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
  • A61K31/395—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

Definitions

• the present invention relates to the process for the preparation of pharmaceutical formulations in dry powder form comprising tiotropium or pharmaceutically acceptable derivatives thereof in order to be used in symptomatic and/or prophylactic treatment of respiratory tract diseases, particularly asthma and COPD.
• Tiotropium is used in the treatment of respiratory tract diseases such as asthma and COPD.
• Tiotropium which has the chemical name of (1 ⁇ ,2 ⁇ ,4 ⁇ ,7 ⁇ )- 7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-
• the inventors have developed dry powder formulationswhich comprise tiotropiumand/or pharmaceutically acceptable derivatives thereof and good flow characteristics and have high homogeneitywherein dosing accuracy is ensured and sufficient amount of active agent can be delivered to the lungs.
• the present invention relates to the process for the preparation of pharmaceutical formulations in dry powder form comprising tiotropium and/or pharmaceutically acceptable derivatives thereof.
• the present invention relates to a process developed for production of a dry powder formulation comprising tiotropium. Said process comprises the following steps:
• the inventors have surprisingly seen that the dry powder formulations comprising tiotropium prepared in accordance with the process of the present invention have good flow characteristics and have high homogeneity resulting in dosing accuracy and delivery of the sufficient amount of active agent to the lungs.
• the excipient is divided into two fractions which are fine grained excipient and coarse grained excipient.
• Each fraction is micronized such that the average particle size of the fine grained excipient is in the range of ⁇ ⁇ to 30 ⁇ , preferably 2- 25 ⁇ and more preferably 5- 20 ⁇ .
• Total weight of the fine grained excipient is 3-55%, preferably 5%-50%, more preferably 10%-45% of the total weight of the formulation.
• Each fraction of the excipient divided into its fractions in the process of the present invention is micronized such that the average particle size of the coarse grained excipient is in the range of 20 ⁇ to 120 ⁇ , preferably 30- 100 ⁇ and more preferably 45- 95 ⁇ .
• Total weight of the coarse grained excipient is 40-95%, preferably 45%-90%, more preferably 50%-85% of the total weight of the formulation.
• the present invention relates to the process for the preparation of the pharmaceutical formulation comprising tiotropium in the dry powder form wherein the fine grained excipient having the average particle size in the range of 1 ⁇ to 30 ⁇ , preferably 2- 25 ⁇ and more preferably 5- 20 ⁇ is used.
• the present invention relates to the process for the preparation of the pharmaceutical formulation comprising tiotropium in the dry powder form wherein the fine grained excipient is used in an amount in the range of 3-55%, preferably 5%-50%, more preferably 10%-45% of the total weight of the formulation.
• the present invention relates to the process for the preparation of the pharmaceutical formulation comprising tiotropium in the dry powder form wherein the coarse grained excipient having the average particle size in the range of 20 ⁇ to 120 ⁇ , preferably 30- 100 ⁇ and more preferably 45- 95 ⁇ is used.
• the present invention relates to the process for the preparation of the pharmaceutical formulation comprising tiotropium in the dry powder form wherein the coarse grained excipient is used in an amount in the range of 40-95%, preferably 45%-90%, more preferably 50%-85% of the total weight of the excipient.
• Step II of the process of the present invention the coarse grained excipient and the fine grained excipient are weighed in a container.
• step III of the process of the present invention the coarse grained and fine grained excipients are mixed at 300- 3000 rpm, preferably 500- 2000 rpm for 30- 300 seconds, preferably 45- 180 seconds in the container and the mixture of coarse grained- fine grained excipient mixture is obtained.
• the present invention relates to the process for the preparation of the pharmaceutical formulation comprising tiotropium in the dry powder form wherein the coarse grained and fine grained excipients are mixed at 300- 3000 rpm, preferably 500- 2000 rpm for 30- 300 seconds, preferably 45- 180 seconds in the container and the mixture of coarse grained- fine grained excipient mixture is obtained.
• step IV of the process of the present invention a hole is digged in the mixture of coarse grained- fine grained excipient mixture and tiotropium active agent is poured into the hole, then it is covered by the excipient which was set aside while digging the hole. A mixture of tiotropium and the excipient is obtained in this step.
• Step V of the process of the present invention the tiotropium- excipient mixture obtained in Step IV is blended at 300- 3000 rpm, preferably 500- 2000 rpm for 1- 20 minutes, preferably 2- 10 minutes and the final dry powder mixture is obtained.
• the inventors have seen that blending tiotropium- excipient mixture at 300- 3000 rpm, preferably 500- 2000 rpm for 1- 20 minutes, preferably 2-10 minutes results in providing a homogenous formulation comprising tiotropium and delivery of sufficient drug to the lungs effectively.
• the present invention relates to the process for the preparation of the pharmaceutical formulation comprising tiotropium in the dry powder form wherein the tiotropium- excipient mixture obtained in Step IV is blended at 300- 3000 rpm, preferably 500- 2000 rpm for 1- 20 minutes, preferably 2-10 minutes and the final dry powder mixture is obtained.
• Step VI of the process of the present invention the final dry powder mixture is filled into the blister cavities of the blister package.
• the inventors When the dry powder formulation prepared in accordance with the process of the present invention is inhaled from blister, the inventors have found that an effective inhalation is performed in the case that cavity volume of the blister comprising the drug in dry powder form comprising tiotropium and/or pharmaceutically acceptable derivatives thereof is in the range of
• the present invention relates to the process characterized in that blister having cavity volume in the range of 18-30 mm , preferably in the range of 20 to 25 mm , more preferably in the range of 21-24 mm 3 is used.
• fullness ratio of the blister cavity used should be in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50-80% in order to inhale the formulation of the present invention from blister without any problem and in order to perform an effective inhalation.
• the present invention relates to the process characterized in that blister having fullness ratio in the range of 15-95%, preferably in the range of 20-85% and more preferably in the range of 50- 80% is used.
• the base and the lid sheets constituting the peelable blister strip pack, wherein the blisters comprising the dry powder formulation of the present invention are collocated, are sealed tightly by any suitable method in order to provide impermeability.
• the base and lid sheets constituting the peelable blister strip package comprising the dry powder formulation of the present invention are composed of many layers. Polymeric layers, aluminium foil and preferably Aclar® fluoropolymer film are among the layers constituting the base and the lid sheets.
• Desiccant agents added to the layers constituting blister strip package comprising dry powder formulation of the present invention are selected from silica gel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activated carbon, hydrophilic chyles.
• Polymeric layers in the base and lid sheets of peelable blister strip package comprising said dry powder formulation are made of the same or different polymers. Thickness of these polymeric layers varies depending on the type and characteristics of the polymeric material used. Therefore, thickness of the polymeric layer varies in the range of 15-55 ⁇ , preferably in the range of 20-30 ⁇ according to the type of the polymeric material used.
• the layer covering the inner surface of the cavity is a polymeric layer because ofthe fact that when the layer in contact with the dry powder formulation in the blister cavity is aluminium foil, some part of dry powder formulation adheres to the inner surface of the blister cavity due to porous structure of the aluminium foil and electrostatic forces and this causes uncontrolled dose inhalation.
• Polymers constituting the polymeric layer can preferably be selected from thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or synthetic polymers.
• tiotropiumactive agent having an average particle size in the range of 1 ⁇ to 10 ⁇ , preferably in the range of 1.5 ⁇ to 7.5 ⁇ , more preferably in the range of 1.5 ⁇ to 5 ⁇ has a significant contribution to the formulation obtained for having proper flow characteristics and for having dose uniformity and to delivery of the active agent to the lungs in sufficient amount.
• the present invention relates to the process for the preparation of the pharmaceutical formulation comprising tiotropiumin the dry powder form wherein tiotropium having average particle size in the range of 1 ⁇ to 10 ⁇ , preferably in the range of 1.5 ⁇ to 7.5 ⁇ ⁇ ⁇ , more preferably in the range of 1.5 ⁇ to 5 ⁇ is used as active agent.
• tiotropiumactive agent is used in an amount in the range of 2 to 60 ⁇ g, preferably in the range of 3 to 50 ⁇ g, more preferably in the range of 5 to 40 ⁇ g.
• the excipient is composed of fine grained excipient and coarse grained excipient.
• This excipient can be selected from monosaccharides (glucose etc.), disaccharides (lactose, saccharose, maltose or pharmaceutically acceptable hydrates, anhydrates or a combination thereof etc.), oligosaccharides and polysaccharides (dextrant etc.), polyalcohols (sorbitol, mannitol, xylitol etc.), salts (sodium chloride, calcium carbonate etc.) or a combination thereof.
• Fine grained and coarse grained excipients are preferably lactose, more preferably lactose anhydrate.
• the amount of the pharmaceutically acceptable excipient is in the range of 1-50 mg, preferably in the range of 2-40 mg, more preferably in the range of 5-35 mg.
• the dry powder medicament prepared according to the process of the present invention is used in the treatment of many respiratory diseases, particularly in allergic or non-allergic asthma, allergic rhinitis and chronic obstructive pulmonary disease (COPD). Accordingly, the dry powder formulation prepared according to the process of the present invention is used in the treatment of, but not limited to, asthma at any stages, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity, bronchiectasis, chronic obstructive pulmonary including emphysema and chronic bronchitis, respiratory diseases or lung diseases (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis, byssinosis.
• ALI acute lung injury
• ARDS acute respiratory distress syndrome
• COAD chronic obstructive pulmonary including em
• the dry powder formulation comprising tiotropium can be obtained by the process of the present invention comprising the following steps;
• lactose The entire amount of lactose is divided into two fractions which are fine grained lactose and coarse grained lactose,

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• Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Otolaryngology (AREA)
• Pulmonology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)

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• 2013
  • 2013-01-16 EP EP13738848.4A patent/EP2804591A2/de not_active Withdrawn
  • 2013-01-16 WO PCT/TR2013/000025 patent/WO2013109213A2/en active Application Filing
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