GB2554091A - Pharmaceutical composition - Google Patents

Pharmaceutical composition Download PDF

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Publication number
GB2554091A
GB2554091A GB1615914.7A GB201615914A GB2554091A GB 2554091 A GB2554091 A GB 2554091A GB 201615914 A GB201615914 A GB 201615914A GB 2554091 A GB2554091 A GB 2554091A
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Prior art keywords
weight
pharmaceutical composition
composition
component
compound
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GB1615914.7A
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GB201615914D0 (en
Inventor
Corr Stuart
James Noakes Timothy
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Mexichem Fluor SA de CV
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Mexichem Fluor SA de CV
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Application filed by Mexichem Fluor SA de CV filed Critical Mexichem Fluor SA de CV
Priority to GB1615914.7A priority Critical patent/GB2554091A/en
Publication of GB201615914D0 publication Critical patent/GB201615914D0/en
Priority to ES17777637T priority patent/ES2877575T3/en
Priority to BR112019005168A priority patent/BR112019005168A2/en
Priority to AU2017328910A priority patent/AU2017328910B2/en
Priority to EP17777637.4A priority patent/EP3515425B1/en
Priority to CA3037107A priority patent/CA3037107C/en
Priority to CN201780057318.5A priority patent/CN109715148A/en
Priority to PCT/GB2017/052764 priority patent/WO2018051133A1/en
Priority to MX2019003099A priority patent/MX2019003099A/en
Priority to JP2019515225A priority patent/JP6781828B2/en
Priority to US16/334,144 priority patent/US10792256B2/en
Publication of GB2554091A publication Critical patent/GB2554091A/en
Priority to US16/883,016 priority patent/US11077076B2/en
Priority to US16/882,979 priority patent/US11311502B2/en
Priority to US17/694,972 priority patent/US11883372B2/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated

Abstract

A pharmaceutical composition is described. The composition comprises: (i) a drug component comprising at least one salmeterol compound (preferably, salmeterol xinafoate) selected from salmeterol and the pharmaceutically acceptable derivatives thereof; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a). Preferably, the composition comprises a long acting muscarinic antagonist (LAMA) such as umeciidinium, ipratropium, tiotropium, aclidinium or glycopyrrolate. Preferably, the composition contains at least one corticosteroid (budesonide, mometasone, beclomethasone, fluticasone). Preferably, the composition comprises a surfactant (polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), oleic acid, lecithin). Composition may further comprise ethanol or other polar excipient. Most preferably, the composition contains less than 5 ppm water. It is claimed that the use of HFA-152a improves the stability of the drug compound relative to the use of other HFA propellants (e.g. HFA-134a). The composition may be used to treat asthma and COPD.

Description

(54) Title of the Invention: Pharmaceutical composition
Abstract Title: Pharmaceutical composition comprising; a salmeterol compound, and 1,1-difluoroethane (HFA-152a) as propellant, for use with an MDI (metered dose inhaler) (57) A pharmaceutical composition is described. The composition comprises: (i) a drug component comprising at least one salmeterol compound (preferably, salmeterol xinafoate) selected from salmeterol and the pharmaceutically acceptable derivatives thereof; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a). Preferably, the composition comprises a long acting muscarinic antagonist (LAMA) such as umeciidinium, ipratropium, tiotropium, aclidinium or glycopyrrolate. Preferably, the composition contains at least one corticosteroid (budesonide, mometasone, beclomethasone, fluticasone). Preferably, the composition comprises a surfactant (polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), oleic acid, lecithin). Composition may further comprise ethanol or other polar excipient. Most preferably, the composition contains less than 5 ppm water. It is claimed that the use of HFA-152a improves the stability of the drug compound relative to the use of other HFA propellants (e.g. HFA-134a). The composition may be used to treat asthma and COPD.
PHARMACEUTICAL COMPOSITION
Kt
The present invention relates to the delivery of drug formulations from a medical device, such as a metered dose inhaler (MDI), using a propellant comprising 1,1~ difluoroethane (HFA-152a), More particularly, the present invention relates to pharmaceutical compositions comprising HFA-152a propeiianl and a drug formulation which is dissolved or suspended In the propellant and to medical devices containing those compositions. The pharmaceutical compositions of the invention are particularly suited for delivery from a pressurised aerosol container usino a metered dose inhaler (MDI).
MDIs are the most significant type of inhalation drug delivery system and are well known to those skilled in the art. They are designed to deliver, on demand, a discrete and accurate amount of a drug to the respiratory tract of a patient using a liquefied propellant In which the drug is dissolved, suspended or dispersed. The design and operation of MDIs is described in many standard textbooks and in the patent literature. They all comprise a pressurised container that holds the drug formulation, a nozzle and a valve assembly that is capable of dispensing a controlled quantity of the drug through the nozzle when it is activated. The nozzle and valve assembly are typically located in a housing that Is equipped with a mouth piece. The drug formulation will comprise a propellant, in which the drug is dissolved, suspended or dispersed, and may contain other materials such as polar excipients, surfactants arid preservatives.
In order for a propellant to function satisfactorily in MDIs, it needs io have a number of properties. These include an appropriate boiling point and vapour pressure so that it can be liquefied in a closed container at room temperature but develop a high enough pressure when the MDI is activated to deliver the drug as an atomised formulation even at iow ambient temperatures. Further, the propellant should be of
3d low acute and chronic toxicity and have a high cardiac sensitisation threshold. It should have a high degree of chemical stability in contact with the drug, the container and the metallic and non-metallic components of the MDI device, and have a iow propensity to extract low molecular weight substances from any elastomeric materials In the MDI device. The propellant should also be capable of maintaining the drug in a homogeneous solution, In a stable suspension or in a stable dispersion for a sufficient time to permit reproducible delivery of the drug in use. When the drug is in suspension In the propellant the density of the liquid propellant is desirably similar to that of' the solid drug In order to avoid rapid sinking er floating of the drug particles in the liquid. Finally, the propellant should not present a significant flammability risk to the patient to use. In particular, it should form a non-flammable or low flammability mixture when mixed with air In the respiratory tract.
Dlchiorodifluoromethane (R-12) possesses a suitable combination of properties arid was for many years the most widely used MDI propellant, often blended with trlchiorofiuoromethane (R-11), Due to international concern that fully and partially halogenated chlorofluorocarbons (CFCs), such as dichlorcdifluoromethane and trlchiorofiuoromethane, were damaging the earth’s protective ozone layer, many countries entered into an agreement, the Montreal Protocol, stipulating that their manufacture and use should be severely restricted and eventually phased out completely. Dlchiorodifluoromethane and trlchiorofiuoromethane were phased out for refrigeration use to the 1990's, but are still used in small quantities in the MDI sector as a result of an essential use exemption in the Montreal Protocol,
1,1,1,2-tetrafiuoroelhane (HFA-134a) was introduced as a replacement refrigerant and MDI propellant for R-12. 1,1,1,2,3,3,3-heptafiuoropropane (HFA-227ea) was also introduced as a replacement propellant for diehlorofetrafiuoroethane (R-114) in the MDI sector and is sometimes used alone or blended with HFA -134a for this application.
Although HFA-134a and HFA-227ea have low ozone depletion potentials (ODPs), 25 they have global warming potentials (GWPs), 1430 and 3220 respectively, which are now considered to be too high by some regulatory bodies, especially for dispersive uses when they are released into the atmosphere.
One industrial area that has received particular attention recently has been the 30 automotive air-conditioning sector where the use of HFA-134a has come under regulatory control as a result of the European Mobile Air Conditioning Directive (2006/40/EC). Industry is developing a number of possible alternatives to HFA134a in automotive air conditioning and other applications that have a low greenhouse warming potential (GWP) as well as a low ozone depletion potential (ODP). Many of these alternatives include hydrofluoropropenes, especially the tefrafiuoropropenes, such as 2.3,3,3-tetrafluoropropene (HFO~1234yf) arid 1,3,3,3tetraf i uoro prope ne (H FO-1234ze),
Although the proposed alternatives to HFA-134a have a low GW'F, the toxicological status of many of the components, such as certain of the fluoropropenes, is unclear and they are unlikely to be acceptable for use in the MDI sector for many years, if at ell.
Salmeteroi and salmeteroi xinafoate are long acting beta-2-agonists (LABA) used in the treatment and control of a number of respiratory-related disorders, but particularly asthma and chronic obstructive pulmonary disease (COPD). Both drugs are conveniently delivered using a MDI. Whilst salmeteroi treatment Is very effective, the performance of salmeteroi In many of these therapies may be Improved by administration in combination with a corticosteroid, such as the glucocorticoid steroid fluticasone.
There is a need for a saimeteroi-based pharmaceutical composition which can be delivered using a MDI and that uses a propellant having a reduced GWP In comparison with HFA-134a and HFA-227ea. There is also a need for a saimeteroibased pharmaceutical composition which exhibits improved stability.
We have found that a propellant comprising 1,1 -dlfluoroefhane (HFA-152a) can be used to successfully deliver saimeteroi-based drug formulations using a MDI, These formulations can exhibit improved chemical stability, particularly where the formulations contain low amounts of water, improved aerosolisafion performance for improved drug delivery, good suspension stability, reduced GWP, good compatibility with standard uncoated aluminium cans as well as good compatibility with standard valves and seals.
According to a first aspect of the present invention, there is ptovided a pharmaceutical composition, e.g, a pharmaceutical suspension or a pharmaceutical solution, said composition comprising:
(i) a drug component comprising at least one salmeteroi compound selected from salmeteroi and the pharmaceutically acceptable derivatives thereof, especially the pharmaceutically acceptable salts thereof; and (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a).
The improved chemical stability is observed, in particular, when the pharmaceutical composition contains less than TOO ppm, preferably loss than 50 ppm, more preferably less than 10 ppm and particularly less than 5 ppm of water based on the total weight of tho pharmaceutical composition, In referring to tho water content of the pharmaceutical composition, we are referring to the content of free wafer in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition is water-free. Alternatively, the pharmaceutical composition of the first aspect may contain greater than 0.5 ppm of wafer, e.g. greater than 1 ppm, but loss than the amounts discussed above, as It can in practice be difficult to remove all the water from the composition and then retain it in such a water-free state,
Accordingly a preferred embodiment of the first aspect of the present Invention provides a pharmaceutical composition, e.g, a pharmaceutical suspension or a pharmaceutical solution, said composition comprising;
(i) a drug component comprising at least one saimeterol compound selected from saimeterol and the pharmaceutically acceptable derivatives thereof,
2V especially the pharmaceutically acceptable salts thereof; and (ii) a propellant component comprising 1,1 -difluoroethane (HFA-152a), wherein the composition contains less than 100 ppm, preferably less than ppm, more preferably less than 10 ppm and especially less than 5 ppm of water based on the total weight of the pharmaceutical composition.
The pharmaceutical composition of the present invention is suitable for delivery to the respiratory tract using a metered dose inhale! (MDI).
1(1
IS
The at least one saimeterol compound may be dispersed or suspended in the propellant. The drug particles in such suspensions preferably have a diameter of less than 100 microns, e.g, less than 50 microns. However, in an alternative embodiment the pharmaoeutical compositions of the invention are solutions with the at least one saimeterol compound dissolved In the propellant, e.g. with the assistance of a polar excipient, such as ethanol,
Suitable pharmaceuiicaiiy acceptable derivatives of salmeteroi include, Inter alia, pharmaceutically acceptable salts, pharmaceutically' acceptable prodrugs, pharmaceutically acceptable solvates, pharmaceuiicaiiy acceptable hydrates, pharmaceutically acceptable esters, solvates of pharmaceutically acceptable salts, solvates of pharmaceutically acceptable prodrugs, hydrates of pharmaceutically acceptable salts and hydrates of pharmaceutically acceptable prodrugs. A preferred pharmaceutically acceptable derivative of salmeteroi is a pharmaceutically acceptable salt thereof, particularly salmeteroi xinafoate. In a particularly preferred embodiment, the at least one salmeteroi compound in the pharmaceutical composition of the first aspect of the Invention is salmeteroi or salmeteroi xinafoafe, especially salmeteroi xinafoate.
VO
V\
30:
The amount ol the drug component in the pharmaceutical composition ol the first aspect of the present invention wili typically be in the range of from 0.01 to 2.5 weight % based on the total weight of the pharmaceutical composition. Preferably, the drug component wili comprise from 0.01 te 2,0 weight %, more preferably fr om 0.05 to 2.0 weight % and especially from 0.05 to 1,5 weight % of the total weight of the pharmaceutical composition. The drug component may consist essentially of or consist entirely of the at least one salmeteroi compound selected from salmeteroi and the pharmaceutically acceptable derivatives thereof. By the term “consists essentially of’, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99,9 weight % of the drug component consists ol the least one salmeteroi compound. Alternatively, the drug component may contain other drugs, such as at least one corticosteroid and/or least one long acting muscarinic antagonist (LAMA).
The propellant component in the pharmaceutical composition of the first aspect of the present invention comprises 1,1-difluoroethane (HFA-152a), Thus, we do not exclude the possibility that the propellant component may include other propellant compounds in addition to the HFA-152a, For example, the propellant component may additionally comprise one or more additional hydrofiuorocarbors or hydrocarbon propellant compounds, e.g. selected from HFA-227ea, HFA-134a, diiluoromethane (HF.A-32), propane, butane, Isobutane and dimethyl ether. The preferred additional propellants are HFA-227ea and HFA-134a, if an additional propellant compound is included, such as HFA-134a cr HFA~22?ea. at least 5 % by weight, preferably at least 10 % by weight and mere preferably at least 50 % by weight of the propellant component should be HFA-152a. Typically, the HFA-152a will constitute at least 90 weight %, e.g, from 90 to 99 weight %, of the propellant component. Preferably, the HFA-152a will constitute at least 95 weight %, e.g, from 95 to 99 weight %, and more preferably at least 99 weight % cf the propellant component.
In an especially preferred embodiment, the propellant component consists entirely of HFA-152a so that the pharmaceutical composition of the invention comprises HFA-152a as the sole propellant. By the term “consists entirely of we do not, of course, exclude the presence of minor amounts, e.g. up to a few hundred parts per million, of impurities that may be present following the process that is used to make the HFA-152a providing that they do not affect tire suitability of the propellant in medical applications.
The amount ef propellant component in the pharmaceutical composition of the invention will vary depending on the amounts of the drugs and other components in the pharmaceutical composition. Typically, the propellant component will comprise from 30.0 to 99.99 weight % of the total weight of the pharmaceutical composition. Preferably, the propellant component will comprise from 90.0 to 99,99 weight %, more preferably from 96.5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the pharmaceutical composition, in one embodiment, the pharmaceutical composition of the first aspect of the present invention consists essentially of and more preferably consists entirely of the two components (I) and (ii) listed above. By the term consists essentially of”, we mean that at least 98 weight %, mere preferably at least 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two listed components.
In another embodiment, the pharmaceutical composition of the first aspect of the present invention additionally Includes a polar excipient, such as ethanol. Polar excipients have been used previously in pharmaceutical compositions for treating respiratory disorders that are delivered using metered dose inhalers (MDIs). They are also referred to as solvents, co-solvents, carrier solvents and adjuvants. Their 6
1δ
3.5
Inclusion can serve to solubilise the surfactant, or the drag in the propellant and/or Inhibit depositions of drug particles on the surfaces of the metered doss inhaler that are contacted by the pharmaceutical composition as it passes from the container in which It is stored to the nozzle outlet. They are also used as bulking agents In two-stage filling processes where the drug Is mixed with a suitable polar excipient. The most commonly used polar excipient Is ethanol. If a polar excipient Is used, it will typically be present in an amount of from 0.5 to 10 % by weight, preferably in an amount of from 1 to 5 % by weight based on the total weight of the pharmaceutical composition.
In one preferred embodiment, the pharmaceutical composition of the present invention is free of polar excipients such as ethanol.
The pharmaceutical composition of the first aspect of the present invention may also Include a surfactant component comprising at least one surfactant compound. Surfactant compounds of the type that have been in use hitherto in pharmaceutieai formulations for MDIs may be used in the pharmaceutical compositions of the present Invention. Preferred surfactants are selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin. By the term oleic acid, we are not necessarily referring to pure (9Z)-ocfadec-9~enoic acid. When sold for surfactant use in medical applications, oleic acid Is typically a mixture of several fatty acids, with {9Z)-ociadec-9-enoic acid being the predominant fatty add, e.g. present in an amount of at least 65 weight % based on the total weight of the surfactant.
In a preferred embodiment, the surfactant component consists essentially of and still more preferably consists entirely of at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycols, oleic acid and lecithin. In a particularly preferred embodiment, the surfactant component consists essentially of and still more preferably consists entirely of at ieast one surfactant compound selected from polyvinylpyrrolidone and polyethylene glycols. By the term “consists essentially of, we mean that at least 95 weight %, more preferably ai least 98 weight % and especially at least 99 weight % of the surfactant component is composed of the listed surfactants.
if a surfactant component is used, it will typically be present in an amount of from 0.1 to 2.5 % by weight, preferably in an amount of from 0.2 to 1,5 % by weight based on the total weight of the pharmaceutical composition.
The pharmaceutical composition of the invention may aiso include a iong acting muscarinic antagonist (LAMA). Any of the long acting muscarinic antagonists that have been in use hitherto for treating chronic obstructive pulmonary diseases and that can be delivered using a MDI can be used In the pharmaceutical compositions of the present invention. Suitable long acting muscarinic antagonists include umeclidinium, ipratropium, tiotroplum, aciidinium and the pharmaceutically acceptable derivatives thereof, especially the pharmaceutically acceptable salts thereof. Preferred compounds include the pharmaceutically acceptable salts of glycopyrroiate (also known as glycopyrronium). Glycopyrroiate is a quaternary ammonium self. Suitable pharmaceutically acceptable counter ions include, for example, fluoride, chloride, bromide, iodrie, nitrate, sulfate, phosphate, formate, acetate, trifiuoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-eh loro benzoate, diphenyl-acetate or triphenyiacefate, o-hydroxybenzoate, p-hydroxybenzoate, i~ hydroxynaphfhaiene2-carboxylate, 3-hydroxynaphthalene~2-carboxylate, mefhanesulfonafe end benzenesuifonafe. A preferred compound is the bromide salt of glycopyrroiate also known as glycopyrronium bromide.
According to a second aspect of the present invention, there is provided a pharmaceutical composition, e.g, a pharmaceutical suspension or a pharmaceutical solution, said composition comprising.;
fi) a drug component comprising: at least one satmeterol compound selected from salmeieroi and the pharmaceuficaily acceptable derivatives thereof, especially the pharmaceutically acceptable salts thereof and at least one long acting muscarinic antagonist, particularly at least one pharmaceutically acceptable salt of glycopyrroiate; and (ii) a propellant component comprising 1,1 -difiuoroethane (HFA-152a).
In this second, aspect of the present invention, the pharmaceutical composition preferably contains less than 100 ppm. more preferably less than 50 ppm, particularly less than 10 ppm and especially less than 5 ppm of water based on the total weight of the pharmaceutical composition, it has been found that small amounts of water alongside the use of HFA-152a as the propellant can result in a pharmaceutical composition with improved chemical stability. In referring to the water content of the pharmaceutical composition, we are referring to the content of free wafer in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition of the second aspect of the present invention Is water-free. Alternatively, the pharmaceutical composition of tbs second aspect may contain greater than 0.5 ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as it can in }Q practice be difficult to remove all the water from the composition and then retain It in such a water-free state.
Suitable and preferred salmeteroi compounds are as discussed above for the pharmaceutical composition of the first aspect of the present invention.
IS
Typical and preferred amounts of the drug component and the propellant component in the pharmaceutical composition of the second aspect of the present invention and suitable, typical and preferred compositions for the propellant component ere as discussed above for the pharmaceutical composition of the first aspect of the invention. The drug component may consist essentially ef or consist entirely of the at least one salmeteroi compound and the at least one long acting muscarinic antagonist. By the term “consists essentially of”, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists ef the at least one salmeteroi compound and the at least one long acting muscarinic antagonist.
in one embodiment, the pharmaceutical composition of the second aspect of the present invention consists essentially of and more preferably consists entirely of the two components (I) and (ii) listed above. By the term “consists essentially of”, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99,9 weight % of the pharmaceutical composition consists of the two ksted components.
In another embodiment, the pharmaceutical composition of the second aspect of tfse invention may contain one or both ef a polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect of the invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect of the invention. Typicai and preferred amounts of the polar excipient and the surfactant component ere as discussed above for the pharmaceutical composition of the first aspect of the invention.
in an especially preferred embodiment of the second aspect of the Invention, the drug component comprises at least one saimeteroi compound selected from saimeteroi and saimeteroi xinafoate and at least one pharmaceutically acceptable
W salt of glycopyrrolate, especially glycopyrronium bromide. Preferably, the at least one selected saimeteroi compound and the at least one selected pharmaceuticaliy acceptable salt of glycopyrrolate are the only pharmaceuticai actives in the pharmaceuticai composition: of the second aspect of the invention,
IS The pharmaceutical composition of the Invention may also: Include a corticosteroid. Any of the corticosteroids that have been In use hitherto: for treating asthma and chronic obstructive pulmonary diseases and that can be delivered using a MDI can be used in the pharmaceutical compositions: of the present love ntion, Sui table corticosteroids include budesonide, mometasone, beciomethasone and fluticasone as well as their pharmaceutically acceptable derivatives, such as their pharmaceutically acceptable salts and esters. Preferred compounds include fluticasone and fluticasone propionate.
Accordingly, a third, aspect of the present invention provides a pharmaceuticai
23: composition,: e.g. a pharmaceuticai suspension or a pharmaceutical solution:, said composition comprising:
(i) a: drug component comprising at least one salraetefol: compound selected from saimeteroi and the pharmaceutically acceptable derivatives thereof, especially the pharmaceutically acceptable salts thereof and at least one .30 corticosteroid, particularly' at least one corticosteroid selected from fluficasone: budesonide, mometasone and beclomethasone and the pharmaceutically acceptable derivatives thereof, especially fluticasone and fluticasone propionate; and (il) a propellant component comprising 1,1 -difluoroethane (HFA-152a).
in this third aspect of the present invention, the pharmaceutical composition preferably contains less than 100 ppm. more preferably less than 50 ppm, particularly less than 10 ppm and especially less than 5 ppm ci water based on the total weight of the pharmaceutical composition, it has been found that small amounts of water alongside the use of HFA~152a as the propellant can result In a pharmaceutical composition with Improved chemical stability. In referring to the water content of the pharmaceutical composition, we are referring to ttie content of free water in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an
IO especially preferred embodiment, the pharmaceutical composition of the third aspect of the present invention is water-free. Alternatively, the pharmaceutical composition of the third aspect may contain greater than 0,5 ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as It can in practice be difficult to remove ail the wafer from the composition and then retain it
In such a water-free state.
Suitable and preferred saimeterol compounds are as discussed above for the pharmaceutical composition of the first aspect of the present invention.
Typical and preferred amounts of the drug component and the propellant component In the pharmaceutical composition of the third aspect of the present invention and suitable, typical and preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the invention. The drug component may consist essentially of or consist entirely of the at least one saimeterol compound and the at least one corticosteroid. By the term “consists essentially of’, we mean that at least 98 weight %, more preferably at. least 99 weight % and especially at least 99.9 weight % of the drug component consists of the at least one saimeterol compound and the at least one corticosteroid.
In one embodiment, the pharmaceutical composition of the third aspect of the present invention consists essentially of and more preferably consists entirely of the five components (I) and (ill listed above. By the term “consists essentially of, we mean that at least 98 weight %, mere preferably at ieast 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two listed components.
to
In another embodiment, the pharmaceutical composition of the third aspect of the invention may contain one or both of a polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect ot the invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect of tire invention. Typical and preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first, aspect of the Invention.
In an especially preferred embodiment of the third aspect of the invention, the drug component comprises at least one salmeterol compound selected from salmeterol and salmeterol xinafoate and fluticasone propionate. Preferably, the at least one selected salmeterol compound and the fluticasone propionate are the only pharmaceutical actives in the pharmaceutical composition of the third aspect of the invention.
The pharmaceutical composition of the invention may also include a long acting muscarinic antagonist (LAMA; and a corticosteroid. Any of the long acting
2d muscarinic antagonists and corticosteroids that have been in use hitherto tor treating asthma and chronic obstructive pulmonary diseases and that can be delivered using a MDI can be used in the pharmaceutical compositions ot the present invention. Suitable and preferred long acting muscarinic antagonists are as discussed above for the second aspect of the invention. Suitable and preferred corticosteroids are as discussed above for the third aspect of the present Invention.
Accordingly, a fourth aspect of the present Invention provides a pharmaceutical composition, e.g, a pharmaceutical suspension or a pharmaceutical solution, said composition comprising;
(I) a drug component comprising at least one salmeterol compound selected from salmeterol and the pharmaceutically acceptable derivatives thereof, especially the pharmaceutically acceptable salts thereof, at least one long acting muscarinic antagonist, particularly at least one pharmaceutically acceptable salt of glycopyrrolate, and at least one corticosteroid, 5 particularly at least one corticosteroid selected from fluticasone, budesonide, mometasone and beclomethasone and the pharmaceutically acceptable derivatives thereof, especially fluticasone and fluticasone propionate: and (II) a propellant component comprising 1,1-dlfluoroethane (HFA-1523).
In this fourth aspect of the present invention, the pharmaceutical composition preferably contains less than 100 ppm, more preferably less than 50 ppm, particularly less than 10 ppm and especially less than 5 ppm of water based on the total weight of the pharmaceutical composition. if. has been found that small amounts of water alongside the use of HFA-152a as the propellant can result in a pharmaceutical composition with improved chemical stability. In referring to the water content of the pharmaceutical composition, we are referring to the content of free water in the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition of the fourth aspect of the present invention Is water-free. Alternatively, the pharmaceutical composition of the fourth aspect may contain greater than CLS ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as it can in practice be difficult to remove all the wafer from the composition and then retain it In such a water-free state.
Suitable and preferred salmeterol compounds are as discussed above for the pharmaceutical composition of the first aspect of the present invention.
Typical and preferred amounts of the drug component and the propellant component in the pharmaceutical composition of the fourth aspect of the present invention and suitable, typical and preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the invention. The drug component may consist essentially of or consist entirely of the at least one salmeterol compound, the at least one long acting muscarinic antagonist (LAMA) and the at least one corticosteroid. By the term ’’consists essentially of, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists of the at least one salmeterol compound, the at least one long muscarinic antagonist (LAMA) and the at least one corticosteroid.
in one embodiment, the pharmaceutics! composition of the fourth aspect cf the present invention consists essentially of and more preferably consists entirely of the two components (i) and (ii) listed above. By the term “consists essentially cf”, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99,9 weight % of the pharmaceutical composition consists of the two listed components.
In another embodiment, the pharmaceutica! composition of the fourth aspect of the invention may contain one or both of a polar excipient and a surfactant component
5? as discussed above for the pharmaceutical composition of the first aspect of the invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect of the invention. Typical and preferred amounts cf the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first respect of is the invention.
In an especially preferred embodiment of the fourth aspect of the invention, the drug component comprises at least one saimeterol compound selected from saimeterol and saimeterol Xinafoate, at least one pharmaceutically acceptable salt of giycopyrroiate, especially olycopyrronium bromide, and fluticasone propionate. Preferably, the at least one selected saimeterol compound, the at least one pharmaceutically acceptable salt of glycopyrrolate and the fluticasone propionate are the only pharmaceutical actives in the pharmaceutical composition of the fourth aspect of the inventien.
It has been found that the use of propellants comprising 1,1-dii'iuoroethane (HFA-152a) in pharmaceutical compositions containing a saimeterol compound, such as saimeterol xinafoate, and the propellant can unexpectedly Improve the chemical stability of the saimeterol compound compared to the stability it exhibits in formulations containing either HFA-134a or HFA-227ea as the propellant.
Accordingly, In a fifth aspect of the present Invention there is provided a method of improving the stability of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one saimeterol compound selected from saimeterol and the pharmaceutically acceptable derivatives thereof, said method comprising using a propeilant component comprising 1,1difluoroethane (HFA-152a).
The pharmaceutical composition in the stabilisation method of the fifth aspect of the present invention may be a suspension or a solution.
The improved chemical stability can result, In particular, when the pharmaceutical composition contains less than 100 ppm, preferably less than 50 ppm, more preferably less than 10 ppm and particularly less than 5 ppm of water based cn the it! total weight of the pharmaceutical composition. In referring to the water content of the pharmaceutical composition, we are referring to the content of free water In the composition and not any water that happens to be present in any hydrated drug compounds that may be used as part of the drug component. In an especially preferred embodiment, the pharmaceutical composition is water-free. Alternatively,
IS the pharmaceutical composition recited in the fifth aspect of the present invention may contain greater than 0.5 ppm of water, e.g. greater than 1 ppm, but less than the amounts discussed above, as it can In practice be difficult to remove all the water from the composition and then retain It in such a water-free state.
Accordingly, in a preferred embodiment of the fifth aspect of the present invention there is provided a method of improving the stability of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one salmeterol compound selected from salmeterol and the pharmaceutically acceptable derivatives thereof, said method comprising using a propellant component comprising 1,1-difiuoroethane (HFA-152a) and selecting the components and conditions for the preparation of the pharmaceutical composition to maintain the water content of the pharmaceutical composition below 100 ppm, preferably below 50 ppm, more preferably below 10 ppm and particularly below 5 ppm based on the total weight of the pharmaceutical composition.
In practice, preparing a pharmaceutical composition with the low water levels recited above Involves using a propellant component with a suitably low water content, as it is the propellant component that can tend to contain adventitious amounts of water, and then preparing the pharmaceutical composition under suitably dry conditions, e.g. in a dry nitrogen atmosphere. Preparing pharmaceutical compositions under dry conditions Is well known and the techniques involved are well understood by those skilled in the art. However, if the pharmaceutical composition contains significant amounts of ether components, e.g. a pharmaceutical excipient such as ethanol., then it may also he important to controi the water content of those components as well as the propeiiant, e.g. by drying to reduce the water content to suitably low levels. Suitable drying techniques are well known to those skilled in the art and include the use of a molecular sieve or other inorganic desiccant and membrane drying processes.
In the stabilisation method of the fifth aspect of the present invention suitable rand it? preferred salmeterol compounds and derivatives thereof are as described above for the pharmaceutical composition of the first aspect of the present invention. In addition, typical and preferred amounts of the drug component and the propellant component in the stabilisation method of the fifth aspect of the present invention and suitable, typical and preferred compositions for the propellant component are as discussed above for the pharmaceutical composition of the first aspect of the invention.
The drug component in the stabilisation method of the fifth aspect of the present invention may consist essentially of or consist entireiy of the at least one salmeterol compound selected from salmeterol and the pharmaceutically acceptable derivatives thereof. By the term “consists essentially off we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the drug component consists of the least one salmeterol compound. Alternatively, the drug component may additionally comprise at least one long acting muscarinic antagonist and/or at least one corticosteroid. When a long acting muscarinic antagonist and/or a corticosteroid are included, suitable arid preferred long acting muscarinic antagonists and suitable and preferred corticosteroids are as described above for the pharmaceutical compositions of the second and third aspects of the present Invention,
In one embodiment,, the pharmaceutical composition In the fifth aspect of the present invention consists essentially of and more preferably consists entirely of the drug component and the propeiiant component as defined above. By the term “consists essentially of', we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99.9 weight % of the pharmaceutical composition consists of the two components, iO
IS
In an alternative embodiment, the pharmaceuticai composition in the fifth aspect of the invention may contain one or both of a polar excipient and a surfactant component as discussed above for the pharmaceuticai composition of the first aspect of the invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect of the invention. Typical and preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceuticai composition of the first aspect of the invention.
in one preferred stabilisation method, the resulting pharmaceutical composition after storage at 4Q~C and 75 % relative humidity for 6 months will produce less than 0.4 % by weight and preferably less than 0.36 % by weight of impurities from the degradation of the at least one salmeteroi compound based on the total weight of the at least one salmeteroi compound and the impurities.
In another preferred stabilisation method In which the pharmaceutical composition also comprises at least one corticosteroid and/or at least one long acting muscarinic antagonist, the resulting pharmaceutical composition after storage at
40°C and 75 % relative humidity for 6 months will produce less than 0.4 % by weight and preferably ;ess than 0.36 % by weight of impurities from the degradation of the at least ono salmeteroi compound based on the total weight of the at least ono salmeteroi compound and the impurities,
In yet another preferred stabilisation method, at least 97,5 % by weight, preferably at least 98.0 % by weight and mere preferably at least 98.5 % by weight of the at least one salmeteroi compound that Is contained originally In the pharmaceuticai composition immediately following preparation will be present in the composition after storage at 4Q°C and 75 % relative humidity for 6 months.
In still another preferred stabilisation meihod in which the pharmaceutical composition also comprises at least one corticosteroid and/or at least one long acting musoarlnic antagonist, at least 97.5 % by weight, preferably at least 98.0 % by weight and more preferably at least 98.5 % by weight of the at least one salmeteroi compound that Is contained originally In the pharmaceutical composition immediately following preparation wilt be present ·η the composition after storage at 4C4C and 75 % relative humidity for 6 months.
In a further preferred stabilisation method, at least 97.5 %, preferably at least 98.0 % and more preferably at least 98.5 % of the original pharmaceutical activity of the composition is retained after storage at 4Q°C and 75 % relative humidity for 6 months.
One preferred pharmaceutical composition ot the first, second, third and fourth
X0 aspects of the present Invention will produce less than 0,4 % by weight and preferably less than 0.36 % by weight of total impurities from the degradation of the at least one saimeterol compound after storage at 4CTC and 75 % relative humidity for 6 months.
The weight % of impurities Indicated above are based on the total weight of the at least one saimeterol compound and the impurities.
In a further preferred pharmaceutical composition of the first, second, third and fourth aspects of the present invention at least 97.5 % by weight, preferably at least
98.Q %. by weight arid more preferably at least 98.5 % by weight of the at least one sal mete rot com pound that is contained originally in the pharmaceutical composition of the invention immediately following preparation will be present in the composition after storage at 40°C and 75 % relative humidity for 6 months in yet: another preferred pharmaceutical composition of the first, second, third and fourth aspects of the present invention at least 97.5 %, preferably at least 98,0 % and more: preferably at least 98.5 % of the original pharmaceutical activity of the pharmaceutical composition of the Invention is retained after storage at 4Q*C and 75 % relative humidity for 6 months.
in referring: to the storage of the pharmaceutical compositions in the above described stabilisation methods, we are referring, in particular to the storage of those compositions: in uncoated aluminium containers. -Similarly, in referring to the storage of the above described pharmaceutical compositions,: we are referring, in particular, to their storage In uncoated aluminium containers.
IS
It has been found that the use of propellants comprising 1,1-dlfluoroethane (HFA152a) in pharmaceutical compositions containing a saimeteroi compound, such as salrnetero! xinafoate, and the propellant hat are designed to be delivered using a metered dose inhaler can unexpectedly improve the aerosolization performance of the pharmaceutical composition when that composition is delivered from the metered dose inhaler compared to the performance that is observed when either HPA-134a or H FA-227ea is used as the propellant in particular, the fine particle fraction of the saimeterol compound in the emitted dose typically comprises at least 40 weight %, preferably at least 42.5 weight % and more preferably at least 45 weight % of fhe emitted dose of the saimeterol compound. We are referring here, in particular, to the emitted dose that is observed immediately after the pharmaceutical composition has been filled into a MDI canister and prior to any long term storage.
Accordingly, in a sixth aspect of the present Invention there is provided a method of improving the aerosolization performance of a pharmaceutical composition comprising a propellant component and a drug component comprising at least one saimeterol compound selected from saimeterol and the pharmaceutically acceptable derivatives thereof, eaid method comprising using a propellant component comprising 1, 1-dlfluoroethahe (HFA-152a),
The pharmaceutical composition in the method of the sixth aspect of the present invention may be a suspension or a solution.
In a preferred embodiment of the sixth aspect of the present invention there is provided a method of improving the aerosolization performance of a pharmaceutical composition comprising: a propellant component arid a drug component comprising at least one saimeterol compound selected from saimeterol and the pharmaceutically acceptable derivatives thereof, said method comprising
30: using a propellant component comprising 1,1-difiuoroethane (HFA-152a) and providing a pharmaceutical composition which when delivered from a metered dose inhaler yields a fine particle fraction of the at least one saimeterol: compound which is at least 40 weight %. preferably at least 42,5 weight % and more preferably at least 45 weight % of the emitted dose of the at least one saimeterol compound.
increasing the fine particle fraction of the emitted dose Is highly beneficial because it is the fine drug particles that are able to penetrate into the deep bronchiole passages and the alveolar passages of the lung to maximise relief from the effects of an asthma attack or COPD,
The fine particle fraction is a widely recognised term in the art. It is a measure of the mass fraction of emitted aerosol particles having a diameter below 5 pm which Is generally accepted as being the most desirable particle size range for effective alveolar drug delivery,
In the method of the sixth aspect of the present invention suitable and preferred salmeteroi compounds are as described above for the pharmaceutical composition of the first aspect of the present invention. In addition, typical and preferred amounts of the drug component and the propellant component in the method of the sixth aspect of the present invention and suitable, typical and preferred compositions for trie propellant component are as discussed above for the pharmaceutical composition of the first aspect of the invention.
The drug component In the method of the sixth aspect of the present invention may consist essentially of or consist entirely of the at least one salmeteroi compound, such as salmeteroi and/or salmeteroi xinafoate. By the term consists essentially of”, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99,9 weight % of the drug component consists of the least one salmeteroi compound. Alternatively, the drug component may additionally comprise at least one long acting muscarinic antagonist and/or at least one corticosteroid. When a long acting muscarinic antagonist and/or corticosteroid are included, suitable and preferred long acting muscarinic· antagonists and suitable and preferred corticosteroids are as described above for the pharmaceutical compositions of the second and third aspects of the present, invention.
In one embodiment, the pharmaceutical composition in the sixth aspect of the present invention consists essentially of and more preferably consists entirely of the drug component and the propellant component as defined above. By the term “consists essentially of’, we mean that at least 98 weight %, more preferably at least 99 weight % and especially at least 99,9 weight % of the pharmaceutical composition consists of the two components, in in an alternative embodiment, the pharmaceutical composition in the sixth aspect of the invention may contain one or both of s polar excipient and a surfactant component as discussed above for the pharmaceutical composition of the first aspect of the invention. Suitable and preferred polar excipients and surfactants are as discussed above for the pharmaceutical composition of the first aspect of the invention. Typical and preferred amounts of the polar excipient and the surfactant component are as discussed above for the pharmaceutical composition of the first aspect of the invention.
In a particularly preferred embodiment of the sixth aspect of the present invention, the drug component comprises salmeterol xinafoate and fluticasone propionate and the fine particle fraction of salmeterol xinafoate in the emitted dose when the pharmaceutical composition is delivered from a metered dose inhaler is at least 40 weight %, preferably at least 42,5 weight % and more preferably at least 45 weight % of the emitted dose of the salmeterol xinafoate, in addition, the fine particle fraction of fluticasone propionate in the emitted dose when the pharmaceutical composition is delivered from a metered dose inhaler is preferably at least 33 weight. %, more preferably at least 36 weight % and still more preferably at least 39 weight % of the emitted dose of the fluticasone propionate.
The pharmaceutical compositions of the invention find particular utility in the delivery of the salmeterol compounds., and where included the corticosteroid and long acting muscarinic antagonist compounds, from a pressurised aerosol container, e.g. using a metered dose Inhaler (MDI), For this application, the pharmaceutical compositions are contained In the pressurised aerosol container and the HFA-152a propellant functions to deliver the drug as a fine aerosol spray.
The pharmaceutical compositions of the invention may comprise one or more other additives of the type that are conventionally used in drug formulations for pressurised MDIs, such as valve lubricants. Where other additives are Included in the pharmaceutical compositions, they are normally used in amounts that are conventional in the art.
The pharmaceutical compositions of the invention are normally stored in a pressurised container or canister which Is to be used in association with a medication delivery device. When so stored. the pharmaceutical compositions are normally a liquid. In a preferred embodiment, the pressurised container is designed tor use in a metered dose inhaler (MDi). In a particularly preferred embodiment, the pressurised container Is a coated aluminium can or an uncoated aluminium $ can, especially the latter.
Accordingly, a seventh aspect of the present invention provides a pressurised container holding the pharmaceutical composition of the first, second, third or fourth aspect of the present invention. In an eighth aspect, the present invention provides to a medication delivery device, especially a metered dose inhaler, having a pressurised container holding the pharmaceutical composition of the first, second.
third or fourth aspect of the present invention.
The pharmaceutical compositions of the present invention are for use In medicine is for treating a patient suffering or likely to suffer from a respiratory disorder and especially asthma or a chronic obstructive pulmonary disease.
Accordingly, the present invention also provides a method for treating a patient suffering or likely to suffer from a respiratory disorder, especially asthma or a m chronic obstructive pulmonary disease, which comprises administering to the patient a therapeutically or prophyiacticaliy effective amount of a pharmaceutical composition as discussed above. The pharmaceutical composition Is preferably delivered to the patient using a MDi.
The pharmaceutical compositions of the invention can be prepared and the MDI devices filled using techniques that are standard in the art, such as pressure filling and cold filling. For example, the pharmaceutical compositions can be prepared by a simple blending operation in which the at least one saimetero! compound, optionally the at least one corticosteroid and/or the at least one long acting muscarinic antagonist, optionally the surfactant component and the HFA-152aconfaining propeiiant are mixed together in the required proportions in a suitable mixing vessel. Mixing can be promoted by stirring as is common in the art. Conveniently, the HFA-152a-containing propeiiant is liquefied to aid mixing. If the pharmaceutical composition is made in a separate mixing vessel, it can then be transferred to pressurised containers for storage, such as pressurised containers that are used as part of medication delivery devices and especially MDis.
co
The pharmaceutical compositions of the Invention can also be prepared within the confines of a pressurised oentaineh such as an aerosol canister or viai, from which the compositions are roltimateiy released as an aerosol spray using a medication delivery device, such as a MOI, In this method, a weighed amount of the at least one salmeteroi compound and optionally the at least one corticosteroid and/or the at least, one long acting muscarinic antagonist, is introduced into the open container. A valve is then crimped onto the container and the HFA-152a-contalning propellant component, in liquid form, introduced through the valve into the container under pressure, optionally after first evacuating the container through the valve. The surfactant component, if included, can be mixed with the drug(s) or, alternatively, introduced Into the container after the valve has been fitted, either alone or as a premix with the propeliant component The whole mixture can then be treated to disperse the drugs in the propeliant/surfaetant mixture, e.g, by vigorous shaking or using an ultrasonic bath. Suitable containers may be made of plastics, metal, e.g. aluminium, or glass. Preferred containers are made of metal, especially aluminium which may be coated or uneoateti, Uncoated aluminium containers are especially preferred.
The container may be filled with enough of the pharmaceutical composition to provide for a plurality of dosages. The pressurized aerosol canisters that are used In MDIs typically contain 50 to 150 individual dosages,
The present invention is now' illustrated but not limited by the following examples.
Example 1
A number of experiments were conducted to investigate the /n w/ro aerosolization performance of combination drug formulations of salmeteroi xinafoate and fluticasone propionate in metered dose inhalers (MDIs) using either HFA~134a or HFA-152a as the propellant.
Pharmaceutical formulations of salmeteroi x-nafcate and fluticasone propionate were prepared in either HFA-134a or HFA-152a (Mexichern, UK). The drugs were weighed directly into standard uncoated 14 ml aluminium canisters (Cl 28, Prosspart, Btecxoun, UK). The canisters were then crimped with a 50 pi valve 23 (Bespak, Kings Lynn. UK) following which the propellant was filled Into the canisters through the valve using a manual Pamasol crimper/filier (Pamasol. Switzerland). Finally, the canisters were sonicated for 20 minutes to aid dispersion of the drug in the suspension. The nominal dose of salmeterol xlnafoate was 25p.g and the nominal dose of fluticasone propionate was 125pg.
High performance liquid chromatography (HPLC) was used to determine drug content following aerosolization studies (see below). A 100 mm x 4,6 mm Ascends Express C-is column with a 2,7 pm particle size was used for the analysis. The m column was coupled to a UV detector operating at a wavelength of 235 and 252 nm. The autosampler was operated at ambient temperature and 100 pi samples were injected into the column for the analyses. The chromatographic conditions are strewn in Table 1 below.
Table 1
Drug Pump Flow Rate (mhmirr*) Mobile Phase UV Wavelength (nm) Column Temperature co
Fluticasone Propionate I.....................:............. 1.8 Methanol, Acetonitrile and Water 45/35/20 % v/v 236 40
Salmeterol Xlnafoate .................................... 1.5 Methanol, Acetonitrile and Water 45/35/20 % v/v 252 40
The in vitro aerosolization performance of the formulations was studied using a Next Generation Impactor (NGi, Copley Scientific, Nottingham UK), which was connected to a vacuum pump (GE Motors, NJ, USA). Prior to testing, the cups of the NGi system were coated with 1 % v/v silicone oil in hexane to eliminate particle bounce. For each experiment, three actuations of the valve were discharged into the NGI at 30 L.min'· as per pharmacopeia guidelines. Following aerosolization, the NGI apparatus was dismantled and the actuator and each part of the NGI was washed down Into known volumes of the HPLC mobile phase. The mass of drug deposited on each pad of the NGI was determined by HPLC using the methodology described above. This protocol was repeated three times for each canister, following which, the tine particle dose (FPD) and fine particle fraction of the emitted dose (FPFeo) were determined. The results are shown in Tables 2 and 3 below.
2>
Table 2. in vitro aerosolIxatlon performance of combination MD1 formulations of salmeteroi xinafoate and fluticasone propionate in HFA~134a as characterised by the emitted dose, fine particle dose, fine particle fraction ofthe emitted dose (FFFes (%)}>
mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD).
Formulation
Emitted Dose i fpg ± S.D.)
Fine particle
Pose (pg ± S.D.)
Fluticasone
Propionate
Salmeteroi
Xinafoate
22.9 ±1.3
1017 ±87 31.6 ±3,3
FPF:-o{%) j MMAD±GSD
31.0
3.4 ± 0 3
Figure GB2554091A_D0001
3.3 ± 2 5
Tabie 3, in vitro aerosoliaation performance of combination MDi formulations of salmeteroi xinafoate and fluticasone propionate in HFA-152a as characterised by the emitted dose, fine particie dose, fine particle fraction of the emitted dose (FPFse {%)}, mass median aerodynamic diameter (MblAD) and geometric standard deviation (GSD).
Formulation
Fluticasone
Propionate
Salmeteroi
Xinafoate
Emitted Dose (pg ± S,D,)
Figure GB2554091A_D0002
Figure GB2554091A_D0003
particle Dose (pg ± S.D-i
1037 ±1.1 43,6 ±3.4
18.8± 1.6
3.9 ± 0 3
FPF£D(%)
40.0
MMADtGSD
2.9 ±2.1 .4 ±2.1
It is evident from the data presented in Tables 2 and 3 above that the fine particle fractions of ihe emitted doses upon aerosolization were significantly better when HFA-152a was used as the propellant for both salmeteroi xinafoate and fluticasone propionate.
Example 2
The stability of saimoterol xinafoate and fluticasone propionate in HFA-134 a and HFA-152a was investigated at lime zero (T~0) and after storage, valve down, for 1 month (T~1M): 3 months (T-3M) and 6 months (T-6M) at 40C and 75% relative humidity (RH) and at 25*C and 60% relative humidity (RH) in uneoatsd aluminium cans.
The drug formulations ware prepared as described in Example 1 and analysed id using HPLC following the stability studies, A 100 mm x 4,6 mm Ascends Express
Cis column with a 2.7 urn panicle size was used for the analysis. The column was coupled to a UV detector operating at a wavelength of 214 nm. The autosampier was operated at ambient temperature and 100 pi samples were injected into the column for the analyses. The chromatographic conditions are shown in Table 4 below.
Table 4
Drug Pump Flow Rate (mimin'1) Mobile Phase UV Wavelength (nm) Column Temperature CC)
Saimeteroi Xinafoate and Fluticasone Propionate (Dual detection) 2.0 Mobile Phase A: 25 mM sodium hydrogen orthophosphate and acetonitrile 80:20 v/v Mobile Phase 8: 25 mM sodium hydrogen orthophospheto end acetonitrile 40:60 v/v 214 60
The composition of the mobile phase was varied as shown in Table 5 below.
Tabl e 5
Time (mins) Volume % of Mobile Phase A Volume % of Mobile Phase B
0 100 0
32.0 0 100
32.1 100 0
37.0 100 0
The results of investigating the chemical stability of the saimeterol xinafoate and fluticasone propionate drug formulations In HFA-152a and HFA-227ea in uncoated aluminium cans are shown, respectively, In Tables 6 to 9 below.
Table 6. Chemical stability of fluticasone propionate in HFA~134a in uncoated aluminium cans based on percentage assay and total impurities upon storage at T~G. T~1M @ 40t:C/75 % RH and 25:1C/6Q % RH, i‘“3M ® 4O’C/75 % RH and 25°C/60 % RH i 0 and T~6M @ 4O’C/75 % RH and 25eC/60 % RH.
Time % Assay (LC) % total impurities
Initial time T ~ 0 160 8 <LoQ
T ~ 1M @ 25/60 100.1 <LoQ
T~ 1M@ 40/75 99,9 <L.cG
T = 3M @ 25/60 99.8 <L.oQ
T = 3M @ 40/75 99.8 <LsQ
T = 6M @ 25/60 97.2 0.32
T = 6M @ 40/75 96.5 0.48
Table 7. Chemical stability of fluticasone propionate in HFA-152a in uncoated 15 aluminium cans based on percentage assay and total impurities upon storage at T«0.
T«1M @ 4IPC/75 % RH and 25*0/60 % RH, T-3IVI @ 40°C/75 % RH and 25°C/60 % RH and T=6M @ 40*0/75 % RH arid 25°C/60 % RH.
Time % Assay (LC) % total Impurities
Initial time T ~ 0 100.5 <LcQ
T = 1M @ 25/60 100.0 <LoQ
T = 1M @ 40/75 100.2 <LcQ
ϊ ~ 3M @ 25/60 99.8 <LoQ
Τ ~ 3M @ 40/75 160.6 <LoQ
T = 6M @ 25/60 98.9 6.25
T = 6M @ 40/75 98.6 0.39
Table 8, Chemical stability of saimeterol xinafoate in HFA-134a in uncoated aluminium cans based on percentage assay and total impurities upon storage at T~8, T-1M @ 40°C/75 % RH and 25X/S8 % RH, T~3M @ 40°C/75 % RH and 2SeC/88 % RH and T~6M @ 4Q°C/75 % RH and 25°C/60 % RH.
Figure GB2554091A_D0004
Table 9, Chemical stability of saimeterol xinafoate in KFA-152a in uneoated aluminium cans based on percentage assay and totaf impurities upon storage at T~8,
T=1M @ 40cC/75 % RH and 25nC/60 % RH, T-3M @ 40eC/?5 % RH and 2S°C/68 % RH and T-6M @ 40cC/75 % RH and 25°G/80 % RH.
Time % Assay (LC) % total impurities
Initial time T = 0 99.9 0.07
Ϊ ~ 1M @ 25/60 99.9 0.03
T= 1M @40/75 99.5 0.08
T = 3M @ 25/60 99.6 0.08
T = 3M @ 40/75 99.1 0.11
T = 6M @ 25/60 98.5 0.28
T = 8M @ 40/75 98.9 0,35
It can be seen from the data in Tables 8 to 9 above that both saimeterol .xinafoate 1' and fluticasone propionate exhibit superior chemical stability when blended with
HFA-152a as the aerosolization propellant rather than HFA~134a.

Claims (73)

  1. Claims:
    1. A pharmaceutical composition comprising:
    (i) a drag component comprising at least one salmeterol compound selected
    5 from salmeterol and the pharmaceutically acceptable derivatives thereof;
    and (ii) a propellant component comprising 1,1-difiuoroethane (HFA-152a).
  2. 2. The pharmaceutical composition of claim 1, wherein the composition 10 contains less than 100 ppm, preferably less than 50 ppm, more preferably less than
    10 ppm and especially less than 5 ppm of water based on the total weight ot the pharma ceut I ca I com posit! on.
  3. 3. The pharmaceutical composition of claim 1 or 2, wherein the at least one 13 salmeterol compound is selected from salmeterol and the pharmaceutically acceptable salts thereof, especially salmeterol xinafoate.
  4. 4. The pharmaceutical composition of any one of the preceding claims, wherein the drug component additionally comprises at least one long acting muscarinic antagonist (LAMA)
  5. 5, The pharmaceutical composition of claim 4, wherein the at least one long acting muscarinic antagonist is selected from the group consisting of umeciidinium, ipratropium, tiotropium, aclidinium and the pharmaceutically acceptable derivatives
    25 thereof.
    G, The pharmaceutical composition of claim 4, wherein the at least one lormi acting muscarinic antagonist Is a pharmaceutically acceptable salt, of glycopyrrolate, especially glycopyrronium bromide.
  6. 7. The pharmaceutical composition of any one ot the preceding claims, wherein the drug component additionally comprises at least one corticosteroid.
  7. 8, The pharmaceutical composition of claim 7, wherein the at least one 35 corticosteroid Is selected from budesonide, mometasone, beclomethasone, fluticasone and the pharmaceutically acceptable derivatives thereof.
    8, The pharmaceutical composition of claim 8, wherein the at least one corticosteroid is selected from fluticasone and the pharmaceutically acceptable derivatives thereof, especially fluticasone propionate.
  8. 10. The pharmaceutical composition of any one of the preceding claims, wherein the drug component comprises from 0.01 to 2.6 weight %, preferably from 0.01 to 2.0 weight %, mors preferably from 0,05 to 2.0 weight % and especially from 0.05 to 1.5 weight % of the total weight of the pharmaceutical composition.
  9. 11. The pharmaceutical composition of any one of the preceding claims, wherein the propellant component comprises from 80.0 to 99.99 weight %, preferably from 90.0 to 99.99 weight %, more preferably from 96.5 to 99.99 'weight % and especially from 97.5 to 99.95 weight % of the total weight of the
    15 pharmaceutical composition.
  10. 12. The pharmaceutical composition of any one of the preceding claims, wherein at least 90 weight %, preferably at least 95 weight % and more preferably at least 99 weight % of the propellant component Is T1 -Oifluoroethane (HFA-152a).
  11. 13. The pharmaceutical composition of any one of claims 1 to 11, wherein the propellant component is entirely 1,1-dlfluoroethane (HFA-152a).
    .30
  12. 14. The pharmaceutical composition of any one of the preceding claims, wherein at least 95 weight %, preferably at least 98 weight % and more preferably at least 99 weight % of the composition consists of the two components (I) and (ii).
  13. 15. The pharmaceutical composition of any one of the preceding claims further comprising a surfactant component comprising at least one surfactant compound.
  14. 16. The pharmaceutical composition of claim 15, wherein the surfactant component comprises at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glyco* surfactants, oleic acid and lecithin.
    35
  15. 17, The pharmaceutical composition of any one comprising a polar excipient.
    Ing claims further
  16. 18. The pharmaceutical composition of claim 17, wherein the polar excipient is ethanol.
    SO
  17. 19. The pharmaceutical composition of any one of claims 1 to 16 which is free of polar excipients.
  18. 20. The pharmaceutical composition of any one of claims 1 to 16 which Is free of ethanol.
  19. 21. The pharmaceutical composition cf any one of claims 1 to 13 which consists entirely of the two components (i) and (ii).
  20. 22. The pharmaceuticai composition of any one of the preceding claims which after storage if': uncoated aluminium containers at 40°C ano 75 % relative humidity for 8 months will produce less than 0.4 % by weight and preferably less than 0.36 % by weight of Impurities from the degradation of the at least one salmeteroi compound based on the totai weight of the at least one salmeteroi compound and the impurities.
  21. 23. The pharmaceuticai composition of any one of the preceding claims, wherein at least S7,5 % by weight, preferably at least 98.0 % by weight and more preferably at ieast 98.5 % by weight of the at least one salmeteroi compound that Is contained originally in the pharmaceuticai composition immediately following preparation will be present in the· composition after storage in uncoated aluminium containers at 40“C and 75 % relative humidity for 6 months.
  22. 24, The pharmaceutical composition of any one of claims 1 to 22, wherein at. least 97.5 %, preferably at least 98.0 % and more preferably at least 98.5 % of the original pharmaceutical activity of the composition is retained after storage in uncoated aluminium containers at 40’C and 75 % relative humidity for 6 months.
  23. 25. The pharmaceutical composition of any one of the preceding claims which when delivered from a metered dose Inhaler yields a fine particle fraction of the at least one salmeteroi compound which Is at ieast 40 weight %, preferably at least
    42.5 weight % and more preferably at least 45 weight % of the emitted dose of the at least one saimeteroi compound.
  24. 26. The pharmaceutical composition of any one of the preceding claims in the form of a suspension.
  25. 27, he pharmaceutical composition of any one of claims 1 to 25 in the form of a solution,
  26. 28, A sealed container that contains a pharmaceutical composition as claimed in anv one of claims 1 to 27,
  27. 29, The sealed container of claim 28 which is an uncoated aluminium can.
  28. 30. The sealed container of claim 28 cr ciaim 29 which is a pressurized aerosol container for use with a metered dose inhaler (MDI).
  29. 31. A metered dose inhaler (MDI) fitted with a sealed container as claimed In 29 claim 30.
  30. 32. A method for treating a patient suffering or likely to suffer from a respiratory disorder which comprises administering to the patient a therapeutically or prophylactically effective amount of a pharmaceutical composition as claimed in
    25 any one of claims 1 to .27.
  31. 33, The method of claim 32, wherein the respiratory disorder is asthma or a chronic obstructive pulmonary disease.
    30
  32. 34. The method of ciaim 32 or 33, wherein the pharmaceutical composition is delivered to the patient using a metered dose Inhaler (MDI).
  33. 35. A method of improving the stability of a pharmaceuticai composition comprising a propellant component and a drug component comprising at least one
    35 saimeteroi compound selected from saimeteroi and the pharmaceutically acceptable derivatives thereof, said method comprising using a propellant component comprising 1.1-difluoroethane (HFA-152a),
  34. 36, The method of claim 35, further comprising selecting the components and conditions for the preparation of the pharmaceutical composition to maintain the water content of the pharmaceutical composition below 100 ppm, preferably below 50 ppm, more preferably below 10 ppm and particularly below 5 ppm based on the total weight of the pharmaceutical composition.
  35. 37. The method of claim or 36, wherein the at least one salmeterol compound is selected from salmeterol and the pharmaceutically acceptable salts thereof, especially salmeterol xinafoate.
    IS
    '.m
  36. 38. The method of any one of claims 35 to 37, wherein the drug component additionally comprises at least one long acting muscarinic antagonist (LAMA).
  37. 39. The method of claim 35, wherein the at least one long acting muscarinic antagonist is selected from the group consisting of umeciidinium, ipratropium, tiotropium, aclidinium and the pharmaceutically acceptable derivatives thereof.
  38. 40. The method of claim 35, wherein the at least one long acting muscarinic antagonist is a pharmaceutically acceptable salt of glycopyrrolate, especially giycopyrronium bromide.
  39. 41. The method of any one of claims 35 to 40, wherein the drug component additionally comprises at least one corticosteroid.
  40. 42. The method of claim 41, wherein the at least one corticosteroid is selected from budesonide, mometasone, beclomethasone, fluticasone and the pharmaceutically acceptable derivatives thereof.
  41. 43. The method of claim 42, wherein the at least one corticosteroid Is selected from fluticasone and the pharmaceutieaily acceptable derivatives thereof, especially fluticasone propionate.
  42. 44, Trie method of any one of claims 35 to 43, wherein the drug component comprises from 0.01 to 2,5 weight %. preferably from 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0 weight % and especially from 0.05 to 1.5 weight % of the total weight of the pharmaceutical composition,
  43. 45, The method of any one of claims 35 to 44, wherein the propeilant component comprises from 80,0 to 99.99 weight %, preferably from 90.0 to 99 99 weight %, more preferably from 96,5 to 99.99 weight % and especially from 97.5 Ό 99.95 weight % of the total weight of the pharmaceutical composition.
    1C
  44. 46, The method of any one of claims 35 to 45, wherein at least 90 weight preferably at least 95 weight % and more preferably at least 99 weight % of the propeilant component is 1,1 -difiuoroethane (HFA-'i 52a),
    15
  45. 47. The method of any one of claims 35 to 45, wherein the propellant component is entirely 1,1-difiuoroethane (HFA-152a),
  46. 48. The method of any one of claims 35 to 47, wherein at least 95 weight %. preferably at least 98 weight % and more preferably at least 99 weight % of the
    20 pharmaceutical composition consists of the drug component and the propeilant. component,
  47. 49. The method of any one of claims 35 to 48, wherein the pharmaceutical composition further comprises a surfactant component comprising at least one
    25 surfactant compound:,
  48. 50. The method of claim 49, wherein the surfactant component comprises at: least one surfactant compound selected from polyvinySpyrraiidene, poiyethylene glycol surfactants, oleic acid and lecithin,
    TO
  49. 51. The method of any one of claims 35 to 50 further comprising a polar excipient.
  50. 52. The method of claim 51, wherein the polar excipient is -ethanol.
  51. 53. The method of any one of claims 35 to 50. wherein the pharmaceutical composition is free of polar exc-plents.
  52. 54. The method of any one of claims 35 to 50, wherein the pharmaceutical
    5 composition is free of ethanol.
  53. 55. The method of any one of claims 35 to 47 wherein the pharmaceutical composition consists entirely of the drug component ano the propellant component, to
  54. 56. The method of any one of claims 35 to 55, wherein the pharmaceutical composition after storage in uncoated aluminium containers at 40’C and 75 % relative humidity for 5 months will produce less than 0.4 % by weight and preferably less than 0,36 % by weight of impurities from the degradation of the at least one salmeteroi compound based on the total weight of the at least one salmeteroi
    IS compound and the impurities.
  55. 57, The method c-f any one of claims 35 to 56, wherein at least 97.5 % by weight, preferably at least 98.0 % by weight and more preferably at least 98.5 % by weight of the at least one salmeteroi compound that is contained originally in the pharmaceutical composition Immediately following preparation will be present in the composition after storage in uncoated aluminium containers at 40<:C and 75 % relative humidity for 6 months.
  56. 58. The method of any one of claims 35 to 56, wherein at least 97.5 %, preferably at least 98.0 % and more preferably at least 98.5 % of the original pharmaceutical activity of the composition -s retained after storage In uncoated aluminium containers at 40°C and 75 % relative humidity for 3 months.
  57. 59. The method of any one of claims 35 to 58, wherein the pharmaceutical composition is in the form of a suspension.
  58. 60. The method of any one of claims 35 to 58, wherein the pharmaceutical composition is in the form of a solution.
    35
  59. 61. A. method of improving the aerosoiizalion performance c-f a pharmaceutical composition comprising a propellant component and a drug component comprising
    3.5 at least one salmeterol compound selected from salmeterol and the pharmaceutically acceptable derivatives rhereof, said method comprising using a propellant component comprising 1.1-difluoroethane (HFA-152a),
  60. 62, The method of claim 61, wherein the method provides a pharmaceutical composition which when delivered from a metered dose inhaler yields a fine particle fraction of the at least one salmeterol compound which is at least 40 weight %, preferably at least 42,5 weight % and more preferably at least 45 weight % of the emitted dose of the at least one salmeterol compound,
  61. 63, The method of claim 61, wherein the pharmaceutical composition is a composition as claimed in any one of claims 1 to 27,
  62. 64, The pharmaceutical composition of claim 1 or 2, wherein the drug component comprises salmeterol xinafoate and fluticasone propionate and the fine particle fraction of salmeterol xinafoate in the emitted dose when the pharmaceutical composition is delivered from a metered dose inhaler is at least 40 weight %, preferably at least. 42,5 weight % and more preferably at least. 45 weight % of the emitted dose of the salmeterol xinafoate.
  63. 65, The pharmaceutical composition of claim 64, wherein the fine particle fraction of fluticasone propionate in the emitted dose when the pharmaceutical composition is delivered from a metered dose inhaler is at least 33 weight %, preferably at least 36 weight % and more preferably at least 39 weight % of the emitted dose of the fluticasone propionate.
  64. 66, The pharmaceutical composition of claim 64 or 65, wherein the drug component comprises from 0.01 to 2.5 weight %, preferably from 0,01 to 2,0 weight %, more preferably from 0.05 to 2,0 weight % and especially from 0.05 to 1.5 weight % of the total weight of the pharmaceutical composition.
  65. 67. The pharmaceutical composition of any one of claims 64 to 66, wherein the propellant component comprises from 80,0 to 99.99 weight %, preferably from 90.0 to 99.99 weight %, more preferably from 96.5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the pharmaceutical composition.
  66. 68. The pharmaceutical composition least 90 weight %, preferably at least 96 weight % of the propellant component Is of any one of claims 84 to 67, wherein at weight % and more preferably at least 99 1, Ί -difluorcethane (HFA-152a),
  67. 69 The pharmaceutica! composition of any one of claims 64 to 87, wherein the propellant component Is entirely 1 ,1-di flue methane JIFA-152a).
  68. 70 The pharmaceutical composition of any one of claims 84 to 89, wherein at least 95 weight %, preferably at least 98 weight % and more preferably at least 99 weight % of the composition consists of the two components (i) and (ii).
  69. 71. The pharmaceutical composition of any one of claims 84 to 70 further comprising a surfactant component comprising at least one surfactant compound.
    15
  70. 72. The pharmaceutical composition of claim 71, wherein the surfactant component comprises at least one surfactant compound selected from polyvinylpyrrolidone, polyethylene glycol surfactants, oleic acid and lecithin.
  71. 73. The pharmaceutical composition of any one of claims 64 to 72 further 20 comprising a polar excipient.
  72. 74. The pharmaceutical composition of claim 73, wherein the polar excipient is ethanol.
    25 75, The pharmaceutical composition cf any one of claims 64 to 72 which is free of polar excipients.
  73. 78. The pharmaceutical composition of any one of claims 64 to 69 which consists entirely of the two components (i) and (Ii),
    Intellectual
    Property
    Office
    Application No: GB1615914.7 Examiner: Mr Robert Goodwill
GB1615914.7A 2016-09-19 2016-09-19 Pharmaceutical composition Withdrawn GB2554091A (en)

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GB1615914.7A GB2554091A (en) 2016-09-19 2016-09-19 Pharmaceutical composition
US16/334,144 US10792256B2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
CN201780057318.5A CN109715148A (en) 2016-09-19 2017-09-18 Pharmaceutical composition
MX2019003099A MX2019003099A (en) 2016-09-19 2017-09-18 Pharmaceutical composition.
AU2017328910A AU2017328910B2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
EP17777637.4A EP3515425B1 (en) 2016-09-19 2017-09-18 Pharmaceutical composition comprising salmeterol
CA3037107A CA3037107C (en) 2016-09-19 2017-09-18 Stable pharmaceutical compositions comprising salmeterol and 1,1-difluoroethane (hfa-152a) suitable for use in metered dose inhalers (mdis)
ES17777637T ES2877575T3 (en) 2016-09-19 2017-09-18 Pharmaceutical composition comprising salmeterol
PCT/GB2017/052764 WO2018051133A1 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
BR112019005168A BR112019005168A2 (en) 2016-09-19 2017-09-18 pharmaceutical composition, sealed container, metered dose inhaler, and methods for treating a patient suffering or likely to suffer from a respiratory disorder, for improving the stability of a pharmaceutical composition and the aerosolization performance of a pharmaceutical composition global warming potential of a pharmaceutical composition
JP2019515225A JP6781828B2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
US16/882,979 US11311502B2 (en) 2016-09-19 2020-05-26 Pharmaceutical composition
US16/883,016 US11077076B2 (en) 2016-09-19 2020-05-26 Pharmaceutical composition
US17/694,972 US11883372B2 (en) 2016-09-19 2022-03-15 Pharmaceutical composition

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CN113244490A (en) * 2020-01-28 2021-08-13 奇斯药制品公司 Pressurized metered dose inhalers comprising buffered pharmaceutical formulations

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WO2012156711A1 (en) * 2011-05-13 2012-11-22 Mexichem Amanco Holding S.A. De C.V. Pharmaceutical compositions

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GB2573297A (en) * 2018-04-30 2019-11-06 Mexichem Fluor Sa De Cv Pharmaceutical composition
WO2019211578A1 (en) * 2018-04-30 2019-11-07 Mexichem Fluor S.A. De C.V. Pharmaceutical composition comprising salbutamol
CN113244490A (en) * 2020-01-28 2021-08-13 奇斯药制品公司 Pressurized metered dose inhalers comprising buffered pharmaceutical formulations

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