WO2011093815A2 - Compositions pharmaceutiques comprenant du formotérol et du mométasone - Google Patents

Compositions pharmaceutiques comprenant du formotérol et du mométasone Download PDF

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Publication number
WO2011093815A2
WO2011093815A2 PCT/TR2011/000017 TR2011000017W WO2011093815A2 WO 2011093815 A2 WO2011093815 A2 WO 2011093815A2 TR 2011000017 W TR2011000017 W TR 2011000017W WO 2011093815 A2 WO2011093815 A2 WO 2011093815A2
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Prior art keywords
dry powder
capsule
olup
blister
bir
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PCT/TR2011/000017
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English (en)
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WO2011093815A3 (fr
Inventor
Mahmut Bilgic
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Mahmut Bilgic
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Priority claimed from TR2010/00684A external-priority patent/TR201000684A2/xx
Priority claimed from TR2010/00727A external-priority patent/TR201000727A2/xx
Application filed by Mahmut Bilgic filed Critical Mahmut Bilgic
Priority to EP11706962A priority Critical patent/EP2533765A2/fr
Publication of WO2011093815A2 publication Critical patent/WO2011093815A2/fr
Publication of WO2011093815A3 publication Critical patent/WO2011093815A3/fr

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    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

Definitions

  • the present invention relates to a pharmaceutical composition in dry powder form comprising formoterol and mometasone and/or their pharmaceutically acceptable derivatives as active agents so as to be used in the treatment of respiratory tract diseases especially in asthma and chronic obstructive pulmonary disease (COPD), and the delivery of this pharmaceutical composition.
  • a pharmaceutical composition in dry powder form comprising formoterol and mometasone and/or their pharmaceutically acceptable derivatives as active agents so as to be used in the treatment of respiratory tract diseases especially in asthma and chronic obstructive pulmonary disease (COPD), and the delivery of this pharmaceutical composition.
  • COPD chronic obstructive pulmonary disease
  • Formoterol which has the chemical name (+/-)-2-Hidroksi-5-((RS))-l-hidroksi-2- ⁇ ((RS)-p- metoksi-alfametilfenil)amino ⁇ etil)-formanilid, is a long-acting broncodilator.
  • Formoterol and its pharmaceutically acceptable, nontoxic salts were first disclosed in the patent numbered US 3994974 by Yamanouchi in 1973. The original drug containing formoterol alone belongs to Novartis under the name Foradil.
  • the molecules which are generally known as p 2 -adrenergic agonists in pharmacology including formoterol present local effects and they lead to open the bronchia by causing relaxation of smooth muscles around the air vessels. With the help of this property, these drugs are used in the treatment of asthma and chronic obstructive pulmonary disorder (COPD). The effect of these drugs, which starts in several minutes following the inhalation, is still evident after 12 hours.
  • COPD chronic obstructive pulmonary disorder
  • Mometasone furoate which has the chemical name (11 ⁇ , 16a)-9,21-dikloro-17-[(2- furanilkarborul)oksi]-l l-bidroksi-16-metil-pregna-l, is an anti-flammatory corticosteroid.
  • the molecule mometasone furoate was first disclosed in the patent numbered US4472393.
  • the original product containing mometasone is Asmanex Twisthaler which belongs to Schering-Plough.
  • Another group of drugs including mometasone which is commonly used in the treatment of asthma and COPD are known as corticosteroids in pharmacology.
  • the molecules included in this group lead to open the airways by controlling inflammation that underlie asthma and reducing mucus secretion, and therefore eliminate the complications of the patients suffering from asthma.
  • they In the case of systemic intake of the drugs in this group, they cause very serious side effects such as osteoporosis, high cholesterol, edema, headache, weight gain, sleeping disorders, various skin problems and growth retardation in children. Therefore, the administration methods in which the least possible amount of the drug enters the systemic circulation are preferred.
  • This type of molecules are administered by the inhalation route in the treatment of asthma to reduce the side effects and to convey the highest possible dose to the lungs.
  • the drugs containing 2-agonist have the potential to trigger respiratory disorders.
  • the administration methods which enable to convey the therapeutic drugs rapidly and directly to the target area; to show the desired effect at lower doses and therefore to alleviate and/or eliminate the side effects are preferred in the transmission of the drugs that show therapeutic effects in body. Taking the very serious side effects of systemic intake of corticosteroids into consideration, it is seen how important it is to transmit this combination effectively.
  • One of the problems that is mostly emphasized in the prior art is the development of these transmission methods and devices.
  • 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 active substances used alone However, decreasing the side effects that arise from the active agents is not sufficient to provide an effective treatment for respiratory diseases.
  • 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 found that therapeutic benefits are obtained through the use of the combination comprising formoterol fumarate and mometasone froate together in dry powder form for simultaneous or sequential administration in the prevention or treatment of respiratory diseases.
  • a combination comprising formoterol fumarate and mometasone froate in dry powder form provides the most stable and therapeutically beneficial combination for simultaneous or sequential aclministration in the prevention or treatment of respiratory diseases.
  • the amount of active agents used in the composition is carefully adjusted in order to prevent side effects that might arise from these agents and it was seen that the adhesive force between the particles forming the composition is reduced and hence, the amount of inhaled particles and efficacy of the formulation increases in addition to observing minimum side effects, when formoterol fumarate and mometasone froate present in the composition is used in an amount that the ratio of formoterol fumarate to mometasone froate is in the range of 1 : 15 to 1 :95 by weight.
  • the particle size of the agents should be adjusted. Although large particle size provides ease in the manufacture 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 in turn causes problems in providing dose accuracy. To prevent these problems, the active agents should have an optimum average particle size. Inventors have found that formoterol fumarate and mometasone froate combination wherein the mean particle size of the active agents is in the range of 1.5 to 4.5 ⁇ reaches lungs effectively and also no problems related to flow properties of the dry powder are observed.
  • the term "mean particle size" refers to particles wherein the size of 50% of the total number of particles is less than the average particle size.
  • present invention is related to dry powder formulations comprising a combination of formoterol fumarate and mometasone froate in dry powder form wherein formoterol fumarate and mometasone froate is present in the composition in an amount such that the ratio of formoterol fumarate and mometasone froate is in the range of 1 : 15 to 1 : 95 by weight and wherein the mean particle size of the active agents (i.e. formoterol fumarateand mometasone froate) is in the range of 1.5 to 4.5 ⁇ .
  • the drug comprising formoterol fumarate and mometasone froate may also contain effective amounts of excipients and/or additional agents apart from active agents.
  • the dry powder formulation containing formoterol fumarate and mometasone froate is transmitted to the patient in dry powder form.
  • Said dry powder formulations also contain some physiologically acceptable excipients along with the active agent.
  • excipients can be monosaccharides (glucose, etc.), disaccharides (lactose, saccharose, maltose, etc.), oligosaccharides and polysaccharides (dextran, etc.), polyalcohols (sorbitol, mannitol, xylitol, etc.), salts (sodium chloride, calcium carbonate, etc.) or a mixture thereof.
  • compositions according to present invention in other words in compositions comprising formoterol fumarateand mometasone froate in dry powder form wherein mean particle size of formoterol fumarateand mometasone froateis in the range of 1.5 to 4.5 ⁇ and wherein formoterol fumarate and mometasone froate are present in the composition in an amount that the ratio of formoterol fumarate to mometasone froate is in the range of 1 :15 to 1:95 by weight, 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.
  • lactose is used as the one and only carrier in dry powder formulations comprising combinations of formoterol fumarate and mometasone froate in dry powder form.
  • the mean particle size of the lactose plays an important role in delivery of the medicament to the target area, i.e. lungs, effectively in the compositions according to the present invention. It was found that the adhesive forces present between the lactose particles and the active agents having the 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 which has a mean particle size less than or equal to 100 ⁇ is used in the compositions comprising formoterol fumarate and mometasone froate in dry powder form wherein the mean particle size of formoterol fumarate and mometasone froate is in the range of 1.5 to 4.5 ⁇ and wherein said active agents are present in the composition with the ratio of 1:15 to 1 :95 respectively.
  • the total water content of the lactose has a considerable effect on the stability of lactose and the drug. It was found that when lactose with total water content in the range of 4%-6% is used in compositions comprising formoterol fumarate and mometasone froate in dry powder form wherein mean particle size of formoterol fumarate and mometasone froate is in the range of 1.5 to 4.5 ⁇ and wherein said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively, lactose shows a highly stable behavior and thus long term stability of the drug is maintained.
  • the present invention provides a composition comprising formoterol fumarate and mometasone froate in dry powder form wherein;
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • lactose which has a mean particle size less than 100 ⁇ and water content in the range of %4-%6 is used as carrier.
  • Lactose which has mean particle size less than 100 ⁇ is preferably used as a mixture of particles which have 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 a 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. Accordingly, the fine lactose particles have a mean particle size less than 10 ⁇ , preferably between 2 ⁇ and 8 ⁇ , and the coarse lactose particles have a mean particle size less than 100 ⁇ , preferably between 30 ⁇ and 80 ⁇ .
  • the ratio between the fine lactose particles which have a mean particle size less than 10 ⁇ and the coarse lactose particles which have a mean particle size in the range of 10 ⁇ to 100 ⁇ is in the range of 20:80% to 40:60% by weight.
  • the amount of pharmaceutically acceptable carrier is preferably in the range of 0-50 mg.
  • the medicament combination of the present invention is in dry powder form and it is inhaled via dry powder inhalers. Accordingly, the medicament can be inhaled via inhalators including a reservoir containing dry powder; a blister pack in which many blisters are placed in an order or capsules. Among these, the inhalers that enable the intake of a single dose in an accurate manner were found to give the best results. This condition is provided by the dosage forms wherein each dose of the medicament is stored in a single unit of dosage form. Accordingly, medicament combination according to present invention is stored in blister packs consisting of blisters or capsules and is inhaled through dry powder inhalation devices where blisters or capsules are used.
  • the inventor has surprisingly found that administering the dry power drug containing formoterol fumarate and mometasone froate wherein;
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • the present invention provides a dry powder drug containing the combination of formoterol fumarate and mometasone froate wherein; • the mean particle size of formoterol fumarate and mometasone froate is in the range of 1.5 to 4.5 ⁇ and
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • ⁇ lactose which has a mean particle size less than 100 ⁇ and total water content in the range of 4%-6% is used as carrier which realizes a simultaneous inhalation from the blister packs or capsules that can guarantee a single dose intake at once in order to achieve dose sufficiency.
  • the present invention provides the inhalation of the dry powder drug containing the combination of formoterol fumarate and mometasone froate wherein;
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • ⁇ lactose which has a mean particle size less than 100 ⁇ and total water content in the range of 4%-6% is used as carrier via a simple, low cost, trustable dry powder inhaler.
  • the present invention provides a drug that provides to realize the use of a composition comprising formoterol fumarate and mometasone froate wherein; ⁇ the mean particle size of formoterol fumarate and mometasone froate is in the range of 1.5 to 4.5 ⁇ and
  • said active agents are present in the composition with the ratio of 1 :15 to 1:95 respectively and lactose which has a mean particle size less than 100 ⁇ and total water content in the range of 4%-6% is used as carrier as stored together in a peelable blister or pierceable capsule packs in the treatment of respiratory diseases such as asthma and COPD.
  • the inventors have found that by storing the dry powder medicament pertaining to the present invention in blister packs comprising blisters and capsules which have the specified properties pertaining to the present invention; • equal dose intake is provided in each use as the dry powder formulation is filled into the blisters or capsules with a good dosage accuracy in the factory after the manufacture,
  • the drug is transmitted to the target area, which is the lungs, without absorbing moisture as the blister or capsule pertaining to the present invention is peeled/torn/pierced immediately before use,
  • devices containing blisters or capsules provide ease of use to the patients as they are small in size resulting from the fact that they work with simple mechanical components compared to other devices.
  • the present invention relates to a delivery method of a drug composition containing a composition comprising formoterol fumarate and mometasone froate wherein;
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • ⁇ lactose which has a mean particle size less than 100 ⁇ and total water content in the range of 4%-6% is used as carrier which is particularly used in the treatment of people suffering respiratory diseases such as asthma, COPD and allergic rhinitis, as stored in a blister or capsule package via a dry powder inhaler.
  • the piercing components which exist in the device to prepare the dry powder drug carried in a capsule for inhalation, pierce the capsule when the device is triggered and the dry powder drug kept in the capsule gets ready 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.
  • the capsule package which is preferred to be used in scope of the present invention, consists of two intertwining parts.
  • the inventors have found that the ideal inhalation conditions are achieved when the volume of the capsule, which comprises the dry powder drug containing formoterol fumarate and mometasone froate wherein;
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and lactose which has a mean particle size less than 100 ⁇ and total water content in the range of 4%-6% is used as carrier, is in the range of 0.1 to 0.52 ml, preferably in the range of 0.1 to 0.45 ml, more preferably in the range of 0.15 to 0.42 ml. Accordingly, the capsule that is used to store and transmit the combination comprising formoterol fumarate and mometasone froate wherein;
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • the capsule package which has high protection against moisture and other negative external factors has a moisture rate between 10%-20%, preferably 15%- 20%.
  • both the active composition is protected from external factors and the probability of moisture arising from the capsule's own structure are prevented.
  • the most effective transmission to the patient is enabled by preventing the agglomeration of the dry powder.
  • the capsule which is preferred to be used in scope of the present invention, can be made of a substance chosen from a group including gelatine, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers as well as consisting intertwined upper and lower parts. These upper and lower parts of said capsule can be produced of identical or different materials.
  • 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 including 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 present invention is characterized in that the capsule cavity used to provide an effective inhalation of the dry powder medicament is filled up to 0.01% to 25% of its total volume, preferably 0.1 to 20% of its total volume, more preferably 0.5 to 17% of its total volume.
  • the present invention comprises dry powder formulations comprising formoterol fumarate and mometasone froate and/or pharmaceutically acceptable derivatives and their administration to patients from a capsule having a total cavity volume in the range of 0.1 to 0.52 ml wherein the capsule cavity is filled up to 0.01% to 25% of the total volume, via a dry powder inhaler.
  • the capsule pack pertaining to the present invention can be in any color or shape as long as it has the properties described above.
  • the capsule or the blister pack which comprises the formulation pertaining to the present invention, can be used with any dry powder inhalation device, for example with devices as described in the patent applications numbered TR2008/03522, TR2008/03523, TR2010/03091 , TR2010/04311.
  • blister packs can be used as the package for the dry powder medicament according to the invention.
  • Blister packages can be a) torn b) pierced or c) peeled to be opened according to the structure of the device and the blister.
  • the inventors have found that it is difficult to use dry powder inhalers which contain pierceable or tearable blister packs for patients as these devices require additional components which increase the size, volume and the complexity of the device.
  • the amount of uninhaled dry powder formulation remaining in the blister cavity increases due to the roughness resulting from being torn and therefore, the rate of utilization from the present dry powder formulation decreases in tearable blisters.
  • the dry powder medicament pertaining to the present invention can be carried in peelable blister packages.
  • Blister packs are comprised of orderly placed blisters each of which contains minimally one dose of the dry powder drug.
  • the blister pack or one of the blisters in the pack is peeled and the drug in dry powder form is prepared for inhalation.
  • the cavity volume of the blisters that are arranged side by side in a certain order on the blister pack which provides to carry and store the drug in dry powder from is 17 to 30 mm , preferably 18 to 23 mm , most preferably 19 to 21 mm .
  • the cavity volume of the blisters pertaining to the present invention which provide to transmit and store the dry powder drug comprising formoterol fumarate and mometasone froate wherein;
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • lactose which has a mean particle size less than 100 ⁇ and total water content in the range of 4%-6% is used as carrier, 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 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 constituted by the blisters having the specified properties, in which the drug in dry powder form pertaining to the present invention is stored, are closed very tightly by any suitable method to provide impermeability.
  • the lid and the base sheets 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 the blister package.
  • 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.
  • 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 ⁇ , 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 composed of 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 blisters which constitute the blister pack in which the dry powder drug pertaining to the present invention is stored can be in any shape as long as they have the properties described above.
  • the dry powder particles Due to the electrostatic interactions between the dry powder particles and the inside layer of the blister cavity or the capsule material which is in contact with the dry powder formulation, the dry powder particles mainly adhere to said inside layer of the blister cavity or said capsule material. Since some uninhaled dry powder formulation is remained in the blister cavity or the capsule during inhalation, sufficient amount of the dry powder formulation for an effective therapy cannot reach to the lungs. Therefore, the inside layer of the blister cavity or the capsule material that is in contact with the dry powder formulation is an antistatic material.
  • antistatic material refers to a material which eliminates the buildup of static electricity.
  • the antistatic material used herein encloses a material which is antistatic itself or which is not antistatic itself but contains antistatic agent(s).
  • an antistatic agent is used for treatment of the layer or their surfaces in order to reduce or eliminate the buildup of static electricity generally caused by the triboelectric effect (charge generation by friction). Its role is to make the surface or the material itself slightly conductive, either by being conductive itself, or by absorbing moisture from the air. Therefore, some humectants can be used.
  • the molecules of an antistatic agent often have both hydrophilic and hydrophobic areas similar to those of a surfactant. The hydrophobic side interacts with the surface of the material while the hydrophilic side interacts with the air moisture and binds the water molecules.
  • Antistatic agents are basically classified into two groups: internal antistatic agents and external antistatic agents. Internal antistatic agents are designed to be mixed directly into the material whereas external antistatic agents are applied to the surface.
  • Antistatic agents used within the scope of the invention are selected from a group comprising long-chain aliphatic amines (optionally ethoxylated) and amides, glycerol monostearate (GMS), saturated fatty acids, (poly)unsaturated fatty acids, quaternary ammonium salts (e.g., behentrimonium chloride or cocamidopropyl betaine), sulfonated organic compounds, esters of phosphoric acid, polyethylene glycol esters, or polyols and combinations thereof. Also, some commercialy available antistatic additives such as OnCap , Larostat ®, Entira , Nourymix®, can be used as antistatic agents.
  • conductive polymers like PEDOT:PSS and conducting polymer nanofibers, particularly polyaniline nanofibers.
  • Processing conditions, polymer base, relative humidity of the environment, material thickness and active agents used in the dry powder formulation play an important role in selecting the most appropriate antistatic agent.
  • the bloom rate (the rate of migration of the antistatic agent to the surface) varies greatly among the antistatic agent choices.
  • the antistatic agents in the material which is the inside layer of the blister cavity or capsule material, are present in a range from 0,1% to 5% by weight of said material.
  • the present invention provides a medicament containing a composition comprising formoterol fumarate and mometasone froate wherein;
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • lactose which has a mean particle size less than 100 ⁇ and total water content in the range of 4%-6% is used as carrier as stored in capsules or blisters wherein the inside layer of the blister cavity or the capsule material that is in contact with the dry powder formulation is an antistatic material.
  • formoterol fumarate which is one of the active agents of the medicament formulation containing the active agent combination includes its pharmaceutically acceptable solvates, polymorphs, crystal forms, amorphous forms and/or combinations thereof.
  • mometasone froate which is one of the active agents of the medicament formulation containing the active agent combination includes its pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, free base, polymorphs, crystal forms, amorphous forms and/or combinations thereof.
  • the amount of formoterol fumarate is in the range of 1 to 30 ⁇ g, preferably in the range of 1 to 20 ⁇ g in the medicament formulation in dry powder form containing the combination of formoterol fumarate and mometasone froate and/or pharmaceutically acceptable derivatives thereof.
  • said active agents are present in the composition with the ratio of 1:15 to 1:95 respectively and
  • lactose which has a mean particle size less than 100 ⁇ and total water content in the range of 4%-6% is used as carrier as stored in capsules or blisters wherein the inside layer of the blister cavity or the capsule material that is in contact with the dry powder formulation is an antistatic material according to the present invention can be used in the treatment of several respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis.
  • COPD chronic obstructive pulmonary disease
  • allergic rhinitis rhinitis
  • these respiratory diseases can be, but not limited to, allergic and non-allergic asthma at any phases, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), intensifying of airways hyperactivity, bronchiectasis, chronic obstructive pulmonary, airways or lung disease including amphizem and chronic bronchitis, pneumokoniosis, aluminosis, antracosis, asbetosis, calicosis, phytilosis, ciderosis, silicosis, tabacosis, bissnosizn.
  • This treatment can be prophylactic or symptomatic.
  • said composition is preferably used for symptomatic treatment of asthma, COPD and allergic rhinitis.
  • a method for preparing the pharmaceutical composition according to the present invention comprises micronizing the formoterol fumarate and mometasone froate, preferably by air jet mill, mixing micronized formoterol fumarate and mometasone froate with lactose and blending the composition to obtain a homogeneous dry powder mixture and then filling the obtained dry powder mixture into capsules or blisters.
  • the pharmaceutical composition pertaining to the present invention can be explained with, but not limited to, the examples given below.
  • the dry powder formulation which is appropriate for a gelatine capsule used in the capsule inhalator comprises 18 parts of formoterol fumarate which was micronized in air jet mill and which has a mean particle size of 1,5 to 4.5 ⁇ ; 200 parts of mometasone froate which was micronized in air jet mill and has a mean particle size of 1.5 to 4.5 ⁇ , and 4500 parts of lactose as carrier which has a mean particle size below ⁇ .
  • Formoterol fumarate given in this example comprises its all pharmaceutically acceptable solvates, polymorphs, amorphous forms and crystalline forms.
  • Mometasone froate given in this example comprises its all pharmaceutically acceptable solvates, hydrates and/or enantiomers, polymorphs, amorphous and crystal forms.
  • Lactose, which is used as carrier, can optionally be added in a higher or a lower amount.
  • the capsule described in the example is made up of gelatine and it can optionally be made of chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and the inside layer of the blister cavity or the capsule material that is in contact with the dry powder formulation is an antistatic material.
  • the amounts given in the table below can be replaced with the amounts given in example 1 :
  • a dry powder formulation which is suitable to be stored in blisters so as to be used in a multiple dosing inhalator comprises 18 parts of formoterol fumarate which has an average particle diameter of 1.5-4.5 ⁇ and was micronized in air jet mill; 200 parts of mometasone froate which was micronized in air jet mill, and 1000 parts of lactose having a particle diameter of less than 100 ⁇ as a carrier.
  • Formoterol fumarate given in this example comprises its all pharmaceutically acceptable solvates, polymorphs, amorphous forms and crystalline forms.
  • Mometasone froate given in this example comprises its all pharmaceutically acceptable solvates, hydrates and/or enantiomers, polymorphs, amorphous and crystal forms.
  • Lactose, which is used as carrier, can optionally be added in a higher or a lower amount.
  • the example can be repeated by replacing the amounts in Example 20 with the amounts given in the table below.

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Abstract

La présente invention concerne des compositions pharmaceutiques sous forme de poudre sèche comprenant du formotérol et du furoate de mométasone et/ou leurs dérivés pharmaceutiquement acceptables utilisés comme principes actifs. Elle concerne également des formes en capsules ou plaquettes alvéolaires contenant ces compositions pharmaceutiques destinées à être utilisées dans le traitement de maladies des voies respiratoires.
PCT/TR2011/000017 2010-01-29 2011-01-28 Compositions pharmaceutiques comprenant du formotérol et du mométasone WO2011093815A2 (fr)

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EP11706962A EP2533765A2 (fr) 2010-01-29 2011-01-28 Compositions pharmaceutiques comprenant du formotérol et du mométasone

Applications Claiming Priority (4)

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TR2010/00684A TR201000684A2 (tr) 2010-01-29 2010-01-29 Formoterol ve mometazon içeren farmasötik bileşimler
TR2010/00684 2010-01-29
TR2010/00727 2010-02-02
TR2010/00727A TR201000727A2 (tr) 2010-02-02 2010-02-02 Formoterol ve mometazon içeren farmasötik bileşimler.

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WO2011093815A3 WO2011093815A3 (fr) 2011-10-20

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109208A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations comprenant du formotérol utilisé comme agent actif
WO2013109211A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations en poudre sèche comprenant du r-formotérol utilisé comme agent actif
WO2013109207A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations de poudre sèche comprenant de la mométasone
WO2014007770A3 (fr) * 2012-07-05 2014-03-20 Arven Ilac Sanayi Ve Ticaret A.S. Compositions d'inhalation comprenant un corticostéroïde et du sorbitol
US10105316B2 (en) 2012-07-05 2018-10-23 Arven llac Sanayi Ve Ticaret A.S. Inhalation compositions comprising muscarinic receptor antagonist
US10111957B2 (en) 2012-07-05 2018-10-30 Arven Ilac Snayi ve Ticaret A.S. Inhalation compositions comprising glucose anhydrous

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US4472393A (en) 1981-02-02 1984-09-18 Schering Corporation 3,20-Dioxo-1,4-pregnadiene-17α-ol 17-aromatic heterocycle carboxylates

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GB9904919D0 (en) * 1999-03-03 1999-04-28 Novartis Ag Organic compounds
SE9900833D0 (sv) * 1999-03-09 1999-03-09 Astra Ab Novel combination
GB0009612D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Therapeutic formulations
JP2002003623A (ja) * 2000-06-22 2002-01-09 Mitsubishi Polyester Film Copp 二軸配向ポリエステルフィルム
US20030018019A1 (en) * 2001-06-23 2003-01-23 Boehringer Ingelheim Pharma Kg Pharmaceutical compositions based on anticholinergics, corticosteroids and betamimetics
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GB0207906D0 (en) * 2002-04-05 2002-05-15 3M Innovative Properties Co Formoterol and mometasone aerosol formulations
WO2005044187A2 (fr) * 2003-10-28 2005-05-19 Glaxo Group Limited Preparations pharmaceutiques inhalables employant de l'anhydrate de lactose, et methodes d'administration desdites preparations

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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
US4472393A (en) 1981-02-02 1984-09-18 Schering Corporation 3,20-Dioxo-1,4-pregnadiene-17α-ol 17-aromatic heterocycle carboxylates

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013109208A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations comprenant du formotérol utilisé comme agent actif
WO2013109211A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations en poudre sèche comprenant du r-formotérol utilisé comme agent actif
WO2013109207A1 (fr) * 2012-01-16 2013-07-25 Mahmut Bilgic Formulations de poudre sèche comprenant de la mométasone
WO2014007770A3 (fr) * 2012-07-05 2014-03-20 Arven Ilac Sanayi Ve Ticaret A.S. Compositions d'inhalation comprenant un corticostéroïde et du sorbitol
US10105316B2 (en) 2012-07-05 2018-10-23 Arven llac Sanayi Ve Ticaret A.S. Inhalation compositions comprising muscarinic receptor antagonist
US10111957B2 (en) 2012-07-05 2018-10-30 Arven Ilac Snayi ve Ticaret A.S. Inhalation compositions comprising glucose anhydrous

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EP2533765A2 (fr) 2012-12-19

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