be a metallic or plastics surface.
  • the interfacial surface is metallic.
  • the component or accessory having an interfacial surface according to the invention is a canister.
  • the component or accessory having an interfacial surface according to the invention is a metering valve, especially a metering chamber.
  • the metered dose inhaler or a component or accessory is suitable for storing and/or dispensing a medicament, and deposition of the medicament on the MDI, component or accessory during storage and/or dispensing may be reduced by between 30%o and 80%, for example, between 40% and 80%, e.g. between 40% and 60%, such as about 50%.
  • the reference to the reduction in deposition of medicament is with respect to the deposition that would occur on a metered dose inhaler, component or accessory which does not comprise an interfacial surface having the properties defined above.
  • a canister as described above for use in a metered dose inhaler containing a pharmaceutical aerosol formulation comprising a medicament and a fluorocarbon propellant.
  • Aerosol formulations which are generally used comprise a suspension of medicament, one or more liquid propellants, optionally with co-propellants and optionally an adjuvant or a surfactant, though the invention may be applicable to the dispensing of any aerosol formulation.
  • a metered dose inhaler comprising a canister, and/or a metering valve, and/or a metering chamber, and/or a channeling device and/or an actuator as described above.
  • the invention provides the use of a metered dose inhaler, component or accessory as described above, for dispensing a pharmaceutical aerosol formulation comprising a medicament and a fluorocarbon propellant.
  • the invention provides a process for obtaining a metered dose inhaler, or a component or accessory for use in a metered dose inhaler as described above, comprising the treatment of an interfacial surface thereof with a linear, non-cross-linked polymeric compound.
  • the interfacial surface is treated to form a multi-molecular layer thereon, which may be applied as separate layers wherein the layers need not be the same polymeric compound. More preferably, the interfacial surface is treated to form amono-molecular layer thereon.
  • the polymeric compound is a fluorocarbon.
  • the compound is highly fluorinated.
  • the linear, non-cross-linked polymeric compound comprises a functional grouping which is capable of anchoring the compound to the surface to be treated.
  • the compound is an organo-phosphate, for example, a phosphate based perfluoroether derivative or a silane derived perfluorpolyoxyalkane.
  • the compound takes the form of a phosphoric ester or a silane derivative of perfluoropolyoxyalkanes having a molecular weight in the range 1600-1750.
  • the inventors have found that such treatment of MDIs or one or more components thereof results in an increase in the uniformity of the dose dispensed with dose number through to the emptying of the drug canister.
  • the present process does not require the re-design or modification of mouldings and mould tools for producing the valve members to allow for insertion of a liner, or the need to use thick component walls in order to avoid deformation as a result of being subject to elevated temperatures, typically in excess of 300°C, which are required for the coating process. Therefore, components may now be formed from thinner sheets ofmaterial which reduces costs and the quantity of waste material. Low temperature treatment also reduces process costs.
  • the process for obtaining a metered dose inhaler, component or accessory as defined above may comprises the treatment of an interfacial surface with a compound: i) having the general formula (I)
  • R 1 comprises a fluoro-alkyl functional group
  • x and y are such that the molecular weight of the compound is 350-1000
  • R 2 comprises a phosphate ester functional group; or ii) having a general formula (II)
  • R 3 comprises -(OCH 2 -CH 2 ) z -OPO(OH) 2 ; x, y and z are such that the molecular weight of the compound is 900-2100; and v and w independently represent 1 or 2; or iii) a silane derivative of perfluoropolyoxyalkane with a molecular weight in the range 1600-1750.
  • the inventors also contemplate that the manufacturing machinery used to produce MDI's, their components and accessories may also comprise the properties defined in accordance with the invention. Furthermore, apparatus for filling empty canisters, or other MDI components, with medicament may also comprise such properties. In this way, inaccuracies due to deposition or drug metering may be prevented at the stage of loading the MDI with its full load of medicament.
  • the metered dose inhalers may be prepared by methods of the art (e.g. see Byron above and US patent 5,345,980) substituting conventional canisters for those treated in accordance with the present invention.
  • the canisters and caps for use in MDI's are made of aluminium or an alloy of aluminium 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 canister may also be fabricated from glass or plastic.
  • the MDI canisters and caps employed in the present invention are made of aluminium or an alloy thereof.
  • the drug metering valve may consist of parts usually made of stainless steel, a pharmacologically resilient polymer, such as acetal, polyamide (e.g. Nylon R ), polycarbonate, polyester, fluorocarbon polymer (e.g. Teflon R ) or a combination of these materials. Additionally, seals and "O" rings of various materials (e.g., nitrile rubbers, polyurethane, acetyl resin, fluorocarbon polymers), or other elastomeric materials are employed in and around the valve.
  • the components of the MDI described hereinabove may be pretreated as coil stock, such as aluminium or stainless steel, before being stamped or drawn into shape.
  • This method is well suited to high volume production due to the high standards of uniformity that can be achieved and to the high speed and precision with which pre-coated stock can be drawn or stamped.
  • the components may be manufactured according to a second process comprising treating pre-formed canisters.
  • the components or coil stock are dipped or bath immersed into a treatment tank containing a solution the polymeric compound as described above or a mixture thereof.
  • the components or coil stock may be treated with 0.1 to 10% w/w, preferably 0.5 to 5%, especially about 1 %, solution of a polymeric compound as described above or a mixture thereof in any suitable solvent such as isopropyl alcohol.
  • the preformed components or the coil stock are immersed in the solution at room temperature for at least one hour, for example, 12 hours, thus being treated both internally and externally.
  • the treatment solution may also be poured inside the MDI components then drained to treat the internal component (e.g. the inner surface of a canister) only.
  • the treated canisters are preferably washed with solvent and dried at an elevated temperature for example 50- 00°C optionally under vacuum.
  • the canisters in accordance with the invention contain a pharmaceutical aerosol formulation comprising a medicament and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.
  • Suitable propellants include, for example, chlorofluorocarbons such as CH 2 CIF, CCIF 2 CHCIF, CF3CHCIF, CHF 2 CCIF 2 , CHCIFCHF 2 , CF 3 CH 2 CI and CCIF 2 CH3; C-
  • mixtures of the fluorocarbons or hydrogen-containing chlorofluorocarbons may be mixtures of the above identified compounds or mixtures, preferably binary mixtures, with other fluorocarbons or hydrogen-containing chlorofluorocarbons for example CHCIF 2 , CH 2 F and CF3CH3.
  • fluorocarbons or hydrogen-containing chlorofluorocarbons for example CHCIF 2 , CH 2 F and CF3CH3.
  • a single fluorocarbon or hydrogen- containing chlorofluorocarbon is employed as the propellant.
  • propellants are C - ⁇ hydrogen-containing fluorocarbons such as 1 ,1 ,1 ,2-tetrafluoroethane (CF3CH 2 F) and 1 ,1 ,1 ,2,3,3,3-heptafluoro-n-propane (CF3CHFCF3) or mixtures thereof.
  • 1 ,1 ,1 ,2-Tetrafluoroethane is of particular interest.
  • the pharmaceutical formulations for use in the canisters of the invention contain no components which provoke the degradation of stratospheric ozone.
  • the formulations are substantially free of chlorofluorocarbons such as CCI3F, CCI 2 F and CF3CCI3.
  • the propellant may additionally contain a volatile adjuvant such as a saturated hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyl ether.
  • a volatile adjuvant such as a saturated hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyl ether.
  • a volatile adjuvant such as a saturated hydrocarbon for example propane, n-butane, isobutane, pentane and isopentane or a dialkyl ether for example dimethyl ether.
  • up to 50% w/w of the propellant may comprise a volatile hydrocarbon, for example 1 to 30% w/w.
  • formulations which are free or substantially free of volatile adjuvants are preferred.
  • a polar co-solvent such as C 2 _g aliphatic alcohols and polyols e.g. ethanol, isopropanol and propylene glycol, preferably ethanol, may be included in the drug formulation in the desired amount to improve the dispersion of the formulation, either as the only excipient or in addition to other excipients such as surfactants.
  • the drug formulation may contain 0.01 to 5% w/w based on the propellant of a polar co-solvent e.g. ethanol, preferably 0.1 to 5% w/w e.g. about 0.1 to 1% w/w.
  • a surfactant may also be employed in the aerosol formulation.
  • conventional surfactants are disclosed in EP 372 777 incorporated herein by reference.
  • the amount of surfactant employed is desirable in the range 0.0001% to 50% weight to weight ratio relative to the medicament, in particular, 0.05 to 5% weight to weight ratio.
  • Preferred surfactants are lecithin, oleic acid and sorbitan trioleate.
  • Preferred formulations, however, are free or substantially free of surfactant.
  • compositions may contain 0.0001 to 50% w/w, preferably 0.001 to 20%, for example 0.001 to 1% of sugar relative to the total weight of the formulation.
  • the ratio of medicament to sugar falls within the range of 1 :0.01 to 1 :100 preferably 1 :0.1 to 1 :10.
  • Typical sugars which may be used in the formulations include, for example, sucrose, lactose and dextrose, preferably lactose, and reducing sugars such as mannitol and sorbitol, and may be in micronised or milled form.
  • the final aerosol formulation desirably contains 0.005-10% w/w, preferably 0.005 to 5% w/w, especially 0.01 to 1.0% w/w, of medicament relative to the total weight of the formulation.
  • Medicaments which may be administered in aerosol formulations according to the invention include any drug useful in inhalation therapy and which may be presented in a form which is substantially completely insoluble in the selected propellant.
  • Appropriate medicaments may thus be selected from, for example, analgesics, e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem; anti-allergies, e.g. cromoglycate (e.g. as sodium salt), ketotifen or nedocromil (e.g. as sodium salt); antiinfectives e.g.
  • analgesics e.g. codeine, dihydromorphine, ergotamine, fentanyl or morphine
  • anginal preparations e.g. diltiazem
  • anti-allergies e.g. cromoglycate (e.g. as sodium salt),
  • cephalosporins e.g. cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; anti-histamines, e.g. methapyrilene; anti-inflammatories, e.g. beclomethasone (e.g. as dipropionate), fluticasone (e.g. as propionate), flunisolide, budesonide, rofleponide, mometasone (e.g. as furoate), ciclesonide, triamcinolone (e.g.
  • anti-tussives e.g. noscapine
  • bronchodilators e.g. albuterol (e.g. as free base or as sulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline, fenoterol (e.g. as hydrobromide), formoterol (e.g.
  • ipratropium e.g. as bromide
  • tiotropium atropine or oxitropium
  • hormones e.g., cortisone, hydrocortisone or prednisolone
  • xanthines e.g. aminophylline, choline theophyllinate, lysine theophyllinate or theophylline.
  • 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.
  • the medicaments may be used in the form of a pure isomer, for example, R-albuterol or RR-formoterol.
  • Particularly preferred medicaments for administration using aerosol formulations in accordance with the invention include anti-allergies, bronchodilators and anti-inflammatory steroids of use in the treatment of respiratory disorders such as asthma by inhalation therapy, for example cromoglycate (e.g. as the sodium salt), salbutamol (e.g. as the free base or the sulphate salt), salmeterol (e.g. as the xinafoate salt), formoterol (e.g. as the fumarate salt), terbutaline (e.g. as the sulphate salt), reproterol (e.g. as the hydrochloride salt), a beclomethasone ester (e.g.
  • cromoglycate e.g. as the sodium salt
  • salbutamol e.g. as the free base or the sulphate salt
  • salmeterol e.g. as the xinafoate salt
  • formoterol e.g. as the fumarate salt
  • a fluticasone ester e.g. the propionate
  • Salmeterol especially salmeterol xinafoate, salbutamol, fluticasone propionate, beclomethasone dipropionate and physiologically acceptable salts and solvates thereof are especially preferred.
  • aerosol formulations according to the invention may, if desired, contain a combination of two or more active ingredients.
  • Aerosol compositions containing two active ingredients are known for the treatment of respiratory disorders such as asthma, for example, formoterol and budesonide, salmeterol (e.g. as the xinafoate salt) and fluticasone (e.g. as the propionate ester), salbutamol (e.g as the free base or sulphate) and beclomethasone (as the dipropionate ester) are preferred.
  • Particularly preferred is a combination of fluticasone propionate and salmeterol, or a salt thereof (particularly the xinafoate salt).
  • Particularly preferred formulations for use in the canisters of the present invention comprise a medicament and a C-
  • preferred formulations are free or substantially free of formulation excipients.
  • preferred formulations consist essentially of (or consist of) the medicament and the selected propellant.
  • a metering valve is crimped onto an aluminium can to form an empty canister.
  • the particulate medicament is added to a charge vessel and liquified propellant is pressure filled through the charge vessel into a manufacturing vessel.
  • the drug suspension is mixed before re-circulation to a filling machine and an aliquot of the drug suspension is then filled through the metering valve into the canister.
  • an aliquot of the liquefied formulation is added to an open canister under conditions which are sufficiently cold such that the formulation does notvaporise, and then a metering valve crimped onto the canister.
  • the canister is fitted with a cap assembly, wherein a formulation metering valve is situated in the cap, and said cap is crimped in place.
  • the cap may be secured onto the canister via welding such as ultrasonic welding or laser welding, screw fitting or crimping.
  • MDIs taught herein may be prepared by methods of the art (e.g., see Byron, above and WO/96/32150) substituting conventional cans for those treated in accordance with the present invention.
  • each filled canister is check-weighed, coded with a batch number and packed into a tray for storage before release testing.
  • Each filled canister is conveniently fitted into a suitable channeling device prior to use to form a metered dose inhaler for administration of the medicament into the lungs or nasal cavity of a patient.
  • Suitable channeling devices comprise for example a valve actuator and a cylindrical or cone-like passage through which medicament may be delivered from the filled canister via the metering valve to the nose or mouth of a patient e.g. a mouthpiece actuator.
  • Metered dose inhalers are designed to deliver a fixed unit dosage of medicament per actuation or "puff, for example in the range of 10 to 5000 microgram medicament per puff.
  • Administration of medicament may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate medicament used and the frequency of administration and will ultimately be at the discretion of the attendant physician. When combinations of medicaments are employed the dose of each component of the combination will in general be that employed for each component when used alone. Typically, administration may be one or more times, for example from 1 to 8 times per day, giving for example 1 ,2,3 or 4 puffs each time. Each valve actuation, for example, may deliver 5 ⁇ g, 50 ⁇ g, 100 ⁇ g, 200 ⁇ g or 250 ⁇ g of a medicament. Typically, each filled canister for use in a metered dose inhaler contains 60, 100, 120 or 200 metered doses or puffs of medicament; the dosage of each medicament is either known or readily ascertainable by those skilled in the art.
  • a still further aspect of the present invention comprises a method of treating respiratory disorders such as, for example, asthma, which comprises administration by inhalation of an effective amount of an aerosol formulation as herein described from a metered dose inhaler of the present invention.
  • Standard 12.5 ml MDI canisters Pressurepart Inc Cary NC
  • a solution of 1% w/w compound of formula (I) in isopropyl alcohol for 12 hours at room temperature.
  • the canisters are then drained and allowed to dry at 80°C under vacuum.
  • the cans are then purged of air and the valves crimped in place, and a suspension of about 31.8mgsalbutamol sulphate in about 19.8g HFA 134a is filled through the valve.
  • Example 1 is repeated except a suspension of about 4.25mg salmeterol xinafoate and about 8g HFA 134a is filled through the valve.
  • Example 3 is repeated except a suspension of about 4.25mg salmeterol xinafoate and about 8g HFA 134a is filled through the valve.
  • Example 1 is repeated except a suspension of 22mg fluticasone propionate and 15g HFA 134a is filled through the valve.
  • Example 1 is repeated except a suspension of about 44mg fluticasone propionate and about
  • Example 1 is repeated except a suspension of about 13.8mg fluticasone propionate with about 4mg salmeterol xinafoate and 8 g HFA 134a is filled through the valve.
  • Example 6 Example 1 is repeated except a suspension of about 29mg fluticasone propionate with about 21.4g HFA 227 is filled through the valve.
  • Examples 1 to 6 are repeated except that a compound of formula (II) is employed instead of a compound of formula (I).
  • Examples 1 to 6 are repeated except that a silane derivative of perfluoropolyoxyalkane with a molecular weight in the range 1600-1750 is employed instead of a compound of formula (I).

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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nozzles (AREA)

Abstract

La présente invention concerne un aérosol-doseur qui comprend une surface interface possédant les propriétés suivantes: i) un angle de contact supérieur à 70 degrés, et ii) une conductivité supérieure à 2,4 mS. Cette invention concerne aussi des processus de préparation et d'utilisation thérapeutique de celui-ci.
EP01917037A 2000-03-01 2001-02-28 Aerosol-doseur Withdrawn EP1259276A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GB0004761A GB0004761D0 (en) 2000-03-01 2000-03-01 Metered dose inhaler
GB0004761 2000-03-01
GB0018653 2000-07-28
GB0018624A GB0018624D0 (en) 2000-07-28 2000-07-28 Metered dose inhaler
GB0018624 2000-07-28
GB0018653A GB0018653D0 (en) 2000-07-28 2000-07-28 Metered dose inhaler
PCT/EP2001/002212 WO2001064273A2 (fr) 2000-03-01 2001-02-28 Aerosol-doseur

Publications (1)

Publication Number Publication Date
EP1259276A2 true EP1259276A2 (fr) 2002-11-27

Family

ID=27255564

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01917037A Withdrawn EP1259276A2 (fr) 2000-03-01 2001-02-28 Aerosol-doseur

Country Status (4)

Country Link
EP (1) EP1259276A2 (fr)
JP (1) JP2003525089A (fr)
AU (1) AU4417001A (fr)
WO (1) WO2001064273A2 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0614621D0 (en) 2006-07-24 2006-08-30 3M Innovative Properties Co Metered dose dispensers
GB0620700D0 (en) 2006-10-19 2006-11-29 3M Innovative Properties Co Metered dose valves and dispensers
GB0721737D0 (en) 2007-11-06 2007-12-19 3M Innovative Properties Co Medicinal inhalation devices and components thereof
CA2704997C (fr) 2007-11-06 2016-05-24 3M Innovative Properties Company Dispositifs d'inhalation medicaux et composants de ceux-ci
GB0721739D0 (en) 2007-11-06 2007-12-19 3M Innovative Properties Co medicinal inhalation devices and components thereof
BRPI1007653A2 (pt) 2009-05-06 2019-09-24 3M Innovative Properties Co "dispositivos para inalação de insumos medicinais e componentes dos mesmos"
CA2760801A1 (fr) 2009-05-06 2010-11-11 3M Innovative Properties Company Dispositif d'inhalation medical
EP2427902B1 (fr) 2009-05-06 2017-01-18 3M Innovative Properties Company Appareil et procédé pour le traitement au plasma de contenants

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1270818B (it) * 1993-04-28 1997-05-13 Ausimont Spa Coatings a base di perfluoropolieteri contenenti gruppi acrilici
US6149892A (en) * 1995-04-14 2000-11-21 Glaxowellcome, Inc. Metered dose inhaler for beclomethasone dipropionate
US5871010A (en) * 1996-06-10 1999-02-16 Sarnoff Corporation Inhaler apparatus with modified surfaces for enhanced release of dry powders
EP0942762A1 (fr) * 1996-11-01 1999-09-22 E.I. Du Pont De Nemours & Company Incorporated Tube rallonge pour aerosols-doseurs empechant l'accumulation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0164273A3 *

Also Published As

Publication number Publication date
WO2001064273A3 (fr) 2002-03-28
AU4417001A (en) 2001-09-12
WO2001064273A2 (fr) 2001-09-07
JP2003525089A (ja) 2003-08-26

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