EP1959942A1 - Procédé pour le traitement de la dyspnée comprenant l' administration combinée de sels de tiotropium et de sels de salmétérol - Google Patents
Procédé pour le traitement de la dyspnée comprenant l' administration combinée de sels de tiotropium et de sels de salmétérolInfo
- Publication number
- EP1959942A1 EP1959942A1 EP06792646A EP06792646A EP1959942A1 EP 1959942 A1 EP1959942 A1 EP 1959942A1 EP 06792646 A EP06792646 A EP 06792646A EP 06792646 A EP06792646 A EP 06792646A EP 1959942 A1 EP1959942 A1 EP 1959942A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- salts
- salmeterol
- tiotropium
- dyspnea
- 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.)
- Withdrawn
Links
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 title claims abstract description 22
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical class C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 150000003839 salts Chemical class 0.000 title claims abstract description 19
- 229960004017 salmeterol Drugs 0.000 title claims abstract description 14
- 208000000059 Dyspnea Diseases 0.000 title claims abstract description 13
- 206010013975 Dyspnoeas Diseases 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title description 5
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000001530 fumaric acid Chemical class 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000001117 sulphuric acid Chemical class 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical class NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 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 3
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical class O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
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- 235000014655 lactic acid Nutrition 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 2
- 239000013543 active substance Substances 0.000 description 36
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- 238000002360 preparation method Methods 0.000 description 14
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
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- 229940110309 tiotropium Drugs 0.000 description 7
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- 150000007513 acids Chemical class 0.000 description 5
- -1 dextranes) Chemical class 0.000 description 5
- 229940037001 sodium edetate Drugs 0.000 description 5
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- 239000003963 antioxidant agent Substances 0.000 description 4
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- 235000010323 ascorbic acid Nutrition 0.000 description 4
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- 235000015165 citric acid Nutrition 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
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- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
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- 150000007522 mineralic acids Chemical class 0.000 description 3
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
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- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 2
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- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Chemical class CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001294 propane Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- 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
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to the use of tiotropium salts in combination with salts of salmeterol for the manufacture of a medicament for the treatment of dyspnea.
- Medicament combinations based on anticholinergics and beta-2-agonists are known in the art.
- the combination of long acting anticholinergics with long acting beta-2- agonists is disclosed in WO00/69468.
- the specific combination of tiotropium salts with salts of salmeterol is also known from WO 02/38154 and WO 04/058233.
- compositions comprising salts of tiotropium and salts of salmeterol.
- Dyspnea is a term known in the art.
- the term dyspnea is used to characterize a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social and environmental factors, and may induce secondary physiological and behavioural responses (see hereto: American Thoracic Society, Dyspnea: mechanisms, assessment, and management. A consensus statement, Am J Respir Crit care Med 159: 321 -340, 1999).
- the invention relates to the use of a tiotropium salt 1 together with a salmeterol salt 2 for the manufacture of a medicament for the treatment of dyspnea.
- the invention relates to the use of a tiotropium salt 1 for the manufacture of a salmeterol salt 2 containing medicament for the treatment of dyspnea.
- the invention relates use of a salmeterol salt 2 for the manufacture of a tiotropium salt 1. containing medicament for the treatment of dyspnea.
- the invention in another embodiment relates to a method for the treatment of dyspnea, comprising the administration of a therapeutically effective amount of a tiotropium salt ⁇ together with a therapeutically effective amount of a salmeterol salt 2 to a patient in need thereof.
- therapeutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher or clinician.
- the combined administration of a 1 and 2 may occur via a single active substance formulation but also via the successive administration of the two active substances in separate formulations. It is preferred according to the invention to administer the two active substance ingredients simultaneously in a single formulation.
- tiotropium is intended to refer to the free cation (V) for the purposes of the present invention.
- the tiotropium salts 1 which may be used within the scope of the present invention include the compounds which contain, in addition to the cation tiotropium V_ an anion with a single negative charge, preferably an anion selected from among chloride, bromide, iodide, methanesulphonate and para- toluenesulphonate.
- the methanesulphonate, chloride, bromide or iodide are preferred, the methanesulphonate or bromide being of particular importance.
- Tiotropium bromide is of exceptional importance according to the invention.
- salts of salmeterol 2 are meant, according to the invention, pharmaceutically acceptable acid addition salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, xinafonic acid or maleic acid.
- the salmeterol salts 2 selected from among hydrochloride, hydrobromide, sulphate, phosphate and xinafoate are preferred.
- the salmeterol xinafoate salt 2 is particularly preferred.
- the ingredients 1 and 2 may be in the form of their enantiomers, mixtures of enantiomers or in the form of the racemates.
- the active substances 1 and 2 may optionally be in the form of the solvates or hydrates thereof.
- Suitable inhalable preparations for the administration of 1 and 2 include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases.
- Inhalable powders according to the invention containing the active substance combination of 1 and 2 may consist solely of the abovementioned active substances or of a mixture of the abovementioned active substances with physiologically acceptable adjuvants.
- the preparations may contain the active substance combination of ⁇ _ and 2 either together in one preparation or in two separate preparations.
- the proportions in which the two active substances 1_ and 2 may be used in the combinations of active substances according to the invention are variable.
- the active substances ! and 2 may optionally be in the form of the solvates or hydrates thereof.
- the weight ratios which may be used for the purposes of the present invention vary on account of the different molecular weights of the various salt forms. Consequently, the weight ratios specified hereinafter are based on the tiotropium cation V and the free base of salmeterol 2[.
- the combinations of active substances according to the invention may contain V_ and 2 ⁇ in weight ratios in the range from 1 :300 to 30:1 , preferably from 1 :230 to 20:1 , particularly preferably from 1 : 150 to 10: 1 , more preferably from 1 :50 to 5: 1 , particularly preferably from 1 :35 to 2:1.
- preferred combinations of 1 and 2 according to the invention may contain tiotropium V_ and salmeterol T_ in the following weight ratios: 1 :40; 1 :20; 1 :11.1 ; 1 :10; 1 :5.6; 1 :5; 1 :2.8; 1 :2.5; 1 :1.4; 1 :1.25; 1.44:1 , 1.6:1.
- compositions according to the invention containing the combinations of ⁇ _ and 2 are normally used so that tiotropium V_ and salmeterol 2 ⁇ are administered together in doses of 0.01 to 10000 ⁇ g, preferably 0.1 to 2000 ⁇ g, particularly preferably from 1 to 1000 ⁇ g, more preferably from 5 to 500 ⁇ g, preferably, according to the invention, from 10 to 200 ⁇ g, preferably from 20 to 100 ⁇ g, most preferably from 30 to 70 ⁇ g per single dose.
- combinations of ⁇ _ and 2 according to the invention contain an amount of tiotropium V and salmeterol 2 ⁇ such that the total dosage per single dose is 30 ⁇ g, 35 ⁇ g, 45 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 90 ⁇ g, 105 ⁇ g, 110 ⁇ g, 110 ⁇ g, 140 ⁇ g or similar.
- the active substances V and 21 are present in the weight rations described hereinbefore.
- the combinations of 1 and 2 according to the invention may contain an amount of tiotropium V and salmeterol 2
- the combinations of active substances 1 and 2 according to the invention are preferably administered by inhalation.
- the ingredients 1 and 2 have to be incorporated in inhalable preparations.
- Suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases.
- Inhalable powders according to the invention containing the active substance combination of 1 and 2 may consist solely of the abovementioned active substances or of a mixture of the abovementioned active substances with physiologically acceptable adjuvants.
- propellant- free solutions for inhalation also includes concentrates or sterile, ready-to-use solutions for inhalation.
- the preparations according to the invention may contain the active substance combination of 1 and 2 either together in one preparation or in two separate preparations. These preparations which may be used within the scope of the present invention are described in detail in the following section of the specification.
- the powders for inhalation according to the invention may contain 1 and 2 either on their own or in admixture with suitable physiologically harmless adjuvants.
- physiologically harmless adjuvants may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextranes), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these adjuvants with one another.
- monosaccharides e.g. glucose or arabinose
- disaccharides e.g. lactose, saccharose, maltose
- oligo- and polysaccharides e.g. dextranes
- polyalcohols e.g. sorbitol, mannitol, xylitol
- salts e.g. sodium chloride, calcium carbonate
- Mono- or disaccharides are preferably used, the use of lactose or glucose, particularly but not exclusively in the form of their hydrates, being preferred.
- the particularly preferred adjuvant according to the invention is lactose, most preferably lactose monohydrate.
- the adjuvants have a maximum mean particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, particularly preferably between 15 and 80 ⁇ m. If desired it may be useful to add finer adjuvant fractions having a mean particle size of 1 to 9 ⁇ m to the abovementioned adjuvants. These latter finer adjuvants are also selected from the abovementioned group of adjuvants which may be used. Finally, in order to prepare the powders for inhalation according to the invention, micronised active substance 1. and 2, preferably having an average particle size of 0.5 to 10 ⁇ m, particularly preferably from 1 to 6 ⁇ m, is added to the adjuvant mixture.
- the powders for inhalation according to the invention may be prepared and administered either in the form of a single powder mixture which contains both ⁇ _ and 2 , or in the form of separate inhalable powders which contain only 1 and 2.
- the inhalable powders according to the invention can be administered using inhalers known from the prior art.
- Inhalable powders according to the invention which contain a physiologically harmless adjuvant in addition to 1 and 2 may for example be administered using inhalers which meter a single dose from a reservoir by means of a measuring chamber, as described in US 4570630A, or by other devices as described in DE 36 25 685 A.
- the inhalable powders according to the invention which contain physiologically harmless adjuvant in addition to 1 and 2 are packed into capsules (to form so-called inhalettes), which are used in inhalers such as those described, for example, in WO 94/28958.
- lnhalable aerosols containing propellant comprising the active substance combinations of 1 and 2 according to the invention: lnhalable aerosols containing propellant according to the invention may contain 1 and 2 dissolved in the propellent gas or in dispersed form. 1 and 2 may be present in separate preparations or in a combined preparation, with ⁇ _ and 2 either both dissolved, both dispersed or only one component dissolved while the other is present in dispersed form.
- propellent gases which can be used to prepare the inhalable aerosols according to the invention are known from the prior art.
- Suitable propellent gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
- the abovementioned propellent gases may be used on their own or in mixtures thereof.
- Particularly preferred propellent gases are halogenated alkane derivatives selected from among TG11 , TG 12, TG 134a and TG227.
- TG134a (1 ,1 ,1 ,2-tetrafluoroethane)
- TG227 (1 ,1 ,1 ,2,3,3,3- heptafluoropropane) and mixtures thereof are preferred according to the invention.
- the propellant-gas-containing inhalable aerosols according to the invention may also contain other ingredients such as cosolvents, stabilisers, surface-active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.
- the propellant-gas-containing inhalable aerosols according to the invention may contain up to 5 % by weight of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 % by weight , 0.01 to 3 % by weight , 0.015 to 2 % by weight , 0.1 to 2 % by weight , 0.5 to 2 % by weight or 0.5 to 1 % by weight of active substance ⁇ _ and/or 2.
- the particles of active substance preferably have a mean particle size of up to 10 ⁇ m, preferably from 0.1 to 5 ⁇ m, particularly preferably from 1 to 5 ⁇ m.
- the present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the abovementioned propellant-gas-containing inhalable aerosols according to the invention.
- Suitable cartridges and methods of filling these cartridges with the propellant-gas-containing inhalable aerosols according to the invention are known from the prior art.
- Suitable solvents for this include aqueous or alcoholic, preferably ethanolic solutions.
- the solvent may be water on its own or a mixture of water and ethanol.
- the relative proportion of ethanol to water is not restricted, but the maximum limit is preferably up to 70 percent by volume, particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remaining percent by volume are made up with water.
- the preferred solvent is water without the addition of ethanol.
- the solutions containing 1 and 2 separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, particularly preferably 2.5 to 3.5, with suitable acids.
- inhalable solutions according to the invention which contain 1 and 2 together have a pH of about 2.9.
- This pH may be achieved using acids selected from among inorganic or organic acids.
- inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
- particularly suitable organic acids include: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and others.
- Preferred inorganic acids are hydrochloric acid and sulphuric acid.
- the acids which are forming an acid addition salt with the active substance or, in the case of combined preparations, with one of the active substances are also possible.
- organic acids ascorbic acid, fumaric acid and citric acid are preferred.
- mixtures of the abovementioned acids may also be used, particularly in the case of acids which have properties other than their acidifying properties, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example.
- hydrochloric acid to adjust the pH.
- EDTA editic acid
- sodium edetate sodium edetate
- the content based on sodium edetate is less than 100 mg / 100 ml, preferably less than 50 mg/100 ml, most preferably less than
- Co-solvents and/or other adjuvants may be added to the propellant-free inhalable solutions according to the invention.
- Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropylalcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
- excipients and additives is meant, in this context, any pharmacologically acceptable substance which is not an active substance, but can be formulated together with the active substance(s) in the pharmacologically suitable solvent, in order to improve the qualitative properties of the active substance formulation.
- these substances do not have any appreciable pharmacological effects or at least have no undesirable effects in the context of the intended therapy.
- the excipients and additives include e.g. surfactants such as e.g.
- soya lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or extend the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art.
- the additives also include pharmacologically harmless salts such as sodium chloride, for example, as isotonic agents.
- the preferred adjuvants include antioxidants, such as ascorbic acid, for example, unless it has already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body.
- Preservatives can be used to protect the formulation from contamination with pathogens. Suitable preservatives are those known from the prior art, particularly cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
- the abovementioned preservatives are preferably present in concentrations of up to 50mg/100ml, particularly between 5 and 20 mg/100ml.
- Preferred formulations contain only benzalkonium chloride and sodium edetate in addition to the solvent water and the active substance combination of 1 and 2. In another preferred embodiment, sodium edetate is omitted.
- the propellant-free inhalable solutions according to the invention may be administered particularly using inhalers which are able to nebulise a small amount of a liquid formulation in the therapeutically necessary dose within a few seconds to form an aerosol suitable for therapeutic inhalation.
- nebulisers are preferred in which a quantity of less than 100 ⁇ l_, preferably less than 50 ⁇ l_, particularly preferably between 20 and 30 ⁇ l_ of active substance solution can be nebulised, preferably in one operation, to produce an aerosol having an average particle size of less than 20 ⁇ m, preferably less than 10 ⁇ m, in such a way that the inhalable part of the aerosol corresponds to the therapeutically effective amount.
- a device of this kind for the propellant-free administration of a metered amount of a liquid pharmaceutical composition for inhalation is described in detail, for example, in International Patent Application WO 91/14468 and also in WO 97/12687 (particularly Figures 6a and 6b).
- the nebulisers (devices) described therein are also known by the name Respimat ® .
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
La présente invention concerne l’utilisation de sels de tiotropium associés à des sels de salmétérol pour la fabrication d’un médicament destiné à traiter la dyspnée.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06792646A EP1959942A1 (fr) | 2005-08-06 | 2006-08-02 | Procédé pour le traitement de la dyspnée comprenant l' administration combinée de sels de tiotropium et de sels de salmétérol |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05107267 | 2005-08-06 | ||
| EP06792646A EP1959942A1 (fr) | 2005-08-06 | 2006-08-02 | Procédé pour le traitement de la dyspnée comprenant l' administration combinée de sels de tiotropium et de sels de salmétérol |
| PCT/EP2006/064957 WO2007017437A1 (fr) | 2005-08-06 | 2006-08-02 | Procédé pour le traitement de la dyspnée comprenant l’administration combinée de sels de tiotropium et de sels de salmétérol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1959942A1 true EP1959942A1 (fr) | 2008-08-27 |
Family
ID=37056590
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP06792646A Withdrawn EP1959942A1 (fr) | 2005-08-06 | 2006-08-02 | Procédé pour le traitement de la dyspnée comprenant l' administration combinée de sels de tiotropium et de sels de salmétérol |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1959942A1 (fr) |
| JP (1) | JP2009504603A (fr) |
| CA (1) | CA2617897A1 (fr) |
| WO (1) | WO2007017437A1 (fr) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7250426B2 (en) | 2002-11-29 | 2007-07-31 | Boehringer Ingelheim Pharma Gmbh & Co Kg | Tiotropium-containing pharmaceutical combination for inhalation |
| CN108451936A (zh) * | 2018-06-19 | 2018-08-28 | 杭州勃锐思莫生物医药科技有限责任公司 | 一种噻托溴铵吸入制剂在制备治疗肺癌药物中应用 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19921693A1 (de) * | 1999-05-12 | 2000-11-16 | Boehringer Ingelheim Pharma | Neuartige Arzneimittelkompositionen auf der Basis von anticholinergisch wirksamen Verbindungen und ß-Mimetika |
| US20040002548A1 (en) * | 1999-05-12 | 2004-01-01 | Boehringer Ingelheim Pharma Kg | Medicament compositions containing anticholinergically-effective compounds and betamimetics |
| DE10056104A1 (de) * | 2000-11-13 | 2002-05-23 | Boehringer Ingelheim Pharma | Neue Arzneimittelkompositionen auf der Basis von Tiotropiumsalzen und Salzen des Salmeterols |
| DE10209243A1 (de) * | 2002-03-04 | 2003-09-18 | Boehringer Ingelheim Pharma | Neue Arzneimittelkombination zur Inhalation |
| CA2459493C (fr) * | 2001-09-14 | 2011-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Nouveaux composes pharmaceutiques d'inhalation |
| DE10145438A1 (de) * | 2001-09-14 | 2003-04-03 | Boehringer Ingelheim Pharma | Neue Arzneimittel zur Inhalation |
| UA83813C2 (ru) * | 2002-12-20 | 2008-08-26 | Бёрингер Ингельхайм Фарма Гмбх & Ко. Кг | Порошковое лекарственное средство, которое содержит соль тиотропия и ксинафоат салметерола |
| US20040152720A1 (en) * | 2002-12-20 | 2004-08-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powdered medicaments containing a tiotropium salt and salmeterol xinafoate |
-
2006
- 2006-08-02 CA CA002617897A patent/CA2617897A1/fr not_active Abandoned
- 2006-08-02 JP JP2008525547A patent/JP2009504603A/ja active Pending
- 2006-08-02 EP EP06792646A patent/EP1959942A1/fr not_active Withdrawn
- 2006-08-02 WO PCT/EP2006/064957 patent/WO2007017437A1/fr not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2007017437A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007017437A1 (fr) | 2007-02-15 |
| JP2009504603A (ja) | 2009-02-05 |
| CA2617897A1 (fr) | 2007-02-15 |
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