TW495362B - New compositions containing taxane derivatives and suitable for the production of injectable perfusion - Google Patents
New compositions containing taxane derivatives and suitable for the production of injectable perfusion Download PDFInfo
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- TW495362B TW495362B TW081105332A TW81105332A TW495362B TW 495362 B TW495362 B TW 495362B TW 081105332 A TW081105332 A TW 081105332A TW 81105332 A TW81105332 A TW 81105332A TW 495362 B TW495362 B TW 495362B
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- 239000000203 mixture Substances 0.000 title claims abstract description 32
- 230000010412 perfusion Effects 0.000 title 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 title abstract 2
- 239000004094 surface-active agent Substances 0.000 claims abstract description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 85
- 239000000243 solution Substances 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000011049 filling Methods 0.000 claims description 11
- -1 glycol ester Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 239000003978 infusion fluid Substances 0.000 claims description 7
- 229920000136 polysorbate Polymers 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 229950008882 polysorbate Drugs 0.000 claims description 5
- 240000008564 Boehmeria nivea Species 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 claims description 4
- 230000002079 cooperative effect Effects 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 244000025254 Cannabis sativa Species 0.000 claims 1
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 claims 1
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 claims 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims 1
- 235000009120 camo Nutrition 0.000 claims 1
- 235000005607 chanvre indien Nutrition 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 239000011487 hemp Substances 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 229920000728 polyester Polymers 0.000 claims 1
- 239000012985 polymerization agent Substances 0.000 claims 1
- 150000005846 sugar alcohols Polymers 0.000 claims 1
- 239000002075 main ingredient Substances 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
- 239000004480 active ingredient Substances 0.000 description 8
- 239000008103 glucose Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 4
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 4
- 229920000053 polysorbate 80 Polymers 0.000 description 4
- 229940068968 polysorbate 80 Drugs 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 239000000052 vinegar Substances 0.000 description 3
- 206010002199 Anaphylactic shock Diseases 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000009472 formulation Methods 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
- 239000000047 product Substances 0.000 description 2
- 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 2
- 238000003756 stirring Methods 0.000 description 2
- 239000004575 stone Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- KWVPFECTOKLOBL-KTKRTIGZSA-N 2-[(z)-octadec-9-enoxy]ethanol Chemical group CCCCCCCC\C=C/CCCCCCCCOCCO KWVPFECTOKLOBL-KTKRTIGZSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical group CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 235000004936 Bromus mango Nutrition 0.000 description 1
- 101100008047 Caenorhabditis elegans cut-3 gene Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 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 1
- 240000007228 Mangifera indica Species 0.000 description 1
- 235000014826 Mangifera indica Nutrition 0.000 description 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 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
- 206010039509 Scab Diseases 0.000 description 1
- 235000009184 Spondias indica Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007792 addition 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
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-VQEHIDDOSA-N benzoic acid Chemical compound OC(=O)C1=CC=C[13CH]=C1 WPYMKLBDIGXBTP-VQEHIDDOSA-N 0.000 description 1
- 235000010233 benzoic acid Nutrition 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
- 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
- 239000003814 drug Substances 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000002309 gasification Methods 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000021243 milk fat Nutrition 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium 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
- 239000010959 steel Substances 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000008673 vomiting Effects 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Biochemistry (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)
- Chemical And Physical Treatments For Wood And The Like (AREA)
- Paints Or Removers (AREA)
Description
425362 第81105332號專利申請案 中々說明書修正頁年1月
五、發明説明() 本發明係關於包含倶有抗腫瘤及抗白血病活性的治療製 劑的組合物反持別是藥學劑型。更特別地ί糸關於適合於注 射的組合物,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
(請先閱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製 其中R代表氫原子或乙醯塞及I代表第三-丁氧基羰基胺 基或笨甲醯胺基。在這些衍生物中,其中R代表乙醯基及 R 1代表苯甲醯胺基者或其中R代表氫原子及R i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K特 克索的名字較著名,而第二個則K特克特爾(Taxot ere)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α )化合物的最佳溶劑,且先前已被認為在 製備含特克 <"索或特克爾之可p射配方為不分散的。 訂
AiSl 495362
Ik ηλί Α6 Β6 五、發明説明( 充 (請先閱讀背面之注意事項再填寫本頁) 例如,根據Rowinsky, Lorraine, Cazenave及 Donehower 於 1990年 8 月發表在 Journal of the National Cancer Instituto, 82 冊,15號,第 1247-12 5 9頁中,可製得在溶劑混合物中含有將近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
- 5 0%體積比的乳脂仿(Creraophor) EU 於注射用時,該溶液與一種包含有氯化鈉或右旋糖(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 狀況下皆穩定的混合物,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毫克/ 毫升(參考上述的發表,1251頁,第1檷,第三段)。 •訂· 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Γ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)〇 •綠· 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,在治療時注射大體積會造成, 甲 4(210X 297’二'发) 495362 第81 1 05332號專利申請案 A7 中文說明書修正頁(85年7月)五、發明説明()
經濟部中央標準局員工消費合作社印製 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組合物,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 乙二醇酯或聚乙二醇與篦麻油的一種酯。 > 根據完成本發明的第一個方私製備一種組合物,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〜酯(pcrlysorbate),例如如 同K ”吐溫”標示的名字,一種標示為聚氧乙二醇酯,例如 ,名字為乳仿(Emulphor),或標示為聚氧化乙烯篦麻油衍 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 後逐漸加人界面活性劑來製備。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1〇到〗00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内部促使含有特烷衍生物的朦體質 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。 * 根撺第二種方法來製備本發明之組合物,在少量(1至 ---------- - 5 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁)
、1T
495362
A B 五、發明説明() (請先《讀背面之注意事項再填寫本頁) 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,及可改菩粉末的濕潤及該組合物的最 後過濾。 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。其是穩定的及含有髙達20 0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。 •打· 一種含特克索的本發明的組合物最好仍然擁有濃度在6 及2 0毫克/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。由上面的姐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。 •綠· 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1 0 0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1 0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 甲 4(210X 297 公发) 495362 年月 A6 B6 7ιΓ 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0 . 1及 0.5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。使用這些溶液 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。 根槠前诚埒菘的吐齩節例 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。該灌注溶液的穩定度超過21小時。 範例1 - 7 將特克特爾(32克)溶解在純酒精(340毫升)中然後加人 甲 4(210X 29711) (請先閲讀背面之注意事項再填宵本頁) •it· •打· •綠· 495362 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。所得到的組合物是穩定 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 〇 .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毫克/毫升)的特克索姐合物 來仿效相同的測試。 结果顯示在表1 (請先閱讀背面之注意事項再填寫本頁) •訂· •線· 8- 甲 4(210X 297 公;¥) 495362 經濟部中央標準局員工消費合作社印製 第8U05332號專利申請案 中文說明書修正頁(85年7月) A7 B7- 五、發明説明() «克龙 Ι.Ϊ 克 14« 聚山如坫 ¥及山 狀山切3/i Vi ill 界面活性劑 20 *克/«71 2〇 «克/«ή 〆丨 12 -^yi/^n 4 0 40 *>£/3Β;| 4〇 «yd/^/ι 6 0 3g Vd/;®;| 組合物之濃度 1 1 «5ΐ/*;Ι 0.3 *兑/*71 ' 1 «兑/«/1 0.5 «5*d/«/l 0.3 ^5Ϊ/«;Ι o.i o.i ««/«;! II ϊ(; 辦念 50 «;|/;| 15 «7丨/升 0 3.3 «;|/Jill. 6 ^;| /7|-. 6.9 «/1/71 2.3 -8 7I//I 1.5 «7丨./外 "-5· <〇·3來外/升 <c.〇〇 ^ηπ\ ·:〇·5 «升/升 0.09老升/升 0.05¾力/升 0.02 > 8小時 >2 4小時 >4 0小时 8 -2 3小時 0 - 2 3小W 29 -Ί5小時 8 -23小ΒΪ Η定度 ¾1. (請先閱讀背面之注意事項再填寫本頁)
、1T 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) _ 9 _ 495362 五、發明説明() 範例8 在一個不綉網的反應爐中,加入特克特爾(258克)及溶 在乙醇(2425克)中拌隨著物理性的攪拌45分鐘。加人聚山 梨酯80(6156克)及利用物理性的攪拌15分鐘來均質化該混 合物。將該組合物倒入一種反應爐中及在10到50毫巴 ( 1 000到5000Pa)的減懕下蒸餾出酒精*維持該溫度在18 及28它之間。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微米的洞徑大小的過 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 (21δ) (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), 在一種旋轉式蒸發囍中在30 C在25mmHg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毫克/ 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 觀察到沈澱的產生。 筋例10 在一個500.毫升的圓椎形燒瓶中加入聚山梨酯 -10- (請先閱讀背面之注意事項再填駕本頁) •it· •訂· •綠· 甲 4(21〇X 297L、沒)
495362 A6 B6 五、發明説明() 80(275·5克)及純酒精(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测試階段在30C,使用一個磁性 棒播拌接近60〇ΓΡιη。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圑狀物消失( 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)。 (請先閲讀背面之注意事項再填寫本頁) •31· •訂· •線· -11- 甲 4(210Χ 297 公发) 495362 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-23 0.DOC\13 1 495362 ::賴 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 將3-特丁氧基羰胺基-3-(2-氟苯基)-2_羥基_(211,;^)_丙酸 4-乙醯氧基-2〇:_苯甲酸基_5/3, 2〇·環氧-丨,7石,1〇々·三羥 基-9-氧特烯--醋(20毫克)置於一圓底燒瓶且溶於無: 乙醇(〇.4毫升)中。溶解後,添加聚山梨酯8〇(〇5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(l〇nm Hg)下被蒸餾一小時。所得溶 政則全然澄清且含有40毫克/毫升3-特丁氧基羰胺基_h(2_氟苯 基卜^羥基-(2R,Μ)-丙酸乙醯氧基_2“ _苯甲酸基乃卢, 裒氧 1,7 yS,1 0 /3 -二备基-9 -氧-1 1 n ;[ 3 ^ _ 酯經 〇 9 % 含水氣化鈉灌注液稀釋達!毫克/毫升濃度後,所得溶液歷以小 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_(211,35)_丙酸__ 4_乙醯氧基苯曱酸基20-環氧' 7/3, 1〇/3_三經 基-^氧·ij-铈締-13"-醋(2ύ毫克)直於一圓底燒瓶且溶於無水 乙醇1〇、4笔升)中。溶解後,添加聚山梨酯8 〇 (〇 5毫升)且利用 和#拌器均質化該混合物。該燒瓶係利用旋轉蒸發器而置於眞 空中丄而該乙醇則於減壓(1〇nm Hg)下被蒸餾一小時。所得溶 液則王…且凊且含有40毫克/毫升3-特丁氧基羰胺基_3_(心氣苯 基)^;^基-(211,3S)·丙酸乙酿氧基苯甲酸基-5万, 写氧 1,7 /3,1 0 _ 二羥基-9 _ 氧-i _ 特烯· ;[ 3 α -酯經 〇 9 % 32941-2.doc 2氣化_线稀釋w毫克/毫升濃度後,所得溶 時後仍爲穩定。 實例1 3 將3_特丁氧基羰胺基-2-羥基-3_苯基_(2R,3S)_丙酸_4“ 二乙酷氧基-2α-苯甲酸基·5/?,2G_環氧•超基-7石 ,M-亞甲基-9-氧-19-去甲_u•特晞_13α_醋(2〇毫克)置於一 圓展燒瓶且溶於無水乙醇(0.4毫升)中。溶解後,添加聚山梨醋 8〇(〇.5毫升G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。謂心)下被 蒸餘-小時。所得溶液則全然澄清且含有4〇毫克/毫升卜特丁 :基羰胺基-2-羥基_3_苯基_(2R,3S)_丙酸、,…-二乙醯 氧基- 2α -苯曱酸某?〇 ^ ^ ^ ^ 广 丞#,2〇d衣乳MyS-羥基-7/3,8石_亞曱基 冬氧-19-去甲-特缔·13〇;-酿經。9%含水氣化鋼灌注液稀 釋達!毫克/毫升濃度後,所得溶液則可狀歷多於叫、時後仍 爲穩定。 32941-2.doc - 2〜
Claims (1)
- 495362 第SU05332號專利申請案 A8 B8 中文串請專利範圍修正本(86年99 ) C8 D8 六、申請專利範圍 種適合藉稀釋製備可注射灌注液之姐合物,該组合物 t \ 乎無乙醇且包含高達200毫克/毫升的具下列通式之水 /,. 溶性特燒衍生物: OR(請先閱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製 其中R代表氫原子或乙醢基,1代表第三-丁氧基羰基 鞍基或笨甲醯胺基* ί?2代表氫原子或第2-或4-位置上之 氯或氟原子,以及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-); 以及一種可為聚山梨酯,聚乙醛二元醇酯,或者聚氧化 乙烯篦麻油衍生物之界面活性劑。 2. 根撺申請專利範圍第1項之组合物,其包含少於5 %的 乙醇。 a 根據由請專利範圍第1項之组合物,其包含少於2 %的 乙醇。 4- 根據申請專利範圍第2項之姐合物,其中,在式(I ) 化合物中,R代表氫及h代表第三-丁氧基羰基胺基。 a 根據申請專利範圍第2項之姐合物,其中,在式(I) 化合物中,R代表乙醯基及Ri代表苯甲醯胺基。 本纸張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 495362 A8 B8 C8 D8 ____ 六、申請專利範圍 a 根據申請專利範圍第1或2項之姐合物,其含有高達 80毫克/毫升的式(I )化合物。 7. 根據申請專利範圍第4項之姐合物’其含有20至80毫克 /毫升的式(I )化合物。 a 根據申請專利範圍第5項之组合物’其含有6至2〇毫克 /毫升的式(I)化合物。 - a 一種製備根據申請專利範圍第1或2項之组合肩之方法 ,其包括將特烷衍生物溶解在乙醇中’加入該界面活性 劑及移除乙酵。 10. 根據申請專利範圍第9項之方法’其中乙醇係藉蒸發移 除。 11 一種製備根據申請專利範圍第1項之姐合物之方法,其 包含在一種含有1到2 %乙酵的界面活性劑中緩慢加入 特烷衍生物。I 12 一種灌注液,其含有少於〇·5毫克/毫升之如申請專利 範圍第4項所定義的化合物,及少於1毫升/升的乙酵 及少於15毫升/升的界面活性劑,該界面活性劑可能為 聚山梨酯,聚乙醛二元醇酯,或一種聚乙烯二醇和篦麻 油的酯。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) ia 根據申請專利範圍第12項之灌注液,其包含自〇·1至 0.3毫克/毫升之如申請專利範圍第4項所定義之化合 物0 Η. 一種灌注液,其包含1毫升/升或少於1毫升/升之如 申請專利範圍第5項所定義的化合物及少於1毫升/升 -2 - ^紙張尺度適用中國國家標準(CNS ) Α4規格(公釐) 495362 A8 B8 C8 D8 申請專利範圍 酯。 梨酯 山的 聚油 為麻 能篦 可和 劑醇 性二 活烯 面乙 界聚 該種 ,1 劑或 性, 活酯 面醇 界元 與二 醇醛 乙乙 的聚 (請先閱讀背面之注意事項再填寫本頁) 、1T 經濟部中央標準局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐)
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