EP2804583A1 - Dry powder formulations comprising r-formoterol as active agent - Google Patents

Dry powder formulations comprising r-formoterol as active agent

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Publication number
EP2804583A1
EP2804583A1 EP13711160.5A EP13711160A EP2804583A1 EP 2804583 A1 EP2804583 A1 EP 2804583A1 EP 13711160 A EP13711160 A EP 13711160A EP 2804583 A1 EP2804583 A1 EP 2804583A1
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EP
European Patent Office
Prior art keywords
range
pharmaceutical formulation
formulation according
excipient
particle size
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Withdrawn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
EP13711160.5A
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German (de)
French (fr)
Inventor
Mahmut Bilgic
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Individual
Original Assignee
Individual
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Publication date
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Publication of EP2804583A1 publication Critical patent/EP2804583A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—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
    • 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

Definitions

  • the present invention relates to pharmaceutical formulations in dry powder form comprising R-formoterol or pharmaceutically acceptable derivatives thereof in order to be used in symptomatic and/or prophylactic treatment of respiratory tract diseases, particularly asthma and COPD.
  • R-formoterol is used in the treatment of respiratory tract diseases such as asthma and COPD.
  • R-formoterol which has the chemical name of ifoc-(R,R)-N-[2-hydroxy-5-[l-hydroxy-2-[l-(4- methoxyphenyl) propan-2-ylamino]ethyl] phenyl] formamide belongs to the group of long- acting p2-agonists.
  • R-formoterol was first disclosed in the patent numbered US3994974.
  • p2-adrenergic agonists used in the treatment of respiratory tract diseases such as asthma and COPD activate p2-adrenergic receptors and affect the muscles around the airways, alleviate or remove bronchospasm.
  • Bronchodilator P2-adrenergic agonists divide into two groups as short-acting and long-acting.
  • R-formoterol is a long-acting p2-adrenergic agonist.
  • the fact that the dry powder formulation comprising R-formoterol has good flow characteristics is an important criterion in terms of inhalation of said formulation effectively and therefore in terms of providing an effective treatment.
  • the active agent is diluted by various non-functional excipients.
  • the physical characteristics of these excipients, used in quite high amounts as compared to the active agent amount in the formulations, such as average particle size have an important role in providing good flow in the dry powder formulation. Since the active agent used is delivered to the lungs in a sufficient amount and in a controlled manner in the dry powder formulation having good flow characteristics, desired therapeutic effect is obtained.
  • the inventors have developed dry powder formulations which comprise R-formoterol and/or pharmaceutically acceptable derivatives thereof and have high homogeneity and good flow characteristics wherein dosing accuracy is ensured and sufficient amount of active agent can be delivered to the lungs.
  • the present invention relates to pharmaceutical formulations in dry powder form comprising R- formoterol and/or pharmaceutically acceptable derivatives thereof.
  • dry powder formulations comprising R-formoterol in the range of 0.5 to 40 ⁇ , preferably in the range of 1 to 25 ⁇ g and also at least one pharmaceutically acceptable fine grained and coarse grained excipient having an average particle size ratio to each other in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 :15 to 1 :10 have good flow characteristics and high homogeneous dispersion, therefore dose accuracy is obtained in the formulations and sufficient amount of active agent can be delivered to the lungs.
  • the fine grained excipient used in the text refers to an excipient having an average particle size less than 10 ⁇ , preferably in the range of 0.1 to 9.9 ⁇ , more preferably in the range of 2 to 8 ⁇ , for instance in the range of 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.3, 2.5, 3.0, 3.5, 4.0, 4.5 to 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 ⁇ ;
  • the coarse grained excipient used in the text refers to an excipient having an average particle size in the range of 10 to 90 ⁇ , preferably in the range of 12 to 85 ⁇ , more preferably in the range of 15 to 80 ⁇ , for instance in the range of 15, 20, 25, 30, 35, 40, 45 to 50, 55, 60, 65, 70, 75, 80, 85 ⁇ .
  • the subject of the present invention is the pharmaceutical formulation in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof, characterized in that - the amount of R-formoterol in said formulation is in the range of 0.5 to 40 ⁇ g, preferably in the range of 1 to 25 ⁇ g,
  • the excipient comprised in said formulation is composed of at least one pharmaceutically acceptable excipient mixture comprising fine grained excipient and coarse grained excipient and
  • the average particle size ratio of the fine grained excipient to the coarse grained excipient is in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1:5, more preferably in the range of 1 : 15 to 1 : 10.
  • R-formoterol and/or pharmaceutically acceptable derivatives thereof which is the active agent comprised in the dry powder formulation of the invention comprise its free base, pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms and/or a combination thereof.
  • the inhalation formulation comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof can be delivered to the patient in dry powder form.
  • Said dry powder formulations further comprise at least one physiologically and pharmaceutically acceptable excipient along with the active agent.
  • This excipient is composed of fine grained excipient, coarse grained excipient or a combination thereof, preferably a combination of fine grained excipient and coarse grained excipient.
  • This excipient can be selected from monosaccharides (glucose etc.), disaccharides (lactose, saccharose, maltose or pharmaceutically acceptable hydrates, anhydrates or a combination thereof etc.), oligosaccharides and polysaccharides (dextrant etc.), polyalcohols (sorbitol, mannitol, xylitol etc.), salts (sodium chloride, calcium carbonate etc.) or a combination thereof. Same or different substances are used as fine grained excipient and coarse grained excipient, though preferably the same substance is used. Fine grained and coarse grained excipients are preferably lactose, more preferably lactose anhydrate. According to the present invention, the amount of the pharmaceutically acceptable excipient is preferably in the range of 1-50 mg, preferably in the range of 2-40 mg, more preferably in the range of 3-30 mg.
  • the average particle size of the active agent used is quite important in order that the formulation to be obtained has good flow characteristics and therefore an effective inhalation is performed.
  • the inventors have seen that use of an active agent having an average particle size in the range of 1 ⁇ to 10 ⁇ , preferably in, the range of 1.5 ⁇ to 7.5 ⁇ , more preferably in the range of 1.5 ⁇ to 5 ⁇ has a significant contribution to the formulation obtained for having proper flow characteristics and for having dose uniformity and to delivery of the active agent to the lungs in sufficient amount.
  • the dose of the drug which is delivered to the lungs is also an important parameter in order to provide an effective inhalation treatment.
  • the Fine Particle Fraction (FPF) value of the drug particles are measured.
  • the inventors have observed that when R-formoterol used as active agent has an average particle size in the range of 1 ⁇ to 10 ⁇ , preferably in the range of 1.5 ⁇ to 7.5 ⁇ , more preferably 1.5 ⁇ to 5 ⁇ , FPF (Fine Particle Fraction) value of the formulation is more than 10%, preferably in the range of 12-45%, more preferably 15-40% indicating high deposition of the drug particles in the lung.
  • the subject of the present invention is pharmaceutical formulations in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof, characterized in that
  • the amount of R-formoterol in said formulation is in the range of 0.5 to 40 ⁇ g, preferably in the range of 1 to 25 ⁇ g,
  • the average particle size ratio of fine grained excipient: coarse grained excipient is in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 :15 to 1 :10 and
  • the average particle size of the active agent used is in the range of 1 ⁇ to 10 ⁇ , . preferably in the range of 1.5 ⁇ to 7.5 ⁇ , more preferably in the range of 1.5 ⁇ to 5 ⁇ .
  • aerodynamic particle size is also important parameter for having proper flow characteristics and for providing the delivery of the active agent to the lungs in sufficient amount.
  • the inventors have observed that the use of R-formoterol active agent having aerodynamic particle size (MMAD) in the range of 0.05 ⁇ to 25 ⁇ , preferably in the range of 1 ⁇ to 20 ⁇ , more preferably in the range of 2 ⁇ to 15 ⁇ has a significant contribution to the delivery of R-formoterol active agent to the lungs in sufficient amount resulting in an effective treatment.
  • the present invention relates to the pharmaceutical formulations in dry powder form comprising.
  • R-formoterol and/or pharmaceutically acceptable derivatives thereof wherein said formulation comprises R-formoterol having aerodynamic particle size (MMAD) in the range of 0.05 ⁇ to 25 ⁇ , preferably in the range of 1 ⁇ to 20 ⁇ , more preferably in the range of 2 ⁇ to 15 ⁇ .
  • MMAD aerodynamic particle size
  • the present invention relates to the pharmaceutical formulations in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof wherein the delivered dose uniformity (DUSA%) of the pharmaceutical formulation in dry powder form comprising R-formoterol is in the range of 65-130%, preferably 70-120%,
  • the amounts of said fine grained and coarse grained excipients constituting the excipient combination having two different average particle sizes as fine grained and coarse grained comprised in the dry powder formulation of the present invention is an important criterion in obtaining the characteristics that can provide an effective treatment.
  • the inventors have seen that characteristics such as proper flow, particularly homogenous particle dispersion and dose uniformity of the formulation are ensured and therefore the sufficient amount of the active agent reaches to the lungs more easily in the case that the ratio of fine grained excipient to coarse grained excipient constituting the excipient combination is in the range of 1 :1 to 1:25 by weight, preferably in the range of 1:1 to 1 :10 by weight, more preferably in the range of 1 :1.5 to 1 :5 by weight.
  • the subject of the present invention is the pharmaceutical formulations in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof, characterized in that
  • the amount of R-formoterol in said formulation is in the range of 0.5 to 40 ⁇ g, preferably in the range of 1 to 25 ⁇ g
  • the average particle size ratio of fine grained excipient: coarse grained excipient is in the range of 1 :30. to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 :15 to 1 :10 and
  • the ratio of fine grained excipient to coarse grained excipient is in the range of 1 :1 to
  • the inventors have observed that the weight ratio of the R-formoterol active agent to the fine grained excipient and coarse grained excipient affects providing proper flow, homogenous particle dispersion and dose uniformity of the formulation. They have seen that when the ratio of R-formoterol active agent to the fine grained excipient is in the range of 1:50- 1 :600, preferably 1 :100- 1 :450 by weight and the ratio of R-formoterol active agent to the coarse grained excipient is in the range of 1 :300- 1 : 1600, preferably 1:400- 1 :1250 by weight, a homogenous particle dispersion and dose uniformity of the formulation are provided so that the sufficient amount of the active agent reaches to the lungs more easily.
  • the present invention relates to the pharmaceutical formulations in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof wherein the ratio of R-formoterol active agent to the fine grained excipient is in the range of 1:50- 1 :600, preferably 1 :100- 1 :450 by weight and the ratio of R-formoterol active agent to the coarse grained excipient is in the range of 1 :300- 1 : 1600, preferably 1 :400- 1 : 1250 by weight.
  • the process for preparation of the pharmaceutical formulations of the present invention in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is composed of the following steps:
  • the present invention relates to inhalation of the dry powder formulations comprising R-formoterol and/ar pharmaceutically acceptable derivatives thereof by using inhalation devices comprising capsule, blister or reservoir.
  • the inhalation is performed most productively when capsule volume comprising the drug in dry powder form of the present invention comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 0.1 to 0.5 ml, preferably in the range of 0.15-0.45 ml, more preferably in the range of 0.2-0.4 ml.
  • the present invention is characterized in that volume of the capsule used for storage and delivery of the drug in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 0.1 to 0.5 ml, preferably in the range of 0.15-0.45 ml, more preferably in the range of 0.2-0.4 ml.
  • the inventors have seen that the active agent comprised in the capsule is protected from external factors as well as the possibility of moistening that can arise from the nature of the capsule itself is removed in the case that moisture ratio of the package in capsule form having high protection property against moisture and other negative external factors is in the range of 5-20%, preferably in the range of 7-15%.
  • moisture ratio of the package in capsule form having high protection property against moisture and other negative external factors is in the range of 5-20%, preferably in the range of 7-15%.
  • the present invention is characterized in that moisture ratio of the package in capsule form used for storage and delivery of the drug in dry powder form comprising R- formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 5-20%, preferably in the range of 7-15%.
  • the capsule preferred to be used in the scope of the present invention can be made of a substance selected from a group comprising gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers, and it is composed of telescoping .body and cap parts.
  • capsule material in the case that the dry powder formulation of the present invention is inhaled from capsule, capsule material can be selected from a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose if the capsule to be used is made of cellulose and its derivatives.
  • capsule material can be selected from a group comprising polyethylene, polyester, polyethyleneterephthalate, polycarbonate or polypropylene if the capsule to be used is made of synthetic polymer.
  • various molecular weighted polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide-propylene oxide block copolymers and/or other poly alcohols and polyethers can be added as adjuvant if the capsule material to be used is made of gelatine.
  • the inventors have found that in the case that fullness ratio of the capsule cavity used is in the range of 0.05 to 25 %, preferably in the range of 0.1 to 20%, more preferably in the range of 0.5-15%, an effective inhalation of the drug is ensured in the case that said dry powder formulation is inhaled from capsule.
  • the present invention is characterized in that fullness ratio of capsule cavity is in the range of 0.05 to 25%, preferably in the range of 0.1 to 20%, more preferably in the range of 0.5 to 15%.
  • the dry powder formulation of the present invention is inhaled from blister, which is one of the inhalation methods
  • the inventors have found that an effective inhalation is performed in the case that cavity volume of the blister comprising the drug in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 18-30 mm 3 , preferably in the range of 20 - 25 mm 3 , more preferably in the range of 21-24 mm 3 .
  • the present invention is characterized in that cavity volume of the blister used for storage and delivery of the drug in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is 18-30 mm 3 , preferably in the range of 20 to 25 mm 3 , more preferably in the range of 21-24 mm 3 in the case that said dry powder formulation is inhaled from blister.
  • fullness ratio of the blister cavity used should be in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50-80% in order to inhale the formulation of the present invention from blister without any problem and in order to perform an effective inhalation.
  • the present invention is characterized in that fullness ratio of the blister used for storage and delivery of the drug in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50-80%.
  • the base and the lid sheets constituting the peelable blister strip pack, wherein the blisters comprising the dry powder formulation of the present invention are collocated are sealed tightly by any suitable method in order to provide impermeability.
  • the base and lid sheets constituting the peelable blister strip package comprising the dry powder formulation of the present invention are composed of many layers. Polymeric layers, aluminium foil and preferably Aclar® fluoropolymer film are among the layers constituting the base and the lid sheets.
  • the inventors have seen that, in the case that the formulation of the present invention is inhaled from blister, adding desiccant to the polymeric layers in order to reduce moisture and gas permeability of base and lid sheets constituting the blister package is effective in protecting stability of said dry powder formulation.
  • Desiccant agents added to the layers constituting blister strip package comprising dry powder formulation of the present invention are selected from silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activated carbon, hydrophilic chyles.
  • polymeric layers in the base and lid sheets of peelable blister strip package comprising said dry powder formulation are made of the same or different polymers. Thickness of these polymeric layers varies depending on the type and characteristics of the polymeric material used. Therefore, thickness of the polymeric layer varies in the range of 15-55 ⁇ , preferably in the range of 20-30 ⁇ according to the type of the polymeric material used.
  • the layer covering the inner surface of the cavity is a polymeric layer because of the fact that when the layer in contact with the dry powder formulation in the blister cavity is aluminium foil, some part of dry powder formulation adheres to the inner surface of the blister cavity due to porous structure of the aluminium foil and electrostatic forces and this causes uncontrolled dose inhalation.
  • Polymers constituting the polymeric layer can preferably be selected from thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or synthetic polymers.
  • the drug composition in dry powder form described in the present invention comprising R- formoterol and/or pharmaceutically acceptable derivatives thereof can be used in the treatment of many respiratory diseases particularly asthma, Chronic Obstructive Pulmonary Disease (COPD) and allergic rhinitis.
  • the drug composition of the present invention is used in the treatment of respiratory tract diseases comprising, but not limited to, allergic or non allergic asthma in every stage, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperactivity, chronic obstructive pulmonary disease including bronchiectasis, emphysema and chronic bronchitis; airways or lung diseases (COPD, COAD or COLD) pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • This treatment may be prophylactic or symptomatic.
  • EXAMPLE 1 Inhalation of dry powder formulations comprising R-formoterol from capsule
  • fine grained lactose and coarse grained lactose are stirred in a mixer after sieved separately.
  • R-formoterol is added into this mixture, sieved again and stirred.
  • the powder mixture obtained at the end of the process is filled into capsules.
  • EXAMPLE 2 Inhalation of dry powder formulations comprising R-formoterol from capsule
  • fine grained lactose and coarse grained lactose are stirred in a mixer after sieved separately.
  • R-formoterol is added into this mixture, sieved again and stirred.
  • the powder mixture obtained at the end of the process is filled into capsules.

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Abstract

The present invention relates to pharmaceutical formulations in dry powder form comprising R-formoterol in order to be used in respiratory tract diseases.

Description

DRY POWDER FORMULATIONS COMPRISING R-FORMOTEROL AS ACTIVE
AGENT
The present invention relates to pharmaceutical formulations in dry powder form comprising R-formoterol or pharmaceutically acceptable derivatives thereof in order to be used in symptomatic and/or prophylactic treatment of respiratory tract diseases, particularly asthma and COPD.
In case of respiratory tract diseases such as asthma or chronic obstructive pulmonary disease (COPD); stimulants such as allergen, infection, good and bad smell, smoke cause constricted muscles covering the airways, in other words bronchoconstriction, excessive secretion in glands and consequently contraction in the airways. In this case, the patient cannot exhale the inhaled air or he/she cannot inhale.
R-formoterol is used in the treatment of respiratory tract diseases such as asthma and COPD. R-formoterol which has the chemical name of ifoc-(R,R)-N-[2-hydroxy-5-[l-hydroxy-2-[l-(4- methoxyphenyl) propan-2-ylamino]ethyl] phenyl] formamide belongs to the group of long- acting p2-agonists. R-formoterol was first disclosed in the patent numbered US3994974. p2-adrenergic agonists used in the treatment of respiratory tract diseases such as asthma and COPD activate p2-adrenergic receptors and affect the muscles around the airways, alleviate or remove bronchospasm. Bronchodilator P2-adrenergic agonists divide into two groups as short-acting and long-acting. R-formoterol is a long-acting p2-adrenergic agonist. The fact that the dry powder formulation comprising R-formoterol has good flow characteristics is an important criterion in terms of inhalation of said formulation effectively and therefore in terms of providing an effective treatment. In the case that a dry powder formulation which does not have good flow characteristics is obtained, it is seen that the formulation has low homogeneity and consequently dosing accuracy cannot be ensured during filling the dry powder formulation prepared into reservoirs of multi dose inhalators comprising more than one dose or into blister cavities of a blister package, each of them comprising one dose, or into capsules comprising one dose. Furthermore, the fact that the dry powder formulation does not have good flow characteristics affects emptying capacity and emptying attribute negatively during inhalation of the formulation from capsule, blister or reservoir. As a result, due to the reasons listed above, the active agent cannot reach to the lungs in sufficient amounts. In order to ease the delivery of the active agent having therapeutic effect in quite small doses by the inhalation route, the active agent is diluted by various non-functional excipients. The physical characteristics of these excipients, used in quite high amounts as compared to the active agent amount in the formulations, such as average particle size have an important role in providing good flow in the dry powder formulation. Since the active agent used is delivered to the lungs in a sufficient amount and in a controlled manner in the dry powder formulation having good flow characteristics, desired therapeutic effect is obtained.
The inventors have developed dry powder formulations which comprise R-formoterol and/or pharmaceutically acceptable derivatives thereof and have high homogeneity and good flow characteristics wherein dosing accuracy is ensured and sufficient amount of active agent can be delivered to the lungs.
Description of the Invention
The present invention relates to pharmaceutical formulations in dry powder form comprising R- formoterol and/or pharmaceutically acceptable derivatives thereof. Surprisingly, the inventors have seen that dry powder formulations comprising R-formoterol in the range of 0.5 to 40 μ , preferably in the range of 1 to 25 μg and also at least one pharmaceutically acceptable fine grained and coarse grained excipient having an average particle size ratio to each other in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 :15 to 1 :10 have good flow characteristics and high homogeneous dispersion, therefore dose accuracy is obtained in the formulations and sufficient amount of active agent can be delivered to the lungs.
The fine grained excipient used in the text refers to an excipient having an average particle size less than 10 μηι, preferably in the range of 0.1 to 9.9 μηι, more preferably in the range of 2 to 8 μπι, for instance in the range of 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.3, 2.5, 3.0, 3.5, 4.0, 4.5 to 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 μιη; the coarse grained excipient used in the text refers to an excipient having an average particle size in the range of 10 to 90 μτη, preferably in the range of 12 to 85 μπι, more preferably in the range of 15 to 80 μπι, for instance in the range of 15, 20, 25, 30, 35, 40, 45 to 50, 55, 60, 65, 70, 75, 80, 85 μηι.
According to this, the subject of the present invention is the pharmaceutical formulation in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof, characterized in that - the amount of R-formoterol in said formulation is in the range of 0.5 to 40 μg, preferably in the range of 1 to 25 μg,
- the excipient comprised in said formulation is composed of at least one pharmaceutically acceptable excipient mixture comprising fine grained excipient and coarse grained excipient and
- the average particle size ratio of the fine grained excipient to the coarse grained excipient is in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1:5, more preferably in the range of 1 : 15 to 1 : 10.
According to the present invention, R-formoterol and/or pharmaceutically acceptable derivatives thereof which is the active agent comprised in the dry powder formulation of the invention comprise its free base, pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms and/or a combination thereof.
According to the present invention, the inhalation formulation comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof can be delivered to the patient in dry powder form. Said dry powder formulations further comprise at least one physiologically and pharmaceutically acceptable excipient along with the active agent. This excipient is composed of fine grained excipient, coarse grained excipient or a combination thereof, preferably a combination of fine grained excipient and coarse grained excipient. This excipient can be selected from monosaccharides (glucose etc.), disaccharides (lactose, saccharose, maltose or pharmaceutically acceptable hydrates, anhydrates or a combination thereof etc.), oligosaccharides and polysaccharides (dextrant etc.), polyalcohols (sorbitol, mannitol, xylitol etc.), salts (sodium chloride, calcium carbonate etc.) or a combination thereof. Same or different substances are used as fine grained excipient and coarse grained excipient, though preferably the same substance is used. Fine grained and coarse grained excipients are preferably lactose, more preferably lactose anhydrate. According to the present invention, the amount of the pharmaceutically acceptable excipient is preferably in the range of 1-50 mg, preferably in the range of 2-40 mg, more preferably in the range of 3-30 mg.
On the other hand, along with the particle size of the excipient comprised in the dry powder formulations of the present invention, the average particle size of the active agent used is quite important in order that the formulation to be obtained has good flow characteristics and therefore an effective inhalation is performed. The inventors have seen that use of an active agent having an average particle size in the range of 1 μηι to 10 μπι, preferably in, the range of 1.5 μηι to 7.5 μπι, more preferably in the range of 1.5 μιη to 5 μηι has a significant contribution to the formulation obtained for having proper flow characteristics and for having dose uniformity and to delivery of the active agent to the lungs in sufficient amount.
In addition to homogenous dispersion of the formulation, the dose of the drug which is delivered to the lungs is also an important parameter in order to provide an effective inhalation treatment. In order to determine the dose of drug that is delivered to the lungs, the Fine Particle Fraction (FPF) value of the drug particles are measured. The inventors have observed that when R-formoterol used as active agent has an average particle size in the range of 1 μιη to 10 μιτι, preferably in the range of 1.5 μιη to 7.5 μιη, more preferably 1.5 μιη to 5 μιη, FPF (Fine Particle Fraction) value of the formulation is more than 10%, preferably in the range of 12-45%, more preferably 15-40% indicating high deposition of the drug particles in the lung. According to this, the subject of the present invention is pharmaceutical formulations in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof, characterized in that
- the amount of R-formoterol in said formulation is in the range of 0.5 to 40 μg, preferably in the range of 1 to 25 μg,
- the average particle size ratio of fine grained excipient: coarse grained excipient is in the range of 1 :30 to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 :15 to 1 :10 and
- the average particle size of the active agent used is in the range of 1 μηι to 10 μπι, . preferably in the range of 1.5 μιη to 7.5 μη , more preferably in the range of 1.5 μπι to 5 μιη.
It is seen that aerodynamic particle size (MMAD) is also important parameter for having proper flow characteristics and for providing the delivery of the active agent to the lungs in sufficient amount. The inventors have observed that the use of R-formoterol active agent having aerodynamic particle size (MMAD) in the range of 0.05 μπι to 25 μιη, preferably in the range of 1 μπι to 20 μηι, more preferably in the range of 2 μιη to 15 μπι has a significant contribution to the delivery of R-formoterol active agent to the lungs in sufficient amount resulting in an effective treatment. In another aspect, the present invention relates to the pharmaceutical formulations in dry powder form comprising. R-formoterol and/or pharmaceutically acceptable derivatives thereof wherein said formulation comprises R-formoterol having aerodynamic particle size (MMAD) in the range of 0.05 μιη to 25 μηι, preferably in the range of 1 μπι to 20 μπι, more preferably in the range of 2 μπι to 15 μπι.
It is known that dose uniformity has also great importance for providing high deposition of the drug particles in the lung and thus effective inhalation treatment. The inventors have observed that when the delivered dose uniformity (DUSA%) of the pharmaceutical formulation in dry powder form comprising R-formoterol is in the range of 65-130%, preferably 70-120%, high delivery of the drug to the lungs can be observed and more effective treatment of inhalation can be provided.
In another aspect, the present invention relates to the pharmaceutical formulations in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof wherein the delivered dose uniformity (DUSA%) of the pharmaceutical formulation in dry powder form comprising R-formoterol is in the range of 65-130%, preferably 70-120%,
The amounts of said fine grained and coarse grained excipients constituting the excipient combination having two different average particle sizes as fine grained and coarse grained comprised in the dry powder formulation of the present invention is an important criterion in obtaining the characteristics that can provide an effective treatment. The inventors have seen that characteristics such as proper flow, particularly homogenous particle dispersion and dose uniformity of the formulation are ensured and therefore the sufficient amount of the active agent reaches to the lungs more easily in the case that the ratio of fine grained excipient to coarse grained excipient constituting the excipient combination is in the range of 1 :1 to 1:25 by weight, preferably in the range of 1:1 to 1 :10 by weight, more preferably in the range of 1 :1.5 to 1 :5 by weight.
In another aspect, the subject of the present invention is the pharmaceutical formulations in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof, characterized in that
- the amount of R-formoterol in said formulation is in the range of 0.5 to 40 μg, preferably in the range of 1 to 25 μg, - the average particle size ratio of fine grained excipient: coarse grained excipient is in the range of 1 :30. to 1 :2, preferably in the range of 1 :20 to 1 :5, more preferably in the range of 1 :15 to 1 :10 and
- the ratio of fine grained excipient to coarse grained excipient is in the range of 1 :1 to
1 :25 by weight, preferably in the range of 1 :1 to 1 :10 by weight, more preferably in the range of 1 : 1.5 to 1 :5 by weight.
The inventors have observed that the weight ratio of the R-formoterol active agent to the fine grained excipient and coarse grained excipient affects providing proper flow, homogenous particle dispersion and dose uniformity of the formulation. They have seen that when the ratio of R-formoterol active agent to the fine grained excipient is in the range of 1:50- 1 :600, preferably 1 :100- 1 :450 by weight and the ratio of R-formoterol active agent to the coarse grained excipient is in the range of 1 :300- 1 : 1600, preferably 1:400- 1 :1250 by weight, a homogenous particle dispersion and dose uniformity of the formulation are provided so that the sufficient amount of the active agent reaches to the lungs more easily. In another aspect, the present invention relates to the pharmaceutical formulations in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof wherein the ratio of R-formoterol active agent to the fine grained excipient is in the range of 1:50- 1 :600, preferably 1 :100- 1 :450 by weight and the ratio of R-formoterol active agent to the coarse grained excipient is in the range of 1 :300- 1 : 1600, preferably 1 :400- 1 : 1250 by weight. The process for preparation of the pharmaceutical formulations of the present invention in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is composed of the following steps:
I. micronizing R-formoterol so as to bring it to the desired particle size,
II. micronizing the excipient so as to bring it to the desired particle size,
mixing the active agent micronized in the Is step firstly with the fine grained excipient and then the coarse grained excipient in a mixer or firstly with the coarse grained excipient and then the fine grained excipient in a mixer and consequently, filling the mixture obtained in dry powder form into appropriate capsules, blisters or reservoirs and making it ready for use. In another aspect, the present invention relates to inhalation of the dry powder formulations comprising R-formoterol and/ar pharmaceutically acceptable derivatives thereof by using inhalation devices comprising capsule, blister or reservoir.
In the case that the dry powder formulation of the present invention is inhaled from capsule, which is one of the inhalation methods, the inventors have found that the inhalation is performed most productively when capsule volume comprising the drug in dry powder form of the present invention comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 0.1 to 0.5 ml, preferably in the range of 0.15-0.45 ml, more preferably in the range of 0.2-0.4 ml. According to this, in the case that the dry powder formulation of the present invention is inhaled from capsule, the present invention is characterized in that volume of the capsule used for storage and delivery of the drug in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 0.1 to 0.5 ml, preferably in the range of 0.15-0.45 ml, more preferably in the range of 0.2-0.4 ml. In another aspect, the inventors have seen that the active agent comprised in the capsule is protected from external factors as well as the possibility of moistening that can arise from the nature of the capsule itself is removed in the case that moisture ratio of the package in capsule form having high protection property against moisture and other negative external factors is in the range of 5-20%, preferably in the range of 7-15%. Thus, effective delivery of the formulation in dry powder form of the present invention to the lungs of the patient is enabled by preventing agglomeration.
According to this, in the case that the dry powder formulation of the present invention is inhaled from capsule, the present invention is characterized in that moisture ratio of the package in capsule form used for storage and delivery of the drug in dry powder form comprising R- formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 5-20%, preferably in the range of 7-15%.
In another aspect, in the case that the dry powder formulation of the present invention is inhaled from capsule, the capsule preferred to be used in the scope of the present invention can be made of a substance selected from a group comprising gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers, and it is composed of telescoping .body and cap parts.
According to this, in the case that the dry powder formulation of the present invention is inhaled from capsule, capsule material can be selected from a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose if the capsule to be used is made of cellulose and its derivatives. In the case that the dry powder formulation of the present invention is inhaled from capsule, capsule material can be selected from a group comprising polyethylene, polyester, polyethyleneterephthalate, polycarbonate or polypropylene if the capsule to be used is made of synthetic polymer.
In the case that the dry powder formulation of the present invention is inhaled from capsule, various molecular weighted polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide-propylene oxide block copolymers and/or other poly alcohols and polyethers can be added as adjuvant if the capsule material to be used is made of gelatine. In another aspect, the inventors have found that in the case that fullness ratio of the capsule cavity used is in the range of 0.05 to 25 %, preferably in the range of 0.1 to 20%, more preferably in the range of 0.5-15%, an effective inhalation of the drug is ensured in the case that said dry powder formulation is inhaled from capsule.
According to this, in the case that said dry powder formulation is inhaled from capsule, the present invention is characterized in that fullness ratio of capsule cavity is in the range of 0.05 to 25%, preferably in the range of 0.1 to 20%, more preferably in the range of 0.5 to 15%.
In the case that the dry powder formulation of the present invention is inhaled from blister, which is one of the inhalation methods, the inventors have found that an effective inhalation is performed in the case that cavity volume of the blister comprising the drug in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 18-30 mm3, preferably in the range of 20 - 25 mm3, more preferably in the range of 21-24 mm3.
According to this, the present invention is characterized in that cavity volume of the blister used for storage and delivery of the drug in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is 18-30 mm3, preferably in the range of 20 to 25 mm3, more preferably in the range of 21-24 mm3 in the case that said dry powder formulation is inhaled from blister.
The inventors have found that fullness ratio of the blister cavity used should be in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50-80% in order to inhale the formulation of the present invention from blister without any problem and in order to perform an effective inhalation.
In the case that said dry powder formulation is inhaled from blister, the present invention is characterized in that fullness ratio of the blister used for storage and delivery of the drug in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof is in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50-80%.
In the case that the dry powder formulation of the present invention is inhaled from blister, the base and the lid sheets constituting the peelable blister strip pack, wherein the blisters comprising the dry powder formulation of the present invention are collocated, are sealed tightly by any suitable method in order to provide impermeability.
The base and lid sheets constituting the peelable blister strip package comprising the dry powder formulation of the present invention are composed of many layers. Polymeric layers, aluminium foil and preferably Aclar® fluoropolymer film are among the layers constituting the base and the lid sheets. The inventors have seen that, in the case that the formulation of the present invention is inhaled from blister, adding desiccant to the polymeric layers in order to reduce moisture and gas permeability of base and lid sheets constituting the blister package is effective in protecting stability of said dry powder formulation. Desiccant agents added to the layers constituting blister strip package comprising dry powder formulation of the present invention are selected from silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activated carbon, hydrophilic chyles.
In the case that dry powder formulation of the present invention is inhaled from blister, polymeric layers in the base and lid sheets of peelable blister strip package comprising said dry powder formulation are made of the same or different polymers. Thickness of these polymeric layers varies depending on the type and characteristics of the polymeric material used. Therefore, thickness of the polymeric layer varies in the range of 15-55 μηι, preferably in the range of 20-30 μηι according to the type of the polymeric material used. The layer covering the inner surface of the cavity is a polymeric layer because of the fact that when the layer in contact with the dry powder formulation in the blister cavity is aluminium foil, some part of dry powder formulation adheres to the inner surface of the blister cavity due to porous structure of the aluminium foil and electrostatic forces and this causes uncontrolled dose inhalation. Polymers constituting the polymeric layer can preferably be selected from thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or synthetic polymers.
The drug composition in dry powder form described in the present invention comprising R- formoterol and/or pharmaceutically acceptable derivatives thereof can be used in the treatment of many respiratory diseases particularly asthma, Chronic Obstructive Pulmonary Disease (COPD) and allergic rhinitis. Accordingly, the drug composition of the present invention is used in the treatment of respiratory tract diseases comprising, but not limited to, allergic or non allergic asthma in every stage, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperactivity, chronic obstructive pulmonary disease including bronchiectasis, emphysema and chronic bronchitis; airways or lung diseases (COPD, COAD or COLD) pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. This treatment may be prophylactic or symptomatic. In addition, the composition of the present invention is particularly used in symptomatic treatment of asthma, allergic rhinitis and COPD.
EXAMPLE 1 : Inhalation of dry powder formulations comprising R-formoterol from capsule
In obtainment of the formulation that shall be used in said invention, fine grained lactose and coarse grained lactose are stirred in a mixer after sieved separately. R-formoterol is added into this mixture, sieved again and stirred. The powder mixture obtained at the end of the process is filled into capsules.
EXAMPLE 2: Inhalation of dry powder formulations comprising R-formoterol from capsule
In obtainment of the formulation that shall be used in said invention, fine grained lactose and coarse grained lactose are stirred in a mixer after sieved separately. R-formoterol is added into this mixture, sieved again and stirred. The powder mixture obtained at the end of the process is filled into capsules.

Claims

1. A pharmaceutical formulation in dry powder form comprising R-formoterol and/or pharmaceutically acceptable derivatives thereof, characterized in that
the amount of R-formoterol in the formulation is in the range of 0.5 to 40 μg, - the excipient comprised in said formulation is composed of an excipient combination comprising a fine grained excipient having an average particle size less than 10 μπι and a coarse grained excipient having an average particle size in the range of 10 μπι to 90 μπι and
the average particle size ratio of the fine grained excipient: the coarse grained excipient is in the range of 1 : 30 to 1 :2.
2. The pharmaceutical formulation according to claim 1, characterized in that the amount of R-formoterol in the formulation is in the range of 1 to 25 μg.
3. The pharmaceutical formulation according to claims 1-2, characterized in that the average particle size ratio of fine grained excipient: coarse grained excipient is in the range of 1 :20 to 1 :5.
4. The pharmaceutical formulation according to claims 1-3, characterized in that the average particle size ratio of fine grained excipient: coarse grained excipient is in the range of 1 :15 to 1 :10.
5. The pharmaceutical formulation according to claims 1-4, characterized in that the average particle size of the fine grained excipient is in the range of 0.1 to 9.9 μιη.
6. The pharmaceutical formulation according to claims 1-5, characterized in that the average particle size of the fine grained excipient is in the range of 2 to 8 μιη.
7. The pharmaceutical formulation according to claims 1-6, characterized in that the average particle size of the fine grained excipient is in the range of 0.3, 0.5, 0.7, 0.9, 1.1, 1.3, 1.5, 1.7, 1.9, 2.3, 2.5, 3.0, 3.5, 4.0, 4.5 to 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 μηι.
8. The pharmaceutical formulation according to claims 1-7, characterized in that the average particle size of the coarse grained excipient is in the range of 12 to 85 μηι.
9. The pharmaceutical formulation according to claims 1-8, characterized in that the average particle size of the coarse grained excipient is in the range of 15 to 80 μιτι.
10. The pharmaceutical formulation according to claims 1-9, characterized in that the average particle size of the coarse grained excipient is in the range of 20, 25, 30, 35, 40, 45 to 50, 55, 60, 65, 70, 75, 80, 85 μπι. *
11. The pharmaceutical formulation according claims 1-10, wherein R-formoterol and/or pharmaceutically acceptable derivatives thereof comprise its free base, pharmaceutically acceptable solvates, hydrates, enantiomers or diastereomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline forms and amorphous forms and/or a combination thereof.
12. The pharmaceutical formulation according to claims 1-1 1, wherein the fine grained and the coarse grained excipients are selected from monosaccharides (glucose), disaccharides (lactose, saccharose, maltose or pharmaceutically acceptable hydrates, solvates, anhydrous forms or a combination thereof), oligosaccharides and polysaccharides (dextrant), polyalcohols (sorbitol, mannitol, xylitol), salts (sodium chloride, calcium carbonate) or a combination thereof.
13. The pharmaceutical formulation according to claims 1-12, wherein the fine grained and the coarse grained excipients are selected from the same or different substances.
14. The pharmaceutical formulation according to claims 1-13, wherein lactose or a pharmaceutically acceptable hydrate, anhydrate or a combination thereof is used as fine grained excipient and coarse grained excipient.
15. The pharmaceutical formulation according to claims 12-14, wherein lactose anhydrate is used as fine grained excipient and coarse grained excipient.
16. The pharmaceutical formulation according to claims 1-15, wherein the total amount of the pharmaceutically acceptable excipient is in the range of 1 -50 mg.
17. The pharmaceutical formulation according to claim 16, wherein the total amount of the pharmaceutically acceptable excipient is in the range of 2-40 mg.
18. The pharmaceutical formulation according to claim 17, wherein the total amount of the pharmaceutically acceptable excipient is in the range of 3-30 mg.
19. The pharmaceutical formulation according to claims 1-18, wherein the average particle size of the active agent comprised in said formulation is in the range of 1 μπι to 10 μπι.
20. The pharmaceutical formulation according to claim 19, wherein the average particle size of the active agent comprised in said formulation is in the range of 1.5 μπι to 7.5 μιτι.
21. The pharmaceutical formulation according to claim 20, wherein the average particle size of the active agent comprised in said formulation is particularly in the range of 1.5 μηι to 5 μηι.
22. The pharmaceutical formulation according to claims 1- 21, wherein FPF (Fine Particle Fraction) value of said formulation is in the range of 12-45%.
23. The pharmaceutical formulation according to claim 22, wherein FPF (Fine Particle Fraction) value of said formulation is in the range of 15-40%.
24. The pharmaceutical formulation according to claim 1-23, wherein said formulation comprises R-formoterol having aerodynamic particle size ( MAD) in the range of 0,05 μπι to 25 μπι.
25. The pharmaceutical formulation according to claim 24, wherein said formulation comprises R-formoterol having aerodynamic particle size (MMAD) in the range of 1 μιη to 20 μιη.
26. The pharmaceutical formulation according to claims 24- 25, wherein said formulation comprises R-formoterol having aerodynamic particle size (MMAD) in the range of 2 μιη to
15 μπι.
27. The pharmaceutical formulation according to claims 1- 26, wherein the delivered dose uniformity (DUSA%) of said pharmaceutical formulation is in the range of 65-130%.
28. The pharmaceutical formulation according to claim 27, wherein the delivered dose uniformity (DUSA%) of said pharmaceutical formulation is in the range of 70-120%).
29. The pharmaceutical formulation according to claims 1-28, wherein the ratio of fine grained excipient to coarse grained excipient is in the range of 1 :1 to 1 :25 by weight.
30. The pharmaceutical formulation according to claim 29, wherein the ratio of fine grained excipient to coarse grained excipient is in the range of 1 : 1 to 1 : 10 by weight.
31. The pharmaceutical formulation according to claim 30, wherein the ratio of fine grained excipient to coarse grained excipient is in the range of 1 : 1.5 to 1 :5 by weight.
32. The pharmaceutical formulation according to claims 1- 31, wherein the ratio of R- formoterol active agent to the fine grained excipient is in the range of 1 :50- 1 :600 by weight and the ratio of R-formoterol active agent to the coarse grained excipient is in the range of 1 :300- 1 : 1600 by weight.
33. The pharmaceutical formulation according to claims 32, wherein the ratio of R-formoterol active agent to the fine grained excipient is in the range of 1 : 100- 1 :450 by weight and the ratio of R-formoterol active agent to the coarse grained excipient is in the range of 1 :400- 1 :1250 by weight.
34. A process for preparation of the pharmaceutical formulation according to claims 1-33, characterized in that said process is composed of the steps of:
I. micronizing R-formoterol so as to bring it to the desired particle size,
II. micronizing the excipients together or separately in order to bring them to the desired particle size, III. mixing the active agent micronized in step I firstly with the fine grained excipient and then with the coarse grained excipient in a mixer or firstly with the coarse grained excipient and then with the fine grained excipient in a mixer and
IV. consequently, filling the mixture obtained in dry powder form into suitable capsules, blisters or reservoirs and making it ready for use.
EP13711160.5A 2012-01-16 2013-01-16 Dry powder formulations comprising r-formoterol as active agent Withdrawn EP2804583A1 (en)

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PCT/TR2013/000023 WO2013109211A1 (en) 2012-01-16 2013-01-16 Dry powder formulations comprising r-formoterol as active agent

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Publication number Priority date Publication date Assignee Title
US3994974A (en) 1972-02-05 1976-11-30 Yamanouchi Pharmaceutical Co., Ltd. α-Aminomethylbenzyl alcohol derivatives
PE20011227A1 (en) * 2000-04-17 2002-01-07 Chiesi Farma Spa PHARMACEUTICAL FORMULATIONS FOR DRY POWDER INHALERS IN THE FORM OF HARD AGGLOMERATES
GB0012261D0 (en) * 2000-05-19 2000-07-12 Astrazeneca Ab Novel process
WO2011093815A2 (en) * 2010-01-29 2011-08-04 Mahmut Bilgic Pharmaceutical compositions comprising formoterol and mometasone
ES2658179T3 (en) * 2010-04-21 2018-03-08 Chiesi Farmaceutici S.P.A. Procedure to provide particles with reduced electrostatic charges

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