WO2011093820A2 - A pharmaceutical combination comprising tiotropium - Google Patents

A pharmaceutical combination comprising tiotropium Download PDF

Info

Publication number
WO2011093820A2
WO2011093820A2 PCT/TR2011/000022 TR2011000022W WO2011093820A2 WO 2011093820 A2 WO2011093820 A2 WO 2011093820A2 TR 2011000022 W TR2011000022 W TR 2011000022W WO 2011093820 A2 WO2011093820 A2 WO 2011093820A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
range
μπι
particle size
mean particle
Prior art date
Application number
PCT/TR2011/000022
Other languages
French (fr)
Other versions
WO2011093820A3 (en
Inventor
Mahmut Bilgic
Original Assignee
Mahmut Bilgic
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Publication of WO2011093820A2 publication Critical patent/WO2011093820A2/en
Publication of WO2011093820A3 publication Critical patent/WO2011093820A3/en
Priority to US13/531,972 priority Critical patent/US8834931B2/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention is related to a pharmaceutical composition
  • a pharmaceutical composition comprising formoterol, fluticasone, tiotropium and/or pharmaceutically acceptable derivatives thereof and the use of this composition in the treatment of respiratory diseases particularly in asthma, allergic rhinitis and chronic obstructive pulmonary diseases (COPD).
  • COPD chronic obstructive pulmonary diseases
  • bronchia are the channels which function to distribute the inhaled air into the lung tissues.
  • stimulants such as allergen, infection, good and bad smell, smoke, genetic factors and exercise cause contractions in the airway muscles (bronchoconstruction) and/or excessive secretion in glands and results in contractions in the airway; hence, respiration gets more difficult as the inhaled air cannot be exhaled.
  • Corticosteroids which are used in the treatment of asthma and COPD, are synthetic and strong anti-inflammatory drugs that are similar to natural corticosteroid hormones produced by adrenal glands. They prevent both the transcription of the inflammatory gene and the activation of the anti-inflammatory gene. In addition to this, they increase the transcription of p2 receptors. Furthermore, corticosteroids prevent the tolerance that develops after a long- term application of ⁇ 2 agonists. Beclomathasone, budesonide, ciclesonide, flunisolide, fluticasone are among the steroids that are used for the treatment of respiratory diseases. Corticosteroids are not preferred in acute asthma crises as they do not have rapid onset of action.
  • corticosteroids may prevent growth in children, they are advised to be used in the lowest possible amount. Long-term use of corticosteroids may cause cataract and glaucoma. In addition, they may cause some serious side-effects such as osteoporosis, high cholesterol, edema, encepholalgia, weight gain, insomnia and some skin problems.
  • ⁇ 2 adrenergic agonists which are used in the treatment of respiratory diseases such as asthma and COPD affect the muscles around the air vessels by activating ⁇ 2 adrenergic receptors. They reduce or eliminate bronchospasm. Bronchodilator 2-agonists are categorized into two groups as long-acting and short-acting.
  • Short-acting beta-agonists such as salbutamol, levosalbutamol, prosaterol, fenoterol, terbutaline, pirbuterol, metoproterenol, bitolterol mesilate have a rather rapid onset of action such as 3-5 minutes and their duration of action is of 4-6 hours. As they have a rapid onset of action, they are given as relaxant but they should be taken very often since they have a short duration of action. Long-acting ⁇ 2 agonists have a slower onset of action compared to the other group but their duration of action is of 12 hours.
  • Salmeterol, formoterol, bambuterol and clenbuterol can be given as examples to long-acting ⁇ 2 agonists.
  • Long-acting 2 -agonists are often used in the treatment of patients who present 5 asthma symptoms at nights and in the treatment of asthma stimulated by exercise.
  • ⁇ 2 agonists are known as the most effective agent in order to eliminate acute asthma symptoms.
  • One of the most important factors for their being used as symptomatolytic is their onset of action.
  • Some long-acting ⁇ 2 agonists can have the onset of action of short acting ⁇ 2 agonists when used at specific doses.
  • LO ⁇ 2 agonists affect the muscles above the air vessels. However, they might affect the muscles around the heart and the bones. In the case that they affect the heart muscles, acceleration of heartbeat and palpitation might be observed.
  • FDA US Food and Drug Administration
  • Anticholinergics are the other active agents which are utilized in the treatment of respiratory diseases. Anticholinergics influence large airways including the muscles above bronchia, while ⁇ 2 agonists influence small airways, in other words bronchioles. Anticholinergics such as ⁇ 2
  • !O agonists are categorized into two groups as long-acting and short-acting.
  • Short-acting anticholinergics containing ipratropium bromide and oxitropium bromide have an onset of action of 15 minutes and their duration of action is 6-8 hours.
  • the long-acting anticholinergic agent is tiotropium. Tiotropium has an onset of action of 20 minutes and its duration of action is 24 hours. Thus, it is enough to take it once a day. Side effects of anticholinergics are weaker
  • combination drugs in the treatment of respiratory diseases such as asthma and COPD is very effective particularly in decreasing asthma attacks. It is possible that the severity or occurrence possibility of the abovementioned side effects decreases as the active substances that are used in combinations are more effective at lower doses compared to the !O active substances used alone. However, decreasing the side effects that arise from the active agents is not sufficient to provide effective treatment for respiratory diseases.
  • the medicaments used in the formulations should be selected in a way to give the best combination and furthermore, they should be in the most stable form. Moreover, the compositions comprising them should be formulated in such a way that the composition is stable and also it reaches to the target area in the most efficient way.
  • the inventor has surprisingly found that unexpected therapeutic benefits are obtained through the use of the combination comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate together for simultaneous or sequential administration in the prevention or treatment of respiratory diseases.
  • a combination comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate provides the most stable and therapeutically beneficial combination for simultaneous or sequential administration in the prevention or treatment of respiratory diseases.
  • a composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is administered simultaneously.
  • Formoterol fumarate used in the formulation is preferably in dihydrate form.
  • said composition comprises tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, fluticasone propionate and lactose.
  • tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, fluticasone propionate are preferably combined in a single dosage form.
  • the amount of active agents used in the composition is carefully adjusted in order to prevent the side effects that might arise from these agents and it was seen that minimum side effects are observed when tiotropium bromide with water content less than or equal to 2.5%:formoterol fumarate:fluticasone propionate ratio in the composition is in the range of 1 :0.3:2 to 1 :4:65 by weight. Furthermore, it was seen that the adhesive force between the particles is less and hence the amount of inhaled particles and efficacy of the formulation increases in the formulation which is constituted with active agents in amounts that has the ratio in the range of 1 :0.3:2 to 1 :4:65. It should be noted that the ratio given above is based on the amounts of tiotropium, formoterol and fluticasone active parts; which are in free form without salt or ester forms.
  • the present invention provides a combined drug preparation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and 5 .
  • fluticasone propionate in amounts in the range of 1:0.3:2 to 1:4:65 for simultaneous or sequential administration in the prevention or treatment of respiratory diseases such as asthma and chronic obstructive pulmonary diseases (COPD).
  • respiratory diseases such as asthma and chronic obstructive pulmonary diseases (COPD).
  • COPD chronic obstructive pulmonary diseases
  • the present invention provides an effective inhalation of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol LO fumarate and fluticasone propionate.
  • the drug pertaining to the present invention is preferred to be administered by the inhalation route as it a) has a more rapid onset of action compared to the administration via oral or parenteral routes b) enables the use at lower doses c) minimizes the side effects.
  • the present invention provides simultaneous or sequential L5 inhalation of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate by the inhalation route.
  • the present invention provides the transmission of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate via single or multi dose inhalers.
  • the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate can be in dry powder form; they can be formulated with propellant gases to give aerosol formulations or they can be formulated with solvents to give nebulizer formulations.
  • the inventors have found that the best way to transfer the medicament comprising tiotropium bromide with water content less than or equal to 2.5%,
  • the components maintain their stability and furthermore, the medicament stable form and is easily used by the patients.
  • the particle size of the agents should be adjusted. Although large particle size provides ease in manufacturing of the dry powder, it may accumulate in throat and lead to insufficient intake of the medicament. Very fine particles, on the other hand, may reach the lungs. However, they might not have a good flow property which causes problems in providing dose accuracy in turn. To prevent these problems, the active agents should have an optimum average particle size.
  • tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, fluticasone propionate having a mean particle size in the range of 1.5 to 4.5 ⁇ reaches the lungs effectively and also no problems related to flow properties of the dry powder are observed.
  • the present invention provides a medicament composition
  • a medicament composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 ⁇ and wherein said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively and said composition can be simultaneously or sequentially administered in the prevention or treatment of respiratory diseases.
  • mean particle size refers to particles wherein the particle size of 50% of the total number of particles is less than the average particle size.
  • the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate may also contain effective amounts of excipients and/or additional agents apart from active agents.
  • the dry powder formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is transmitted to the patient in dry powder form.
  • Said dry powder formulations also contain some physiologically acceptable excipients along with the active agent. These excipients can be monosaccharides (glucose, etc.), disaccharides (lactose, saccharose, maltose, etc.), oligosaccharides and polysaccharide (dextran, etc.), polyalcohols (sorbitol, mannitol, xylitol, etc.), salts (sodium chloride, calcium carbonate, etc.) or a mixture thereof.
  • compositions pertaining to the present invention in other words in compositions comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 ⁇ and wherein said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively, using lactose as the one and only carrier provides optimum homogeneity and flow properties to the dry powder and this way dose accuracy is maintained.
  • the mean particle size of the carrier plays an important role in delivery of the medicament to the target area, i.e. lungs, effectively in the compositions pertaining to the present invention. It was found that the adhesive forces between the lactose particles and the active agents having a mean particle size in the range of 1.5 to 4.5 ⁇ are minimized and thus, an effective inhalation of the active agents takes place when lactose having a mean particle size less than or equal to 100 ⁇ is used in compositions comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 ⁇ and wherein said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively.
  • the present invention provides a composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein;
  • the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 ⁇ and
  • said active agents are present in the composition with the ratio of 1 :0.3:2 to 1:4:65 respectively and
  • lactose which has a mean particle size less than 100 ⁇ is used as carrier.
  • Lactose which has a mean particle size less than 100 ⁇ is preferably used as a mixture of particles having two different mean particle sizes. Accordingly, lactose which has a mean particle size less than 100 ⁇ can be present as a mixture of particles having a mean particle size less than 10 ⁇ (fine) and particles having mean particle size in the range of 10 ⁇ to 100 ⁇ (coarse). The inventors have observed that the adhesive force between the active agents and lactose is even less when lactose which has two different mean particle sizes is used.
  • the weight ratio of lactose which has a mean particle size less than 10 ⁇ (fine) to lactose which has a mean particle size in the range of 10 ⁇ to 100 ⁇ (coarse) is in the range of 1 : 1 to - 1 :25, preferably in the range of 1 : 1 to 1 : 10, more preferably in the range of 1 : 1 ,5 to 1 : 5
  • the amount of pharmaceutically acceptable carrier is preferably in the range of 0-50 mg.
  • the present invention provides a method to transmit the drug combination comprising tiotropium, formoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof via a dry powder inhaler in which the drug is stored in peelable blister packs, capsules or a reservoir for use in the treatment of patients suffering from respiratory diseases.
  • the capsule can be made of a substance chosen from a group comprising gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers as well as consisting intertwined upper and lower compartments.
  • the capsule material can be selected from, but not limited to, a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose.
  • the capsule material can be selected from, but not limited to, a group comprising polyethylene, polyetheleneteraphtalate, polycarbonate or polypropylene.
  • capsule material used in the present invention is gelatine
  • additional agents such as polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymers and/or other polyalcohols or polyethers at different molecular weights can be added into it.
  • the dry powder drug pertaining to the present invention can also be stored in blister packs apart from reservoirs and capsules.
  • Blister packs are comprised of orderly placed blisters each of which contains minimally one dose of the dry powder drug. Blister packs can be pierced or peeled to be opened according to the device design. However, peelable blister packs are preferred according to the present invention. When the device is triggered, the blister pack or one of the blisters in the pack is pierced or peeled and the drug in dry powder form is prepared for inhalation.
  • the cavity volume of the blisters pertaining to the present invention, which are placed side by side in an order and which provide to transmit and store the dry powder drug in blister pack is in the range of 17-30 mm , preferably in the range of 18-23 mm ' most preferably in the range of 19-21 mm 3
  • the cavity volume of the blisters pertaining to the present invention which provide to transmit and store the dry powder drug comprising tiotropium bromide having water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 17-30 mm 3 , preferably in the range of 18-23 mm ' most preferably in the range of 19-21 mm and each blister cavity having the volume described above is filled up to 25-100 %, preferably up to 70- 100 %, most preferably up to 90-100 % of said volume in order to meet the specified needs for an effective inhalation.
  • the lid and the base sheets of said blister pack are closed very tightly by any suitable method to provide impermeability.
  • the lid and the base sheet constituting the blister package consist of several layers.
  • Polymeric layers, aluminum foil and preferably Aclar® fluoropoylmer film are among the layers that form the lid and the base sheet.
  • Aclar® fluoropolymer film is a polymeric film which is used in blister packs and provides excellent moisture barrier. This chemically inert polymeric film does not cause any change in the taste of the formulation when it is in contact with the dry powder formulation. In addition, it easily constitutes a layered structure with the other polymeric layers which are composed of various polymers. It is appropriate to be transacted with heat.
  • desiccant agents are added to the polymeric layers to preserve the stability of the dry powder formulation stored in blisters that are arranged in an order on blister strips.
  • Silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon and clay which have the property of water absorption can be given as examples to desiccant agents.
  • the thickness of the aluminum foil that is used in the lid and the base sheets of the blister pack is chosen to be in the range of 10 to 40 ⁇ , preferably of 15 to 30 ⁇ .
  • the polymeric layers in the lid and the base sheets of the blister pack mentioned in the present invention are made from the same or different polymers.
  • the thickness of these polymeric layers varies according to the type of the polymeric substance used and its properties. Therefore, the thickness of the polymeric layer varies in the range of 15-60 ⁇ , preferably of 20-35 ⁇ depending on the type of the polymer used.
  • the inside layer of the blister cavity of the said blister pack which is in contact with the dry powder formulation is a polymeric layer because of the fact that some of the dry powder formulation sticks onto the inside layer of the blister cavity due to the porous structure of aluminum foil and electrostatic forces, and hence causes uncontrolled dosing.
  • the polymers used to form the polymeric layers are preferably selected from a group comprising thermo-plastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or other synthetic polymers.
  • the blisters which constitute the blister pack pertaining to the present invention can be in any shape as long as they have the properties described above.
  • tiotropium bromide with water content less than or equal to 2.5% can be in crystal form and/or amorphous form or combination thereof.
  • formoterol fumarate can be in the form of its solvates, hydrates enantiomers, diastereomers, racemates and/or in crystal form and/or amorphous form and/or a combination thereof.
  • fluticasone propionate can be in the form of its solvates, hydrates, enantiomers or diastereoisomers, racemates and/or in crystal form and/or in amorphous forms and/or a combination thereof.
  • the amount of tiotropium bromide water content less than or equal to 2.5% included in the drug formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1-50 ⁇ g, preferably 1-40 ⁇ g per dose.
  • the amount of formoterol fumarate included in the drug formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1-40 ⁇ g, preferably 1-30 ⁇ g per dose.
  • the amount of fluticasone propionate included in the drug formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 5-1000 ⁇ g, preferably 20-700 ⁇ g per dose.
  • the pharmaceutical composition mentioned in the present invention which comprises tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein; • the particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 ⁇ and
  • said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively and
  • ⁇ lactose which has a mean particle size less than 100 ⁇ is used as carrier.
  • the respiratory diseases include, but not restricted to, allergic or non-allergic asthma at any phases, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperactivity, bronchiectasis, chronic obstructive pulmonary, airways or lung diseases (COPD, COAD or COLD) including emphysema and chronic bronchitis, pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.
  • the treatment of said diseases may be prophylactic or symptomatic.
  • the pharmaceutical composition pertaining to the present invention is used especially for the symptom
  • a method for preparing the pharmaceutical composition according to the present invention comprises micronizing the tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate, preferably by air jet mill, mixing the micronized tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate with lactose, then blending the composition to obtain a homogeneous dry powder mixture, and then filling the obtained dry powder mixture into capsules or blisters.
  • the active substance tiotropium bromide with water content less than or equal to 2.5% given in this example includes its pharmaceutically acceptable amorphous and crystal forms thereof; formoterol fumarate includes its all pharmaceutically acceptable racemates, enantiomers or diastereomers, solvates, hydrates and/or amorphous and crystal forms and fluticasone propionate includes its all pharmaceutically acceptable solvates, hydrates and/or enantiomers and/or amorphous and crystal forms. Lactose in this example can optionally be added in a higher or a lower amount.
  • Example 1 The amounts in Example 1 can be replaced by the amounts given in the table below and the example can be repeated.
  • a dry powder formulation which is appropriate for a gelatine capsule used in a capsule inhaler comprises 21 parts of tiotropium bromide with water content less than or equal to 2.5%, 12 parts of formoterol fumarate, 200 parts of fluticasone propionate all of which are micronized in air jet mill and have a mean particle size in the range of 1.5-4.5 ⁇ and 5750 parts of lactose as carrier which has a mean particle size less than 100 ⁇ .
  • the active agent tiotropium bromide with water content less than or equal to 2.5% given in this " example includes its all pharmaceutically acceptable amorphous and/or crystal forms thereof; formoterol fumarate includes its all pharmaceutically acceptable racemates, enantiomers or diastereomers, solvates, hydrates and/or amorphous and/or crystal forms and fluticasone propionate includes its all pharmaceutically acceptable solvates, hydrates and/or enantiomers, and/or amorphous and/or crystal forms. Lactose given in this example can optionally be added in a higher or a lower amount.
  • the capsule in this example is made of gelatin but it can optionally be made of chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers.
  • Example 20 The combination of the pharmaceutical composition pertaining to the present invention can be explained with, but not restricted to, the examples given below.
  • the amounts used in Example 20 can be replaced by the amounts given in the table below and the example can be repeated.

Abstract

A pharmaceutical composition comprising tiotropium bromide, formoterol fumarate and fluticasone propionate, and its use in the symptomatic and/or prophylactic treatment of respiratory diseases especially asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD).

Description

A PHARMACEUTICAL COMBINATION COMPRISING TIOTROPIUM
DESCRIPTION
.The present invention is related to a pharmaceutical composition comprising formoterol, fluticasone, tiotropium and/or pharmaceutically acceptable derivatives thereof and the use of this composition in the treatment of respiratory diseases particularly in asthma, allergic rhinitis and chronic obstructive pulmonary diseases (COPD).
Airways, in other words bronchia, are the channels which function to distribute the inhaled air into the lung tissues. In the case of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD), stimulants such as allergen, infection, good and bad smell, smoke, genetic factors and exercise cause contractions in the airway muscles (bronchoconstruction) and/or excessive secretion in glands and results in contractions in the airway; hence, respiration gets more difficult as the inhaled air cannot be exhaled.
Corticosteroids, which are used in the treatment of asthma and COPD, are synthetic and strong anti-inflammatory drugs that are similar to natural corticosteroid hormones produced by adrenal glands. They prevent both the transcription of the inflammatory gene and the activation of the anti-inflammatory gene. In addition to this, they increase the transcription of p2 receptors. Furthermore, corticosteroids prevent the tolerance that develops after a long- term application of β2 agonists. Beclomathasone, budesonide, ciclesonide, flunisolide, fluticasone are among the steroids that are used for the treatment of respiratory diseases. Corticosteroids are not preferred in acute asthma crises as they do not have rapid onset of action. Since inhaled corticosteroids may prevent growth in children, they are advised to be used in the lowest possible amount. Long-term use of corticosteroids may cause cataract and glaucoma. In addition, they may cause some serious side-effects such as osteoporosis, high cholesterol, edema, encepholalgia, weight gain, insomnia and some skin problems. β2 adrenergic agonists which are used in the treatment of respiratory diseases such as asthma and COPD affect the muscles around the air vessels by activating β2 adrenergic receptors. They reduce or eliminate bronchospasm. Bronchodilator 2-agonists are categorized into two groups as long-acting and short-acting. Short-acting beta-agonists such as salbutamol, levosalbutamol, prosaterol, fenoterol, terbutaline, pirbuterol, metoproterenol, bitolterol mesilate have a rather rapid onset of action such as 3-5 minutes and their duration of action is of 4-6 hours. As they have a rapid onset of action, they are given as relaxant but they should be taken very often since they have a short duration of action. Long-acting β2 agonists have a slower onset of action compared to the other group but their duration of action is of 12 hours. Salmeterol, formoterol, bambuterol and clenbuterol can be given as examples to long-acting β2 agonists. Long-acting 2-agonists are often used in the treatment of patients who present 5 asthma symptoms at nights and in the treatment of asthma stimulated by exercise. β2 agonists are known as the most effective agent in order to eliminate acute asthma symptoms. One of the most important factors for their being used as symptomatolytic is their onset of action. Some long-acting β2 agonists can have the onset of action of short acting β2 agonists when used at specific doses.
LO β2 agonists affect the muscles above the air vessels. However, they might affect the muscles around the heart and the bones. In the case that they affect the heart muscles, acceleration of heartbeat and palpitation might be observed. In 2005, US Food and Drug Administration (FDA) revealed that many long-acting β2^οηΪ8ΐ drugs increase wheezing symptom in patients. Following this, in a study carried out by Cornell and Stanford Universities, it was found out
L5 that regular intake of β-agonists in the treatment of COPD increases health problems resulting from respiratory tract.
Anticholinergics are the other active agents which are utilized in the treatment of respiratory diseases. Anticholinergics influence large airways including the muscles above bronchia, while β2 agonists influence small airways, in other words bronchioles. Anticholinergics such as β2
!O agonists are categorized into two groups as long-acting and short-acting. Short-acting anticholinergics containing ipratropium bromide and oxitropium bromide have an onset of action of 15 minutes and their duration of action is 6-8 hours. The long-acting anticholinergic agent is tiotropium. Tiotropium has an onset of action of 20 minutes and its duration of action is 24 hours. Thus, it is enough to take it once a day. Side effects of anticholinergics are weaker
!5 than the side effects of β2 agonists.
The use of combination drugs in the treatment of respiratory diseases such as asthma and COPD is very effective particularly in decreasing asthma attacks. It is possible that the severity or occurrence possibility of the abovementioned side effects decreases as the active substances that are used in combinations are more effective at lower doses compared to the !O active substances used alone. However, decreasing the side effects that arise from the active agents is not sufficient to provide effective treatment for respiratory diseases. The medicaments used in the formulations should be selected in a way to give the best combination and furthermore, they should be in the most stable form. Moreover, the compositions comprising them should be formulated in such a way that the composition is stable and also it reaches to the target area in the most efficient way.
The inventor has surprisingly found that unexpected therapeutic benefits are obtained through the use of the combination comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate together for simultaneous or sequential administration in the prevention or treatment of respiratory diseases.
It was seen that a combination comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate provides the most stable and therapeutically beneficial combination for simultaneous or sequential administration in the prevention or treatment of respiratory diseases. Preferably a composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is administered simultaneously.
Formoterol fumarate used in the formulation is preferably in dihydrate form.
In another aspect, said composition comprises tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, fluticasone propionate and lactose. In another aspect, tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, fluticasone propionate are preferably combined in a single dosage form.
Furthermore, the amount of active agents used in the composition is carefully adjusted in order to prevent the side effects that might arise from these agents and it was seen that minimum side effects are observed when tiotropium bromide with water content less than or equal to 2.5%:formoterol fumarate:fluticasone propionate ratio in the composition is in the range of 1 :0.3:2 to 1 :4:65 by weight. Furthermore, it was seen that the adhesive force between the particles is less and hence the amount of inhaled particles and efficacy of the formulation increases in the formulation which is constituted with active agents in amounts that has the ratio in the range of 1 :0.3:2 to 1 :4:65. It should be noted that the ratio given above is based on the amounts of tiotropium, formoterol and fluticasone active parts; which are in free form without salt or ester forms.
Accordingly; the present invention provides a combined drug preparation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and 5 . fluticasone propionate in amounts in the range of 1:0.3:2 to 1:4:65 for simultaneous or sequential administration in the prevention or treatment of respiratory diseases such as asthma and chronic obstructive pulmonary diseases (COPD).
According to another aspect, the present invention provides an effective inhalation of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol LO fumarate and fluticasone propionate.
The drug pertaining to the present invention is preferred to be administered by the inhalation route as it a) has a more rapid onset of action compared to the administration via oral or parenteral routes b) enables the use at lower doses c) minimizes the side effects.
According to another aspect, the present invention provides simultaneous or sequential L5 inhalation of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate by the inhalation route.
According to another aspect, the present invention provides the transmission of the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate via single or multi dose inhalers. iO The drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate can be in dry powder form; they can be formulated with propellant gases to give aerosol formulations or they can be formulated with solvents to give nebulizer formulations. The inventors have found that the best way to transfer the medicament comprising tiotropium bromide with water content less than or equal to 2.5%,
!5 formoterol fumarate and fluticasone propionate is using this medicament combination in dry powder form.
In this way, the components maintain their stability and furthermore, the medicament stable form and is easily used by the patients. In order to ensure effective absorption of the active agents into the lung tissue, the particle size of the agents should be adjusted. Although large particle size provides ease in manufacturing of the dry powder, it may accumulate in throat and lead to insufficient intake of the medicament. Very fine particles, on the other hand, may reach the lungs. However, they might not have a good flow property which causes problems in providing dose accuracy in turn. To prevent these problems, the active agents should have an optimum average particle size. The inventors have found that tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, fluticasone propionate having a mean particle size in the range of 1.5 to 4.5 μπι reaches the lungs effectively and also no problems related to flow properties of the dry powder are observed.
In one aspect, the present invention provides a medicament composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 μπι and wherein said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively and said composition can be simultaneously or sequentially administered in the prevention or treatment of respiratory diseases.
The term "mean particle size" refers to particles wherein the particle size of 50% of the total number of particles is less than the average particle size. According to the present invention, the drug comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate may also contain effective amounts of excipients and/or additional agents apart from active agents.
According to the present invention, the dry powder formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is transmitted to the patient in dry powder form. Said dry powder formulations also contain some physiologically acceptable excipients along with the active agent. These excipients can be monosaccharides (glucose, etc.), disaccharides (lactose, saccharose, maltose, etc.), oligosaccharides and polysaccharide (dextran, etc.), polyalcohols (sorbitol, mannitol, xylitol, etc.), salts (sodium chloride, calcium carbonate, etc.) or a mixture thereof. The inventors have found that in the compositions pertaining to the present invention, in other words in compositions comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 μπι and wherein said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively, using lactose as the one and only carrier provides optimum homogeneity and flow properties to the dry powder and this way dose accuracy is maintained.
It was also seen that the mean particle size of the carrier plays an important role in delivery of the medicament to the target area, i.e. lungs, effectively in the compositions pertaining to the present invention. It was found that the adhesive forces between the lactose particles and the active agents having a mean particle size in the range of 1.5 to 4.5 μπι are minimized and thus, an effective inhalation of the active agents takes place when lactose having a mean particle size less than or equal to 100 μπι is used in compositions comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 μπι and wherein said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively.
In another aspect, the present invention provides a composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein;
• The mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 μπι and
• said active agents are present in the composition with the ratio of 1 :0.3:2 to 1:4:65 respectively and
• lactose which has a mean particle size less than 100 μπι is used as carrier.
Lactose which has a mean particle size less than 100 μπι is preferably used as a mixture of particles having two different mean particle sizes. Accordingly, lactose which has a mean particle size less than 100 μιη can be present as a mixture of particles having a mean particle size less than 10 μιη (fine) and particles having mean particle size in the range of 10 μπι to 100 μπι (coarse). The inventors have observed that the adhesive force between the active agents and lactose is even less when lactose which has two different mean particle sizes is used.
The weight ratio of lactose which has a mean particle size less than 10 μπι (fine) to lactose which has a mean particle size in the range of 10 μπι to 100 μπι (coarse) is in the range of 1 : 1 to - 1 :25, preferably in the range of 1 : 1 to 1 : 10, more preferably in the range of 1 : 1 ,5 to 1 : 5
According to the present invention, the amount of pharmaceutically acceptable carrier is preferably in the range of 0-50 mg.
According to another aspect, the present invention provides a method to transmit the drug combination comprising tiotropium, formoterol and fluticasone and/or pharmaceutically acceptable derivatives thereof via a dry powder inhaler in which the drug is stored in peelable blister packs, capsules or a reservoir for use in the treatment of patients suffering from respiratory diseases.
In the inhalation devices which are designed to transmit dry powder drugs, an effective amount of the dry powder drug is prepared for inhalation when the device is triggered. In order to prepare the dry powder formulation stored in capsules, the supplementary components in the device provides the capsule to open or be pierced when the device is triggered and the dry powder formulation is prepared for inhalation. After the inhalation is completed, the empty capsule is ejected from the device and a new capsule is placed immediately before the following inhalation takes place. According to the present invention, the capsule can be made of a substance chosen from a group comprising gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers as well as consisting intertwined upper and lower compartments.
In the case that the capsule used in the present invention is made of cellulose or its derivatives, the capsule material can be selected from, but not limited to, a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose. In the case that the capsule used in the present invention is synthetic polymer, the capsule material can be selected from, but not limited to, a group comprising polyethylene, polyetheleneteraphtalate, polycarbonate or polypropylene.
In the case that the capsule material used in the present invention is gelatine, additional agentssuch as polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymers and/or other polyalcohols or polyethers at different molecular weights can be added into it.
The dry powder drug pertaining to the present invention can also be stored in blister packs apart from reservoirs and capsules. Blister packs are comprised of orderly placed blisters each of which contains minimally one dose of the dry powder drug. Blister packs can be pierced or peeled to be opened according to the device design. However, peelable blister packs are preferred according to the present invention. When the device is triggered, the blister pack or one of the blisters in the pack is pierced or peeled and the drug in dry powder form is prepared for inhalation.
The cavity volume of the blisters pertaining to the present invention, which are placed side by side in an order and which provide to transmit and store the dry powder drug in blister pack is in the range of 17-30 mm , preferably in the range of 18-23 mm ' most preferably in the range of 19-21 mm3
The cavity volume of the blisters pertaining to the present invention, which provide to transmit and store the dry powder drug comprising tiotropium bromide having water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 17-30 mm3 , preferably in the range of 18-23 mm ' most preferably in the range of 19-21 mm and each blister cavity having the volume described above is filled up to 25-100 %, preferably up to 70- 100 %, most preferably up to 90-100 % of said volume in order to meet the specified needs for an effective inhalation. The lid and the base sheets of said blister pack are closed very tightly by any suitable method to provide impermeability.
According to the present invention, the lid and the base sheet constituting the blister package consist of several layers. Polymeric layers, aluminum foil and preferably Aclar® fluoropoylmer film are among the layers that form the lid and the base sheet. Aclar® fluoropolymer film is a polymeric film which is used in blister packs and provides excellent moisture barrier. This chemically inert polymeric film does not cause any change in the taste of the formulation when it is in contact with the dry powder formulation. In addition, it easily constitutes a layered structure with the other polymeric layers which are composed of various polymers. It is appropriate to be transacted with heat.
In order to decrease the gas and moisture permeability of the layer, preferably desiccant agents are added to the polymeric layers to preserve the stability of the dry powder formulation stored in blisters that are arranged in an order on blister strips. Silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon and clay which have the property of water absorption can be given as examples to desiccant agents.
As it is common to use aluminum in lid and base sheets of high protection blister packs, aluminum is used both in the lid and the base sheets of the blister pack of the present invention in order to provide high moisture and gas protection. These aluminum foils must be thick enough to provide the desired protection for the stability of the moisture sensitive dry powder formulation stored in the blister cavity. Due to this reason, the thickness of the aluminum foil that is used in the lid and the base sheets of the blister pack is chosen to be in the range of 10 to 40 μπι, preferably of 15 to 30 μπι.
The polymeric layers in the lid and the base sheets of the blister pack mentioned in the present invention are made from the same or different polymers. The thickness of these polymeric layers varies according to the type of the polymeric substance used and its properties. Therefore, the thickness of the polymeric layer varies in the range of 15-60 μιη, preferably of 20-35 μπι depending on the type of the polymer used.
The inside layer of the blister cavity of the said blister pack which is in contact with the dry powder formulation is a polymeric layer because of the fact that some of the dry powder formulation sticks onto the inside layer of the blister cavity due to the porous structure of aluminum foil and electrostatic forces, and hence causes uncontrolled dosing.
According to the present invention, the polymers used to form the polymeric layers are preferably selected from a group comprising thermo-plastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or other synthetic polymers.
In addition, the blisters which constitute the blister pack pertaining to the present invention can be in any shape as long as they have the properties described above. According to the present invention, tiotropium bromide with water content less than or equal to 2.5% can be in crystal form and/or amorphous form or combination thereof.
According to the present invention, formoterol fumarate can be in the form of its solvates, hydrates enantiomers, diastereomers, racemates and/or in crystal form and/or amorphous form and/or a combination thereof. According to the present invention, fluticasone propionate can be in the form of its solvates, hydrates, enantiomers or diastereoisomers, racemates and/or in crystal form and/or in amorphous forms and/or a combination thereof.
According to the present invention, the amount of tiotropium bromide water content less than or equal to 2.5% included in the drug formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1-50 μg, preferably 1-40 μg per dose.
According to the present invention, the amount of formoterol fumarate included in the drug formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1-40 μg, preferably 1-30 μg per dose.
According to the present invention, the amount of fluticasone propionate included in the drug formulation comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 5-1000 μg, preferably 20-700 μg per dose. The pharmaceutical composition mentioned in the present invention which comprises tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein; • the particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 μπι and
• said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively and
· lactose which has a mean particle size less than 100 μιη is used as carrier. can be used in the treatment of many respiratory diseases such as asthma, chronic obstructive pulmonary disorder (COPD) and allergic rhinitis. Accordingly, the respiratory diseases include, but not restricted to, allergic or non-allergic asthma at any phases, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperactivity, bronchiectasis, chronic obstructive pulmonary, airways or lung diseases (COPD, COAD or COLD) including emphysema and chronic bronchitis, pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. The treatment of said diseases may be prophylactic or symptomatic. In addition, the pharmaceutical composition pertaining to the present invention is used especially for the symptomatic treatment of asthma, allergic rhinitis and COPD.
A method for preparing the pharmaceutical composition according to the present invention comprises micronizing the tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate, preferably by air jet mill, mixing the micronized tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate with lactose, then blending the composition to obtain a homogeneous dry powder mixture, and then filling the obtained dry powder mixture into capsules or blisters.
The combination of the pharmaceutical composition pertaining to the present invention can be explained with, but not restricted to, the examples given below. EXAMPLE 1
So as to be used in a multiple dose inhaler, a dry powder drug formulation which is appropriate to be stored in blisters comprises 21 parts of tiotropium bromide with water content less than or equal to 2.5%, 12 parts of formoterol fumarate, 200 parts of fluticasone propionate all of which are micronized in air jet mill and have a mean particle size in the range of 1.5-4.5 μπι, and 10000 parts of lactose as carrier which has a mean particle size less than 100 μπι. The active substance tiotropium bromide with water content less than or equal to 2.5% given in this example includes its pharmaceutically acceptable amorphous and crystal forms thereof; formoterol fumarate includes its all pharmaceutically acceptable racemates, enantiomers or diastereomers, solvates, hydrates and/or amorphous and crystal forms and fluticasone propionate includes its all pharmaceutically acceptable solvates, hydrates and/or enantiomers and/or amorphous and crystal forms. Lactose in this example can optionally be added in a higher or a lower amount.
The amounts in Example 1 can be replaced by the amounts given in the table below and the example can be repeated.
Figure imgf000013_0001
EXAMPLE 20
A dry powder formulation which is appropriate for a gelatine capsule used in a capsule inhaler comprises 21 parts of tiotropium bromide with water content less than or equal to 2.5%, 12 parts of formoterol fumarate, 200 parts of fluticasone propionate all of which are micronized in air jet mill and have a mean particle size in the range of 1.5-4.5 μπι and 5750 parts of lactose as carrier which has a mean particle size less than 100 μηι.
The active agent tiotropium bromide with water content less than or equal to 2.5% given in this " example includes its all pharmaceutically acceptable amorphous and/or crystal forms thereof; formoterol fumarate includes its all pharmaceutically acceptable racemates, enantiomers or diastereomers, solvates, hydrates and/or amorphous and/or crystal forms and fluticasone propionate includes its all pharmaceutically acceptable solvates, hydrates and/or enantiomers, and/or amorphous and/or crystal forms. Lactose given in this example can optionally be added in a higher or a lower amount. The capsule in this example is made of gelatin but it can optionally be made of chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers.
The combination of the pharmaceutical composition pertaining to the present invention can be explained with, but not restricted to, the examples given below. The amounts used in Example 20 can be replaced by the amounts given in the table below and the example can be repeated.
Figure imgf000014_0001
35 21 12 250 5690
36 12 12 100 5010
37 12 12 250 4720
38 12 12 500 5450
I

Claims

1. A pharmaceutical composition used for simultaneous or sequential administration in the symptomatic and/or prophylactic treatment of respiratory diseases comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein
o the mean particle size of tiotropium bromide with water content less than or equal to or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 μπι and
o said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively and
o lactose which is used as carrier has a mean particle size less than 100 μπι.
2. The pharmaceutical formulation in dry powder form according to claim 1, wherein said formulation consists of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, fluticasone propionate and lactose.
3. The pharmaceutical formulation in dry powder form according to claim 1, wherein tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate, fluticasone propionate are combined in a single dosage form.
4. The pharmaceutical composition according to claim 1, wherein the amount of formoterol fumarate and/or its pharmaceutically acceptable solvates, hydrates enantiomers, diastereomers, racemates is in the range of 1-40 μg per dose.
5. The pharmaceutical composition according to claim 1, wherein the formoterol fumarate is dihydrate.
6. The pharmaceutical composition according to claim 1, wherein the amount of fluticasone propionate and/or its pharmaceutically acceptable solvates, hydrates, enantiomers or diastereoisomers, racemates is in the range of 5-1000 μg per dose.
7. The pharmaceutical composition according to claim 1, wherein the amount of tiotropium bromide with water content less than or equal to 2.5% is in the range of 1-50 μg per dose.
8. The pharmaceutical composition according to claim 1, wherein lactose which has a mean particle size less than 100 μιη is used as a mixture of particles having two different mean particle sizes.
9. The pharmaceutical composition according to claim 8, wherein lactose which has a mean particle size less than 100 μπι present as a mixture of particles having a mean particle size less than 10 μπι and particles having a mean particle size in the range of 10 μπι to 100 μπι
10. The pharmaceutical composition according to claim 9, wherein the weight ratio of lactose which has a mean particle size less than 10 μπι (fine) to lactose which has a mean particle size in the range of 10 μιη to 100 μπι (coarse) is in the range of 1 : 1 to 1 :25.
11. The pharmaceutical composition according to claim 10, wherein the weight ratio of lactose which has a mean particle size less than 10 μπι (fine) to lactose which has a mean particle size in the range of 10 μπι to 100 μπι (coarse) is in the range of 1 :1 to 1 :10
12. The pharmaceutical composition according to claim 11, wherein the weight ratio of lactose which has a mean particle size less than 10 μηι (fine) to lactose which has a mean particle size in the range of 10 μπι to 100 μπι (coarse) is in the range of 1 : 1 ,5 to 1:5
13. The pharmaceutical composition according to claim 1, wherein the amount of lactose is in the range of 0-50 mg.
14. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition in dry powder form can be stored in capsules, reservoirs or blister packs.
15. The pharmaceutical composition in dry powder form according to claim 14, wherein said pharmaceutical composition in dry powder form can be stored in blister packs.
16. The blister pack according to claim 15, wherein each blister cavity constituting the blister pack contains at least one dose.
17. The blister pack according to claim 16, wherein the cavity volume of the blister is in the range of 17-30 mm 3.
18. The blister pack according to claim 17, wherein the cavity volume of the blister is in the range of 18-23 mm .
19. The blister pack according to claim 18, wherein the cavity volume of the blister is in the range of 19-21 mm .
20. The blister pack according to any of the claims from 15 to 19, wherein the blister cavity is filled up to 25-100% of the total volume.
21. The blister pack according to any of the claims from 15 to 19, wherein the blister cavity is filled up to 70-100% of the total volume.
22. The pharmaceutical composition in dry powder form according to claim 14, wherein said pharmaceutical composition in dry powder form can be stored in capsules.
23. The capsule according to claim 22, wherein said capsule is made of a material selected from a group consisting of gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers.
24. The capsule according to claim 22, wherein the capsule material can be selected from a group consisting of hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose,hydroxy ethyl cellulose, in the case that said capsule is made of cellulose or cellulose derivatives.
25. The capsule according to claim 22, wherein the capsule material can be selected from a group consisting of polyethylene, polyester, polyethyleneterephythalate, polycarbonate or polypropylene, in the case that said capsule is made of synthetic polymer.
26. The capsule according to claim 22, wherein polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide, polypropylene oxide block copolymer and/or other polyalcohols and polyether which have various molecular weights can be added into the capsule as adjuvant, in the case that said capsule is made of gelatine.
27. The pharmaceutical composition comprising tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate in dry powder form wherein
o the mean particle size of tiotropium bromide with water content less than or equal to 2.5%, formoterol fumarate and fluticasone propionate is in the range of 1.5 to 4.5 μπι and
o said active agents are present in the composition with the ratio of 1:0.3:2 to 1:4:65 respectively and
o lactose which is used as carrier has a mean particle size less than 100 μιη
administered simultaneously or sequentially for use in treatment of respiratory diseases especially asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD).
28. The pharmaceutical composition according to claim 1, wherein said composition is used for simultaneous administration in the symptomatic and/or prophylactic treatment of respiratory diseases.
PCT/TR2011/000022 2009-12-25 2011-01-28 A pharmaceutical combination comprising tiotropium WO2011093820A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/531,972 US8834931B2 (en) 2009-12-25 2012-06-25 Dry powder formulation containing tiotropium for inhalation

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2010/00622A TR201000622A2 (en) 2010-01-28 2010-01-28 Pharmaceutical combinations containing tiotropium.
TR2010/00622 2010-01-28

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2011/000023 Continuation-In-Part WO2011105975A1 (en) 2009-12-25 2011-01-28 Dry powder formulations administered by the inhalation route comprising a combination of tiotropium bromide, salmeterol xynafoate and fluticasone propionate.

Related Child Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2011/000021 Continuation-In-Part WO2011093819A2 (en) 2009-12-25 2011-01-28 New combination comprising tiotropium

Publications (2)

Publication Number Publication Date
WO2011093820A2 true WO2011093820A2 (en) 2011-08-04
WO2011093820A3 WO2011093820A3 (en) 2012-02-23

Family

ID=43928910

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2011/000022 WO2011093820A2 (en) 2009-12-25 2011-01-28 A pharmaceutical combination comprising tiotropium

Country Status (2)

Country Link
TR (1) TR201000622A2 (en)
WO (1) WO2011093820A2 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109209A1 (en) * 2012-01-16 2013-07-25 Mahmut Bilgic Dry powder formulations comprising fluticasone
WO2013109219A1 (en) * 2012-01-16 2013-07-25 Mahmut Bilgic Dry powder formulations comprising tiotropium and carmoterol
WO2013109213A3 (en) * 2012-01-16 2013-09-06 Mahmut Bilgic Pharmaceutical formulations comprising tiotropium
JP2014105171A (en) * 2012-11-26 2014-06-09 Clinipro Co Ltd Production method of powder for inhalation
US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
WO2015181360A1 (en) * 2014-05-30 2015-12-03 Teva Pharmaceuticals Europe B.V. An inhalable medicament
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0009591D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Medical combinations
DE10130371A1 (en) * 2001-06-23 2003-01-02 Boehringer Ingelheim Pharma New drug compositions based on anticholinergics, corticosteroids and betamimetics
SE0303571D0 (en) * 2003-12-03 2003-12-22 Microdrug Ag Medical product for moisture-sensitive drugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
US FOOD AND DRUG ADMINISTRATION, 2005

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109209A1 (en) * 2012-01-16 2013-07-25 Mahmut Bilgic Dry powder formulations comprising fluticasone
WO2013109219A1 (en) * 2012-01-16 2013-07-25 Mahmut Bilgic Dry powder formulations comprising tiotropium and carmoterol
WO2013109213A3 (en) * 2012-01-16 2013-09-06 Mahmut Bilgic Pharmaceutical formulations comprising tiotropium
WO2013109216A3 (en) * 2012-01-16 2014-04-17 Mahmut Bilgic Preparation of dry powder formulations comprising tiotropium
US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US9822142B2 (en) 2012-05-08 2017-11-21 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10954263B2 (en) 2012-05-08 2021-03-23 Nicox Ophthalmics, Inc Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
JP2014105171A (en) * 2012-11-26 2014-06-09 Clinipro Co Ltd Production method of powder for inhalation
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
WO2015181360A1 (en) * 2014-05-30 2015-12-03 Teva Pharmaceuticals Europe B.V. An inhalable medicament

Also Published As

Publication number Publication date
TR201000622A2 (en) 2011-08-22
WO2011093820A3 (en) 2012-02-23

Similar Documents

Publication Publication Date Title
EP2528585B1 (en) Pharmaceutical compositions comprising tiotropium, formoterol and budesonide
EP2528596B1 (en) Dry powder formulations administered by the inhalation route comprising a combination of tiotropium bromide, salmeterol xynafoate and fluticasone propionate.
WO2011093819A2 (en) New combination comprising tiotropium
EP2533777B1 (en) Pharmaceutical compositions comprising fluticasone, tiotropium and sodium cromoglycate
WO2011093820A2 (en) A pharmaceutical combination comprising tiotropium
EP2528600B1 (en) Dry powder pharmaceutical composition comprising tiotropium and fluticasone
WO2011093815A2 (en) Pharmaceutical compositions comprising formoterol and mometasone
WO2011093818A2 (en) Pharmaceutical compositions comprising salmeterol and fluticasone
EP2528597B1 (en) Dry powder formulation comprising a pharmaceutical combination of tiotropium bromide, formoterol fumarate and mometasone furoate
EP2480203B1 (en) Dry powder formulation of tiotropium carried in blister strip
WO2013109220A1 (en) Dry powder formulations comprising tiotropium, formoterol and budesonide
WO2011093811A2 (en) Pharmaceutical preparations comprising formoterol and fluticasone
EP2804590A1 (en) Dry powder formulations comprising tiotropium and carmoterol
EP2480202B1 (en) Carrying of a combination containing tiotropium in a blister strip
EP2515845B1 (en) Dry powder combination of tiotropium, formoterol and a cromoglicic acid derivative
WO2011093812A2 (en) Pharmaceutical formulation comprising tiotropium and budesonide in dry powder form
WO2011093814A2 (en) A pharmaceutical combination comprising formoterol and ciclesonide
EP2490681B1 (en) The pharmaceutical composition in dry powder form for inhalation
WO2011049539A1 (en) Compositions comprising a corticosteroid, a beta2 agonist as well as cromoglicic acid or ndeocromil
EP2515888A1 (en) Dry powder formulation containing tiotropium for inhalation
WO2011093810A2 (en) Dry powder pharmaceutical composition comprising tiotropium and mometasone
WO2013109218A1 (en) Dry powder formulations comprising carmoterol and ciclesonide
WO2011093809A2 (en) Dry powder pharmaceutical composition comprising tiotropium and ciclesonide
WO2011049538A2 (en) Pharmaceutical composition in dry powder form
WO2013109207A1 (en) Dry powder formulations comprising mometasone

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11706369

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11706369

Country of ref document: EP

Kind code of ref document: A2