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US20130089617A1 - Crystalline microparticles of a beta-agonist coated with a fatty acid - Google Patents

Crystalline microparticles of a beta-agonist coated with a fatty acid Download PDF

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Publication number
US20130089617A1
US20130089617A1 US13/649,336 US201213649336A US2013089617A1 US 20130089617 A1 US20130089617 A1 US 20130089617A1 US 201213649336 A US201213649336 A US 201213649336A US 2013089617 A1 US2013089617 A1 US 2013089617A1
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Prior art keywords
microparticles
fatty acid
acid
beta
agonist
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Inventor
Gaetano Brambilla
Paolo Colombo
Francesca Buttini
Michele Miozzi
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Assigned to CHIESI FARMACEUTICI S.P.A. reassignment CHIESI FARMACEUTICI S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRAMBILLA, GAETANO, BUTTINI, FRANCESCA, COLOMBO, PAOLO, MIOZZI, Michele
Publication of US20130089617A1 publication Critical patent/US20130089617A1/en
Priority to US15/152,835 priority Critical patent/US10993916B2/en
Priority to US16/738,231 priority patent/US20200138724A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61M11/02—Sprayers or atomisers specially adapted for therapeutic purposes operated by air or other gas pressure applied to the liquid or other product to be sprayed or atomised
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    • A61M15/00—Inhalators
    • A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
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    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • the present invention relates to crystalline microparticles comprising a beta 2 -agonist suitable for use in formulations to be administered by inhalation for the treatment of respiratory diseases.
  • the present inventions also relates to pharmaceutical aerosol formulations comprising said microparticles and to a process for preparing them.
  • the present invention further relates to methods of treating/preventing certain diseases and conditions by administering such microparticles.
  • Inhalable preparations include dry powders formulations, pressurized metered dose (pMDI) formulations containing propellants such as hydrofluoroalkanes (HFA), or propellant-free aqueous formulations to be administered by suitable devices such as nebulizers.
  • pMDI pressurized metered dose
  • HFA hydrofluoroalkanes
  • the drugs present in the formulations can either be dissolved or suspended.
  • a specific group of drugs administered by the pulmonary route are bronchodilators having a local therapeutic action in the lungs and/or a systemic therapeutic action after absorption in the blood.
  • bronchodilators are beta2-agonists belonging to the class of the phenylalkylamino derivatives such as rac-(R,R)-N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyliformamide, also known as formoterol.
  • formoterol as well as other drugs belonging to said class may suffer of chemical stability problems due to the susceptibility to oxidative conditions of the functional groups present on the molecules such as formamide and hydroxyethyl groups. Some of said groups such as formamide are also susceptive to solvolysis reactions.
  • molecules belonging to said class may also incur problems of physical stability of their suspension formulations. This is because of partial solubility of the drugs in the liquefied gas propellant. This partial solubility, in turn, may lead to an undesirable increase in the particle size during storage and/or the formation of aggregates.
  • formulations of beta 2 -agonists in HFA propellant might be susceptible to absorption of the drug into the rubber components of the valves of the administration device. This may then cause the valves to seize resulting in a reduction of fine particle mass and/or the aggregates of particles will penetrate less well into the fine lower respiratory pathways, subsequently causing problems with dose uniformity.
  • WO 92/08447 and WO 91/04011 teach coating the active agent by a process involving the steps of dissolving the surfactant in a solvent in which the pharmaceutically active agent is substantially insoluble, mixing a quantity of the pharmaceutically active agent, in micronized form, into the surfactant solution and isolating particles of surfactant coated active agent either by filtration and drying, or by removal of the solvent by evaporation.
  • WO 2006/059152 discloses the preparation of coated particles with dispersing agents such as surfactants by mechano-fusion processes. However, it is known that particles obtained in this way are prevalently amorphous. On the other hand, amorphous or prevalently amorphous materials tend to absorb water in larger amounts than crystalline ones, and this could be a pitfall for active ingredients liable to degradation by hydrolysis.
  • WO 00/61108 discloses salmeterol particles coated with a surfactant and free of any other coating excipient. They are obtained by a process involving the steps of suspending the active ingredient in form of particles in a medium, preferably water, then dispersing the surfactant, and subjecting the suspension to spray -drying. However, also in this case, it is well known that the use of water could yield some amorphous material. Moreover, it is difficult to achieve a uniform coating if the surfactant is dispersed and not dissolved in said medium.
  • WO 2008/152398 discloses particles coated with polymers such as PVP without any mention of their chemical stability.
  • US 2004/101483 discloses suspension aerosol formulations based on hydrofluoroalkanes comprising micronized particles of active ingredients and calcium salts, magnesium salts, and zinc salts of palmitic acid and of stearic acid as solid excipients.
  • the demonstrated advantage is that said suspensions show a markedly improved valve accessibility.
  • US 2004/013611 discloses suspension aerosol formulations comprising a therapeutically effective amount of micronized albuterol sulfate, from about 5 to 15 percent by weight of ethanol, from about 0.05 to about 0.5 percent by weight of a surfactant selected from the group consisting of oleic acid and sorbitan trioleate, and HFC 227 as substantially the only propellant.
  • Said formulations are characterized in that they exhibit substantially no growth in particle size or change in crystal morphology of the drug over a prolonged period, are substantially and readily redispersible, and upon redispersion do not flocculate so quickly as to prevent reproducible dosing of the drug. None is said about their chemical stability.
  • crystalline microparticles consisting of a phenylalkylamino beta 2 -adrenergic agonist coated with a C12-C20 fatty acid in an amount comprised between 0.2 and 2.5% by weight.
  • the invention is directed to crystalline microparticles comprising a phenylalkylamino beta 2 -adrenergic agonist coated with a C12-C20 fatty acid in an amount comprised between 0.2 and 2.5% by weight.
  • the crystalline microparticles preferably consist of a phenylalkylamino beta 2 -adrenergic agonist coated with a C12-C20 fatty acid in an amount comprised between 0.2 and 2.5% by weight.
  • said beta 2 -agonist is selected from a derivative belonging to the general formula (I):
  • R 1 is CH 2 OH or NHCOR 10
  • R 1 when R 1 is CH 2 OH, R 2 is hydrogen, while, when R 1 is NHCOR 10 , R 2 and R 10 can be independently hydrogen or form together a vinylene (—CH ⁇ CH—) or ethoxy (—CH 2 —O—) radical;
  • n is an integer from 0 to 5, preferably 0 or 5;
  • n is an integer from 0 to 4, preferably 0, 2 or 4;
  • p is an integer from 0 to 2, preferably 0 or 1;
  • A represents oxygen or a bond
  • R 3 and R 4 are hydrogen or methyl; otherwise, when m is 1, n, p are 0, A and B are bonds, and R 3 is hydrogen, R 4 can form with R 5 a methylene bridge —(CH 2 )q- where q is 1 or 2, preferably 1;
  • R 5 , R 6 , R 7 , R 8 , and R 9 which are the same or different, are each independently selected from hydrogen, hydroxyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen atoms, SO 2 NH 2 , and 2-hydroxy-2-phenyl-ethylamino; preferably they are hydrogen, halogen atoms, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy,
  • the invention provides pharmaceutical aerosol formulations for pressurized metered dose inhalers (pMDIs) comprising the above microparticles in suspension in a liquefied propellant gas.
  • pMDIs pressurized metered dose inhalers
  • the invention provides pressurized metered dose inhalers (pMDI) comprising a canister filled with the aforementioned aerosol pharmaceutical formulation, and a metering valve for delivering a daily therapeutically effective dose of the active ingredient.
  • pMDI pressurized metered dose inhalers
  • the invention concerns dry powder pharmaceutical formulations comprising the above microparticles and, optionally a carrier.
  • the invention provides dry powder inhalers filled with the aforementioned dry powder formulation.
  • the present invention is directed to a process for preparing the microparticles of the invention, said process comprising the steps of:
  • the present invention is also directed to the microparticles of the invention for use for the prevention and/or treatment of a respiratory disease.
  • the present invention is further directed to the use of the microparticles of the invention in the manufacture of a medicament for the prevention and/or treatment of a respiratory disease.
  • the present invention provides methods for preventing and/or treating a respiratory disease in a patient, comprising administering a therapeutically effective amount of the microparticles of the invention.
  • the present invention concerns crystalline microparticles consisting of a phenylalkylamino beta 2 -adrenergic agonist coated with a C12-C20 fatty acid in an amount comprised between 0.2 and 2.5% by weight, said microparticles obtainable by a process comprising the steps of:
  • the present invention provides a process for preparing crystalline microparticles consisting of a drug to be administered by inhalation coated with a C12-C20 fatty acid, said process comprising the steps of:
  • the invention is also directed to the crystalline coated microparticles obtainable by said process.
  • FIG. 1 is a thermogram of microparticles of the present invention in comparison to crystalline microparticles of formoterol fumarate dihydrate (top line).
  • halogen atoms as used herein includes fluorine, chlorine, bromine and iodine.
  • C 1 -C 4 alkyl refers to straight-chained and branched alkyl groups wherein the number of carbon atoms is in the range 1 to 4.
  • Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl, preferably methyl and ethyl.
  • C 1 -C 4 alkoxy refers to straight and branched chain alkoxy groups wherein the number of carbon atoms is in the range 1 to 4.
  • Exemplary groups are methoxy, ethoxy, and butyloxy.
  • coated refers to microparticles having their surface covered by a continuous film of the fatty acid.
  • single therapeutically effective dose means the quantity of active ingredient administered at one time by inhalation upon actuation of the pMDI or DPI inhaler.
  • Said dose may be delivered in one or more actuations, preferably one actuation (shot) of the inhaler.
  • actuation refers to the release of active ingredient from the device by a single activation (e.g. mechanical or breath).
  • fluorinated model propellant it is meant a fluorinated alkane derivative liquid at room temperature and at atmospheric pressure in which common beta 2 -agonists are insoluble.
  • Typical members of this class are perfluoropentane, 2H,3H-perfluoropentane, perfluorohexane, and 1H-perfluorohexane.
  • 2H,3H-perfluoropentane is also known as HPFP (see Rogueda P. Drug Dev. Ind. Pharm., 2003, 29(1), 39-49, which is incorporated herein by reference in its entirety).
  • substantially insoluble refers to an active ingredient having a solubility in the desired medium of less than 1.0% w/v, preferably of less than 0.5%, more preferably less than 0.1% w/v.
  • the particle size of the particles is quantified by measuring a characteristic equivalent sphere diameter, known as volume diameter, by laser diffraction.
  • the particle size can also be quantified by measuring the mass diameter by means of suitable instruments and techniques known to the skilled person, such as sieving.
  • the volume diameter (VD) is related to the mass diameter (MD) by the density of the particles (assuming the size being independent from the density of the particles).
  • the particle size interval is expressed in terms of mass diameter. Otherwise, the particle size distribution is expressed in terms of: i) the volume median diameter (VMD) which corresponds to the diameter of 50 percent by weight or volume respectively, of the particles, e.g. d(v0.5), and ii) the volume diameter (VD) in microns of 10% and 90% of the particles, respectively, e.g. d(v0.1) and d(v0.9).
  • VMD volume median diameter
  • the particle size is expressed as mass aerodynamic diameter (MAD) and the particle size distribution as mass median aerodynamic diameter (MMAD).
  • MAD mass aerodynamic diameter
  • MMAD mass median aerodynamic diameter
  • the MAD indicates the capability of the particles of being transported as suspended in an air stream.
  • the MMAD corresponds to the mass aerodynamic diameter of 50 percent by weight of the particles.
  • physically stable refers to formulations which exhibit substantially no growth in particle size or change in crystal morphology of the suspended particles over a prolonged period, are readily redispersible, and upon redispersion, do not flocculate so quickly as to prevent reproducing dosing of the active ingredient.
  • chemically stable refers to a formulation that, upon storage, meets the requirements of the EMEA Guideline CPMP/QWP/122/02 referring to “Stability Testing of Existing Active Substances and Related Finished Products”.
  • respirable fraction refers to an index of the percentage of active particles which would reach the deep lungs in a patient.
  • the respirable fraction also termed fine particle fraction (FPF)
  • FPF fine particle fraction
  • NMI Next Generation Impactor
  • MLSI Multi Stage Liquid Impinger
  • the delivered dose is calculated from the cumulative deposition in the apparatus, while the fine particle mass is calculated from the deposition on Stage N (herein N is an integer number) to filter (AF) corresponding to particles ⁇ 5.0 microns.
  • terapéuticaally effective amount means the amount of active ingredient that, when delivered to the lungs, provides the desired biological effect.
  • prevention means an approach for reducing the risk of onset of a disease.
  • treatment means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • the present invention concerns crystalline microparticles comprising or consisting of a phenylalkylamino beta 2 -adrenergic agonist and pharmaceutically acceptable salts and/or solvates thereof.
  • Phenylalkylamino beta 2 -adrenergic agonists are drugs having a bronchodilator activity and include for example salbutamol (albuterol), bambuterol fenoterol, procaterol, salmeterol, indacaterol, and formoterol.
  • Pharmaceutically acceptable salts include those obtained by reacting the amino group of the compound with an inorganic or organic acid to form a salt, for example, hydrochloride, hydrobromide, sulphate, phosphate, methane sulfonate, camphor sulfonate, oxalate, maleate, fumarate, succinate, citrate, cinnamate, xinafoate, and trifenatate.
  • a salt for example, hydrochloride, hydrobromide, sulphate, phosphate, methane sulfonate, camphor sulfonate, oxalate, maleate, fumarate, succinate, citrate, cinnamate, xinafoate, and trifenatate.
  • said beta 2 -agonist is selected from a derivative belonging to the general formula (I).
  • the compounds of general formula (I) may contain asymmetric centers. Therefore the present invention includes all the optical stereoisomers and mixtures thereof
  • a first class of preferred compounds is that wherein
  • R 1 is NHCOR 10 with R 10 ⁇ H, R 4 is methyl, m is 1, n, p are 0, A and B are bonds, R 3 , R 5 , R 6 , R 8 and R 9 are H, and R 7 is methoxy.
  • the compound When the phenolic group is adjacent to R I , the compound is known as formoterol.
  • formoterol is preferably used in the form of 1:1 (R,R), (S,S) racemate or (R,R) enantiomer, more preferably as the racemate.
  • a particularly preferred salt is the fumarate dihydrate.
  • a second class of preferred compounds is that wherein:
  • the compound When the phenolic group is adjacent to R 1 , the compound is known as indacaterol.
  • indacaterol is preferably used in the form of R-enantiomer, more preferably as maleate salt.
  • a third class of preferred compounds is that wherein:
  • R 1 is CH 2 OH
  • R 2 R 6 , R 7 and R 8 are H
  • R 5 and R 9 are chlorine atoms
  • a and B are O
  • m is 5
  • n is 2
  • p is 1.
  • the compound When the phenolic group is adjacent to R 1 , the compound is known as vilanterol.
  • Vilanterol is preferably used in the form of R-enantiomer as trifenatate salt
  • a fourth class of preferred compounds is that wherein:
  • the phenolic group is meta to R 1 the compound is known as olodaterol, that is preferably used as R-enantiomer.
  • a fifth class of preferred compounds is that wherein:
  • R 1 is NHCOR 10 with R 10 ⁇ H, R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are H, m is 1, A and B are bonds, n and p are 0, and R 7 is 2-hydroxy-2-phenyl-ethylamino.
  • milveterol When the phenolic group is adjacent to R 1 the compound is known as milveterol. As it contains two chiral centers, milveterol is preferably used in the form of (R,R)-enantiomer, more preferably as the hydrochloride salt.
  • a sixth class of preferred compounds is that wherein:
  • R 1 is CH 2 OH
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 8 and R 9 are H, m is 5, n is 4, p is 0, A is O, and B is a bond.
  • salmeterol When the phenolic group is adjacent to R 1 the compound is known as salmeterol. As it contains one chiral center, salmeterol is preferably used in the form of racemic form (R,S), more preferably as a xinafoate salt.
  • the compound of formula (I) is a long-acting beta 2 -agonist selected from the group consisting of formoterol, salmeterol, vilanterol, olodaterol, milveterol, indacaterol, and pharmaceutically acceptable salts and/or solvates thereof.
  • preferred compounds are those wherein R 1 is NHCOR 10 , R 2 and R 10 are H, and the other substituents and indexes have the meanings reported above.
  • phenylalkylamino derivatives bearing said group are particularly sensitive to solvolysis reactions.
  • the preferred compound of said class is formoterol, preferably in the form of fumarate dihydrate salt.
  • preferred compounds are those wherein R 1 CH 2 OH, R 2 is H, and the other substituents and indexes have the meanings reported above.
  • the preferred compound of said class is salmeterol, preferably in the form of a xinafoate salt.
  • the particle size of said microparticles is lower than 15 microns, preferably lower than 10 microns.
  • at least 90% of the particles have a volume diameter lower than about 5 micron. More advantageously no more than 10% of the microparticles have a volume diameter [d(v,0.1)] lower than 0.6 micron, and no more than 50% of particles have a volume diameter [d(v,0.5)] lower than 1.5 micron.
  • the [d(v,0.5)] is comprised between 1.5 and 3.0 micron.
  • the particle size method could be measured by laser diffraction according to known methods.
  • microparticles of the compound of general formula (I) are coated with a C12-C20 fatty acid in an amount comprised between 0.2 and 2.5% by weight of said particles, preferably between 0.5 and 2.0% by weight.
  • the preferred amount may be comprised between 1.0 and 2.0% by weight, while in other embodiment, it may be comprised between 0.5 and 1.0% by weight.
  • the C12-C20 fatty acid is advantageously selected from the group consisting of saturated and monounsaturated compounds such as lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), palmitoleic acid (C16:1), stearic acid (C18:0), oleic acid (C18:1), and arachidic acid (C20:0) or mixtures thereof.
  • saturated and monounsaturated compounds such as lauric acid (C12:0), myristic acid (C14:0), palmitic acid (C16:0), palmitoleic acid (C16:1), stearic acid (C18:0), oleic acid (C18:1), and arachidic acid (C20:0) or mixtures thereof.
  • the fatty acid it is a saturated fatty acid selected from the group consisting of myristic acid, palmitic acid, stearic acid, and arachidic acid.
  • the fatty acid is myristic acid.
  • myristic acid is capable of giving rise to higher performances in terms of respirable fraction (FPF) as it can be appreciated from the Examples.
  • oleic acid may be preferably used.
  • the fatty acid shall form a continuous film on the surface of the microparticles.
  • the coating may cover part of the microparticles or all of them (complete coating), preferably all of them.
  • beta 2 -adrenergic agonist The amount of beta 2 -adrenergic agonist will depend on its single therapeutically effective dose, which in turn, depends on the kind and the severity of the disease and the conditions (weight, sex, age) of the patient.
  • the single therapeutically effective dose could be 6 or 12 ⁇ g, calculated as fumarate dihydrate salt.
  • the relevant suspensions turned out to be chemically and physically stable over time and capable of giving rise to excellent respirable fraction.
  • said formulations show a lower sedimentation speed than the corresponding formulations comprising uncoated microparticles.
  • the present invention provides for pressurized metered dose inhalers (pMDIs) comprising the above microparticles in suspension in a liquefied propellant gas.
  • pMDIs pressurized metered dose inhalers
  • any liquefied propellant gas may be used, preferably a hydrofluoroalkane (HFA) propellant.
  • HFA hydrofluoroalkane
  • the liquefied propellant gas is 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227) or 1,1,1,2-tetrafluoroethane (HFA 134a), and mixtures thereof.
  • the formulations of the present invention may also comprise other pharmaceutically acceptable excipients, for instance surfactants.
  • Suitable surfactants are known in the art and include: sorbitan esters such as sorbitan trioleate, sorbitan monolaurate, sorbitan mono-oleate and their ethoxylated derivates such as polysorbate 20, polysorbate 80; ethylene oxide/propylene oxide co-polymers and other agents such as natural or synthetic lecithin, oleic acid, polyvinylpyrrolidone (PVP), and polyvinyl alcohol.
  • PVP polyvinylpyrrolidone
  • the amount of surfactant, which may be present in the pMDI formulation according to the invention, is usually in the range of 0.001 to 3.0% (w/w), preferably between 0.005 to 1.0% (w/w).
  • formulations according to the present invention may further comprise other active ingredients useful for the prevention and/or treatment of respiratory diseases, for instance corticosteroids or antimuscarinic drugs suspended or dissolved in the liquefied propellant gas.
  • active ingredients useful for the prevention and/or treatment of respiratory diseases for instance corticosteroids or antimuscarinic drugs suspended or dissolved in the liquefied propellant gas.
  • corticosteroids examples include beclometasone dipropionate (BDP), fluticasone propionate, fluticasone furoate, mometasone furoate, budesonide, and ciclesonide.
  • antimuscarinic drugs examples include ipratropium bromide, tiotropium bromide, glycopyrronium bromide, and aclidinium bromide.
  • the present invention provides a pMDI comprising a canister filled with the pharmaceutical formulation of the invention and a metering valve for delivering a daily therapeutically effective dose of the active ingredient.
  • the aerosol formulation according to the invention shall be filled into pMDIs.
  • Said pMDIs comprise a canister fitted with a metering valve. Actuation of the metering valve allows a small portion of the spray product to be released.
  • Part or all of the internal surfaces of the canister may be made of glass or of a metal, for example aluminum or stainless steel or anodized aluminum.
  • the metal canister may have part or all of the internal surfaces lined with an inert organic coating.
  • preferred coatings are epoxy-phenol resins, perfluorinated polymers such as perfluoroalkoxyalkanes, perfluoroalkoxyalkylenes, perfluoroalkylenes such as poly-tetrafluoroethylene (Teflon), fluorinated-ethylene-propylene, polyether sulfone, fluorinated-ethylene-propylene (FEP), and fluorinated-ethylene-propylene polyether sulfone (FEP-PES) mixtures or combination thereof.
  • Other suitable coatings may be polyamide, polyimide, polyamideimide, polyphenylene sulfide or their combinations.
  • the canister is closed with a metering valve for delivering a daily therapeutically effective dose of the active ingredient.
  • the metering valve assembly comprises a ferrule having an aperture formed therein, a body molding attached to the ferrule which houses the metering chamber, a stem constituted of a core and a core extension, an inner- and an outer seal around the metering chamber, a spring around the core, and a gasket to prevent leakage of propellant through the valve.
  • the gasket may comprise any suitable elastomeric material such as, for example, low density polyethylene, chlorobutyl, black and white butadiene-acrylonitrile rubbers, butyl rubber, neoprene, EPDM (a polymer of ethylenepropylenediene monomer) and TPE (thermoplastic elastomer). EPDM rubbers are particularly preferred.
  • Suitable valves are commercially available from manufacturers well known in the aerosol industry, for example, from Valois, France, Bespak, plc UK and 3M, Neotechnic Ltd UK.
  • the formulation shall be actuated by a metering valve capable of delivering a volume of between 25 ⁇ l and 100 ⁇ l, e.g. 25 ⁇ l, 50 ⁇ l, 63 ⁇ l or 100 ⁇ l.
  • the MDI device filled with the formulation may be equipped with a dose counter.
  • the microparticles of the inventions when administered as a powder by a suitable device, give rise to a significantly higher respirable fraction than the corresponding uncoated microparticles.
  • the invention also provides a dry powder pharmaceutical formulation comprising the above microparticles and optionally a carrier.
  • the carrier particles may be made of any physiologically acceptable, pharmacologically inert material or combination of materials suitable for inhalatory use.
  • the carrier particles may be composed of one or more materials selected from sugar alcohols; polyols, for example sorbitol, mannitol and xylitol, and crystalline sugars, including monosaccharides and disaccharides.
  • the carrier particles are made of lactose, more preferably of alpha-lactose monohydrate.
  • said carrier particles have a mass diameter (MD) of at least 50 microns, more advantageously greater that 90 microns.
  • MD mass diameter
  • the MD is comprised between 50 microns and 500 microns.
  • the MD may be comprised between 90 and 150 microns.
  • the MD may be comprised between 150 and 400 micron, with a MMD preferably greater than 175 microns, and more preferably the MD may be comprised between 210 and 355 microns.
  • the desired particle size may be obtained by sieving according to known methods.
  • the aforementioned powder formulation may also advantageously comprise an additive material, preferably bound to the surface of the carrier particles.
  • Said additive material may be an amino acid, preferably selected from leucine or isoleucine, or a water soluble surface active material, for example lecithin, in particular soya lecithin, or a lubricant selected from the group consisting of stearic acid and salts thereof such as magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, and stearyl alcohol.
  • dry powder formulations herein described may be used in all customary dry powder inhalers, such as unit dose or multidose inhalers.
  • said formulations may be filled in hard gelatine capsules, in turn loaded in a unit dose inhaler such as the AerolizerTM or the RS01/7 model available from Plastiape, Italy.
  • a unit dose inhaler such as the AerolizerTM or the RS01/7 model available from Plastiape, Italy.
  • a multidose inhaler comprising a powder reservoir as described in WO 2004/012801, which is incorporated herein by reference in its entirety.
  • the present invention further provides a process for preparing the microparticles of the invention, said process comprising the steps of:
  • the microparticles of the present invention have a crystalline degree, expressed as weight % of the crystalline compound with respect to the total weight of the compound, of at least 90%, preferably of at least 95%, even more preferably of at least 98%, determined according to methods know in the art such as differential scanning calorimetry (DSC), microcalorimetry or X-ray powder diffractometry.
  • DSC differential scanning calorimetry
  • microcalorimetry microcalorimetry
  • X-ray powder diffractometry X-ray powder diffractometry
  • the fatty acid is added as a solution, a uniform and extensive coating of microparticles is achieved. Said coating with the fatty acid is performed in the absence of any other coating excipient.
  • said uniform and extensive coating may contribute to improve the chemical stability of the active ingredient. Furthermore, it prevents both the partial solubilization and formation of aggregates of the drug, once suspended in a liquefied propellant gas, making possible to obtain formulations characterized by an improved physical stability.
  • the fluorinated model propellant shall be selected depending on the solubility characteristics of both the active ingredient and the fatty acid.
  • said model propellant is perfluoropentane or 2H,3H-perfluoropentane (HPFP), more preferably 2H,3H-perfluoropentane.
  • HPFP 2H,3H-perfluoropentane
  • the amount of the fatty acid in the solution will vary depending on the amount of active ingredient added in stage (b) and will be selected so as to obtain a percentage in the final coated microparticles comprised between 0.2 and 2.5% by weight.
  • the content of the active ingredient in the suspension prepared in stage (b) can vary within wide limits, usually within the range from 1 to 40% w/v, preferably from 2 to 20% w/v, more preferably from 5 to 10% w/v.
  • the micronized drug powder may be added to the solution of the fatty acid and then mixed with techniques known in the art, e.g. sonicating or stirring, to give a homogeneous suspension (stage (c).
  • stage (d) the obtained suspension, maintained under stirring, is subjected to spray drying in an appropriate apparatus.
  • the operating parameters of the apparatus such as the flow rate of the suspension arriving in the drying chamber, the size of the nozzle, the inlet and outlet temperature, the atomizing pressure and the flow rate of the atomizing air, may be adjusted by any skilled person according to the recommendations of the manufacturer.
  • a suitable spray dryer is, for example, the Büchi 191 Mini Spray Dryer (Büchi Company, Switzerland).
  • Typical parameters are the following:
  • inlet air temperature 60 to 150° C., preferably 95 to 105° C., more preferably 100° C.;
  • outlet temperature 40 to 110° C., preferably 55 to 65° C., more preferably 60° C.;
  • the microparticles have a diameter less than 15 micron.
  • they may be subjected to conventional milling techniques to adjust their size.
  • Administration of the microparticles of the invention may be indicated for prevention and/or the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment of an inflammatory or obstructive airways disease such as asthma and chronic obstructive pulmonary disease (COPD).
  • an inflammatory or obstructive airways disease such as asthma and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • inlet air temperature 100° C.
  • the yield of the process was 69.0%.
  • FF formoterol fumarate dehydrate
  • microparticles as obtained in Example 1 were subjected to the following analysis.
  • SEM Scanning electron microscopy
  • DSC Differential scanning calorimetry
  • the crystalline properties were further investigated by differential scanning calorimetry (DSC).
  • the data were obtained on a Mettler Toledo Instrument DSC821c, software STARe.
  • the calibration standard used is indium.
  • Approximately 2 to 5 mg of a sample is placed into a DSC pan, and the weight is accurately measured and recorded.
  • the pan is hermetically sealed.
  • the sample is heated under nitrogen at a rate of 20° C./min, from 25° C. to a final temperature of 200° C.
  • the thermogram reported in FIG. 1 shows that the characteristic endothermic transition ending at about 160° C., typical of crystalline formoterol fumarate dihydrate, is still present in the microparticles of the invention, indicating that the spray-drying process has not modified the solid characteristics of the drug.
  • microparticles coated with amounts of additive ranging from 1.0 to 2.0% w/v are more crystalline than microparticles coated with a lower amount, i.e. 0.5% w/v.
  • the particle size of the microparticles of the invention does not substantially change in comparison to that of raw formoterol fumarate dihydrate.
  • pMDI aerosol suspension formulations with a nominal dose of the active ingredient of 12 the aluminum canisters were filled in a controlled atmosphere room, by successively introducing 2.4 mg the microparticles of Example 1 and then 10 ml pressurized HFA134a gas. The devices were fitted with a 50 ⁇ l APTAR valve and a Bespak actuator of 0.3 mm.
  • a pMDI aerosol suspension formulations comprising micronized formoterol fumarate dihydrate was also prepared. The sedimentation rate was determined using a Turbiscan apparatus (Formulaction SA, France).
  • the pMDI formulations obtained with microparticles of the invention exhibit a good homogenous distribution of the suspended particles as well as a higher level of physical stability than the comparative formulation, as the particles sediment more slowly and are less liable to form agglomerates.
  • the pMDI formulations were also characterized in terms of aerosol performances. They were assessed using a Next Generation Impactor to according to the procedure described in the European Pharmacopoeia 7 th edition, 2011, part 2.9.18.
  • Example 1 FF-myr 0.5 and Ff-myr 2.0 were mixed in a Turbula mixer with alpha-lactose monohydrate having a mass diameter comprised between 90 and 150 ⁇ m as a carrier, to obtain a ratio of 6 ⁇ g of drug to 10 mg of carrier.
  • a powder formulation comprising micronized formoterol fumarate dihydrate was also prepared. Each powder was filled in hard HMPC gelatine capsules, in turn loaded in a RS01/7unit dose inhaler (Plastiape, Italy).
  • inlet air temperature 100° C.
  • microparticles with oleic acid were prepared.
  • the microparticles have the following composition:
  • pMDI aerosol suspension formulations with a nominal dose of the active ingredient of 25 ⁇ g, canisters coated with FEP were filled in a controlled atmosphere room, by successively introducing 3.0 mg the microparticles of Example 5 and then 6 ml pressurized HFA134a gas. The devices were fitted with a 50 ⁇ l APTAR valve and a Bespak actuator of 0.3 mm.
  • a pMDI aerosol suspension formulations comprising micronized salmeterol xinafoate was also prepared.
  • the pMDI formulations were characterized in terms of aerosol performances. They were assessed as described in Example 3. The results (as a mean ⁇ S.D.) are summarized in Table 4.

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6524557B1 (en) * 1994-12-22 2003-02-25 Astrazeneca Ab Aerosol formulations of peptides and proteins
US20030180283A1 (en) * 2002-03-20 2003-09-25 Batycky Richard P. Method and apparatus for producing dry particles
US20070009445A1 (en) * 2005-07-08 2007-01-11 Xemplar Pharmaceuticals, Llc Aerosol compositions and methods
WO2010007447A1 (en) * 2008-07-18 2010-01-21 Prosonix Limited Process for improving crystallinity

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS54163101A (en) * 1978-06-14 1979-12-25 Toray Industries Nonnwaterrrequiring flat printing plate material* and printing plate
DE2901335A1 (de) * 1979-01-15 1980-07-31 Basf Ag Verfahren zur abtrennung von hydrophoben organischen fluessigkeiten aus wasser
GB8921222D0 (en) * 1989-09-20 1989-11-08 Riker Laboratories Inc Medicinal aerosol formulations
GB9024366D0 (en) 1990-11-09 1991-01-02 Glaxo Group Ltd Medicaments
US5182097A (en) * 1991-02-14 1993-01-26 Virginia Commonwealth University Formulations for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content
US20040013611A1 (en) * 1991-12-18 2004-01-22 Minnesota Mining And Manufacturing Company, Now 3M Company Suspension aerosol formulations
SE9501384D0 (sv) 1995-04-13 1995-04-13 Astra Ab Process for the preparation of respirable particles
WO2000061108A1 (en) 1999-04-14 2000-10-19 Glaxo Group Limited Pharmaceutical aerosol formulation
IT1308286B1 (it) * 1999-06-15 2001-12-10 Leonardo Masotti Sorgenti e ricevitori ottici estesi continui e barriere otticheutilizzanti dette sorgenti e detti ricevitori
DK1372608T3 (da) * 2001-03-30 2007-12-27 Jagotec Ag Medicinske aerosolformuleringer
TWI324934B (en) * 2001-08-28 2010-05-21 Schering Corp Pharmaceutical compositions for the treatment of asthma
SE0200313D0 (sv) * 2002-02-01 2002-02-01 Astrazeneca Ab Novel process
PT1658872E (pt) 2002-07-31 2011-05-12 Chiesi Farma Spa Inalador de p?
US20060009410A1 (en) 2002-11-13 2006-01-12 Crooke Rosanne M Effects of apolipoprotein B inhibition on gene expression profiles in animals
GB0426301D0 (en) 2004-11-30 2004-12-29 Vectura Ltd Pharmaceutical formulations
US8337815B2 (en) 2004-12-23 2012-12-25 Discovery Laboratories, Inc. Pulmonary surfactant formulations
TW200744612A (en) 2005-08-26 2007-12-16 Astrazeneca Ab New combination
DE102006053886A1 (de) * 2006-11-14 2008-05-15 Henkel Kgaa Rückstandsarmer kosmetischer oder dermatologischer Stift auf Basis einer Öl-in-Wasser-Dispersion/Emulsion III
WO2008152398A2 (en) 2007-06-14 2008-12-18 Cipla Limited Formulations for inhalation
EP2050437A1 (en) * 2007-10-15 2009-04-22 Laboratoires SMB Improved pharmaceutical dry powder compositions for inhalation.
PL2515855T6 (pl) * 2009-12-23 2023-12-18 Chiesi Farmaceutici S.P.A. Terapia skojarzona dla POChP

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6524557B1 (en) * 1994-12-22 2003-02-25 Astrazeneca Ab Aerosol formulations of peptides and proteins
US20030180283A1 (en) * 2002-03-20 2003-09-25 Batycky Richard P. Method and apparatus for producing dry particles
US20070009445A1 (en) * 2005-07-08 2007-01-11 Xemplar Pharmaceuticals, Llc Aerosol compositions and methods
WO2010007447A1 (en) * 2008-07-18 2010-01-21 Prosonix Limited Process for improving crystallinity

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Frijlink et al. Expert Opinion in Drug Delivery 2004 1(1):67-86 *
Vervaet et al. International Journal of Pharmaceutics 1999 186:13-30 *

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