TW577752B - Compositions suitable for the production of injectable perfusion - Google Patents
Compositions suitable for the production of injectable perfusion Download PDFInfo
- Publication number
- TW577752B TW577752B TW081105332A TW81105332A01A TW577752B TW 577752 B TW577752 B TW 577752B TW 081105332 A TW081105332 A TW 081105332A TW 81105332A01 A TW81105332A01 A TW 81105332A01A TW 577752 B TW577752 B TW 577752B
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- Prior art keywords
- ethanol
- patent application
- cold
- solution
- compound
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- 239000000203 mixture Substances 0.000 title claims abstract description 29
- 230000010412 perfusion Effects 0.000 title claims abstract description 13
- 239000004094 surface-active agent Substances 0.000 claims abstract description 15
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 claims abstract 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 85
- 239000000243 solution Substances 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 28
- -1 polyoxyethylene Polymers 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- 229920000136 polysorbate Polymers 0.000 claims description 9
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 8
- 229950008882 polysorbate Drugs 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 240000008564 Boehmeria nivea Species 0.000 claims description 5
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical group NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 claims description 5
- 239000003978 infusion fluid Substances 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- 229940068968 polysorbate 80 Drugs 0.000 claims description 4
- 238000012856 packing Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000013589 supplement Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims 3
- 239000001257 hydrogen Substances 0.000 claims 3
- 229910052739 hydrogen Inorganic materials 0.000 claims 3
- 239000003921 oil Substances 0.000 claims 3
- 235000019198 oils Nutrition 0.000 claims 3
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 2
- 239000004593 Epoxy Substances 0.000 claims 2
- 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 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 claims 1
- 239000005711 Benzoic acid Substances 0.000 claims 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 claims 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 claims 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229910052801 chlorine Chemical group 0.000 claims 1
- 239000000460 chlorine Chemical group 0.000 claims 1
- 238000007865 diluting Methods 0.000 claims 1
- 229910052731 fluorine Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 238000003760 magnetic stirring Methods 0.000 claims 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 claims 1
- 239000008159 sesame oil Substances 0.000 claims 1
- 235000011803 sesame oil Nutrition 0.000 claims 1
- 239000004575 stone Substances 0.000 claims 1
- 238000000034 method Methods 0.000 description 9
- 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 8
- 239000008103 glucose Substances 0.000 description 7
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000002075 main ingredient Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 206010002199 Anaphylactic shock Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 235000021243 milk fat Nutrition 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241000219823 Medicago Species 0.000 description 1
- 235000017587 Medicago sativa ssp. sativa Nutrition 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- 235000014443 Pyrus communis Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940124650 anti-cancer therapies Drugs 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 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 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000009736 wetting Methods 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K9/0043—Nose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Epoxy Compounds (AREA)
- Saccharide Compounds (AREA)
- Paints Or Removers (AREA)
- Chemical And Physical Treatments For Wood And The Like (AREA)
Description
經濟部中央標準局員工消費合作社印製 577752 第81105332號專利申讅案 中V說明害修TF苜 (8 4 年 1 月） Α7 ，―一1 Β7 五、發明説明（） 年丨4曰 補无 本發明係關於包含俱有抗腫瘤及 Κ白血病活性的治療製 劑的組合物及特別是藥學劑型。更特別地係關於適合於注 射的姐合物，其包含特烷衍生物，例如，特別是，式I的 持克索或其類似物或衍生物之一：
OR
其中R代表氫原子或乙醯-及。代表第三-丁氧基羰基胺 基或苯甲醯胺基。在這些衍生物中，其中R代表乙醯基及 Ri代表笨甲醯胺基者或其中R代表氫原子及^代表第三-丁氧基羰基胺基者較好。這兩個化合物中的第一個是以特 克索的名字較著名，而第二個則以特克特爾（Taxotere)的 名字出名。 這些產物在活體内表現出>對抗惡性腫瘤的實質活性，因 此將它們用於研究對於其它抗癌治療法俱有抗性的疾病處 理。 不幸地，這些產物在水中的溶解度如此的低，因此必須 包含界面活性劑及乙醇Μ用來製餚用於注射的製劑。乙醇 是用來溶解式（I )化合物的最佳溶劑，且先前已被認為在 製餚含特克¥或持克爾之可$射配方4不分散的。 (請先閱讀背面之注意事項再填寫本頁)
本紙張尺度適用申國國家標準（CNS ) Α4規格（210Χ297公釐） 83. 3.10,000 577752
五、發明説明（） A6 B6 例如，根據 Rowinsky， Lorraine， Cazenave及 Donehower 於 1990年 8 月發表在 Journal of the National Cancer Institutes 82 冊，15號，第 1247-1259頁中，可製得在溶劑混合物中含_將近6毫克/毫升 的特克索的第一種溶液，稱為”母溶液”，該溶液包括： -50%體積比的乙醇 - 50%體積比的乳脂仿（Cremophor) EL> 於注射用時，該溶液與一種包含有氯化納或右旋糖（葡萄 糖）的一種灌注流體混合。為獲得一種於生理及化學二者 狀況下皆稱定的混合物，該篇報告的作者陳述必須限制該 灌注溶液中主要活性成份的濃度至大約0.03到0.6奄克/ 毫升考上述的發表，1251頁，第1檷，第三段）。 現在，希望能夠注射足夠劑量的活性主要成份；為了此 目標，臨床家可能要注射含有濃度接近於0.3及1毫克/ 毫升的主要活性成份的灌注流體；在上述的這些劑量中， 可觀察到很難控制的急性過敏休克的現象，主要是由於乳 脂仿（參考由Rowinsky所發表，1250頁，第二檷，最後一 段）。 仍舊是根據該篇發表文章，必須注射包含，在與活性主 要成份同時，下面每種化合物的濃度，乙醇及最特別的乳 脂仿，接近每100毫升8克的一種溶液才能得到這種濃度 (0.3到1毫克/毫升之間）。因為一般都要求給予如此高 劑量的活性主要成份的處理，而且由於在溶液中此活性主 要成份的濃度是相當的低，在治療時注射大髏積會造成， 中 4(210X 297 公发） {請先聞讀背面之注意事項再填寫本页) •装· •打· •綠· 577752 第08 1 1 05332號專利申請案 中文說明書修正頁（91年6月） A7 B7
五、發明説明（ 除了急性過敏的症狀，酒精中毒症狀的效果。 琨已驚人地發現可製備可注射之配方，如含特克索或特 克特爾之灌注液，其中乙醇濃度已大幅降低，及乳脂肪與 乙醇已完全除去之配方。 本發明因而提供幾乎無乙醇之组合物，其包含如上述定 義之式I化合物及一界面活性劑，其可為聚山梨酯、聚氧 乙烯乙二醇酯或聚氧乙烯篦麻油衍生物。 根據完成本發明的第一個方法製備一種組合物，包括在 乙醇混合物中的如同上述定義的式I化合物*及一種界面 活性劑*它可能是一種聚山梨醋（polysorbate) *例如如 同K ”吐溫”標示的名字，一種標示為聚氧乙烯乙二醇酯， 例如，名字為乳仿（Eraulphor) *或標示為聚氧乙烯篦麻油 衍生物，例如，名字為”乳脂仿” •及接著除去乙醇。 初始組合物可藉將式I之主要活性成份溶於乙醇中，然 後逐漸加入界面活性劑來製備。在這個方法中可製備在一 種含有50%的界面活性劑的混合物中有10到100毫克/毫 升的主要活性成份的溶液。然後完全，或幾乎完全去除乙 醇·最好係藉蒸發。在此方法中，將該特烷衍生物溶於乙 醇中，及接著加入界面活性劑，其在一種水液介質中稀釋 後它可布界面活性劑的內部促运含有特烷衍生物的膠體質 點的形成。至少部份可在真空下利用蒸發或利用其它合適 的方法來去除包在該溶液中的乙醇。 根據第二種方法來製備本發明之组合物，在少量（1至 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 577752 - — • ▲’ ；各1八_補充 一 五、發明説明（） 2 % )乙醇存在下，直接將特烷衍生物分散於界面活性劑 之中。根據一種較佳的方法，製備一種含1到2 %的乙醇 之界面活性劑的混合物，在此溶液中一面攪拌一面持縝地 加入特烷衍生物，例如使用一種螺旋狀的研磨器或一種離 心的分解器。小量的乙醇的存在提供了幾個優點：該介質 擁有較低的黏稠度，及可改善粉末的濕潤及該組合物的最 後過瀘。 該姐合物最好含有少於5 %的乙醇；另外更好的是含有 少於2 %的乙醇。其是穩定的及含有高達200毫克/毫升 ，高達80毫克/毫升較好，於界面活性劑中的活性主要成 份。 一種含特克索的本發明的姐合物最好仍然擁有濃度在6 及20½克/毫升之間的於界面活性劑中的活性主要成份。 此姐合物可與灌注體，它可是生理食鹽水或一種葡萄糖溶 液，混合，特別是得到每毫升在0 . 1及1毫克之間的最後 濃度。由上面的組合物所製備含有較低乙醇的灌注液最好 仍然含有於0.3及0.5毫克/毫升之間的特克索及少於1毫 升/升的乙醇。 包含主要活性成份而沒有乙醇的特克索灌注液具有8小 時到大約100小時之間的生理活性。所瞭解的生理活性是 指在室溫下儲存8到10小時後該溶液並不會存在有任何可 見的沈澱物。 一種含特克特爾的本發明之姐合物最好擁有於界面活性 劑中濃度在20及80毫克/毫升之間的活性主要成份。此姐 A6 B6 (請先閱讀背面之注意事項再填寫本頁) .¾. •打· •綠· 甲 4(210X 297公发） 577752 A6 B6 五、發明説明（ 合物可與灌注體，它可是一種生理食鹽水或一種葡萄糖溶 液，混合，特別是得到最後濃度在每毫升中是在（K 1及 〇·5毫克之間。由上述姐合物製備含有較低量乙醇的灌流 液最好是仍含有在0.1及0.3毫克/毫升之間的特克酮； 它們最好含有少於15毫升/升的界面活性劑及少於1毫升 /升的乙醇。 包含活性主要成份而沒有乙醇的特克特爾灌注液擁有的 生理穩定性可達到數個月。 可注射至人體内的特克索或特克特爾灌注液的預定流速 係取決於所期望注射的活性主要成份的量。使用逭些溶液 可避免使用先前溶液所觀察到的過敏性休克現象。 因此，這些灌注液可減少，相對於前面的技藝，將近 80%注射入人體的界面活性劑的量及將近100 %的乙醇量 利用下述的範例來敘述本發明。 粮墟前沭抟菡的bh齩節例 將特克索（0.180克）溶解在乙醇（15毫升）中。將乳脂仿 納入該混合物的體積中而得到一種含特克索（6毫克/毫 升）的溶液（30毫升）。 K 1毫克/毫升的比例將該溶液在5 %的葡萄糖溶液中 稀釋；該灌注溶液含有87.7毫升/升的乳脂仿及87.7毫升 /升的乙醇。該灌注溶液的穗定度超過21小時。 齡例1 - 7 將特克特爾（32克）溶解在純酒精（340毫升）中然後加入 甲 4(210X 297公发） (請先聞讀背面之注意事項再填宵本頁) •打· •線· 577752 1丨多、ji»補充 蚪\年(o月（ A6 B6 五、發明説明（ 聚山梨酯（830克）。在15毫米汞注的壓力在301C下於旋轉 式蒸發器中2小時將乙酵蒸發掉。所得到的姐合物是穩定 的；它包括特克特爾（40毫克/毫升）。 在一種5 %葡萄糖灌注液中稀釋後濃度在0.1 ，0.3及 0 .5毫克/毫升，可觀察到所得到姐合物的穩定度。 可使用一種含有特克特爾（6 0毫克/毫升）的姐合物來仿 效相同的方法。 可使用含有特克索（12及20奄克/奄升）的特克索姐合物 來仿效相同的測試。 结果顯示在表1 (請先閲讀背面之注意事項再填寫本頁) •装· •訂· •線· 甲 4(210X 297 公沒） 75 77 5 經濟部中央標準局員工消費合作社印製 第81105332號專利申請案 中文說明書修正頁U5年7月） A7 _Bl· 五、發明説明（） W克絮 Η克龙 W克笊 Ι·ϊ 克 1，ϊ«Ι，Γ8ί W克WW SU丨丨梨Μ MiliiWKf K山梨fiS W山似韶 站山ί,ϊ滟 ν^ιΙιί/,ΜΗ VfiliWiS 界面活性劑 2〇 «克/¾升 2〇 «克/«力 12 «>¥/«· ' 4〇 ^νι/^η 4 0 «克/考外 4 0洧兕/«/| 6 0 3gyi/« J| 組合物之濃度 ‘ 1 帝克/«外 0.3 «>Ϊ/«；Ι 1 1 〇δ5Ϊ/«；Ι 0.5 «Vd/«；l • 0.3 ^3Ϊ/«；Ι 0.1 0.1 73： ρτ^ P'lr fl 50 «；|/；| 15 *；|/；|· 03.3笼歼/外 11.6 ^η/η . 6.9 «7|/?| 2.3 «歼/外 1.5 Jd Ji /n φ ^ φ 声V <〇·3 *升/升 <c.〇〇 ^ηπ[ ·:0·5 «升/升 0.09 «；|/?Ι 0.05窀外/升 η.02 «；|/7Ι -0.01 «/|/71 \ 乙 ur > 8小時 >24小時 HO小时 0 -23小時 0 -2 3小時 29 -4 5小时 8 -23小峙 Η定度 0 1. (請先閱讀背面之注意事項再填寫本頁) 衣. 訂 本紙張尺度適用中國國家標準（CNS ) A4規格（2IOX297公釐） -9 _ 577752
五、發明説明（） 節例8 在一®不銹網的反應爐中，加入特克特爾（258克）及溶 在乙醇（2 425克）中拌随著物理性的攪拌45分鐘。加入聚山 梨酯80(61 56克）及利用物理性的攪拌15分鐘來均質化該混 合物。將該姐合物倒入一種反應爐中及在10到50奄巴 ( 1000到5000Pa)的減壓下蒸餾出酒精，維持該溫度在18 及28¾之間。蒸餾出該酒精直到它的含量小於2 %。 所獲得的姐合物經由一個含有0.2微米的洞徑大小的遇 濾器過濾。它含有： -乙醇（1 · 3% ) -特克特爾（39.6毫克/毫升） 在一種含有5 %葡萄糖的灌注液袋中稀釋至1毫克/毫 升後，該所得之灌注液是穩定的且沒有明顯沈澱產生達超 過2個月的時間。 節例9 在純酒精（2毫升）及乳脂仿EL (218) (8毫升）的一種 混合物中分散特克特爾（160毫克）或特克索（160毫克）， 在一種旋轉式蒸發耱中在30C在25 mmHg的壓力下蒸發該乙 醇3小時。所得到的姐合物是穩定的。它們含有20奄克/ 毫升的特克特爾或特克索。在一種5 %葡萄糖灌注溶液中 穩釋後的濃度是0. 1及0.5毫克/毫升，在30及95小時之間 観察到沈澱的產生。 筋例1 0 在一個500.毫升的圓椎形燒瓶中加入聚山梨酯 -10- 甲 4(210X 297公沒） (請先閱讀背面之注意事項再填寫本頁) •装· •訂· •綠· 577752
曰I A6 B6 五、發明説明（ 80(275.5克）及纯酒精（5.4克）·然後使用一個磁性棒攒拌 該混合物直到完全均質化。 在一個50毫升燒瓶中的上述製備之混合物（26.13克）， 先放於水浴中及維持整個測試階段在301C，使用一個磁性 棒攪拌接近600 r pm。使用一個試藥匙，分成許多部份加入 特克特爾（1· 076克）使得在二次加入之間該團狀物消失（ 操作的時間將近1小時）。在加入最後一部份的特克特爾 後，維持該攪拌直到姐合物變成澄清（大約2小時）。 (請先閱讀背面之注意事項再填寫本頁) •襄· •訂. .綠· -11- 甲 4(210X 297 乂沒）
Claims (1)
- 577752 A BCD第081105332號專利申請案 中文申請專利範圍修正本（91年6月) 六、申請專利範圍 1* 一種適合藉稀釋製備可注射灌注液之组合物，該组合物 含少於5%之乙醇且包含12至80毫克/毫升的具下列通式 之水不溶性特综（taxane)衍生物： OR其中R代表氫原子或乙醯基，Rdt表第三-丁氧基羰基 胺基或苯甲醯胺基，R2代表氫原子或第2-或4-位置上之 氯或氟原子* K及R3代表羥基或者1?3與接於第8-位置上 之甲基構成連接至第7-及8-位置上之伸甲基（-CH2-); Μ及一種為聚山梨酯或者聚氧乙烯篦麻油衍生物之界面 活性劑。 2. 根據申請專利範圍第1項之姐合物，其包含少於2 %的 乙醇。 3. 根據申請專利範圍第2項之組合物，其中，在式（I) 化合物中，R代表氫及1^代表第三-丁氧基羰基胺基。 4 根據申請專利範圍第2項之1且合物，其中，在式（I ) 化合物中，R代表乙醯基及h代表苯甲醯胺基。 ^ 根據申請專利範圍第1項之组合物，其係用以製備一種 灌注液，其含有少於0.5毫克/毫升之式（I )化合物（ 其中R代表氫及1代表第三-丁氧羰基胺基），及少於1 本纸張尺度適用中國國家標準(CNS) A4規格(210x 297公釐) 577752 A8 B8 C8 _ D8___ 六、申請專利範圍 毫升/升的乙醇及少於15毫升/升的可為聚山梨酯或聚 氧乙烯篦麻油衍生物之界面活性劑。 a 根據申請專利範圍第1項之姐合物，其係用以製備一種 灌注液，其包含自0.1至0.3毫克/毫升之式（I )化合 物（其中r代表氫及“代表第三-丁氧羰基胺基），及少 於1毫升/升的乙醇及少於15毫升/升的可為聚山梨酯 或聚氧乙烯篦麻油衍生物之界面活性劑。 裝 7. 根據申請專利範圍第1項之姐合物，其係用K製備一種 灌注液，其包含1毫升/升或更少之式（I )化合物（其中 R代表乙醯基及h代表苄醯胺基），及少於1毫升/升 之乙醇，及可為聚山梨酯或聚氧乙烯篦麻油衍生物之界 面活性劑。 訂 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 577752 第八—〇五三三二號專利申請案 中文補充説明書（八十六年九月） 活性成份 灌注液中之乙醇 灌注液中之 活性成性 原料溶液中 之活性成份 原料溶液 中之乙醇 特克索 < 0.3毫升/升 1毫克/毫升 20毫克/毫升 < 0.6 % 特克索 < 0.09毫升/升 0.3毫克/毫升 20毫克/毫升 <0.6% 特克索 < 0.5毫升/升 1毫克/毫升 12毫克/毫升 < 0.6 % 特克特爾 0.09毫升/升 0.5毫克/毫升 40毫克/毫升 < 0.72 % 特克特爾 0.05毫升/升 0.3毫克/毫升 40毫克/毫升 < 0.67 % 特克特爾 0.02毫升/升 0.1毫克/毫升 40毫克/毫升 < 0.8 % 特克特爾 < 0.01毫升/升 0.1毫克/毫升 60毫克/毫升 < 0.6 % U:\TYPE\MFY\MFY-230.DOC\13 1 ^ αχ· 補充 第八 〇五三三二號專利申請案 中文補充説明書（八十三年七月） 實例1 1 將3_特丁氧基羰胺基-3-(2-氟苯基）-2-¾基-(2R，3S)_丙酸_ 4 -乙醯氧基- 2α -苯甲酸基-5冷，20 -環氧q，7冷，1〇冷·三羥 基-9-氧-U-特烯-13 α _酯（20毫克）置於一圓底燒瓶且溶於無水 乙醇（〇·4亳升）中。溶解後，添加聚山梨酯8〇(〇5亳升）且利用 磁力攪拌备均質化該混合物。該燒瓶係利用旋轉蒸發器而置於眞 2中’而該乙醇則於減壓（1 On m H g)下被蒸餾一小時。所得溶 液則全然澄清且含有40毫克/毫升3 -特丁氧基羰胺基-3_(2_氟苯 基）-2-經基_(2R，3S) -丙酸―心乙醯氧基苯甲酸基_5万， 2 0 -壤氧-1，7 0，1 〇 0 -三羥基-9 -氧-1 1 -特烯3 α •酯經〇 9 % 含水氯化劍灌注液稀釋達1毫克/毫升濃度後，所得溶液歷2 4小 時後仍爲穩定。 實例1 2 將3 -特丁氧基羰胺基- 3- (4 -氣苯基）-2 -羥基-(2R，3S) -丙酸一 4 -乙醯氧基-2α-苯甲酸基-5/3，20-環氧·ι，7冷，10石-三羥 基-9 -氧-! i -特烯_ | 3 α -酯（2 〇毫克）直於一圓底燒瓶且溶於無水 乙醇（0.4毫升）中。溶解後，添加聚山梨酯80(0 5毫升）且利用 磁力攪掉器均質化該混合物。該燒瓶係利用旋轉蒸發器而置於眞 空中，而該，乙醇則於減壓（1 〇 n m H g )下被蒸餾一小時。所得溶 液則全然澄清且含有4 0毫克/毫升3 -特丁氧基羰胺基-3 - ( 4 -氣苯 基）-2-羥基-(2R，3S)-丙酸-4-乙醯氧基-2α-苯甲酸基-5/3, 2 〇 -環氧-1，7冷，1 〇冷-三羥基_ 9 —氧_ ! ! _特烯· 1 3 α -酯經〇 9 0/〇 32941-2.doc 一 1 一 含水氣化鈉灌注液稀釋達1毫克/亳升濃度後，所得溶液歷24小 時後仍爲穩定。 實例1 3 蒸餾一小·時。所得溶液則全然澄清且含有4〇毫克/毫升Ο —特丁 氧基羰胺基-2-經基-3-苯基_(2R，3S)_丙酸二乙酿 氧基- 2α -苯甲酸基- 5/3，20-環g 〜甘1 衣虱-1万·踁基- 7/?，8石_亞甲基 -氧-19 -去甲-11-特烯妹 ^。。/人 知經0 · 9 %含水氣化鈉灌注液稀 釋達1毫克/毫升濃度後，所彳畧兮、、产 町侍，合硬則可穩定歷多於24小時後仍 爲穩定。 將3_特丁氧基羰胺基-2-裡基-3-苯基-(2R，3S)-丙酸-4α ，1〇冷-二乙醯氧基_2α -苯甲酸基-5冷，20 -環氧--經基 ，8冷-亞甲基-9-氧-19-去甲-11-特烯- I3j -酯（2〇毫克）置於一 圓底燒瓶且溶於無水乙醇（0 · 4毫升）中。溶解後，添加聚山梨酯 8〇(〇.5毫升〇且利用磁力授拌器均質化該混合物。該燒瓶係利用 旋轉蒸發器而置於眞空中，而該乙醇則於減壓（1〇nm Hg)下被 32941-2.doc
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| FR9108527A FR2678833B1 (fr) | 1991-07-08 | 1991-07-08 | Nouvelles compositions pharmaceutiques a base de derives de la classe des taxanes. |
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| TW081105332A TW577752B (en) | 1991-07-08 | 1992-07-06 | Compositions suitable for the production of injectable perfusion |
| TW081105332A TW495362B (en) | 1991-07-08 | 1992-07-06 | New compositions containing taxane derivatives and suitable for the production of injectable perfusion |
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| US4206221A (en) * | 1979-01-03 | 1980-06-03 | The United States Of America As Represented By The Secretary Of Agriculture | Cephalomannine and its use in treating leukemic tumors |
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| US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
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