WO2011037550A2 - Combinaison de poudre sèche de tiotropium - Google Patents

Combinaison de poudre sèche de tiotropium Download PDF

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Publication number
WO2011037550A2
WO2011037550A2 PCT/TR2010/000184 TR2010000184W WO2011037550A2 WO 2011037550 A2 WO2011037550 A2 WO 2011037550A2 TR 2010000184 W TR2010000184 W TR 2010000184W WO 2011037550 A2 WO2011037550 A2 WO 2011037550A2
Authority
WO
WIPO (PCT)
Prior art keywords
medicament composition
dry powder
tiotropium
nedocromil
salt
Prior art date
Application number
PCT/TR2010/000184
Other languages
English (en)
Other versions
WO2011037550A3 (fr
Inventor
Bilgic Mahmut
Original Assignee
Bilgic Mahmut
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 Bilgic Mahmut filed Critical Bilgic Mahmut
Priority to EP10787588A priority Critical patent/EP2480287A2/fr
Publication of WO2011037550A2 publication Critical patent/WO2011037550A2/fr
Publication of WO2011037550A3 publication Critical patent/WO2011037550A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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

Definitions

  • the present invention relates to a medicament.
  • Tiotropium (Formula I) is an anticholinergic agent with chemical name (la, 2 ⁇ , 4 ⁇ , 5a, 7 ⁇ )-7- [(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.0 2 ' 4 ] nonane.
  • Tiotropium is described in European patent application EP0418716 for the first time.
  • the patent relates to processes for preparing tiotropium, pharmaceutical compositions containing tiotropium, long-acting, strong anticholinergic activity of tiotropium and use of it in the treatment of respiratory disorders.
  • Tiotropium is a long acting, strong anticholinergic bronchodilator administered orally for the treatment of respiratory diseases.
  • This drug is available in the market with the trademark of "Spiriva” which consists of capsules containing tiotropium in dry powder from and it is administered by using a dry powder inhalation device called as "Handyhaler".
  • Tiotropium antagonizes the effect of acetylcholine by blocking cholinergic muscarinic receptors. Tiotropium is separated slowly from Ml and M3 receptors that cause broncho-construction and it is separated rapidly from M2 receptors that inhibit release of acetylcholine from cholinergic nerve endings. This situation occurred in lung receptors demonstrates long acting bronchodilator activity of the drug. Inhalation route is a commonly preferred treatment method for respiratory disorders especially chronic disorders such as asthma and chronic obstructive pulmonary disorder (COPD) which threaten a large portion of the society.
  • COPD chronic obstructive pulmonary disorder
  • Medicament composition can be administered locally by dry powder inhalers, metered dose inhalers or nebulizer inhalers.
  • Lactose which is a disaccharide
  • lactose is generally used as a carrier in dry powder formulations developed for use via inhalation.
  • the amount of lactose used is usually in the range of 10 mg to 50 mg, which is approximately 500-2500 times more than the amount of active agent, for a single dose. While the active agent has a weight in the unit of microgram, lactose has a weight in the unit of milligram.
  • dry powder formulations containing large amount of lactose when used by patient with allergy and/or lactose intolerance cause symptoms such as nausea, stomach cramps, overfullness of the stomach, swelling of stomach, flatus, diarrhea, hives plaque.
  • 15 to 25% of each dose of the drugs administered by inhalation can reach the target area, the rest is mostly swallowed. Accordingly, dry powder inhalation formulations containing tiotropium and pharmaceutically acceptable salts thereof need to be improved in terms of safety and efficacy.
  • Salts of cromoglicic acid and nedocromil are used for the treatment of bronchospasm in pharmacology. Because of this property, it is used for the treatment of asthma, allergic rhinitis, allergic and vernal conjunctivitis diseases. Products which are marketed by the trademarks of "Intal” and “Cromohexal” provide 20 mg sodium cromoglicate per dose. It is known that cromoglicic acid derivatives are used as a solubility enhancing agent in some aerosol formulations.
  • US6475467 relates to use of a compound selected from cromoglicic acid and nedocromil derivatives in an ineffective amount in aerosol formulation that is in the form of suspension for increasing the dispersion of active agent in this suspension.
  • the present invention relates to use of salts of cromoglicic acid and/or nedocromil (K) for the preparation of dry powder formulations containing tiotropium and/or pharmaceutically acceptable derivatives thereof (A).
  • K salts of cromoglicic acid and/or nedocromil
  • A tiotropium and/or pharmaceutically acceptable derivatives thereof
  • the present invention provides a medicament composition containing tiotropium or pharmaceutically acceptable derivatives (pharmaceutically acceptable salts, solvates, crystals) thereof as well as salts of cromoglicic acid and/or nedocromil in an effective amount for use in the treatment of respiratory diseases.
  • the medicament composition in accordance with invention optionally contains a carrier in addition to the substances mentioned above.
  • the invention provides use of A and B defined hereinbefore in effective amounts for the preparation of a medicament which is used for the treatment of respiratory diseases especially allergic diseases.
  • the inventors encountered a problem of inability to deliver an effective amount of dose to the lungs which is a problem widely encountered during inhalation of dry powder formulations..
  • various methods and devices are developed in order to deal with this problem.
  • the most suitable method for delivering effective amount of dose to target area which is lung of the patient, and for making patient bring about inhalation in a most suitable way is to inhale said medicament composition as dry powder form and to inhale said medicament from a peelable blister strip. It is found that compared to the other methods for delivery of dry powder formulation which comprise inhalation of dry powder formulation containing A and B in effective amounts from capsule or from reservoir or from separate blister strips each of which contains a kind of active agent, the method of delivering said dry powder formulation from a peelable blister strip minimize the drawbacks caused by adhesion force of micronized dry powder, and the amount of medicament formulation which reaches the lungs increases.
  • the present invention provides a method comprising delivery of medicament composition containing A and B in effective amounts and optionally a pharmaceutically acceptable carrier from a peelable blister strip by using a dry powder inhaler for the treatment of respiratory diseases especially allergic disease.
  • tiotropium (A) may be in the form of pharmaceutially acceptable salts and solvates thereof, preferably, tiotropium bromide is used. All of crystal and amorphous forms of tiotropium, which shows different polymorphic forms, can be used within the scope of invention. Also, tiotropium used within the scope of invention can be in the form of anhydrate and hydrate, preferably, tiotropium bromide anhydrate is used.
  • a salt of cromoglicic acid and/or nedocromil (B) can be selected from pharmaceutically acceptable salts of cromoglicic acid and/or nedocromil.
  • it is either sodium cromoglicate and/or nedocromil sodium.
  • Dry powder formulation in accordance with the present invention administered via inhalation route optionally contains pharmaceutically acceptable carrier.
  • the carrier can be selected from a group comprising arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starches, dextran, sugar alcohols such as mannitol and saccharides.
  • the medicament composition in accordance with the present invention is in the form of micronized dry powder particles.
  • the active agent present in said medicament composition has average particle size in the range of 1 to 20 ⁇ , preferably in the range of 1 to 5 ⁇ .
  • the carrier present in said medicament composition typically has average particle size of not more than 300 ⁇ , preferably not more than 210 ⁇ .
  • the cavity volume of each blister in said blister strip contained in the dry powder inhaler which is used for delivery of said medicament composition to the lung is in the range of 20 to 30 mm , preferably in the range of 21 to 25 mm , most preferably in the range of 22 to 23 mm .
  • a lid sheet and a base sheet of said blister strip are closed very tightly to provide impermeability by using suitable method.
  • the lid sheet or the base sheet of the peelable blister strip consists of three layers. Two of these layers are polymeric layers and the other one is aluminium foil. Aliminium foil is used in both the lid sheet and the base sheet of the peelable blister strip to provide high humidity and gas protection because of that aluminium foil is conventionally used in both the lid sheet and the base sheet of the blister strip for high humidty and gas protection. These layers must have the sufficient thickness which provides the protection for the stability of humidity sensitive dry powder formulation which is stored in the blister cavity. Because of this reason, the thickness of aluminium foil that is used in the lid sheet and the base sheet of the peelable blister strip is in the range of 10 to 40 ⁇ , preferably of 15 to 30 ⁇ .
  • Two of the layers contained by the lid sheet and the base sheet of the peelable blister strip according to the present invention are polymeric layers. These polymeric layers may be made from either same or different polymers. The thickness of these polymeric layers depends on the type of polymeric substance used and its properties. Therefore, the thickness of each polymeric layer which is used in the lid sheet and the base sheet of said blister strip is in the range of 15 to 60 ⁇ , preferably of 20 to 35 ⁇ depending on the type of polymer used.
  • the inside layer of blister cavity of said blister strip which is in contact with dry powder formulation is polymeric layer because of the fact that aluminium foil causes adhesion of a part of dry powder formulation to inside layer of the cavity due to electrostatic forces, and hence cause uncontrolled dosing.
  • the polymers used for forming the polymeric layers are preferably selected from a group comprising thermo-plastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane.
  • each of the blister cavities of the peelable blister strip can be different in shape as long as it has properties defined above.
  • Devices used to inhale the dry powder formulation in accordance with the present invention may be multi dose inhalers present in the prior art. For this reason, the invention provides a medicament composition as it is mentioned before. In another aspect, the invention provides a method for delivery of said medicament composition to patient's lungs effectively as it is mentioned before.
  • the medicament composition in accordance with the present invention containing active agents, which is preferably in dry powder form is stored in the peelable blister strip and during inhalation 2 to 50 milligram of said medicament composition is delivered to patients by using a multi dose inhaler, after each movement of the device.
  • the medicament composition A is present in the amount of 1 to 50 ⁇ g
  • B is present in the amount of 5 to 50 mg. Accordingly, the ratio of the weight of A to the weight of B in said medicament composition is in the range of 1:400 to 1:6000.
  • pharmaceutically acceptable carrier can be used for the purpose of adjusting the weight of each dose of medicament composition to the range of 2 to 50 mg which is in dry powder form.
  • the medicament composition in accordance with present invention can be used for the treatment of many respiratory diseases such as asthma, chronic obstructive pulmonary disorder (COPD) and allergic rhinitis.
  • the respiratory diseases include but are not restricted to allergic or non-allergic asthma in various 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 medicament composition in accordance with the present invention is used especially for the symptomatic treatment of asthma, allergic rhinitis and COPD
  • Example 1 The present invention, is explained with examples given below, but it is not restricted to these examples. Parts given in examples represent the weights of ingredients. Example 1
  • the medicament composition in dry powder form which is stored in a blister strip to be delivered by using multi-dose inhaler described in GB2242163 or a similar one to this and is prepared by mixing 18 parts of tiotropium bromide anhydrate and 12000 parts of sodium cromoglicate, having average particle size of 1 to 5 ⁇ , and 12000 parts of sodium cromoglicate having average particle size of not more than 300 ⁇ , which are micronized in an air jet mill, and 2000 parts of a carrier such as lactose as second carrier.
  • a carrier such as lactose
  • Tiotropium bromide anhydrate (A) given in this example may be extended pharmaceutically acceptable salts and polymorphous forms thereof
  • sodium cromoglicate (B) given in this example may be extended pharmaceutically acceptable salts cromoglicic acid and nedocromil
  • more or less amount of pharmaceutically acceptable carrier may optionally be added and thus example number 1 is repeated as following:

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

Abstract

L'invention concerne une composition pharmaceutique contenant du tiotropium préparé avec une quantité efficace d'un dérivé de cromolyn utilisé pour le traitement de maladies respiratoires par voie d'inhalation.
PCT/TR2010/000184 2009-09-23 2010-09-22 Combinaison de poudre sèche de tiotropium WO2011037550A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10787588A EP2480287A2 (fr) 2009-09-23 2010-09-22 Association de tiotropium sous forme de poudre sèche

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2009/07237 2009-09-23
TR2009/07237A TR200907237A2 (tr) 2009-09-23 2009-09-23 Tiotropyum kuru toz kombinasyonu

Publications (2)

Publication Number Publication Date
WO2011037550A2 true WO2011037550A2 (fr) 2011-03-31
WO2011037550A3 WO2011037550A3 (fr) 2011-09-15

Family

ID=43643869

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2010/000184 WO2011037550A2 (fr) 2009-09-23 2010-09-22 Combinaison de poudre sèche de tiotropium

Country Status (3)

Country Link
EP (1) EP2480287A2 (fr)
TR (1) TR200907237A2 (fr)
WO (1) WO2011037550A2 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418716A1 (fr) 1989-09-16 1991-03-27 Boehringer Ingelheim Kg Esters aminoalcohol d'acide thienylcarboxyliques leurs produits quaternaires, leur préparation et l'utilisation de ces composés
GB2242163A (en) 1990-03-20 1991-09-25 Kenrick & Jefferson Ltd Parking voucher, ticket or card.
US6475467B1 (en) 1998-08-04 2002-11-05 Jago Research Ag Medicinal aerosol formulations

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8712251D0 (en) * 1987-05-23 1987-07-01 Fisons Plc Formulation
GB0009592D0 (en) * 2000-04-18 2000-06-07 Glaxo Group Ltd Respiratory combinations
UA76435C2 (en) * 2000-10-31 2006-08-15 Boehringer Ingelheim Pharma Inhalation formulation of tiotropium salt
WO2006076222A2 (fr) * 2005-01-10 2006-07-20 Glaxo Group Limited Formulations pharmaceutiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418716A1 (fr) 1989-09-16 1991-03-27 Boehringer Ingelheim Kg Esters aminoalcohol d'acide thienylcarboxyliques leurs produits quaternaires, leur préparation et l'utilisation de ces composés
GB2242163A (en) 1990-03-20 1991-09-25 Kenrick & Jefferson Ltd Parking voucher, ticket or card.
US6475467B1 (en) 1998-08-04 2002-11-05 Jago Research Ag Medicinal aerosol formulations

Also Published As

Publication number Publication date
EP2480287A2 (fr) 2012-08-01
TR200907237A2 (tr) 2011-04-21
WO2011037550A3 (fr) 2011-09-15

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