[go: up one dir, main page]

GB2554088A - Pharmaceautical composition - Google Patents

Pharmaceautical composition Download PDF

Info

Publication number
GB2554088A
GB2554088A GB1615908.9A GB201615908A GB2554088A GB 2554088 A GB2554088 A GB 2554088A GB 201615908 A GB201615908 A GB 201615908A GB 2554088 A GB2554088 A GB 2554088A
Authority
GB
United Kingdom
Prior art keywords
weight
pharmaceutical composition
long acting
pharmaceutically acceptable
component
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Withdrawn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
GB1615908.9A
Other versions
GB201615908D0 (en
Inventor
Corr Stuart
James Noakes Timothy
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.)
Mexichem Fluor SA de CV
Original Assignee
Mexichem Fluor SA de CV
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
Application filed by Mexichem Fluor SA de CV filed Critical Mexichem Fluor SA de CV
Priority to GB1615908.9A priority Critical patent/GB2554088A/en
Publication of GB201615908D0 publication Critical patent/GB201615908D0/en
Priority to EP17777636.6A priority patent/EP3515451B2/en
Priority to KR1020197010383A priority patent/KR102279445B1/en
Priority to EP19199776.6A priority patent/EP3610877A1/en
Priority to JP2019515271A priority patent/JP6781832B2/en
Priority to CN202110273940.8A priority patent/CN113069417A/en
Priority to CN202310774818.8A priority patent/CN116898804A/en
Priority to IL265349A priority patent/IL265349B2/en
Priority to BR112019005113-9A priority patent/BR112019005113B1/en
Priority to CN201780057285.4A priority patent/CN109789151A/en
Priority to PE2019000675A priority patent/PE20191044A1/en
Priority to US16/334,156 priority patent/US20190388436A1/en
Priority to PH1/2019/500577A priority patent/PH12019500577B1/en
Priority to AU2017328908A priority patent/AU2017328908B2/en
Priority to MYPI2019001314A priority patent/MY202030A/en
Priority to UAA201902773A priority patent/UA124240C2/en
Priority to MX2019003103A priority patent/MX2019003103A/en
Priority to PCT/GB2017/052762 priority patent/WO2018051131A1/en
Priority to ES17777636T priority patent/ES2841649T5/en
Priority to GEAP201715034A priority patent/GEP20217240B/en
Priority to NZ752434A priority patent/NZ752434B2/en
Priority to EP19199786.5A priority patent/EP3607951A1/en
Priority to CA3037257A priority patent/CA3037257C/en
Priority to EA201990501A priority patent/EA201990501A1/en
Priority to MYPI2023001168A priority patent/MY210122A/en
Publication of GB2554088A publication Critical patent/GB2554088A/en
Priority to CONC2019/0002555A priority patent/CO2019002555A2/en
Priority to ZA2019/02052A priority patent/ZA201902052B/en
Priority to US16/582,710 priority patent/US20200016174A1/en
Priority to US16/582,964 priority patent/US20200016175A1/en
Priority to JP2020042092A priority patent/JP6980050B2/en
Priority to AU2020202651A priority patent/AU2020202651C1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/13—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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/33—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • 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
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
    • C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
    • C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Organic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A pharmaceutical composition comprises;(i) a drug component comprising at least one beclomethasone compound selected from beclomethasone, and the pharmaceutically acceptable derivatives thereof, and at least one long acting beta-2-agonist (LABA); (ii) a propellant component comprising 1,1-difluoroethane (HFA-152a); and (iii) glycerol. Most preferably, the composition has less than 5 ppm water. Most preferably, the LABA is formoterol fumarate dihydrate. Preferably, the composition additionally comprises a muscarinic agonist, most preferably; glycopyrronium bromide. Preferably, the composition also comprises a polar excipient; most preferably, ethanol. Preferably, the composition is surfactant-free and also free of acid stabilisers. The composition may be used with a metered dose inhaler (MDI) Also disclosed is a method for improving the stability of a pharmaceutical composition comprising a propellant component, a drug component comprising at least one beclomethasone compound, glycerol and ethanol, said method comprising using a propellant component comprising 1,1-difluoroethane.

Description

I, often resulting in a significant reduction In the storage life of formulated products. Whilst this reduced
SO stability cars be partly ameliorated through refrigerated storage, this is not always possible or convenient. Other approaches to improving the stability of FFD/BDP MDI formulations Include the Incorporation of a mineral acid such as HCi or an organic acid such as citric- acid resulting in relatively acidic formulations. However, such acidic formulations have the potential for incompatibility with the materials of construction of a MDI device including the potential to corrode the aluminium cans in which the formulations are typically contained. Whilst this corrosion problem can be addressed through coating aluminum cans with Inert polymeric coatings or through the use of stainless steel cans, both approaches add additional cost and/or complexity to the manufacture of MDIs.
There is a need for a pharmaceutical composition comprising a beclomethasone compound, such as beclomethasone dipropionate (BDP), and a long acting, beta2-agonist (LABAs), such as formoterol fumarate dlhydrate, which can be delivered using a MDI end that uses a propellant having a reduced GWP in comparison with
HFA-134a and HFA-227ea, There is also a need for a pharmaceutical composition which exhibits satisfactory stability without the use of acid stabilizers.
'-r
We have Found that the issues associated with the use of beciomethasone-based formulations in MDIs may be overcome by using a propellant that comprises 1,1difluoroethane (HFA~152a), particularly where the Formulations contain low amounts of water. These formulations can exhibit Improved chemical stability, improved aerosolisation 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 provided a pharmaceutical composition, e.g. a pharmaceutical suspension or a pharmaceutical solution, said composition comprising:
(I) a drug component comprising at least one beclornethasone compound selected From beclornethasone and the pharmaceutically acceptable derivatives thereof, particularly beclornethasone dipropionate (BDP), and at least one long acting beta-2-agonist, particularly formoteroi fumarate dihydrate:
(ii) a propellant component comprising 1,1-difluoroethane (HFA-152a); and (ill) glycerol.
The Improved chemical stability is observed, in particular, when the pharmaceutical composition contains less than 100 ppm, preferably less than 50 ppm, mere preferably less than 10 ppm and particularly less than 5 ppm of water based on the 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 trie composition and not any wafer 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 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 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:
(ί) a drug component comprising at least one beciomethasone compound selected from beciomethasone ano the pharmaceutically acceptable derivatives thereof, particularly beciomethasone dipropionate (BDP), and at least one long acting beta~2~agonlst, particularly formoteroi furnarete dihydrate;
(ii) a propellant component comprising 1,1~difiuoroethane (HFA~152a); and (ill) glycerol, 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 io based on the total weight of the pharmaceutical composition.
The pharmaceutical composition of the present invention is suitable tor delivery to the respiratory tract using a metered dose inhaler (MDi),
The pharmaceutical composition of the first aspect of the Invention includes a drug component comprising at least one beciomethasone compound selected from beciomethasone and the pharmaceutically acceptable derivatives thereof, A particularly preferred beciomethasone compound is beciomethasone dipropionate (BDP).
The drug component also includes at least one long acting beta-2-agonist (LABA). Any of the long acting beta-2-agonists 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 invention, Suitable long acting beta-2-agonists include formoteroi, arformoterol, bamhuteroi, olenbuterol, salmeterol, indacateroi, olodateroi arid vllanterol as well as their pharmaceutically acceptable derivatives, such as their pharmaceutically acceptable sails.
Preferred long acting beta-2~agonists are selected from formoteroi, the pharmaceutically acceptable salts of formoteroi, the hydrates of formoteroi and the hydrates of pharmaceutically acceptable salts of formoteroi. Suitable pharmaceutically acceptable salts of formoteroi include acid addition salts derived from organic and inorganic acids, such as the hydrochloride, sulphate, phosphate, .35 maleate, fumarate, tartrate, citrate, benzoate, methoxybenzoate, hydroxybenzoate, chiorobenzoate, p-toluenesulphonate, methanesulphonate,
IS ascorbate, salicylate, acetate, succinate, lactate, giutarate, gluconate and oleate. The fumarate salt of formoterol is preferred and In a particularly preferred embodiment the pharmaceuticai composition of the Invention Includes formoterol fumarate dlhydrate. Especially preferred pharmaceutical compositions of the invention are those in which the at least one long acting beta~2~agonisl consists essentially of formoterol fumarate dihydrate. By the term “consists essentially of, we mean that at least 95 weight %, more preferably at least 98 weight % and especially at (east 99 weight % of the at least one long acting beta-2-agonist is formoterol fumarale dlhydrate. Most preferred are pharmaceutical compositions in which the at least one long acting beta-2-agonist is entirely formoterol fumarate dlhydrate.
The at least one beclomethasone compound and/or the at least one long acting beta-2-agonlst 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 pharmaceutical compositions of the Invention are solutions with the at least one beclomethasone compound (BDP) and the at least one long acting beta-2-agonist dissolved in the propellant, e.g. with the assistance of a polar excipient, such as ethanol.
The amount of the drug component in the pharmaceutical composition of the first aspect of the present invention will 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 will comprise 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. The drug component may consist essentially of or consist entirely of the at least one beclomethasone compound, especially beclomethasone dipropionate. and the at least one long acting beta-2-agonist, especially formoterol fumarate dihydrate. 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 beclomethasone compound and the at least one long acting beta-2-agonsst. Alternatively, the drug component may contain other drugs, such as at 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-difiuoroethane (HFA~152a), Thus, we de not exclude the possibility that the propeiiant component may include other propellant compounds in addition to the HFA-152a. For example, the propellant component may additionally comprise one or more additional hydrofiuorecarbon or hydrocarbon propeiiant compounds, e.g. selected from HFA-227ea, HFA-134a, difluoromethane (HFA-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 dr HFA-227ea, at least 5 % by weight, preferably at least 10 % by weight and more preferably at least 50 % by weight of the propeiiant 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 % of the propeiiant component.
In an especially preferred embodiment, the propellant component consists entirely of HFA-152a so that the pharmaceutical composition of the invention comprises
2d 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 the suitability of the propeiiant In medical applications,
The amount of propellant component in the pharmaceutical composition of the invention will vary depending on the amounts of the drugs arid other components in the pharmaceutical composition. Typically, the propellant component will comprise from 80.0 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 98.5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the pharmaceutical composition.
The amount of glycerol in the pharmaceutical composition of the first aspect of the 35 present Invention will typically be In the range of from 0.05 to 5.0 weight % based on the total weight of the pharmaceutical composition. Preferably, the glycerol will comprise from 0.1 to 3.0 weight %, more preferabiy from 0.1 to 2.5 weight % and especially from 0.5 to 2.5 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 three components (I) to (iii) listed above. By the term “consists essentially of”, ws 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
η) three 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 es solvents:, co-solvents, carrier solvents and adjuvants. Their inclusion can serve to solubilise the surfactant or the drug fn the propellant and/or Inhibit deposition of drug particles on the surfaces of the metered dose 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 C.5 to 15 % by weight, preferably fn an amount of from 0.5 to 10 % by weight,: and more preferably in an amount of from
1 to 5 % by weight based on the total weight of the pharmaceutical composition.
Even those pharmaceutical compositions of the Invention that contain further components in addition to the defined drug component, the defined propellant component and the glycerol, such as a: polar excipient, should be surfactant-free.
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 beclomethasone compound selected from beclomethasone: and the pharmaceutically acceptable derivatives thereof, particularly beeiomefhasone di propionate (BDP), and at least one long acting befa-x-agonist, particularly formoteroi f'umarate dihydrate:
(ii) a propellant component comprising 1,1-difiuoroethane (HFA-152a); and (ill) glycerol, wherein the composition is surfactant-free and 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, fe In a preferred embodiment, the pharmaceutical composition of the first aspect of the present invention is free of acid stabilisers, such as organic and inorganic acids.
The pharmaceutical composition of the invention may also include a tong 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 salt. Suitable pharmaceutically acceptable counter Ions include, for example, fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate, formate, acetate, tnfluoroacetate, propionate, butyrate, lactate, citrate, tartrate, malate, maleate, succinate, benzoate, p-chlorobenzoate, diphenyl-acetate or friphenylaeetate, o-hydroxybenzoafe, p-hydroxybenzcate, 1- hydroxynaphthalene2-carboxyiate, 3-hydroxynaphthalene-2-carboxylaie, methanesulfcnate and 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 beciomethasone compound selected from beciomethasone and the pharmaceutically acceptable derivatives thereof, particularly beciomethasone dipropionate (BDP). at least one long acting beta-2-agonist, particularly formoterol fumarate dihydrate, and at least ane long acting muscarinic antagonist, particularly at least one pharmaceutically acceptable salt of giycopyrroiate;
(Ii) a propellant component, comprising 1,1 -difluoroethane (HFA-152a); and 5 (lit) glycerol.
In this second aspect of fhe 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 trie 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 io 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 he 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 the 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 practice be difficult to remove all the waterfrom the composition and then retain it in such a water-free state
Suitable and preferred long acting beta-2-agonists 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 fhe propellant component In fhe pharmaceutical composition o the second 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 beclomethasone compound, the at tea stonelong acting beta~2~agonist and the at least one long acting muscarinic antagonist. By the terra “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 beclomethasone compound, the at least one long acting beta -2-agcnist, 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 end more preferably consists entirely of the three components (I) to (iii) listed shove. 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 three listed components.
In another embodiment, the pharmaceutical composition of the second aspect of IP the invention may contain a polar excipient as discussed above for the pharmaceutical composition of the first aspect of the invention. Suitable and preferred polar excipients are as discussed above for the pharmaceutical composition of the first aspect of the invention. Typical and preferred amounts of the polar excipient are as discussed above for the pharmaceutical composition of is the first aspect of the invention.
In an especially preferred embodiment of the second aspect of the invention, the drug component comprises beclomethasone dipropionate, formoterol fumarate dihydrate and at least one pharmaceutically acceptable glycopyrroiate salt, especially glycopyrronium bromide. Preferably, the beclomethasone dipropionate, formoterol fumarate dihydrate and the at least one pharmaceutically acceptable glycopyrroiate salt are the only pharmaceutical actives in the pharmaceutical composition of the second aspect of the invention.
As with the pharmaceutical composition of the first aspect of the invention, the pharmaceutical composition of the second aspect of the Invention should be surfactant-free. Furthermore, in a preferred embodiment, the pharmaceutical composition of the second aspect of the Invention is free of acid stabilisers, such as organic and inorganic acids.
ft has been found that the use of propellants comprising 1,1-difluoroethane (HFA152a) in pharmaceutical compositions containing at least one beclomethasone compound selected from beclomethasone and the pharmaceutically acceptable derivatives thereof, glycerol, ethanol and the propellant can unexpectedly improve the chemical stability of the beclomethasone compound compared to the stability it exhibits in formulations containing either HhA-134a or HFA-227ea as the propellent.
Accordingly, In a third aspect of the present invention there is provided a method of improving the stability of a pharmaceutical composition comprising a propellant component, a drug component comprising at least one beciomethasone compound selected from heciomethasone and the pharmaceutically acceptable derivatives thereof, particularly beciomethasone dipropionate (BDP), glycerol and ethanol, said method comprising using a propellant component comprising 1,1td difluoroethane (HFA-152a),
The at least one beciomethasone compound may be dissolved or suspended In the pharmaceutical composition.
is The Improved chemical stability Is observed, 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 on the 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
2.0 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 recited in the third 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 si. in such a water-free state.
Accordingly, in a preferred embodiment of the third aspect of the present invention there is provided a method of improving the stability of a pharmaceutical composition comprising a propellant component, a drug component comprising at. least one beciomethasone compound selected from heciomethasone and the pharmaceutically acceptable derivatives thereof, particularly beciomethasone dipropionate (BDP), glycerol and ethanol, said method comprising using a propellant component comprising 1,1-difluoroethane (HFA-152e) 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 particuiariy below 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 fend 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. If the pharmaceutical composition contains a significant amount of ethanol, then it may also be important to control the water content of the ethanol as well as the propellant, e.g. by drying to reduce the water content to suitably low levels. Suitable drying techniques are well known to those skiiied 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 third aspect of the present invention suitable and preferred beciomefhasone 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, the propellant component, the glycerol and the ethanol in the stabilisation method 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 in the stabilisation method of the third aspect of the present invention may consist essentially of or consist entirely of the at least one beclomelhasone compound. 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 beclomethascne compound. .Alternatively, the drug component may additionally comprise at least one long acting beta-2-agonist or at least one long acting beta-2-agonist together with at least one long acting muscarinic antagonist as discussed for the pharmaceutical compositions of the first and second aspects of the present invention. When a long acting beta-2-agonist either alone or together with a long acting muscarinic antagonist is included, suitable and preferred long acting beta-213 agonists and suitable and preferred Song acting muscarinic antagonists are as described above for the pharmaceutical compositions of the first and second aspects of the present invention.
IS
In one embodiment, the pharmaceutical composition in the stabilisation method of the third aspect of the present invention consists essentially of ano more preferably consists entirely of the drug component., the propellant component, the glycerol and the ethanol as defined above. By the term ''consists essentially of”, we mean that at least 98 weight %, more preferably at least 99 weight % ano especially at least 99.9 weight % of the pharmaceutical composition consists of the four components.
in a preferred embodiment, the pharmaceutical composition that Is provided in the stabilisation method of the third aspect of the present invention is free of surfactants, in a. particularly preferred embodiment, the pharmaceutical composition that is provided in the stabilisation method of the third aspect of the present invention Is free of acid stabilisers, such as organic and inorganic acids.
In one preferred stabilisation method of the- third aspect of the present Invention, a pharmaceutical composition containing up to 15 weight % of ethanol based on the total weight of the pharmaceutical composition will produce less than 2.0 % by weight, preferably less than 1.5 % by weight and more preferably less than 1.0 % by weight of impurities from the degradation of the at least one beclomethasone compound based on the total weight of the at least one beclomethasone compound and the impurities after storage at 40*C and 75 % relative humidity for 1 month.
in another preferred stabilisation method of the third aspect of the present invention, a pharmaceutical composition containing up to 15 weight % of ethanol based on the total weight of the pharmaceutical composition will produce less than 2.5 % by weight, preferably less than 2,3 % by weight and more preferably less than 1,5 % by weight of impurities from the degradation of the at least one beclomethasone compound based on the total weight of the at least one beclomethasone compound and the Impurities after storage at 40°C and 75 % relative humidity lor 3 months, us
One preferred pharmaceutical composition of the first and second aspects of the present invention containing up to 15 weight % of ethanol based on the total weight 14 of the pharmaceutical composition wiii produce less than 2.0 % by weight, preferably less than 1,5 % by weight and mere preferably less than 1.0 % by weight of total impurities from the degradation of the at least one beclomethasone compound after storage at 4<PC and 75 % relative humidity for 1 month.
Another preferred pharmaceutical composition of the first and second aspects of the present invention containing up to 15 weight % of ethanol based on the total weight, of the pharmaceutical composition will produce less titan 2.5 % by weight, preferably less than 2.0 % by weight and more preferably less than 1.5 % by weight of total impurities from the degradation of the at least one beclomethasone compound after storage at 40°G and 75 % relative humidity for 3 months.
The weight % of Impurities Indicated above are based on the total weight of the at least one beclomethasone compound and the Impurities.
'5
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.
The pharmaceutical compositions of the invention find particular utility in the delivery of the drug component 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 component 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 tor 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 he used in association wilts a medication delivery device. Wnen 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 oars or an unseated aluminium can, especially the latter.
Accordingly, a fourth aspect of the present invention provides a pressurised container holding the pharmaceutical composition of the first or second aspect of the present invention, in a fifth aspect, the present invention provides a medication delivery device, especially a metered dose inhaler, having a pressurised container holding the pharmaceutical composition of the first or second aspect of the present invention.
The pharmaceutical compositions of the present invention are for use in medicine 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 chronic obstructive pulmonary disease, which comprises administering to the patient a therapeutically or prophylacticaliy 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 beciomethasone compound, the at least one long acting beta-2 agonist, the glycerol, optionally the at least one long acting muscarinic antagonist, optionally the polar excipient, and the HFA30 152a-containing propellant ere 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-containlng propellant 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.
The pharmaceutical compositions of the invention can aiso co prepared within the confines of a pressurised container, such as an aerosol canister or vial, from which the compositions are ultimately released as an aerosol spray using a medication delivery device, such as a MDI. in this method, a weighed amount of the at least one beclornethasone compound, the at least one long acting beta-2 agonist, the glycerol, optionally the at least, one long acting muscarinic antagonist and optionally the polar excipient are introduced into the open container. A valve is Then crimped onto the container and the HFA-152a-containlng propellant component, in liquid form, introduced through the valve into the container under pressure, optionally io after first evacuating the container through the valve. Other components·,· if included, can be mixed with the drug component or, alternatively, introduced info the container after the valve has been fitted, either alone or as a premix with the propellant component The whole mixture can then be treated to disperse the drugs in the propellant component, 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 maybe coated or uh coated. 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 foliowing examples.
Example 1
A number of experiments were conducted to investigate the /n wfro aerosolization performance of combination drug formulations of beclornethasone dipropienate and formoterol fumarate dihydrate delivered from a metered dose inhaler (MDl) using: either HP A-134a or HFA--152a as the propellant.
Pharmaceutical formulations Of beclornethasone dipropionate and formoterol fumarate dihydrate were prepared in either HFA~134a or HFA-152a (Mexlehem, UK). The drugs; were weighed: directly into Standard uncoafed 14 ml aluminium canisters (Cl 28. Presspart, Blackburn, UK) and 10 weight % of anhydrous ethanol (based on the total weight of the formulation) was then added to fully solubilise the drugs. The canisters were then crimped with a 50 pL valve (Bespak, Kings Lynn, UK) following which the propellant was filled into the canisters through the valve using a manual Pamasol crimper/fiiier (Pamasof, Switzerland), The nominal dose of beclomethasone dipropionate was 250,ug and the nominal dose of formoterol fumarate dihydrate was 8ug,
IQ
The in vitro aerosoilzatfon performance of the formulations following storage at ambient conditions for 1 month was studied using a Next Generation Impactor (NGI, Copley Scientific, Nottingham UK) 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’1 as per pharmacopeia guidelines. Following asrosoiizaticn, 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 (see below). The mass of drug deposited on each part of the NGI was determined by HPLC (see below). This protocol was repeated three times for each canister, following which, the fine particle dose (FPD) and fine particle fraction of the emitted dose (FPFed) were determined.
2(5 High performance liquid chromatography (HPLC) was used to determine drug content following the aerosoiizalion studies. A 50 mm x 3 mm Accucore C<8 column with a 2.6 pm particle size was used for the analysis. The column was coupled to a UV defector operating at wavelengths of 212 nm and 240 nm depending on which drug was being analyzed. 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 1 below.
?S
Tablet
Drug Pump Flow Rate (mimin'·) Mobile Phase (gradient elution) UV Wavelength (nm) Column Temperature CC)
Beclomethasone Dipropionate and Formoterol Fumarate Dihydrate i.o Mobile Phase A: 10 mM Ammonium □hydrogen Orthophosphate at pH 3.0 Mobile Phase 6: Methanol and Acetonitrile (45:55 v/v) 212 and 240 40
L/t
The composition of the mobile phase was varied as shown <n Table 2 below.
Table 2
Time (mins) Percentage of j Percentage of
Mobile Phase A (v/v) Mobile Phase B (v/v)
0 90 10
2.4 0 too
2.7 0 too
2.8 90 10
4.0 90 10
The results are shown in Tables 3 and 4 below.
to
Table 3, in vitro aerosolization performance of combination drug formulations of beoiomethasone dipropionate and formoterol fumarate dlhydrate in HFA*t34a and ethanol as characterised by the fine parturte dose, fine particle fraction of the emitted dose (FPF:;n (%)), mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD),
Beclomethasone Dipropionate Formoterol Fumarate Dlhydrate
Fine Particle Dose (99) 98.92 3,6?
FPFsc % 63.16 88,36
MMAD ± GSD(um) 1.41 ± 1.95 1.36 ±2.00
Table 4, /n Wfro aerosofeation performance of combination drug formulations of beciomethasone dipropionate and formoteroi furnarate dihydrate in HFA~152a and ethanol as characterised by the fine particle dose, fine particle fraction of the emitted dose {FPF=-:& (%)). mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD).
Beclomethascne Dipropionate Formoteroi Furnarate Dihydrate
Fine Particle Dose (PS) 10S.11 3.57
FPFa; % 55.67 (50.01
MMAD ± GSD(um) 1.57 i 1.98 1.51 ± 2.08
Example 2
IO
A number of experiments were conducted to investigate the effects of glycerol on the /n vitro aerosoiization performance of drug formulations of beclomethascne dipropionate delivered from a metered dose inhaler (MDI) using HFA-152a as the propellant. The aerosoiization performance of the combination drug formulations
IS was investigated after initial preparation and after storing under stress storage conditions.
Pharmaceutical formulations of beclomethascne dipropionate were prepared in HFA-T52a (Mexichem, UK), The drugs were weighed directly into standard uncoated 14 ml aluminium canisters (C128, Presspart, Blackburn, UK). Anhydrous ethanol in an amount of 5, 10 or 15 weight % based on the total weight of the formulation and glycerol in an amount of 0. 1 or 2 weight %, again based on the total weight of the formulation, were then added to the canisters. The canisters were subsequently crimped with a 50 uL valve (Bespak, Kings Lynn, UK) following :?? which the propellant was filled into the canisters through Hie valve using a manual Pamasol crlmper/fllier (Pamasol, Switzerland). The nominal dose of beciomethasone dipropionate was 250pg.
The in vitro aerosoiization performance of the formulations was tested immediately after preparation with a Next Generation Impactor using the method described in Example 1 above. The results are shown in Table 5 below.
Table 5. to Wire aerosofoation performance of formulations of beciomethasone dipropionate in HFA-152a with varying amounts of ethanol and glycerol as characterised by the fine particle dose (FPSVI), fine particle fraction of the emitted dose (FPFeb (%)}, mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD).
Wt. % Ethanol Wt % Glycerol MMAD(pm)±GSD FPA/Kpg) FPFec (%)
5 0 1.27 ± 1.80 114.38 65.17
1 1.55 ±1.93 123.94 67.97
2.................................. 1,82 ±2.08 120.25 85.89
10 0 1.33 ± 1,84 117.15 59.47
1 2.09 ±1.92 116.83 58.84
2 2.19 ±2.12 104,23 55.76
15 0 1.42 ± 2.02 102.86 50.99
1 2.29 ± 2,06 98.11 48.85
2 2.59 ±2.12 83.04 43.57
Addition of glycerol acts to increase the MMAD of the formulation thus allowing the deposition of the drug in the various portions of the lung to be optimised.
io
Example 3
The stability of combination drug formulations of beciomethasone dipropionate and formoteroi fumarate dihydrate In HFA-134a and HFA-152a propellant was investigated at time zero (T~0) and after storage, valve down, tor 1 month (T~1M) and 3 months (T~3M) at 40°C and 75% relative humidity (RH) and at 25°C and 60% relative humidity (RH) in uncoated aluminium cans.
The drug formulations were prepared as described In Example 1 above and analysed using the HPLC technique described in Example 1 above.
The results of Investigating the chemical stability of the combination drug formulations of beciomethasone dipropionate and formoteroi fumarate dihydrate In RFA-152a and HFA~134a in uncoated aluminium cans are shown., respectively, in
Tables 6 to 9 below.
Table 8. Chemical stability of heciomethasone dipropionate in HFA-134a and 10 weight % ethanol in uncoated aluminium cans based on percentage assay and total impurities at T ~ 0, after storage for 1 month (T ” 1M) @ 40°C/75 % RH and 25°C/60 % RH and after storage for 3 months (Τ ~ 3M) @ 40°C/7S % RH and 25^0/80 % RH,
Time % Assay (LC) % total impurities
Initial time T = 0 98,9 0.16
T = 1M @ 25/60 98.5 0..22.
T = 1M@ 40/75 98.2 0.38
T = 3M @ 25/60 98,1 0.41
T = 3M @ 40/75 97,2 j 0.82
Table 7, Chemical stability of beciomethasone dipropionate in HFA-152a and 10 weight % ethanol in u π coated aluminium cans based on percentage assay and total impurities at T - 0, after storage for 1 month {Τ ~ 1M) @ 40°C/75 % RH and 25°C/60 % ΰ RH and after storage for 3 months (Τ - 3M) @ 40°C/7f> % RH and 2 YC/en % RH,
Figure GB2554088A_D0001
Table 8, Chemioai stability of formoferoi fumarate dihydrate in HFA-134a and 10 Weight % ethanol in uncoated aluminium cans based on percentage assay and totai impurities at T - 0, after storage for 1 month (T “ 1M) © 40“C/75 % RH and 25nC/60 % RH and after storage for 3 months (T = 3l¥l) @ 40“C/75 % RH and 2S°C/60 % RH, j Time I % Assay (LG) j % total impurities
J initial time Τ ~ 0 ί 99.9 | 0.07 j T=FiM @25/60 | 99.7 ~~~ ...........| 0Ό8...............................
j T - 1M @ 40/75 .....................t'99'2.....................................................ί'ΟΊΪ...................
...........................935.........................................................
..................................................... (q23
Of
Table 9. Chemical stability of formoterol fumarate dihydrate in HFA-152a and 10 weight % ethanol in uncoated aluminium cans based on percentage assay and total impurities at T “ 0, after storage for 1 month (ϊ ™ 1M) @40BC/75 % RH and 25°C/60 % RH and after storage for 3 months (T ” 3M) @ 40QC/7S % RH and 25°C/60 % RH.
Time % Assay (LC) % total Impurities
Initial time T ~ 0 90.9 0.05
T- 1M @25/60 90.9 6.07
T= 1M @40/75 99.5 6.09
f = 3M @ 25/60 90.6 0.09
T = 3M @ 40/75 99.1 0,11
It can be seen from the data in Tabiss 6 to 9 above that pharmaceutical formulations of beclomethasone diproplonate and formoterol fumarate dihydrafe exhibit superior chemical stability when blended together with HFA-152a as the aerosoiization propellant rather than HFA-134a,
The results also suggest that coated or stainless steel cans are not necessary' with HFA-152a based formulations in order for the formulations tc demonstrate acceptable chemical stability. Similarly, adequate stability can be attained without
1.5 the addition ci mineral or organic acid to the HFA-152a formulations.
Example 4
A number of experiments were conducted to investigate the stability of 20 beclomethasone diproplonate In HFA-134a and HFA-152a.
Pharmaceutical formulations of beclomethasone diproplonate were prepared In either HFA-134a or HFA-152a (Mexicham, UK). The drugs were weighed directly into standard uncoated 14 mi aluminium canisters (Cl 28, Presspart, Blackburn,
UK). Anhydrous ethanol in an amount of 5, 10 or 15 weight % based on the total weight of the formulation and glycerol in an amount of 0, 1 or 2 weight %, again based on the total weight of the formulation, were then added to the canisters. The canisters were subsequently crimped with a 50 pi. valve (Bespak, Kings Lynn, UK) following which the propellant was filled into the canisters through the valve using io a manual Pamasol erimper/fliler (Pamasol, Switzerland). The nominal dose of beclomethasone diproplonate was 250pg.
The stability of the various beclomethasone dipropionate drug formulations was investigated at time zero (T=Q) and after storage, valve down, for 1 month (T^IM) and 8 months (T-8M) at 40°C and 75% relative humidity (RHj in uncoated aluminium cans.
The results of investigating the chemical stability of the beciomethasone dipropionate formulations in HFA~152a and HFA~134a in uneoated aluminium cans are shown, respectively, in Tables 10 and 11 below.
Table 10. Chemical stability of beclomethasone dipropionate in HFA~134a propellant with varying amounts of ethanol and glycerol in uncoated aluminium cans based on iota! impurities at T ~ 0 and upon storage for 1 month (T = 1M) @ 4bC/75 % RH and for 3 months (T ” 3M) @ 40°C/7S % RH.'
Wt. % Ethanol Wt, % Glycerol % Total imps T~Q % Total imps T~1M@ 40”C/75 % RH % Total Imps T~3M @ 49°C/75 % RH
5 0 0.89 1.58 2.08
1 0.34 1.91 2.14
2 0.55 0.78 1.18
to 0 1.16 1,82 2.21
1 1.34 2.25 2.49
2 1,49 1.97 2.35
15 0 1.08 2.35 4.21
1 2.88 3.15 3.99
2 2.95 4.22 4.89
Table 11. Chemical stability of beclomethasone dipropionate in HFA-152a propellant with varying amounts of ethanol and glycerol in uncoated aluminium cans based on total impurities at T ~ δ and upon storage for 1 month (T ” 1M) @ 40KC/75 % RH and for 3 months (T ~ 3WI) @ 40°C/7S % RH,
Wt % Ethanol Wt.% Glycerol % Total imps T~G % Total imps T-1M @40cC/75 % RH % Total Imps T~3M @ 49*0/75 % RH
5· 0 0,08 0.16 0,35
1 0.11 0.15 0.28
2 0.09 0.21 0.34
10 0 0.21 0.35 9.42
1 0,34 0.36 0.55
2 0,23 0.29 0.31
15 0 0.56 0.89 1.11
1 0.66 0.79 1.56
2 0.72 0.89 1.48
It is clear from the data in 'Tables 10 arid 11 above that the stability of beciomethasone dipropionate is significantly higher at all Investigated levels of ethanol and glycerol when HFA-152a is used as the propellant rather than HFA134a,

Claims (1)

  1. C la sms’
    1. A pharmaceutical composition comprising:
    (I) a drug component comprising at least one beclomethasone compound selected from beclomethasone and the pharmaceutically acceptable derivatives thereof and at least one long acting beta-2-agonlst;
    (ii) a propellant component comprising 1,1 -difluoroethane (HFA-152a); and (iii) glycerol,
    2, The pharmaceutical composition of claim 1, wherein the composition 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 of the pharmaceutical composition, i,5 3,. The pharmaceutical composition of claim 1 or 2, wherein the at least one beclomethasone compound is beclomethasone dipropionate.
    4. The pharmaceutical composition of any one of the preceding claims, wherein the at least one long acting beta-2-agonlst (LABA) is selected from the group consisting of formoterol. arformoterol, bambuterol, cienbuleroi, salmeterol. indacateroi, olodaterei, vllanteroi and the pharmaceutically acceptable derivatives thereof,
    5, The pharmaceutical composition of claim 4, wherein the at least one long acting heta~2~agonist (LABA) Is selected from the group consisting of formoterol, the pharmaceutically acceptable salts of formoterol, the hydrates of formoterol and the hydrates of pharmaceutically acceptable salts of formoterol.
    so
    8. The pharmaceutical composition of claim 4, wherein the at least one long acting beta-2-agonist (LABA) is formoterol fumarate dihydrate.
    7. she pharmaceutical composition of any one of the preceding claims, wherein the drug component additionally comprises at least one long acting m us ca rinse antag onist.
    AZ<
    8,. The pharmaceutical composition of claim 7, wherein the at least one long acting muscarinic antagonist is selected from the group consisting of umeclidinium, ipratropium, tiotroplum. aciidinium and the pharmaceutically acceptable derivatives thereof,
    9, The pharmaceutical composition of claim 7, wherein the at least one long acting muscarinic antagonist Is a pharmaceutically acceptable salt of glycopyrroiate, especially glycopyrronium bromide.
    m 10. The pharmaceutical composition of any one of the preceding claims, wherein the drug component comprises from 9.01 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.
    is 11. The pharmaceutical composition of any one of the preceding claims, wherein the propeiiant 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 ρ ha r m ace utica I composition.
    12. The pharmaceutical composition: of any one of the preceding claims, wherein et least 90 weight %, preferably at least 95 weight % and more preferably at least 99 weight % of the propeiiant component is 1,1 -difiuoroethane (HFA-152a),
    13. The pharmaceutical composition Of any on© of claims 1 to 11, wherein the propeiiant component Is entirely 1,1-difiuoroethane (HFA-1i52a).
    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 three components (I), (if) and (iii),
    15, The ph a rm a ceu tica I composition of any one of the p reced I ng claims further comprising a polar excipient
    16, The pharmaceutical composition of ciaim 15, wherein the polar excipient is ethanol17. The pharmaceutical composition of any one of claims 1 to 13 which consists entirely of the three components (i), (Ii) and (iii).
    18. The pharmaceutical composition of any one of claims I to 16 which is surfactant-free.
    io 19. The pharmaceutical composition of any one of claims 1 to 18 and 18 which is free of acid stabilisers.
    20, The pharmaceutical composition of any one of the preceding claims which produces less than 2.0 % by weight, preferably less than 1,5 % by weight and more ;? preferably less than 1.0 % by weight of total impurities from the degradation of the at least one beclomethasone compound after storage in uncoated aluminium containers at 40cC and 75 % relative humidity for 1 month for amounts of ethanol up to 15 weight % based on the total weight of the pharmaceutical composition.
    21, The pharmaceutical composition of any one of the preceding claims which produces less than 2.5 % by weight, preferably less than 2.0 % by weight and more preferably less than 1.5 % by weight of total impurities from the degradation of the at least one beclomethasone compound after storage io unseated aluminium containers at 40;:C and 75 % relative humidity for 3 months for amounts of ethanol up to 15 weight % based on the total weight of the pharmaceutical composition.
    22. The pharmaceutical composition of any one of the preceding claims in the form of a suspension.
    23. The pharmaceutical composition of any one of claims 1 to 21 in the form of solution.
    24. A sealed container that contains a pharmaceutical composition as claimed in any one of claims 1 to 23.
    25. The sealed container of claim 24 which is an uncoated aluminium can.
    26. The sealed container of claim 24 or claim 25 which is a pressurized aerosol container for use with a metered dose Inhaler (MDI).
    27. A metered dose inhaler (MDi) fitted with a sealed container as claimed in claim 26.
    28. A method for treating a patient suffering or likely to suffer from a respiratory disorder which comprises administering to the patient a therapeuticafiy or to prophylacticaily effective amount of a pharmaceutical composition as claimed in any one of claims 1 to 23.
    29. The method of claim 28, wherein the respiratory disorder ·κ asthma or a chronic obstructive pulmonary disease.
    :15
    30. The method: of claim 28 or 29, wherein the pharmaceutical composition is delivered to the patient using: a metered dose Inhaler (MDI),
    31. A method of improving the stability of a pharmaceutical composition 30 comprising a propellant component, a drug component comprising at least one heclomethasone compound selected from beciomethasone and the pharmaceutically acceptable derivatives thereof, glycerol and ethanol, said method comprising using a propellant component comprising 1,1-diflue roe I hone (HFA~ 152a).
    32:, The method of claim 31, further comprising selecting the components and conditions for the preparation of the pharmaceutical composition td maintain the water content of the pharmaceutical composition beiow 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.
    38. The method of claim 31 or 82, wherein the at least one beciomethasone compound is beciomethasone dipropionate,
    34. The method of any one of claims 31 to 33, wherein the drug component additionally comprises at least one: long acting beta-2~agonisi (LABA),
    The method of claim 34, wherein the at least one long acting hsta -2-agonist (LABA) is selected from the group consisting of formoteroi, arformoteroi, ba.mbuterol, clenbuferol, salmeteroi, intiacaterol, olodaterol. vllantero! and the pharmaceutically acceptable derivatives thereof.
    to
    36. The method of claim 34, wherein the at least one long acting beta-2-agorsist (LABA) is selected from the group consisting of formoteroi, the pharmaceutically acceptable salts of formoteroi, the hydrates of formoteroi and the hydrates of pharmaceutically acceptable salts of formoteroi.
    The method of claim 34,. wherein the at least one long acting beta~2~agonlst (LABA) is formoteroi fumarate dihydrate.
    38. The method of any one of claims 31 to 37, wherein the drug component additionally comprises at least one long acting muscarinic antagonist.
    39. The method of claim 38, wherein the at least one long acting muscarinic antagonist is selected from the group consisting of umeclidinium. ipratropium, tiotroplum, aciidlnium and the pharmaceutically acceptable derivatives thereof.
    40. The method of claim 38, wherein the at least one long acting muscarinic antagonist is a pharmaceutically acceptable salt of glycopyrroiate, especially glycopyrronium bromide.
    41. The method of any one of claims 31 to 40, 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,
    42. The method of any one of claims 31 to 41, wherein the propellant component comprises from 80.0 to 99.99 weight %, preferably from 90.0 to 99.99 weight %, more preferably from 98.5 to 99.99 weight % and especially from 97.5 to 99.95 weight % of the total weight of the pharmaceutical composition.
    43. The method of any one of claims 31 io 42, wherein at feast 90 weight %, preferably at least 95 weight % and mors preferably at least 99 weight % of the propellant component is 1,1-difluoroethane (HFA-152a).
    44, The method of any one of claims 31 to 42, wherein the propellant component is entirely 1,1-difluoroethane IHFA-152a).
    45, The method of any one of claims 31 to 44, wherein at least 95 weight %, preferably at least 98 weigh! % and more preferably at least 99 weight % of the pharmaceutical composition consists of the drag component, the propellant component, glycerol and ethanol.
    46. The method of any one of claims 31 to 45, wherein the pharmaceutical composition is surfactant-free,
    47. The method of any one of claims 31 to 46, wherein the pharmaceutical composition <s tree of acid stabilisers.
    48. The method of any one ol claims 31 to 47, wherein the pharmaceutical composition consists entirely of the drug component, the propellant component, glycerol and ethanol.
    49. The method of any one of claims 31 to 48, wherein the pharmaceutical composition after storage in uncoated aluminium containers at 40<:C and 75 % relative humidity for 1 month produces less than 2,0 % by weight, preferably less than 1,5 % by weight and more preferably less than 1.0 % by weight of impurities from the degradation of the at least one beclomethasone compound based on the total weight of the at least one beclomethasone compound and the impurities for amounts of ethanol up to 15 weight % based on the total weight of the pharmaceutical composition.
    50. The method of any one of claims 31 to 49, wherein the pharmaceutical composition after storage In uncoated aluminium containers at 40”C and 75 % relative humidity for 3 months produces less than 2.5 % by weight, preferably less than 2.0 % by weight and more preferably less than 1.5 % by weight of impurities from the degradation of the at least one beclomethasone compound based on the total weight of the at least os amounts of ethanol up to pharmaceutical composition.
    e beclomethasone compound and the impurities 15 weight % based on the total weight, of tor the
    51. The method of any one of siaims 31 to 50, wherein the pharmaceutical composition is in the form of a suspension.
    52. The method of any one: of claims 31 to 50, wherein the pharmaceutical composition Is in the form of a solution.
    is
    Intellectual
    Property
    Office
    Application No: GB1615908.9 Examiner: Mr Robert Goodwill
    Claims searched: 1-30 Date of search: 25 May 2017
    Patents Act 1977: Search Report under Section 17
    Documents considered to be relevant:
    Category Relevant to claims Identity of document and passage or figure of particular relevance A - WO 2012/156711 Al (MEXICHEM AMANCO HOLDING), see EPO abstract AN GB2012051059-W A Chiesi Limited, Fostair 100/6 micrograms per actuation pressurised inhalation solution, medicines.org.uk, [online], Available from: https://www.medicines.org.uk/emc/medicine/21474 [Accessed 15 May 2017]
    Categories:
    X Document indicating lack of novelty or inventive step A Document indicating technological background and/or state of the art. Y Document indicating lack of inventive step if combined with one or more other documents of same category. P Document published on or after the declared priority date but before the filing date of this invention. & Member of the same patent family E Patent document published on or after, but with priority date earlier than, the filing date of this application.
    Field of Search:
    Search of GB, EP, WO & US patent documents classified in the following areas of the UKCX :
    International Classification:
    Subclass Subgroup Valid From A61K 0031/573 01/01/2006 A61K 0009/00 01/01/2006 A61K 0031/167 01/01/2006 A61K 0047/06 01/01/2006 A61P 0011/06 01/01/2006 A61P 0011/08 01/01/2006 C07J 0005/00 01/01/2006
    Intellectual Property Office is an operating name of the Patent Office www.gov.uk/ipo
GB1615908.9A 2016-09-19 2016-09-19 Pharmaceautical composition Withdrawn GB2554088A (en)

Priority Applications (31)

Application Number Priority Date Filing Date Title
GB1615908.9A GB2554088A (en) 2016-09-19 2016-09-19 Pharmaceautical composition
MYPI2023001168A MY210122A (en) 2016-09-19 2017-09-18 Pharmaceutical composition
MYPI2019001314A MY202030A (en) 2016-09-19 2017-09-18 Pharmaceutical composition
UAA201902773A UA124240C2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
EP19199776.6A EP3610877A1 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
JP2019515271A JP6781832B2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
CN202110273940.8A CN113069417A (en) 2016-09-19 2017-09-18 Pharmaceutical composition
CN202310774818.8A CN116898804A (en) 2016-09-19 2017-09-18 pharmaceutical composition
IL265349A IL265349B2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
BR112019005113-9A BR112019005113B1 (en) 2016-09-19 2017-09-18 PHARMACEUTICAL COMPOSITION
PCT/GB2017/052762 WO2018051131A1 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
PE2019000675A PE20191044A1 (en) 2016-09-19 2017-09-18 PHARMACEUTICAL COMPOSITION
US16/334,156 US20190388436A1 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
PH1/2019/500577A PH12019500577B1 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
AU2017328908A AU2017328908B2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
EP17777636.6A EP3515451B2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
MX2019003103A MX2019003103A (en) 2016-09-19 2017-09-18 Pharmaceutical composition.
ES17777636T ES2841649T5 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
CN201780057285.4A CN109789151A (en) 2016-09-19 2017-09-18 Pharmaceutical composition
KR1020197010383A KR102279445B1 (en) 2016-09-19 2017-09-18 pharmaceutical composition
GEAP201715034A GEP20217240B (en) 2016-09-19 2017-09-18 Pharmaceutical composition
NZ752434A NZ752434B2 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
EP19199786.5A EP3607951A1 (en) 2016-09-19 2017-09-18 Pharmaceutical composition
CA3037257A CA3037257C (en) 2016-09-19 2017-09-18 Pharmaceutical compositions comprising beclomethasone dipropionate, and formoterol fumarate dihydrate
EA201990501A EA201990501A1 (en) 2016-09-19 2017-09-18 PHARMACEUTICAL COMPOSITION
CONC2019/0002555A CO2019002555A2 (en) 2016-09-19 2019-03-19 Pharmaceutical composition
ZA2019/02052A ZA201902052B (en) 2016-09-19 2019-04-02 Pharmaceutical composition
US16/582,710 US20200016174A1 (en) 2016-09-19 2019-09-25 Pharmaceutical composition
US16/582,964 US20200016175A1 (en) 2016-09-19 2019-09-25 Pharmaceutical composition
JP2020042092A JP6980050B2 (en) 2016-09-19 2020-03-11 Pharmaceutical composition
AU2020202651A AU2020202651C1 (en) 2016-09-19 2020-04-20 Pharmaceutical composition

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB1615908.9A GB2554088A (en) 2016-09-19 2016-09-19 Pharmaceautical composition

Publications (2)

Publication Number Publication Date
GB201615908D0 GB201615908D0 (en) 2016-11-02
GB2554088A true GB2554088A (en) 2018-03-28

Family

ID=57288606

Family Applications (1)

Application Number Title Priority Date Filing Date
GB1615908.9A Withdrawn GB2554088A (en) 2016-09-19 2016-09-19 Pharmaceautical composition

Country Status (1)

Country Link
GB (1) GB2554088A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113244490A (en) * 2020-01-28 2021-08-13 奇斯药制品公司 Pressurized metered dose inhalers comprising buffered pharmaceutical formulations

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012156711A1 (en) * 2011-05-13 2012-11-22 Mexichem Amanco Holding S.A. De C.V. Pharmaceutical compositions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012156711A1 (en) * 2011-05-13 2012-11-22 Mexichem Amanco Holding S.A. De C.V. Pharmaceutical compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chiesi Limited, "Fostair100/6 micrograms per actuation pressurised inhalation solution", medicines.org.uk, [online], Available from: https://www.medicines.org.uk/emc/medicine/21474 [Accessed 15 May 2017] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113244490A (en) * 2020-01-28 2021-08-13 奇斯药制品公司 Pressurized metered dose inhalers comprising buffered pharmaceutical formulations

Also Published As

Publication number Publication date
GB201615908D0 (en) 2016-11-02

Similar Documents

Publication Publication Date Title
US11883372B2 (en) Pharmaceutical composition
AU2020202651B2 (en) Pharmaceutical composition
US11260052B2 (en) Pharmaceutical composition
AU2020202650B2 (en) Pharmaceutical composition
US20210244688A1 (en) Pharmaceutical composition comprising salbutamol
GB2554091A (en) Pharmaceutical composition
GB2554088A (en) Pharmaceautical composition
GB2554090A (en) Pharmaceutical compound
NZ752434B2 (en) Pharmaceutical composition
BR112019005113B1 (en) PHARMACEUTICAL COMPOSITION
EA041358B1 (en) PHARMACEUTICAL COMPOSITION

Legal Events

Date Code Title Description
WAP Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1)