JP2006509802A - レバルブテロール塩 - Google Patents
レバルブテロール塩 Download PDFInfo
- Publication number
- JP2006509802A JP2006509802A JP2004559144A JP2004559144A JP2006509802A JP 2006509802 A JP2006509802 A JP 2006509802A JP 2004559144 A JP2004559144 A JP 2004559144A JP 2004559144 A JP2004559144 A JP 2004559144A JP 2006509802 A JP2006509802 A JP 2006509802A
- Authority
- JP
- Japan
- Prior art keywords
- levalbuterol
- tartrate
- pharmaceutical composition
- crystals
- ethanol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NDAUXUAQIAJITI-LBPRGKRZSA-N (R)-salbutamol Chemical class CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-LBPRGKRZSA-N 0.000 title claims abstract description 73
- 229950008204 levosalbutamol Drugs 0.000 claims abstract description 66
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims abstract description 50
- 239000013078 crystal Substances 0.000 claims abstract description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 72
- 239000000203 mixture Substances 0.000 claims description 35
- 238000009472 formulation Methods 0.000 claims description 28
- 239000000443 aerosol Substances 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 239000002245 particle Substances 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000003380 propellant Substances 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000006184 cosolvent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 229940124630 bronchodilator Drugs 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 229940112141 dry powder inhaler Drugs 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical group FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 3
- 230000007883 bronchodilation Effects 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims 1
- 239000000243 solution Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000843 powder Substances 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- VNVNZKCCDVFGAP-FPDJQMMJSA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 VNVNZKCCDVFGAP-FPDJQMMJSA-N 0.000 description 6
- 229940076884 levalbuterol tartrate Drugs 0.000 description 6
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- OWNWYCOLFIFTLK-YDALLXLXSA-N 4-[(1r)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol;hydron;chloride Chemical compound Cl.CC(C)(C)NC[C@H](O)C1=CC=C(O)C(CO)=C1 OWNWYCOLFIFTLK-YDALLXLXSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 4
- 229940087642 levalbuterol hydrochloride Drugs 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229940057282 albuterol sulfate Drugs 0.000 description 3
- -1 at least 0.4% Chemical compound 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- BLUGYPPOFIHFJS-UUFHNPECSA-N (2s)-n-[(2s)-1-[[(3r,4s,5s)-3-methoxy-1-[(2s)-2-[(1r,2r)-1-methoxy-2-methyl-3-oxo-3-[[(1s)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidin-1-yl]-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]-3-methyl-2-(methylamino)butanamid Chemical compound CN[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 BLUGYPPOFIHFJS-UUFHNPECSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- ZRVIYEJYXIDATJ-UHFFFAOYSA-N 4-Heptyloxybenzoic acid Chemical compound CCCCCCCOC1=CC=C(C(O)=O)C=C1 ZRVIYEJYXIDATJ-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 208000007934 ACTH-independent macronodular adrenal hyperplasia Diseases 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940125388 beta agonist Drugs 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- 238000012430 stability testing Methods 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- KXGFMDJXCMQABM-UHFFFAOYSA-N 2-methoxy-6-methylphenol Chemical compound [CH]OC1=CC=CC([CH])=C1O KXGFMDJXCMQABM-UHFFFAOYSA-N 0.000 description 1
- VNVNZKCCDVFGAP-NMFAMCKASA-N 4-[(1R)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol 2,3-dihydroxybutanedioic acid Chemical compound OC(C(O)C(O)=O)C(O)=O.CC(C)(C)NC[C@H](O)c1ccc(O)c(CO)c1.CC(C)(C)NC[C@H](O)c1ccc(O)c(CO)c1 VNVNZKCCDVFGAP-NMFAMCKASA-N 0.000 description 1
- NDAUXUAQIAJITI-GFCCVEGCSA-N 4-[(1s)-2-(tert-butylamino)-1-hydroxyethyl]-2-(hydroxymethyl)phenol Chemical compound CC(C)(C)NC[C@@H](O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-GFCCVEGCSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- BNPSSFBOAGDEEL-UHFFFAOYSA-N albuterol sulfate Chemical compound OS(O)(=O)=O.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1.CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 BNPSSFBOAGDEEL-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003822 epoxy resin Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920001568 phenolic resin Polymers 0.000 description 1
- 239000005011 phenolic resin Substances 0.000 description 1
- 238000005498 polishing Methods 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000004043 trisaccharides Chemical class 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229940061637 xopenex Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
- C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
- C07C215/60—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- 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
-
- 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
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0001—Details of inhalators; Constructional features thereof
- A61M15/002—Details of inhalators; Constructional features thereof with air flow regulating means
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
-
- 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
-
- 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
-
- 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
- A61P11/08—Bronchodilators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K3/00—Materials not provided for elsewhere
- C09K3/30—Materials not provided for elsewhere for aerosols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/04—Liquids
- A61M2202/0468—Liquids non-physiological
- A61M2202/0484—Alcohol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/04—Liquids
- A61M2202/0468—Liquids non-physiological
- A61M2202/0488—Surfactant, e.g. for the lung
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2202/00—Special media to be introduced, removed or treated
- A61M2202/06—Solids
- A61M2202/064—Powder
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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Abstract
Description
MDIを用いて患者の肺へ送達するための活性成分の粒子は、幾つかの非常に厳しい基準を満たさなければならない。患者は、肺深くに、安全で有効な量の粒子を再現性ある用量で摂取可能である必要がある。従って、活性成分の粒子が、安定で、許容される分布範囲内の顕微鏡サイズである必要がある。特に、それらが凝集してより大きな粒子のクラスターになることに抵抗し、そして温度と相対湿度の異なる条件下で、または製剤成分、例えば担体もしくは噴射剤の存在下で保存する際に、サイズもしくは形態が変化しない必要がある。好ましくは、それらは空力的に有利な形状、例えば繊維状の形状を有するべきである(Crowder T. M., et al., Pharmaceutical Research, Vol. 19, No. 3, March 2002)。
1つの態様によって、従って、本発明はレバルブテロール L−酒石酸塩を提供する。
レバルブテロール L−酒石酸塩は、ヘミ酒石酸塩であり、言い換えればそれはレバルブテロール1モル当たりL−酒石酸半モルを含む。
実施例1の方法によって得られる結晶は、おおよそ長さ10〜50ミクロン、幅0.2〜4ミクロン(顕微鏡試験による)の針状であり、そして極めて少量の残留物を含むことが見出されている。エタノール含量(結晶溶媒より)は、乾燥後、約0.5重量%であることが見出された。
減少した(0.3%)エタノール含量を含む結晶は、微細化後に安定な粒子サイズ分布を容易に与えないことが見出されている。
従って、別の態様によって、本発明は、薬学的に許容される担体と共に、本明細書中で記載したレバルブテロール L−酒石酸塩を含む医薬組成物を提供する。
好ましくは、キャニスターの内部表面を、例えば保護ポリマーでコートする。吸入器は、好ましくは、0.25から0.58mmの、より好ましくは0.25から0.48mmの、例えば0.30から0.36mmの範囲の直径を有する口を有する。
本発明は、従って、上記のレバルブテロール L−酒石酸塩の乾燥粉末エアゾール製剤を含む乾燥粉末リザーバー、および定量チャンバーを含む、多回用量乾燥粉末吸入器を提供する。
好ましくは、レバルブテロール L−酒石酸塩が、パラジウム/炭素の存在下で、R−ベンジルアルブテロールを水素化することによって製造される。R−ベンジルアルブテロールからこのように製造したレバルブテロールから出発して製造した結晶は、高純度であることが見出されている。
(R)−ベンジルアルブテロールを、米国特許第 5,545,745 号に記載された方法によって得てもよい。
好ましくは、レバルブテロール L−酒石酸塩の微細化された結晶を、定用量吸入器を用いた吸入によって患者に投与する。
さらに別の態様によって、本発明は、気管支拡張剤として使用するための医薬の製造において、レバルブテロール L−酒石酸塩の使用を提供する。
下記の実施例は本発明を説明する。
結晶形のレバルブテロール L−酒石酸塩の製造
下記において、エタノールは、5%メタノールで変性させたエタノールである市販の溶媒を言う。
L−酒石酸(4.11kg)およびエタノール(21.9kg)を一次リアクターに充填した。次にリアクターの内容物を20から25℃の範囲の温度で激しく撹拌し、透明な溶液を形成した。次に溶液を使用するまで保存した。
レバルブテロール L−酒石酸塩の結晶の微細化
実施例1の方法によって得られるレバルブテロール L−酒石酸塩の結晶を、手作業の篩過によって粉砕した。次に篩過した物質を4インチ(10.16cm)の pancake-style fluid energy mill を用いて、ベンチュリ圧力50psi(3.45bar)およびミル圧力100psi(6.895bar)で微細化した。ミル・オペレーターは、振動フィーダーを用いて、微細化していないレバルブテロール L−酒石酸塩を、1.4±0.4kg/時の速度で、ミルに供給する。
必要量の脱水したエタノール(約94%)の一部を、フィルター通した窒素で前もって清浄化し、適切な風袋重量測定済み製剤ベッセルに加える。必要な脱水したエタノールですすぐ(定量的な輸送を確実にする)目的で、オレイン酸を脱水エタノールを含む製剤ベッセルに加える。ベース・ミキサー(約250rpm)を開始し、バッチを約1分間ホモジナイズする。次にベッセルおよび内容物を約2〜6℃まで冷却する。次にベース・ミキサーのスピードを約100rpmまで減らし、微細化したレバルブテロール L−酒石酸塩をベッセルに注意深く加える。次にベース・ミキサーを約250rpmに戻し、バッチを約10分間ホモジナイズする。次に脱水したエタノールの残りを、必要な重量に達するまでバッチに加え、次に約250rpmで約10分間撹拌する。次にベッセルおよび内容物を冷却し(2〜6℃)、この温度を次の充填プロセスの間中維持する。
安定性試験は、上記のように製造されたバッチの、1作動当たり45μgおよび90μgのバッチで行った。結果は以下の通りである。
25℃/60%RH, バルブ方向:上;
25℃/60%RH, バルブ方向:下;
40℃/75%RH, バルブ方向:上;
40℃/75%RH, バルブ方向:下.
結果を以下に表に示す。
空力的直径:対照の粒子と同じ最終沈降速度を有する単位密度球の直径。それを用いて、呼吸管において該粒子がどこで沈積するかを予測する。
空力的(同等)直径:対照の粒子と同じ重力沈降速度を有する単位密度球の直径。1つの空力学直径は、粒子の形、凹凸度(roughness)、および空力的抵抗を考慮する。ガスによる粒子の移動のために用いられる。
幾何標準偏差(GSD):対数正規分布における分散の測定値(常に1.0以上)。
質量中位空力的直径(MMAD):幾何平均空力的直径。50重量%の粒子がMMADより小さく、50重量%が大きい。
微細粒子フラクション(fpf):Anderson Cascade impactor のフィルターに段階3で集められた、放出された投与の割合。
相対標準偏差(RSD):
1. Aerosol Measurement: Principles, Techniques and Applications. Edited by Klaus Willeke and Paul A. Baron. Van Nostrand Reinhold, New York, 1993.
2. Fundamentals of Aerosol Sampling. Gregory D. Wight. Lewis Publishers, CRC Press, 1994.
Claims (27)
- レバルブテロール L−酒石酸塩。
- 結晶形である、請求項1に記載のレバルブテロール L−酒石酸塩。
- 0.3から0.7%のエタノールを含む、請求項2に記載のレバルブテロール L−酒石酸塩。
- 微細化された形態である、請求項2または3に記載のレバルブテロール L−酒石酸塩。
- 針状粒子の形態である、請求項4に記載のレバルブテロール L−酒石酸塩。
- 薬学的に許容される担体と共に、請求項1から5の何れか1項に記載のレバルブテロール L−酒石酸塩を含む、医薬組成物。
- 定用量吸入器を用いた投与に適合させたエアゾール製剤である、請求項6に記載の医薬組成物であって、該エアゾール製剤が結晶形のレバルブテロール L−酒石酸塩および噴射剤を含む、医薬組成物。
- 噴射剤が、1,1,1,2−テトラフルオロエタンである、請求項7に記載の医薬組成物。
- さらに界面活性剤を含む、請求項7または8に記載の医薬組成物。
- さらに共溶媒を含む、請求項7から9の何れか1項に記載の医薬組成物。
- 共溶媒がエタノールである、請求項10に記載の医薬組成物。
- 請求項7から11の何れか1項に定義されたエアゾール製剤を含むキャニスター(canister)、定量バルブ、およびバルブステムを含む、定用量吸入器。
- 乾燥粉末吸入器もしくは注入器を用いた投与に適合させた、請求項6に記載の医薬組成物。
- レバルブテロール L−酒石酸塩の結晶の製造方法であって、レバルブテロールの溶液をL−酒石酸の溶液と混合し、レバルブテロール L−酒石酸塩の結晶を回収することを含む方法。
- それぞれの溶液の溶媒がエタノールを含む、請求項13に記載の方法。
- 結晶化条件が、10から50ミクロンの長さおよび0.2から4ミクロンの幅を有する結晶を提供するよう選択される、請求項14または15に記載の方法。
- レバルブテロール L−酒石酸塩が、パラジウム/炭素の存在下で、R−ベンジルアルブテロールを水素化することによって製造されたものである、請求項14から16の何れか1項に記載の方法。
- 水素化が、他の官能基を過剰に還元することなく、少なくとも99.9%のR−ベンジルアルブテロールを変換するよう選択された条件下で行われる、請求項16に記載の方法。
- 結晶を乾燥し、微細化し、該結晶化および乾燥の条件が、微細化後に針状粒子を得るよう選択される、請求項14から18の何れか1項に記載の方法。
- 請求項13から19の何れか1項に記載の方法によって得られる、すべてのレバルブテロール L−酒石酸塩結晶。
- 気管支拡張が必要な患者において気管支拡張を起こす方法であって、有効量のレバルブテロール L−酒石酸塩を投与することを含む方法。
- レバルブテロール L−酒石酸塩の微細化された結晶が、定用量吸入器を用いて吸入することによって投与される、請求項21に記載の方法。
- 治療に使用するための、レバルブテロール L−酒石酸塩。
- 気管支拡張剤として使用するための医薬の製造における、レバルブテロール L−酒石酸塩の使用。
- 気管支拡張剤として使用するための、レバルブテロール L−酒石酸塩および薬学的に許容される担体を含む医薬組成物。
- 本明細書中の実施例1および実施例2に記載されているのと実質的に同じ方法によって製造される、すべてのレバルブテロール L−酒石酸塩の結晶。
- 本明細書中の実施例1および実施例2に記載されているのと実質的に同じ方法によって製造されるレバルブテロール L−酒石酸塩の結晶を含み、かつ本明細書中の実施例3の表に記載されているのと実質的に同じ組成を有する医薬組成物。
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US7579505B2 (en) | 2004-12-17 | 2009-08-25 | Cipla Limited | Crystalline levosalbutamol sulphate and polymorphic forms thereof |
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WO2021188809A1 (en) * | 2020-03-19 | 2021-09-23 | Cai Gu Huang | Inhalable formulation of a solution containing levalbuterol tartrate |
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- 2011-03-11 CY CY20111100273T patent/CY1111330T1/el unknown
- 2011-04-14 IL IL212369A patent/IL212369A/en active IP Right Grant
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2012
- 2012-10-02 US US13/633,801 patent/US20130028845A1/en not_active Abandoned
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2013
- 2013-04-29 US US13/873,084 patent/US8765153B2/en not_active Expired - Lifetime
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2014
- 2014-05-21 US US14/283,754 patent/US20150071969A1/en not_active Abandoned
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2016
- 2016-01-22 US US15/003,883 patent/US20160368858A1/en not_active Abandoned
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2017
- 2017-10-18 US US15/786,917 patent/US20180222845A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11509433A (ja) * | 1995-04-14 | 1999-08-24 | グラクソ、ウェルカム、インコーポレーテッド | アルブテロール用計量投与用吸入器 |
CN1382685A (zh) * | 2001-04-26 | 2002-12-04 | 中国科学院成都有机化学研究所 | R-沙丁胺醇酒石酸盐的制备方法 |
Non-Patent Citations (1)
Title |
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JPN6010010592, 新・薬剤学総論, 1987, 改訂第3版, p.30 * |
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