TW438605B - New aqueous pharmaceutical composition for the production of propellant-free aerosols - Google Patents
New aqueous pharmaceutical composition for the production of propellant-free aerosols Download PDFInfo
- Publication number
- TW438605B TW438605B TW086119428A TW86119428A TW438605B TW 438605 B TW438605 B TW 438605B TW 086119428 A TW086119428 A TW 086119428A TW 86119428 A TW86119428 A TW 86119428A TW 438605 B TW438605 B TW 438605B
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- Taiwan
- Prior art keywords
- pharmaceutical composition
- patent application
- chinese
- scope
- active ingredient
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- 239000000443 aerosol Substances 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000243 solution Substances 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000004480 active ingredient Substances 0.000 claims abstract description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000008139 complexing agent Substances 0.000 claims abstract description 17
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 229960005070 ascorbic acid Drugs 0.000 claims abstract description 6
- 235000010323 ascorbic acid Nutrition 0.000 claims abstract description 6
- 239000011668 ascorbic acid Substances 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 11
- 230000002079 cooperative effect Effects 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- -1 gadolinium dimethylammonium chloride Chemical compound 0.000 claims description 8
- 229960001361 ipratropium bromide Drugs 0.000 claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 229960002052 salbutamol Drugs 0.000 claims description 6
- 239000003380 propellant Substances 0.000 claims description 5
- AWRLZJJDHWCYKN-UHFFFAOYSA-N 5-bromo-2-ethoxy-3-nitropyridine Chemical compound CCOC1=NC=C(Br)C=C1[N+]([O-])=O AWRLZJJDHWCYKN-UHFFFAOYSA-N 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- 238000012937 correction Methods 0.000 claims description 4
- 229960001037 fenoterol hydrobromide Drugs 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims description 3
- 239000000808 adrenergic beta-agonist Substances 0.000 claims description 3
- 239000000043 antiallergic agent Substances 0.000 claims description 3
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 3
- 229940125715 antihistaminic agent Drugs 0.000 claims description 3
- 239000000739 antihistaminic agent Substances 0.000 claims description 3
- 230000003454 betamimetic effect Effects 0.000 claims description 3
- 239000000812 cholinergic antagonist Substances 0.000 claims description 3
- 229940097478 combivent Drugs 0.000 claims description 3
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims description 3
- LCELQERNWLBPSY-YAYGZGPXSA-M oxivent Chemical compound [Br-].C1([C@@H](CO)C(=O)OC2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-YAYGZGPXSA-M 0.000 claims description 3
- 230000001078 anti-cholinergic effect Effects 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 229960000797 oxitropium Drugs 0.000 claims description 2
- NVOYVOBDTVTBDX-PMEUIYRNSA-N oxitropium Chemical compound CC[N+]1(C)[C@H]2C[C@@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)[C@H](CO)C1=CC=CC=C1 NVOYVOBDTVTBDX-PMEUIYRNSA-N 0.000 claims description 2
- 229960001609 oxitropium bromide Drugs 0.000 claims description 2
- LCELQERNWLBPSY-KHSTUMNDSA-M oxitropium bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CC)=CC=CC=C1 LCELQERNWLBPSY-KHSTUMNDSA-M 0.000 claims description 2
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 claims 4
- XNSPQPOQXWCGKC-UHFFFAOYSA-N C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.[N] Chemical group C(C)(=O)O.C(C)(=O)O.C(C)(=O)O.[N] XNSPQPOQXWCGKC-UHFFFAOYSA-N 0.000 claims 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 2
- OEXHQOGQTVQTAT-BZQJJPTISA-N [(1s,5r)-8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate Chemical compound C([C@H]1CC[C@@H](C2)[N+]1(C)C(C)C)C2OC(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-BZQJJPTISA-N 0.000 claims 2
- 235000021478 household food Nutrition 0.000 claims 2
- 235000015170 shellfish Nutrition 0.000 claims 2
- PCTMTFRHKVHKIS-BMFZQQSSSA-N (1s,3r,4e,6e,8e,10e,12e,14e,16e,18s,19r,20r,21s,25r,27r,30r,31r,33s,35r,37s,38r)-3-[(2r,3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10 Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2.O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 PCTMTFRHKVHKIS-BMFZQQSSSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 230000003266 anti-allergic effect Effects 0.000 claims 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 229910052742 iron Inorganic materials 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 claims 1
- HJMZMZRCABDKKV-UHFFFAOYSA-N carbonocyanidic acid Chemical compound OC(=O)C#N HJMZMZRCABDKKV-UHFFFAOYSA-N 0.000 abstract 1
- 239000007921 spray Substances 0.000 description 10
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 230000005856 abnormality Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 229960000890 hydrocortisone Drugs 0.000 description 5
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 4
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 4
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- 229960001664 mometasone Drugs 0.000 description 4
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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- 229960003957 dexamethasone Drugs 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229950001669 tipredane Drugs 0.000 description 1
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 description 1
- 229960003114 tixocortol pivalate Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960004320 triamcinolone diacetate Drugs 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960001670 trilostane Drugs 0.000 description 1
- YIXVXFVKVAPMDM-UHFFFAOYSA-N trimethyl-[2-(trimethylazaniumyl)ethyl]azanium Chemical compound C[N+](C)(C)CC[N+](C)(C)C YIXVXFVKVAPMDM-UHFFFAOYSA-N 0.000 description 1
- 229960001530 trospium chloride Drugs 0.000 description 1
- 229960000859 tulobuterol Drugs 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- General Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Cosmetics (AREA)
Description
A7 ______B7___ 五、發明說明（1) 本發明是關於用於製造吸入用無推進劑氣溶膠的水溶液 形式醫藥製劑。 過去的二十年來，使用適量氣溶膠以治療阻塞性肺部疾 病已成為療程中的重要部分，特別是治療氣喘此種肺部疾 病。通常，推進劑氣體以氟氯碳氫化合物為主。但由於認 知到這些推進劑氣體對臭氧層的破壞可能性，發展替代品 的需求曰漸提高。其中發展出的一種方法為使用噴霧器， ~τ將醫藥活性物質的水溶液在高壓下喷;(麗而產生霧狀可吸 入的粒子，這些喷霧器的優點是他們可完全不需使用推進 劑氣體。 此類噴霧器在如PCT專利申請案wo 91/14468號中敘 逑’在此納入作為參考文獻。使用此處所敘述的喷霧器， 可將特定體積的活性成分溶液在高壓下經由小的喷嘴來噴 灑’以使可吸入的氣溶膠其平均顆粒大小在3至微米 之間。之前所敘述的噴霧器的進一步發展的具體實例在 PCT/EP96/〇4351號中敘述。在圖6中所描述的噴霧器其商 標為雷斯皮美特®。 通常，將用來吸入的藥物溶在水或酒精溶液中，且根據 活性物質的溶液特性，水及乙醇的溶劑混合物也適合。 除了水及/或乙醇外，溶劑的其他成分選擇性地為其他 的共溶劑，同時藥物製備也可額外地含有香料及其他藥理 學的添加物。其溶劑的實例為那些含有㈣或其他極性 基，例如醇類一特別是異丙醇’乙二醇一特別是丙二醇， 聚乙-醇，水丙—醇，乙二醇喊，甘油，聚氧化乙缔醇及 -4- ^紙張尺度適用中關家標準（CNS)A4規格-(21G x 297 {請先閱讀背面之注意事項再填寫本頁)
i d n I n ϋ J 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（） 聚氧化乙烯脂肪酸酯。其共溶劑適合用來增加輔助劑材科 及1如果需要的話，活性成分的溶解度^ 溶解的藥物在已完成的藥物製備的比例為在0 001及 30%之間一較佳地在0 〇5及3%之間，特別是〇 〇1至2〇/。 (全部為重量/體積比）。藥物的最大濃度依溶劑的溶解度 及所需達到預期治療效果的劑量而定。 適合吸入施用及溶在特定溶劑的所有物質可在新的製備 中做為藥物。治療呼吸道疾病的藥物尤其有趣。因此，特 別值仔i王意者為貝他擬似物（betamimetics)，抗膽鹼能藥， 抗過敏藥，抗組織胺，及類固醇，以及這些活性成分的合 併。 在一連串的審查中發現以上所敘述的喷霧器可在使用藥 物水溶液時（一般，使用雙蒸餾或脫礦質（離子交換的）水 作為溶劑）使噴霧的異常特別明顯。這些喷霧的異常代表 氣溶膠噴霧形式的改變，結果在極端的例子中由於平均小 滴大小分佈的改變，而使得無法再確保病人的精確劑量 (肺接近到氣溶膠的部分的改變）^些噴霧異常特別地在 間歇地使用噴霧器時發生，例如在使用之間有將近3或3 天以上的中斷。這些在極端的例子中會導致喷霧器故障的 嘴霧異常可能為在噴嘴開口區域有細微沈積物的結果。 令中驚詩的是，發現當喷霧的水性醫藥製劑含有一定有 效量的絡合劑，特別是EDTA (乙二胺四醋酸）或其鹽⑽ 些噴霧異常就不再發生。根據本發明的水性醫藥製劑含有 水作為溶劑，但假如需要的話，可加入乙醇以增加溶解度 本紙張尺度適用1f1國國家標準（CNS)A4規格（210 X 297公髮"7 i請先閱讀背面之注意事項再填寫本頁) Μ --- t---I I J 1--- 經濟部智慧財產局負工消費合作社印制^ 經濟部中央標準局負工消費合作杜印繁 14386 05 ^ Δ7 Α7 Β7五、發明説明（3 ) 至70% (體積比），較佳地在30至60%之間（體積比）。 也可加其他的藥物輔助劑如防腐劑，尤其是氣苄娱•銨。 附腐劑的較佳量，尤其是氣苄烷銨在8到12毫克/100毫 升溶液。 適當的絡合劑爲那些藥學上可接受的，尤其是那些已由 醫學調解權當局審核通過的。EDTA ，氮川三醋酸，檸檬 酸及抗壞血酸及其鹽類特別適合。乙二胺四醋酸的二鈉鹽 特別地較佳。 選擇絡合劑的量以加入有效量的絡合劑來防止噴霧異常 進一步地發生。 絡合劑Na-EDTA的有效量爲介於10及1000毫克/ 100毫 升溶液之間，特別是介於10至100毫克/100毫升溶液之 間。絡合劑的量的較佳範圍爲25至75毫克/100毫升溶液 之間，特別是25至50毫克/100毫升溶液之間。 以下所命名的化合物可主要單一地或合併地用來做爲根 據本發明的水性醫藥物製劑的活性成分。在個別的例子， 可能需要加入較高量的乙醇或溶液調節劑以增加溶解度。 溴化提歐卓皮恩，3-[(羥基二-2-嘧嗯基乙醯基）氧]-8,8-二甲基-8-偶氮寧二環卩，2,1]辛-6-烯-溴化物。 作爲貝他擬似物： 班比特洛（bambuterol)比托特洛（Bitolterol)卡布特洛 (Carbuterol)弗模特洛（Formoterol)克蘭比特洛（Clenbuterol)芬 諾特洛（Fenoterol)赫梭普納琳（Hexoprenaline)普洛卡特洛 (Procaterol)伊比特洛（Ibuterol)皮爾比特洛（Pirbuterol)塞爾米 -6 - (讀先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（2〖〇X297公釐） 〇 A7 B7 4 五、發明說明（） 特洛（Salmeterol)特洛比特洛（Tulobuterol)雷普羅特洛 (Reproterol)塞爾比達爾（Salbutamo丨）硫特洛（Sulfonterol)特比 達琳（Terbutaline) 1_ ( 2-氟-4-輕基苯基）-2- [4-(1-苯並吐基）-2-甲基-2_ 丁基 胺基]乙醇， 赤-5'-控基-8'- ( 1-經基-2-異丙基胺基丁基）-2H-1，4-氧氮 雜莕-3-(4H)-酮， 1- ( 4-胺基-3-氯-5-三氟甲基苯基）-2-第三丁基-胺基）乙 醇， 1- ( 4-乙氧基羰基胺基）-3-氰基-5-氟苯基）-2-(第三丁基 胺基）乙醇。 作為抗膽鹼藥： 漠化依普拉卓皮恩（Ipratropium bromide) Atrovent ® 漠化歐可喜卓皮恩（Oxitropium bromide) Oxivent® 氯化卓恩皮恩（Trospium chloride) Ν-β-氟乙烯原水解龍葵鹼苄酯甲溴化物 作為類囷醇： 布迪松耐德（Budesonide) 貝可羅美達松出6(：1〇11^&50116)或17,21-二丙酸鹽 德沙美沙松（Dexamethasone)-21-異於驗鹽 弗朗尼索賴德（Fiunisolide) 作為抗過敏藥： 色甘酸二納 内朵:克羅米爾（Nedocromil) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁) ------II 訂---- -----\ 經濟部智慧財產局員X消費合作社印製 A7 B7 黏芬語應莫菲提爾(Mycophenolate mofedl) 智洛同(Zileutone) 布達松奈德(Budesonide) 五、發明説明（ 伊皮納斯亭（Epinastine) 用來在根據本發明的藥物製備中作爲活性成分的類固醇實 例爲： 沙拉楚達斯特(Seratrodast) 普朗魯克斯特(Pranlukast) 布提索可特(Butixocort) 达富雷可特(Deflazacort) 富盧提卡松(Fluticasone) 普羅米卓爾(Promedrol) 莫米塔松氟洛鹽(Mom玫asone fiiroate) 提普雷敦(Tipredane) 貝可羅美沙松’道格拉斯(Beclomethasone, Douglas)伊可美沙松英比特鹽(Icomethasone enbutate) (請先聞讀背面之注意事項再填寫本頁) 經濟部中央橾準局員工消費合作社印製 西可羅美塔松(Ciclometasone) 弗羅可丁丁基(Fluocortin butyl) 連弗樂沙可特(Deflazacort) 西可羅美塔松(Ciclommsone) 普利尼卡貝鹽(Predni carbate) 提可松柯醇-特戊酸g旨(Tixocortol-Pivalate) 羅翠松(Lotrisone) 迪普洛登酮(Deprodone) 甲基普利尼索龍亞西波ft(Mdliylpredaisolcne~Acq)cnale) 莫美塔松(Mometasone) 氫可體松亞西波鹽(Hydrocortisone-aceponate) 屋羅貝塔索-丙酸鹽(Uobetasol-propionate) 三安西諾龍(Triamcinolone) 可羅普里迪謀(Cloprednol) 哈羅美塔松(Halometasone) 艾爾可羅美塔松(Alclometasone) 艾利沙克泰德(Alisactide) 氫可禮松"丁酸绝(Hydrocortisone~butyrate) 丙酸 M (propionate) 艾爾可羅美塔松二丙酸曼(AlclcaueUsciie»d^ropiaiate) 坎納斯登(Canesten-HC) 弗祿提可松' 丙酸鹽(Fluticasone^propionate) 哈羅普雷敦-乙酸绝(Halopredone>acetate) 莫美塔松·弗洛特(Mometasone^fUroate) 莫美塔松(Mometasone) 阿米諾哥綠提思邁德(Aminoglutethimide) 氫可醴松(Hydrocortisone) 訂 -8 · 本紙張尺度適用中國國家標準（CNS ) A4規格（210X29?公釐） A7 B7 經濟部中央標準扃員工消費合作社印製 三美西錯龍班納技对德(Trimacinolon Boietonide) 9-oc·氣-6-oc-氟 _11·β·17·α-二經基 _16-α·甲基-3-氧-1，4-雄二 烯-17-β·羧酸·甲基酯-17·丙酸鹽。 其他特別適合用來生產吸入施用的水性醫藥製劑的活性 成分爲： 五、發明説明（6 ) 美普尼松(IVteprednisone) 德沙美沙松(Dexamethasone) 来醉松(Medrysone) 弗羅西諾陸:乙磁奈德(F丨uocinolone acetonide) 迪普洛登酮丙酸鹽(Dqjr〇donePrq)ionate) 弗羅昔諸奈德(Fhiocinonide) 戴弗錄普雷德鹽(Difluprednate) 德沙美沙松異於松S(Dexam技hasone isonicotinate) 弗羅可妥龍卡普洛梭鹽(Fluocortolone capronate) 三安西兹龍-六乙姑奈德(Trianiciiiolone^Hexacetonide) 佛美博龍(Formebolone) 安醉松(Endrisone) 海西諾耐德(Halcinonide) 可羅貝塔索(Clob戌asol) 迪富羅拉松(Diflorasone) 安西諾对德(Amcinonide) 柯提華索(Cortivazol) 弗羅迪森(Fluodexane) 布迪森财德(Budesonide) 迪美德克斯(Demetex) 氟美碩龍(Fluorometholone) 貝塔美沙松(Betamethasone) 弗祿可羅若龍乙癒耐德(Fluclorolone acetonide) 帕雷美沙松** 乙酿鹽(Paramethasone^acetate) 阿里斯托寇特-二乙酸鹽(Aristocort-diacetate) 馬智普雷登(Mazipredone) 貝塔美沙松戊酸鹽(Betamethasone valerate) 貝可羅美沙松-二丙酸 SKBeclomethasone^Dipropianate) 弗莫柯妥(Formocortal) 可羅貝塔松(Cloprednol) 可羅普雷德醇(Clobetasone) 弗朗规索顧德(Flunisolide) 弗鹵沙寇特(Fluazacort) 氫可趙松 17-丁陵鹽(Hydrocortisone"17，Butyrate) 弗羅可辞(Fluocortin) 貝塔美沙松二丙酸鹽(Beam沒hasone Dipropionate) 貝塔美沙松，金剛酸S(Betam说hasoneadamantoate) 三洛斯丹(Trilostane) 克羅貝塔松(Clbetasone) (讀先聞讀背面之注意事項再填寫本頁) <^τ 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ 297公釐） 經濟部中央標準局員工消費合作社印製 A 7 B7五、發明説明（7 ) β-辛帕提柯擬似物（β-Sympatico-mimetics) 例如芬諸特羅（Fenoterol)，沙布塔摩（Salbutamol)，弗模 特羅（Formoterol)，特布塔林（Terbutalin); 抗膽鹼能藥； 例如伊帕卓皮恩（Ipatropium)，氧卓皮恩（Oxitropium)，破 卓皮恩（Thiotropium); 類固醇； 例如，貝可羅美沙松（Beclomethasone)，二丙酸鹽 (dipropionate)，布德松耐德（Budesonide)，弗朗妮索賴德 (Flunisolide)； 胜肽； 例如，騰島素； 止痛劑； 例如，枸橼酸芬太尼鹽（Fentanyl) 0 明顯地，如果需要的話，將使用那些溶在根據本發明的 溶劑的醫藥上可接受的鹽類。 在以下的文章中，將以實例更清楚地解釋根據本發明的 醫藥製劑的優點° 作爲醫藥溶液，使用溴化伊普拉卓皮恩（c=333毫克/100 毫升），pH値爲3.4 ，及防腐劑氣化芊二甲烴銨（c=10毫 克/100毫升）。測試溶液-則不含EDTA或濃度爲c=0· 1毫 克，1毫克，50毫克及75毫克/100毫升的EDTA二鈉 鹽。 使用未用過的雷斯皮美特®喷霧器來做測試（技術數據： -10- 本紙張尺度適用中國國家標準（CNS ) A4规格（2丨0X297公f ) (詩先聞讀背面之注意事項再填寫本頁) •衣 ,π ^438605
7 7 A B 五、發明说明（8 ) 施用的醫藥製劑的體積將近15微升，壓力將近300帕， 從兩個大小爲5x8微米的喷嘴開口衝擊出來的兩條水 流）。設定測試的操作方式使單位使用次數5次’並使其 靜置3天’然後再使用5次，重複此形式。在每一個連績 的測量中檢視15個單位，關於噴霧異常的結果顯示於表 表1 經濟部中央標準局員工消費合作社印製 測試號碼 EDTA的濃度(以毫 有噴霧異常的喷 測試的期間 克/100毫升計） 霧器的數目 (以天計） 1 〇毫克/100毫升 2 20 2 〇毫克/100毫升 5 9 3 (U毫克/100毫升 5 6 4 1毫克/100毫升 6 6 5 50毫克/100毫升 0 200 6 50毫克/100毫升 0 200 7 75毫克/100毫升 0 200 8 75毫克/100毫升 0 200 (請先閩讀背面之注項再填寫本頁) ·*?τ •11· 本紙張尺度適用中國國家標率（CNS ) A4規格（210X297公釐） 經濟部中央標準局員工消費合作社印製 m r r「t -i- ^ . L, 第86119428號專利申請案 A7 中文說明書修正頁(89年9月1 B7 五、發明説明（9 ) 配方實例(芬諾特及溴化伊帕卓皮恩） 成分 組合物（以毫克/100毫升） 芬謀特 833.3毫克 氯化芊二甲烴銨 10.0毫克 EDTA* 50.0毫克· Hcl (自然對數） 至 pH3.2 成分 組合物（以毫克/100毫升） 溴化伊帕卓皮恩 333.3毫克 氣化芊二甲烴銨 10.0毫克 EDTA* 50.0毫克 Hcl (自然對數） 至 pH3.4 相似於以上的實例 生產以下的溶液。 活性成分 濃度(毫克八〇〇毫升） 氯化苄二甲烴銨 EDTA* 溶劑 畢若鐵克® 104-1667 10毫克 50毫克 水 艾卓芬特® 83-1333 10毫克 50毫克 水 畢若杜爾® (阿特羅凡特） (畢若鐵克®) 41-667 104-1667 10毫克 50毫克 水 沙布塔摩 104-1667 —10毫克 50毫克 水 ---—：I ------.ri------訂 (請先閱讀背面之注意事項再填寫本頁) -12 -本紙張尺度適用中國國家橾準（CNS ) A4規格（2H)X 297公釐） 第86119428號專利申請案 A7 中文說明書條正阶89年9月） B7 五、發明説明（10) 康必凡特® (阿特羅凡特） (沙布塔摩） 167-667 833-1667 10毫克 50毫克 水 Ba 679 Br 4-667 10毫克 50毫克 水 (溴化提歐卓皮恩） BEA 2108 Br 17-833 1〇毫克 50毫克 水 歐西凡特® 416-1667 10毫克 50毫克 水 *以二鈉鹽的形式 畢若鐵克®表芬式醇氫澳化物（Fenoterolhydrobromide) 艾卓芬特®表溴化依普拉卓皮恩（Ipratropiumbromide) 畢若杜爾@表溴化依普拉卓皮恩與芬忒醇氫溴化物之結 合（Ipratropiumbromide in combination with fenoterolhydrobromide) (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印装 康必凡特®表溴化依普拉卓皮恩與沙布塔摩之結合 (Ipratropiumbromide in combination with salbutamol) 歐西凡特⑧表溴化氧卓皮恩（Oxitropiumbromide) 活性成分的濃度範園自1〇毫克至20,000毫克/ 100毫升 為可接受的，依每一次操作的劑量及其溶解度而定。以每 一次操作將近12微升的治療上有效單一劑量為基礎來計 算特定劑量°當個別劑量的體積改變時可改變醫藥製劑的 活性成分濃度。 絡合劑（例如二鈉-EDTA)的渡度範圍為10到1000毫克 / 100毫升之間（依溶液的pH值而定）。較佳的範圍為25 毫克至100毫克/100毫升之間。 -13 - 本紙張尺度適用中國國家標準（CNS ) A4規格（公釐） 第86119428號專利申請案 中文說明書修正頁(89年9五、發明说明（1〇4 A7 B7 一 .-------- 氯化芊二甲烴銨的量應在8刻12毫克/ 100毫升的範圍 之間。 溶液以0.1或1 N的HC1設定溶液的pH值在3 2至3-4 之間。所有的濃度關於100毫升的 液。 已完成的活性成分溶 ί.^^------士表------1Τ------t I , {請先閔讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印裝 -13a- 本纸張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐）
Claims (1)
- 經濟部中央镖隼局貝工消費合作社印装 第86119428號專利申請案 g丨 ： 中文申請專利範圍修正本（89年II月丨 LJQ ^ j 六、申請專利範圍 1. 一種用於製造吸入用無推進劑氣溶膠的醫藥組合物， 其特徵為該醫藥组合物為溶液形式，活性成分係溶於 水含有至高70 % (體積比）乙醇，以及選自乙二胺四乙 酸（EDTA)，氮川三醋酸，檸檬酸，抗壞血酸或其鹽 類之絡合劑。 2. 根據申請專利範圍第丨項的醫藥组合物，其特徵為活性 成份係選自：貝他擬似物（betamimetics)，抗膽鹼能藥， 抗過敏藥及/或抗組織胺藥。 3. 根據申請專利範圍第1或2項的醫藥組合物，其特徵為 活性成份係選自： 芬諾特羅（Fenotrol)，溴化伊帕卓皮恩（Ipatropium bromide) ’畢若鐵，艾卓芬， 畢若杜爾@(36『〇(1113丨），沙布塔摩（Salbutamol)，康必凡特 ® (Combivent)，溴化提歐卓皮恩（Ba 679 Br)，2 - ( 2 -嘧 吩基）甘酵酸-卓皮醇酯-溴化甲基（Di_(2_thienyl) glycolicacid-tropenolester-methobromide，BEA 2108 Br)，歐 西凡特 ® (Oxivent)。 4·根據申清專利範圍第1，2或3項中任一項的醫藥組合 物’其特徵為該絡合劑為氮川三醋酸，檸檬酸，抗壞 血酸或其鹽類。 5·根據申請專利範圍第丨，2或3項中任一項的醫藥组合 物’其特徵為該絡合劑為乙二胺四乙酸（EDTA )或其鹽 本麟尺度咖中咖家料（CNS ) Α4·_ (2丨G χ 297公着） --ΊΙ.-----裝------訂------Λ (請先閱讀背面之注意事項再填寫本頁) ABCD 申請專利範圍 類。 6·根據申請專利範圍第1，2或3項中任一項的醫藥组合 物’其特徵為該絡合劑的濃度為1〇至1〇〇毫克/1〇〇毫升 溶液之間。 7. 根據申請專利範圍第1，2或3項的醫藥組合物，其特徵 為絡合劑的濃度在25至75毫克/ 100毫升溶液之間。 8. 根據申請專利範圍第I，2或3項中任一項的醫藥組合 物其特欲為该醫藥組合物含活性成分的濃度為〇.〇Q 1 至2克/ 100毫升溶液β 9. 根據申請專利範圍第1，2或3項中任一項的醫藥組合 物*其係用於製備吸入用無推進劑氣溶膠。 (請先閱讀背面之注意事項再填寫本莧) t- Γ 經濟部中央標準局負工消費合作社印製 本紙铁尺度速用中國國家揉準（CNS ) A4说格（210X 297公釐） 申請曰期 86.12.20 案 號 86119428 頡 (以上各保由本局填註） 438605 (89年11月修正頁) ||靈專利説明書 發明 一、名稱 新型 1 中 文 用於製造無推進劑氣溶膠之新穎水性醫藥組合物 英 文 "NEW AQUEOUS PHARMACEUTICAL COMPOSITION FOR THE PRODUCTION OF PROPELLANT-FREE AEROSOLS" ! 姓 名 1. 伯納德佛瑞德 2. 伯德茲倫伯格 發明 二' 人 創作 國 籍 均德國 住 '居所 1. 德國格-艾吉斯翰市卡爾-多迪-街28號 2. 德國賓根萊恩市格斯街1號 姓 名 (名稱） 德商百靈佳殷格翰股份有限公司 國 籍 德國 三，申請人 住、居所 (事務所） 德國萊茵區英格翰市D-55216 1 1 i ί 代表人 姓 名 戴特.勞頓 洛道夫.霍夫曼 訂 線 本纸張尺度边用中國國家標準（CN；； ) A4現格（2丨0X297公釐） 裝 經濟部中央標準局員工消費合作社印製 m r r「t -i- ^ . L, 第86119428號專利申請案 A7 中文說明書修正頁(89年9月1 B7 五、發明説明（9 ) 配方實例(芬諾特及溴化伊帕卓皮恩） 成分 組合物（以毫克/100毫升） 芬謀特 833.3毫克 氯化芊二甲烴銨 10.0毫克 EDTA* 50.0毫克· Hcl (自然對數） 至 pH3.2 成分 組合物（以毫克/100毫升） 溴化伊帕卓皮恩 333.3毫克 氣化芊二甲烴銨 10.0毫克 EDTA* 50.0毫克 Hcl (自然對數） 至 pH3.4 相似於以上的實例 生產以下的溶液。 活性成分 濃度(毫克八〇〇毫升） 氯化苄二甲烴銨 EDTA* 溶劑 畢若鐵克® 104-1667 10毫克 50毫克 水 艾卓芬特® 83-1333 10毫克 50毫克 水 畢若杜爾® (阿特羅凡特） (畢若鐵克®) 41-667 104-1667 10毫克 50毫克 水 沙布塔摩 104-1667 —10毫克 50毫克 水 ---—：I ------.ri------訂 (請先閱讀背面之注意事項再填寫本頁) -12 -本紙張尺度適用中國國家橾準（CNS ) A4規格（2H)X 297公釐） 第86119428號專利申請案 A7 中文說明書條正阶89年9月） B7 五、發明説明（10) 康必凡特® (阿特羅凡特） (沙布塔摩） 167-667 833-1667 10毫克 50毫克 水 Ba 679 Br 4-667 10毫克 50毫克 水 (溴化提歐卓皮恩） BEA 2108 Br 17-833 1〇毫克 50毫克 水 歐西凡特® 416-1667 10毫克 50毫克 水 *以二鈉鹽的形式 畢若鐵克®表芬式醇氫澳化物（Fenoterolhydrobromide) 艾卓芬特®表溴化依普拉卓皮恩（Ipratropiumbromide) 畢若杜爾@表溴化依普拉卓皮恩與芬忒醇氫溴化物之結 合（Ipratropiumbromide in combination with fenoterolhydrobromide) (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印装 康必凡特®表溴化依普拉卓皮恩與沙布塔摩之結合 (Ipratropiumbromide in combination with salbutamol) 歐西凡特⑧表溴化氧卓皮恩（Oxitropiumbromide) 活性成分的濃度範園自1〇毫克至20,000毫克/ 100毫升 為可接受的，依每一次操作的劑量及其溶解度而定。以每 一次操作將近12微升的治療上有效單一劑量為基礎來計 算特定劑量°當個別劑量的體積改變時可改變醫藥製劑的 活性成分濃度。 絡合劑（例如二鈉-EDTA)的渡度範圍為10到1000毫克 / 100毫升之間（依溶液的pH值而定）。較佳的範圍為25 毫克至100毫克/100毫升之間。 -13 - 本紙張尺度適用中國國家標準（CNS ) A4規格（公釐） 第86119428號專利申請案 中文說明書修正頁(89年9五、發明说明（1〇4 A7 B7 一 .-------- 氯化芊二甲烴銨的量應在8刻12毫克/ 100毫升的範圍 之間。 溶液以0.1或1 N的HC1設定溶液的pH值在3 2至3-4 之間。所有的濃度關於100毫升的 液。 已完成的活性成分溶 ί.^^------士表------1Τ------t I , {請先閔讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印裝 -13a- 本纸張尺度適用中國國家標準（CNS ) A4規格（2丨0X297公釐） 05 05 A5 B5 第86119428號專利申請案 中文說明書修正頁（89年11月） 四、中文發明摘要（發明之^稱：用於製造無推進劑氣溶膠之新穎水性醫藥组" 合物 本發明是關於用於製造無推進劑氣溶膠的水溶液形式醫 藥組合物。 —^---------1丨 (請先閱讀背面之注意事項再填寫本頁各襴) 英文發明摘要（發明之名稱："NEW AQUEOUS PHARMACEUTICAL ) COMPOSITION FOR THE PRODUCTION OF PROPELLANT-FREE AEROSOLS" The present invention, relates to pharmaceutical composition in the form of aqueous solutions for the production of propellant-free aerosols· 訂 經濟部智慧財產局員工消費合作社印製 2 本纸張尺度適用中國國家標準（CNS } A4規格（210X297公釐} 經濟部中央镖隼局貝工消費合作社印装 第86119428號專利申請案 g丨 ： 中文申請專利範圍修正本（89年II月丨 LJQ ^ j 六、申請專利範圍 1. 一種用於製造吸入用無推進劑氣溶膠的醫藥組合物， 其特徵為該醫藥组合物為溶液形式，活性成分係溶於 水含有至高70 % (體積比）乙醇，以及選自乙二胺四乙 酸（EDTA)，氮川三醋酸，檸檬酸，抗壞血酸或其鹽 類之絡合劑。 2. 根據申請專利範圍第丨項的醫藥组合物，其特徵為活性 成份係選自：貝他擬似物（betamimetics)，抗膽鹼能藥， 抗過敏藥及/或抗組織胺藥。 3. 根據申請專利範圍第1或2項的醫藥組合物，其特徵為 活性成份係選自： 芬諾特羅（Fenotrol)，溴化伊帕卓皮恩（Ipatropium bromide) ’畢若鐵，艾卓芬， 畢若杜爾@(36『〇(1113丨），沙布塔摩（Salbutamol)，康必凡特 ® (Combivent)，溴化提歐卓皮恩（Ba 679 Br)，2 - ( 2 -嘧 吩基）甘酵酸-卓皮醇酯-溴化甲基（Di_(2_thienyl) glycolicacid-tropenolester-methobromide，BEA 2108 Br)，歐 西凡特 ® (Oxivent)。 4·根據申清專利範圍第1，2或3項中任一項的醫藥組合 物’其特徵為該絡合劑為氮川三醋酸，檸檬酸，抗壞 血酸或其鹽類。 5·根據申請專利範圍第丨，2或3項中任一項的醫藥组合 物’其特徵為該絡合劑為乙二胺四乙酸（EDTA )或其鹽 本麟尺度咖中咖家料（CNS ) Α4·_ (2丨G χ 297公着） --ΊΙ.-----裝------訂------Λ (請先閱讀背面之注意事項再填寫本頁)
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| DE19653969A DE19653969A1 (de) | 1996-12-20 | 1996-12-20 | Neue wässrige Arzneimittelzubereitung zur Erzeugung treibgasfreier Aerosole |
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| DE19615422A1 (de) | 1996-04-19 | 1997-11-20 | Boehringer Ingelheim Kg | Zweikammer-Kartusche für treibgasfreie Dosieraerosole |
| DE19733651A1 (de) * | 1997-08-04 | 1999-02-18 | Boehringer Ingelheim Pharma | Wässrige Aerosolzubereitungen enthaltend biologisch aktive Markomoleküle und Verfahren zur Erzeugung entsprechender Aerosole |
| DE19808295A1 (de) | 1998-02-27 | 1999-11-11 | Boehringer Ingelheim Int | Behälter für eine medizinische Flüssigkeit |
| DE19847968A1 (de) * | 1998-10-17 | 2000-04-20 | Boehringer Ingelheim Pharma | Verschlußkappe und Behälter als Zweikammer-Kartusche für Vernebler zur Erzeugung von Aerosolen |
| SE9803770D0 (sv) * | 1998-11-05 | 1998-11-05 | Astra Ab | Dry powder pharmaceutical formulation |
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