TWI284041B - Freeze-dried pantoprazole preparation and pantoprazole injection - Google Patents
Freeze-dried pantoprazole preparation and pantoprazole injection Download PDFInfo
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- TWI284041B TWI284041B TW090127545A TW90127545A TWI284041B TW I284041 B TWI284041 B TW I284041B TW 090127545 A TW090127545 A TW 090127545A TW 90127545 A TW90127545 A TW 90127545A TW I284041 B TWI284041 B TW I284041B
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- pan
- injection
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- preparation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 title abstract 3
- 229960005019 pantoprazole Drugs 0.000 title abstract 3
- 229940026447 pantoprazole injection Drugs 0.000 title 1
- 238000002347 injection Methods 0.000 claims abstract description 22
- 239000007924 injection Substances 0.000 claims abstract description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 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 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 238000004108 freeze drying Methods 0.000 claims abstract description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 29
- 239000002245 particle Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- -1 pyridine-ethyl-methylsulfinyl-1H-benzopyrazole Chemical compound 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 239000012906 subvisible particle Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000002504 physiological saline solution Substances 0.000 claims description 3
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 229960001484 edetic acid Drugs 0.000 claims 3
- 230000002265 prevention Effects 0.000 claims 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 1
- 241000283973 Oryctolagus cuniculus Species 0.000 claims 1
- 230000001668 ameliorated effect Effects 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- BDUPRNVPXOHWIL-UHFFFAOYSA-N dimethyl sulfite Chemical compound COS(=O)OC BDUPRNVPXOHWIL-UHFFFAOYSA-N 0.000 claims 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims 1
- 229930182490 saponin Natural products 0.000 claims 1
- 150000007949 saponins Chemical class 0.000 claims 1
- PNYYBUOBTVHFDN-UHFFFAOYSA-N sodium bismuthate Chemical compound [Na+].[O-][Bi](=O)=O PNYYBUOBTVHFDN-UHFFFAOYSA-N 0.000 claims 1
- 229940037001 sodium edetate Drugs 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000008215 water for injection Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- JNOJDURFZLCLSX-UHFFFAOYSA-N O.O.O.[Na].[Na] Chemical compound O.O.O.[Na].[Na] JNOJDURFZLCLSX-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 5
- 239000003125 aqueous solvent Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000013618 particulate matter Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012905 visible particle Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 229940071106 ethylenediaminetetraacetate Drugs 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 235000007575 Calluna vulgaris Nutrition 0.000 description 1
- QZKRHPLGUJDVAR-UHFFFAOYSA-K EDTA trisodium salt Chemical compound [Na+].[Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O QZKRHPLGUJDVAR-UHFFFAOYSA-K 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
- 239000004471 Glycine Substances 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- VEUACKUBDLVUAC-UHFFFAOYSA-N [Na].[Ca] Chemical compound [Na].[Ca] VEUACKUBDLVUAC-UHFFFAOYSA-N 0.000 description 1
- VYTBPJNGNGMRFH-UHFFFAOYSA-N acetic acid;azane Chemical compound N.N.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O VYTBPJNGNGMRFH-UHFFFAOYSA-N 0.000 description 1
- 238000004378 air conditioning Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000012538 light obscuration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 239000009671 shengli Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- NEUOBESLMIKJSB-UHFFFAOYSA-J tetrasodium;tetraacetate Chemical compound [Na+].[Na+].[Na+].[Na+].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O NEUOBESLMIKJSB-UHFFFAOYSA-J 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
- A61K31/33—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
-
- 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
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
1284041 玖、發明說明： 【發明所屬之技術領域】 本發明係關於醫藥技術領域，並描述凍乾的5_二氟甲氧 基-2-[(3,4-二甲氧基-2-吡啶基）甲基亞硫醯基]_1H_苯并咪 唑製劑及5-二氟甲氧基_2_[(3,4_二曱氧基定基）甲基亞 硫醯基]-1Η-苯并味嗤注射劑。此外，本發明也關於生產康 乾的5-二氟甲氧基-2_[(3,4_二甲氧基_2_〇比咬基）甲基亞硫醒 基]-1Η-苯并咪唑及5_二氟甲氧基_2_[(3,4_二甲氧基_2_吡啶 基）甲基亞硫醯基]-1Η-苯并咪唑注射劑的方法。 【先前技術】 WO 94/02141說明含2-[(2-吡啶基）甲基亞硫醯基]_苯并咪 唑化合物及水性溶劑、然無非水性溶劑的注射劑，其中注 射劑的pH不小於9.5及不大於丨丨乃。其中述及該注射劑不會 引起溶血作用，只引起很少的局部刺激。 DE 43 24 014說明於-25至-30°C之生產溫度下、在作為助 劑的蔗糖之存在下之泛派索-鈉倍半水合物凍乾物之製 備。其揭示此凍乾物具有改良之儲存安定性，於室温下至 少可儲存18個月，且容易重組成適宜劑量的液體以供使用。 CN 1235018說明不含結晶水、且具{^值9-12 5的泛派索 鈉之凍乾的注射劑粉末，此注射劑粉末含泛派索鈉、凍乾 的粉末支撐劑，金屬離子複合劑及pH調節劑。 WO 99/1 8959說明一種水性醫藥組合物，其係物理性地及 化學性地安定而可作靜脈注射劑，其包含抗潰瘍化合物及 於載劑内作為安定劑的甘胺酸。
O:\74\74412-930428.DOC -6- 1284041 【發明内容】 藉載劑溶液重組凍乾的醫藥化合物以供使用可能導致溶 液中可目視及/或次可見的（sub visible)粒子之形成。可注射 的溶液’包括由滅菌固體組成的供非經腸使用的溶液，應 是基本上無肉眼檢查可看得見的粒子，為病人的安全起 見’亦希望僅有少量的次可見的粒子。美國藥典（usp 24) 第24版說明計數次可見的特定大小範圍内的外來粒子的物 理试驗方法，並界定作為單一劑量輸液的大量注射劑及小 容積注射於此試驗中之粒子物質限度（usp 24, <788>Particulate Matter in Injections)。 令人驚訝地，本發明發現到，藉由冷凍乾燥泛派索、乙 二胺四乙酸及/或其適當鹽類、及氩氧化鈉及/或碳酸鈉的水 /谷液 了獲传到一束乾物，與此技藝中之已知方法製得之 凍乾物比較，本發明凍乾物在以溶劑重組後乃具有明顯較 低數目的次可見粒子。本發明凍乾物相當安定，且容易以 適當溶劑重組。特定地說，本發明泛派索注射劑具有次可 見少於130個、較佳係少於12〇個/每瓶之稍可目視粒子，粒 子的大小等於或大於10微米，粒子數目是根據美國藥典第 24版（<788>Particle Matter in响⑻―以光陰暗試驗計數 (light obscuration particle test count)測定。 5-二氟甲氧基-2-[(3,4_二甲氧基〜比。定基）甲基亞硫醯 基]-1H-苯并》米唾（INN:泛派索，本發明稱為泛派索）已知揭 示於ΕΡ-Α-0 166 287。泛派索係一種手性化合物，本發明 中’泛派索-詞也包括泛派索的純的對映體及其任何混合
O:\74\744I2-930428.DOC 1284041 比例的混合物。（s)_泛派索[㈠-泛派索]便為一例。此處所 用的，：索是其原形，或較佳是其與鹼所生成的鹽的形 式、。可提及的與驗所生成的鹽的例是納、卸、鎮及舞鹽。/ 泛派索及/或其鹽在以晶體形式分離出時可含不同量的溶 劑。^發明所謂的泛派索也指其所有的溶劑化物，特別是 5既^基_2_[(3,4_二甲氧基_2_〇比唆基）甲基亞硫酿 基]1H本并咪唾及其鹽的水合物。此類泛派索與驗生成的 鹽的水合物見於，例如’ wo91/19710。較佳地，泛派索是 指泛派索納倍半水合物（=泛派索鈉xl.5 H2〇)及泛派索鎮二 水合物。 根據本發明’用於冷凍乾燥方法中的泛派索溶液可藉將 乙-版四乙酸及/或其適當鹽類、及氫氧化納及/或碳酸納加 於水溶劑中而製得。本發明所用的適當之乙二胺四乙酸的 -一舉例而吕’可為乙二胺四乙酸四納鹽，乙二胺四乙酸 鈣一鈉鹽’乙二胺四乙酸三鈉鹽及乙二胺四乙酸四鈉睡。 乙二胺四乙酸及/或其適當鹽類的重量比，以所用泛派索的 篁為基準，是〇·05至25%，較佳是〇.25至12.5%，或更佳七 至5%。水性溶劑較佳是注射用水。之後，再將泛派索加於 此溶液内並以㈣使溶解。較佳係製成其中泛派索的重量 比Ο是〇.5至1〇%的，特佳是！細。於本發明較佳 具體貫施例中，用於冷;東乾燥方法的溶液的戯8或高於 8’特佳係师10至13範圍内。然後將此溶液過遽滅菌，再 載入小疏内。接著以已知方法將此溶液凌乾。 根據本發明的泛派索注射劑可藉以下方式製備：將如上
O\74\74412-930428.DOC 1284041 東乾產物岭於可溶性溶劑中，例如 5〇/〇葡萄糖水溶液或注射用—輪 > 生里艮鹽水、 伙4庄射用瘵餾水。根據本 射劑較佳係以靜脈注射劑形式使用。 月的泛派索注 旦=ΓΓΓ乏派索注射劑較佳含治療各疾病的習用劑 、^索。根據本發明的隸產物及泛派索注射劑可用 以治療及預防被認為可用 々j用比疋-2_基甲基亞硫醯基·1Η 咪唑治療的或避免的疾病。特 、、 饤心兄根據本發明的凍乾 屋物及泛派索注射劑可用 二底 "用以…療月疾病。此特定的凍乾產 物含5至150毫克、較祛| ς 古士/ 曰 1 又佳疋5至60笔克泛派索。可提及的實例 疋含10’ 2G’ 4G’ 5G或96毫克泛派索的;東乾產物或注射劑。 細劑量（例如40毫克活性化合物）可為投藥，例如，以個別 客’!里的形式投藥或根據本發明藉數個劑量投藥(例如毫 克活性化合物作2次投藥）。根據本發明注射劑内泛派索的 濃度可因投藥途徑而改變，一般比例是〇〇5_1〇毫克/毫升， 較佳是(U至5毫克/毫升，此係以自由態化合物為基準。例 如’供快速投藥a夺’可將20至120毫克之本發明康乾產物用 1 〇毫升生理鹽水重組。 凍乾產物及泛派索注射劑的生產可藉下述實例說明。下 述實例更詳細地說明本發明而不是限制本發明。 【實施方式】 實例 廉乾泛派索製劑的生產 實例1 將0.276克乙二胺四乙酸二鈉鹽及6·7克氫氧化鈉（1N水溶
O:\74\74412-930428.DOC 1284041 液）在氮氣下加於480克4。(：至8°C的注射用水内。加12.47克 泛派索鈉倍半水合物，同時攪拌，獲得澄清溶液。藉加注 射用水將溶液重量調整至500克。溶液？11為11 76。將溶液 用〇.2微米膜的過濾器過濾，裝入玻璃小瓶〇81克每小瓶） 内。將裝好的小瓶蓋住一半，置於凍乾器（GT4 Edwards/ Kniese或GT8 Amsco)内凍乾。將小瓶冷卻至_45它，再將溫 度於真空（0.1至0.5毫巴）升至·20至说乾燥。在主要乾燥進 行終了後，將溫度升至3(TC，真空調至〇〇1毫巴，再繼續 乾燥3小時。獲得灰白色;東乾產物，此產物易於用生理鹽水 重組成為澄清溶液。 j匕車父貫例 實例2 將12.47克泛派索鈉倍半水合物在氮氣下加於48〇克4它 至8°C的注射用水内，同時攪拌，獲得澄清溶液。藉加注射 用水將浴液重1調整至5〇〇克。溶液？11為1〇·85。將溶液用 〇·2微米膜的過濾器過濾，裝入玻璃小瓶〇 81克每小瓶） 内。將裝好的小瓶蓋住一半，置於凍乾器（GT4 Edwards/ Kniese或GT8 Amsco)内凍乾。將小瓶冷卻至-^，再將溫 度於真空（0·1至0.5毫巴）升至_2〇至_5〇c乾燥。在主要乾燥進 行、，冬了後，將度升至30°C，真空調至〇 〇1毫6，再繼續 乾燥3小時。獲得灰白色東乾產物。 實例3 將2.45克氫氧化鈉（1N水溶液）在氮氣下加於48〇克4。(：至8 C的注射用水内。再加1247克泛派索鈉倍半水合物，同時
O:\74\74412-930428 DOC -10- 1284041 攪拌’成為澄清溶液。藉加注射用水將溶液重量調整至5〇〇 克。溶液pH為12.02。將溶液用〇·2微米膜的過濾器過濾， 裝入玻璃小瓶（1·81克每小瓶）内。將裝好的小瓶蓋住一半， 置於凍乾器（GT4 Edwards/Kniese或GT8 Amsco)内；;東乾。將 小瓶冷卻至-45。(：，再將溫度於真空（0.1至0.5毫巴）升至_2〇 至-5°C乾燥。在主要乾燥進行終了後，將溫度升至3〇。〇， 真空凋至0 · 0 1宅巴，再繼續乾燥3小時。獲得灰白色床乾產 物0 實例4 將〇·〇5克乙二胺四乙酸二鈉鹽在氮氣下加於48〇克4艺至 8°C的注射用水内。加12.47克泛派索鈉倍半水合物，同時 攪拌，得澄清溶液。藉加注射用水將溶液重量調整至5〇〇 克。浴液pH為10.2。將溶液用0·2微米膜的過濾器過濾，裝 入玻璃小瓶（1 ·81克每小瓶）内。將裝好的小瓶蓋住一半，置 於凍乾器（GT4 Edwards/Kniese或GT8 Amsco)内凍乾。將小 瓶冷卻至-45°C，再將溫度於真空（〇1至〇·5毫巴）升至_2〇至 -5 C乾燥。在主要乾燥進行終了後，將溫度升至π。。，真 空調至0.01毫巴，再繼續乾燥3小時。獲得灰白色凍乾產物。 光陰暗粒子試驗計赵 根據美國某典第 24 版（<788>Particulate Matter in
InjeCti〇nS)，以光陰暗粒子試驗計數測定由實例丨至4所製得 凍乾產物組成的小瓶内溶液内的粒子物質。 每J瓶内大J、為等於或大於j 〇微米的外來粒子數目測定 結果如表10從表1可看出，每小瓶以本發明（實例D產物組
O:\74\744I2-930428.DOC -11· 1284041 成的溶液内次可見的（等於 同於本發明方法所得產物(;例2至^ 子數。 、貫例2至4)所製成的溶液内的粒 表1: --_ 實例1 (藉凍乾泛派索鈉倍 半水合物氫氧化鈉 及乙二胺四乙酸二 鈉鹽製成的產物） 實例2 (藉康乾泛派索鈉倍 半水合物所得產物） ---_ 實例3 (藉康乾泛派索納倍 半水合物及氫氧化 鈉所得產物） 實例4 (藉凍乾泛派索鈉倍 半水合物及乙二胺 四乙酸二納鹽製成 的產物） 粒子/每瓶>=1〇微米 粒子/每瓶>=1〇微米 粒子/每瓶>==1 〇微米 粒子/每瓶>=1 〇微米 109 458 144 211 ------ O:\74\74412-930428.DOC -12-
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1284^)4(127545號專利申請 中文申請專利範圍替^本(95年8月） 拾、申請專利範園·· ι· 一種製備含有5_二 -一~~liiil 基）甲基亞硫酿基]_1Η苯土 -2-[(3,4·二甲氧基·2-則 、其發、泛料u ㈣f—咖_) 其 _二：二 物、乙二胺四乙酸及/或其適當鹽類兔、|之納合劑化 碳酸鈉的水溶液。 虱氧化鈉及/或 2·根據申請專利範圍第旧之方法 芬/々甘、a i 匕括將乙二胺四乙酸 鈉J H，：‘類'合於水中’藉添加氫氧化鈉及/或碳酸 :將胸整至8或8以上，再於此溶液中加泛派索、其 ^ 泛派索或其鹽之溶劑化物。 3.根據申請專利範圍第旧之方法，其中該乙二胺四乙酸 =/或曰其適當鹽類的重量比，以所含泛派索的量為基 準，疋 0.05至 25%，0.25至 12.5%，或 α5〇/〇。 4·根據中請專利範圍第旧之方法，其中該泛派索是泛派 索鈉倍半水合物。 5·根據申請專利範圍第1項之方法，其中該水溶液的阳是 10 至 13 〇 6· 一種根據申請專利範圍第1至5項中任一項之方法製得 之凍乾的泛派索製劑，當其於適於溶劑中重組以形成注 射劑時，係產生具有顯著較低次可見粒子（subcisible particles)數目之注射劑。 7. 一種用以治療及預防所有被認為可用吡唆-乙β基甲基 亞硫醯基-1H-苯并吡唑治療或避免之疾病之床乾的泛 74412-950830.doc 1284041 派索製劑’其係由泛派索、其鹽、泛派索或其鹽之溶劑 化物、乙二胺四乙酸及/或其適當鹽類、及α氧化納所 構成。 8· 9. 10. 11. 12. 13. 根據申請專利範圍第7項之;東乾泛派索製劑，其係由泛 派索，、疏泛派索或其鹽之溶劑化物、乙二胺四乙酸 之二鈉鹽、及氫氧化鈉所構成。 一種用以治療及預防所有被認為可用吡啶_乙_基曱基 亞硫醯基-1Η-苯并吡唑治療或避免之疾病之供快速投 藥（bolus adminiseration)的泛派索注射劑，其係藉由以 適當溶劑重組治療有效量之根據申請專利範圍第6項之 泛派索製劑而製得。 根據申請專利範圍第9項之泛派索注射劑，其中該溶劑 是生理鹽水。 一種用以治療及預防所有被認為可用吡啶-乙-基甲基 亞硫酿基-1H-苯并吡唑治療或避免之疾病之注射劑套 組，其包括根據申請專利範圍第6項之凍乾的泛派索製 劑’及適合供快速投藥的溶劑。 根據申請專利範圍第9項之泛派索注射劑，其具有少於 1 30個/每小瓶的次可見粒子數目，此等粒子係等於或大 於10微米。 根據申請專利範圍第12項之泛派索注射劑，其具有少於 120個/每小瓶的次可見粒子數目，此等粒子係等於或大 於10微米。 74412-950830.doc -2 -
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