TW438586B - An aqueous, injectable rapamycin pharmaceutical composition its product and a process for preparing thereof - Google Patents

An aqueous, injectable rapamycin pharmaceutical composition its product and a process for preparing thereof Download PDF

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Publication number
TW438586B
TW438586B TW83108922A TW83108922A TW438586B TW 438586 B TW438586 B TW 438586B TW 83108922 A TW83108922 A TW 83108922A TW 83108922 A TW83108922 A TW 83108922A TW 438586 B TW438586 B TW 438586B
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Taiwan
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rapamycin
solution
injection
range
concentration
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TW83108922A
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Chinese (zh)
Inventor
Robert P Waranis
Thomas W Leonard
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American Home Prod
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Priority claimed from US08/302,190 external-priority patent/US5616588A/en
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Abstract

Disclosed herein is an aqueous, injectable rapamycin solution comprising 40 to 75 volume percent of a concentrate solution of rapamycin in propylene glycol, at concentrations of rapamycin ranging from 0.25 mg/ml to 8 mg/ml, in combination with a diluent solution comprising water, wherein the diluent comprises 60 to 25 volume percent of the combined solution and the concentration of rapamycin in the combined solution ranges from 0.1 mg/ml to 4 mg/ml.

Description

五、發明説明(^ ) A7 B7 經濟部中央揉準局貝工消费合作社印製 本發明体有Η雷帕徽素靜脈注射配方及其製法。此處 掲示的發明提供一種無需界面活性贿的靜脈注射(iv)S 帕徽素水配方。於一《態樣中,本發明包括當帕徽素於 丙二酵之囊缩_溶液輿由水組成之稀轉_,以下述特定 比例組合。 霣帕撇素是由吸水鰱(Streptoiyces hygroscopicus) 生産的巨環類抗生素,首先供發現其作為抗徽雄Μ之用 途。其對徽β如白色念珠«((Candida albicans}及吉替 妻小芽鼸0 (Microsporun 83^36111)等徽69之生長有不 良彩響。雷帕徽素,其轚備及其抗生活性揭示於1975 年12月30日飆予8\^611〇&861^&1等之美國第3,929,992 轚専利案。1977年Hftrtel R.R.等於加拿大生理藥理學 期刊55,45-51(1977)鞴告雷粕徽索對實驗性遍敏性臞炎 及佐藥性R節炎具有免疫抑制性β 1989年Calne,B.Y.等 於刺胳針 1989, Νο.2, ρ·227 及 Morris, R.E.及 ifeiser, Β,Μ.於内科學研究1 98 9 Ho.l7,p. 603-10分別嫌告於異 讎移植雪帕徽索可抑刺活鍾排斥作用》接著有無數文獻 描述雷帕撤索之免疫抑制及排斥抑制性霣,醑始遒行tt 床研究雷輪徽索用於人《移植中抑制排斥的用途β «帕徽索不溶於水僅《溶於賜外配方製備時常用的增溶 _如丙二酵,甘油及ΡΕ6 400。儀殆不溶於ΡΕ8 3 0 0以及 不溶於或極微溶於常用注射用助溶_水条统,如20%乙 酵 / 水,10% DMA/ 水,20¾ Cre 屋 ophor EL»/ 水及 20%泊立索倍(9〇1以〇1^816)80//水》因此理由故難以 請 先 鬩. 讀 背 面 之 注V. Description of the invention (^) A7 B7 Printed by the Shellfish Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs The present invention has a rapamycin intravenous injection formula and its preparation method. The invention presented here provides an intravenous (iv) S-palatinate water formulation that does not require interfacial bribes. In one aspect, the present invention includes the cystic dehydration of malicin in malonase, a solution of dilute transmutation consisting of water, combined in the following specific ratios. Sparpaline is a macrocyclic antibiotic produced by Streptoiyces hygroscopicus, which was first used to find its use as an anti-huixiong M. It has a bad effect on the growth of emblem 69 such as white rosary «((Candida albicans) and Jisui's wife, Microsporun 83 ^ 36111) and other emblems 69. Rapain, its preparation and its anti-life reveal On December 30, 1975, it was awarded to the US 3,929,992 case of 8 \ ^ 611〇 & 861 ^ & 1 and so on. In 1977, Hftrtel RR was equal to the Canadian Journal of Physiology and Pharmacology 55,45-51 (1977). The thunderbolt emblem is immunosuppressive to experimental percutaneous allergic rheumatitis and adjuvant R ganglionitis. Calne, BY equals thorn needle 1989, No. 2, ρ 227 and Morris, RE and ifeiser, Β, 1989. Μ. In Internal Medicine Research 1 98 9 Ho. 17, p. 603-10 respectively suspected of xenopus transplantation Xuepahuixin can inhibit stabbing clock rejection "followed by numerous documents describing the immunosuppressive and Rejection inhibitory 霣, 醑 醑 研究 bed study Thunder wheel emblem cable for human use "inhibition of rejection in transplantation β« pa emblem cable is not soluble in water only "soluble in the solubilization commonly used in the preparation of foreign-made formula _ such as C Two enzymes, glycerol and PE6 400. Yexi is insoluble in PE8 3 0 0 and insoluble or slightly soluble in commonly used injection-assisted solubilizing _ water strip system, such as 20% B / Water, 10% DMA / Water, 20¾ Cre House ophor EL »/ Water and 20% Perisox (901 to 〇1 ^ 816) 80 // Water" For this reason, it is difficult to ask first. Read the back Note

I ί 裝 訂 本紙張尺度適用肀國國家橾準(0阳>人4规格(210><297公釐) 85 8 6 A7 B7 經濟部中央樣率局負工消费合作社印装 五、發明説明(>) 製成雷帕徽索之«床及商業上坷接受的注射配方β雷帕 徽素注射組合物教逑於1381年12月16曰公告的緻洲専利 公告案第004179 5號。此翟注射配方中《帕徽索先濬於 低襻黏有機溶痛,亦即丙_,甲_或乙酵一然後此溶 液典非麯子界面活性_灌合,界面活性爾供龌自聚《乙 基化脂肪酸類;聚氣乙基化臛肪酵類;及聚氣乙基化甘 油羥基釅肪酸醱類,例如«氧乙基化S麻油,以克摩供 (Creaophor)® SL為例;及聚氣乙基化氫化霣麻油,以 克摩佛》BB 4Q及克摩彿® KB60為例·克摩佛《*EL為實 例中使用的主費非麯子羿菌活性 目前用於人《累_罌宮移櫨抑Μ拂斥的主饔免疫抑刺 Μ 為環孢靈(cyclosporine HSandiaaune·)•琢遼鼸偽 由11«胺基酸组成的環形多肽〇靜K注射配方 Sandtuune® (IV)是每·1含有50·β璨袍靈,650_g充摩供必 EL及酵pH Helv. ( 3 2 . 9 96酾稹比)(於氰下)的_ _安tt · 投蕖時此灌合枚又以0.9%氯化Μ注射液或5%fi菊糖注 射掖於用前稀釋(_阖來面手册45tb ed.,1991,p.p.l902 -64, Medical Ec〇n〇Mics Coapany,Inc·)·定名為 FK506 的巨琢類抗生索分子,某些銪構類似索,目拥也 用於人讎興饑籌宮移植抑觸排斥,正在遒行_床研究》 FK506係由 Streptoiyces tsuskubaensis分離且教述於 1990年1月16日顦予Okuhar a等之美園第4,894,36 β號專 利案》R _ V e n k a t a r a κ a n a η 等於移植饑事錄 2 2 , Ν 〇 . 1 , S u ρ ρ 1. 1 ρρ 52-5β( 1 9 9 0年2月)報吿FK5fl8靜脈注射配方提供呈 J3. ~請先閲讀背面之注意事項再填寫本頁) -»I ί The size of the bound paper is applicable to the national standards of the country (0 Yang > People 4 specifications (210 > < 297 mm) 85 8 6 A7 B7 Printed by the Central Consumer Samples Bureau of the Ministry of Economic Affairs and Consumer Cooperatives. 5. Description of the invention (≫) The «Bed and Commercially Acceptable Injection Formula β-Rapamin Injection Composition Made into Rapamoxide» was issued on Dec. 16, 1381, to Chiu Chau Lee Proclamation No. 004179 5. In this Zhai injection formula, "Pa Hui Suo Xun was first dissolved in low-viscosity organic sore, that is, C, A, or acetic fermentation. Then this solution can be used for interfacial activity of non-Koji, perfusion, interfacial activity, and self-aggregation." "Ethylated fatty acids; polyethylated fatty acids; and polyethylated glycerol hydroxy fatty acids, such as« oxyethylated S sesame oil, with Creaophor® SL as Examples; and polygas ethylated hydrogenated ramie oil, using CMOFO BB 4Q and CMOFO® KB60 as examples. CMOFO "* EL as an example. The main cost of A. aspergillus fungi is currently used for People "Tired_Pygmy Palace 栌 Μ M Μ 斥 斥 饔 饔 饔 饔 饔 饔 饔 饔 饔 饔 饔 为 cyclo cyclo cyclo cyclosporine HSandiaaune ·) • Zhuo Liao 鼸 puppet by 11« amino acid Sanduune® (IV) is a circular peptide formulated with injection of Sanduune® (IV). It contains 50 · β Canpalin per 1: 1, 650_g charge and supply EL and fermentation pH Helv. (3 2. 9 96) (in cyanide) Bottom) _ _ Antt · At the time of injection, this filling piece was injected with 0.9% HCl injection or 5% fi inulin and diluted before use (_ 阖 来 面 手册 45tb ed., 1991, ppl902 -64, Medical EcnoMics Coapany, Inc.). A macromolecule antibiotic molecule named FK506, with some structures similar to that of ropes. It is also used for transplantation to suppress rejection.遒 行 _ 床 研究》 FK506 was separated by Streptoiyces tsuskubaensis and taught in the patent case No. 4,894,36 β issued to Okuhar a et al on January 16, 1990. R _ V enkatara κ ana η is equal to the transplant hunger record 2 2, Ν 〇. 1, Su ρ ρ 1. 1 ρρ 52-5β (February 190) reported FK5fl8 intravenous injection formula is provided J3. ~ Please read the precautions on the back before filling this page )-»

I 本紙張尺度逍用中國國家橾率< CNS ) A4規格(210X297公釐) 經濟部中央橾準局員工消费合作杜印製I This paper is scaled according to China's national rate < CNS) A4 size (210X297 mm) Printed by the staff of the Central Government Bureau of the Ministry of Economic Affairs for consumer cooperation

:b o D A7 _B7__ 五、發明説明(々) 10·8/·1 FK50B於聚氧乙基化萬麻油(HCO-efl,界面活性 _)及_之溶液。IWK製麵必須以蠻水或葡鹫籣豨釋且 以輪注經歷1至2小時投麵。 申讅人今曰出人意外地發現醫蕖可接受性雷»徽索注 射水溶掖可嫵需使用界面活性麵獲得,供經由使用丙二 酵溶解嘗帕ft索且分成雷«徽索濃纗Μ及水轘釋劃之二 部式条統0待殊優酤為使用水作為單一成份式囅__, 因组織耐受性故為較隹注射溶液。此外可避免鼉合其它 稀釋爾成份》本發明之言帕徽索注射配方極為遽合大_ 量注射及输注。 本發明之一戆樣為一種以水為主的雷粕ft素注射疲, 包括雷粕徽素與丙二酵之濃&爾禳液輿包括水之稱釋劑 溶液组合*待別,申請人之發明為一種注射用霄柏黴索 水溶液,包括40至75V%笛帕徽索於丙二_之囊鏞Μ溶 掖,笛帕徽素囊度於由〇.25ig/il至8ig/d之箱麵,輿 包括水之稀釋Μ溶液組合,其中該稀譯麵占組合溶液之 60至25V%及雷帕徽素於組合瘠液之濃度供於〇.1·β/·1 至4·β/·1之鮪鼷。較佳注射用笛帕徽索水溶液為其中稀 霉繭溶掖占組合溶液之40至60V9^稀ϋΜ較佳為水, 但也包括小量例如1β%讎積比或以下其它溶爾如丙二醪β 本發明之此種戆樣之較佳注射用當帕徽橐水溶液為其 中霣帕ft素於丙二酵濃纗癲之囊度供於由0.5ig/il至4 g/al之範_·更佳為其中《帕徽素於丙二酵濃繡Μ之 濃度馕於由〇.6·β/·1至3.3·β/·1β也鼷較佳的本發明之 本紙張尺度逍用中國困家搮串·( CNS ) A4规格(2I0X297公釐) I---------^------1Τ------^ i;請先聞讀背面之注意事項再填寫本頁) 經濟部十央搮準局員工消费合作社印製 A7 B7_ 五、發明説明(4 ) 注射用雷帕徽索水溶液為其中《帕徽索於組合液之濃度 供於由0 . 2 5 g / 1至2 g / 1之範,及其中丙二酵占组 合溶液之β〇至40V96者* 根癱本發明之此«樣,特佳之注射用《帕徽素水溶液 包括40至60%富粕徽素於丙二醻之濃鐮Μ裢液,笛帕徽 素濃度於由〇.5·β/·1至4ag/«l之範_ ,輿包括水之ϋ « Μ禳液組合,其中該稀釋_占組合溶液之60至40V%及 霣帕徽索於组合溶液之囊度供於〇.25ig/*l至2ag/ai之 範匾。 本發明也提供一種供大_最注射的前述注射用霣帕徽 窶水溶掖,其中雷帕徽素於注射溶掖之濃度較佳供於D.25 ·β/·1 至 2_g/al之範 _ · 本發明之第二態樣為一種當_徽索注射用水溶液,該 溶液包括雪帕徽索輿丙二酵及水之溶液,其中水占瘩疲 之40至75V96及雷帕徽索於瘩液之濃度供於0_l«g/il至 4·β/·1之範鼷· 本發明之此觼樣之較佳注射用雷_徽索水溶液為其中 雷帕徽索於溶液之囊度係於0.25·£/·1至lig/il之範· « S外也羼較佳者為其中水占溶液之60至40¥%者。 本發明又提供一種産«包含有雷粕徽素之囊繡_溶液 舆豨轉剤,里組合供於_鼸注射前蘸合»得具有霱 帕徽素濃度於〇.1·8/·1至範之瀋液;該囊编爾 溶掖包括當帕徽素典丙二_於0.2 5μ/·1至8·β/·1之範 ;該稀釋則榕液包括水,濃编爾鰣稀I»爾之比供於由 本紙張尺度逋用中國國家樣準(CNS ) A4規格(2丨0X297公釐> ----------#------1Τ------0 i請先鬩讀背面之注意事項再填寫本頁) 經濟部中央揉準局I工消费合作社印褽 A7 B7 五、發明説明(r ) 40: βΟ至75: 2 5鱷積百分率之幢 當帕徽索靜鼷用濃鑣爾之製造包括添加雷帕徽素至丙 二_及溉合至生成溶液,此種遇程甩於室瀣充成》然後 溶掖以Β知方式通濾滅麵。鳙麗醞稹之_纗_溶液熵充 入安餌内随後藉Β知方式密封《根鐮注射雨之欉奉製備 程序,於全部邏濾熇充及密封操作Μ持__條件》産物 雷帕徽索囊繡Μ最佳冷蘸傭存》 當帕撇索靜黼稀轉_条銑之製迪包括以)(量讎稹_釀 水瑱充小級,Μ後S上小雇密封並离應蒸氣滅篇·當《 徽索稀釋Μ溶液成品可餹存於室瀑或冷麵· 調配最終投麵配方之程序包括將一份雷帕徽索_鼸潰 缩爾注入含笛柏徽素靜脈豨釋劑之小板内,规大約1分 鏡或至生成灌澝瀋掖為止》讕配後的溶液須在指示的使 用期内投謂配後笛帕徽索注射溶液之使用期為調£ 後溶掖可嫌持捶淸無色的期閧^使用期可長達4小時, 但以至多1小時為佳β 醫蕖用丙二酵容易由各種商業來灝取得〇 因此本發明也提供一種製備注射用«帕徽素水溶液之 方法,包括混合40至75¥%雷_徽索於丙二醪之濃鐮爾 溏液(S帕徽素瀵度於由〇 . 25·β/·1至8|^/«1之範 >典 包括水之稀路液,其中裼釋南占組合游液之60至 25V% ;因此雷帕徽素於注射溶掖之濃度供於0.1·β/·1 至4ig/al之ffi國》 下列實例進一步示例投明本S明之實施》 -7 - 本紙張尺度逍用中困S家標準(CNS)A4规格(210X297公釐) I I I I I I I I I 訂—— 線 C請先閨讀背面之注意ί項再填寫本頁) ^Δ38586 α7 Β7 五、發明説明( 黄例1 窗帕徽索注射S方之ϋ備(lag/· 1) 八.霣粕徽索1?嬝鐮爾里2|g/Bl於丙二酵之製備 gg 方(密度-1 · 〇 3 β g / 1 > : 當帕徽素β 100% 丙二醇,WSP 適置 程序: 1. 稱蛋霣帕徽索至漉當校準之容器· 2. 使用丙二酵調整讎積至i〇“i· 3. 混合至生成均勻溶液· 4. 無醣《濾溶篏。 5. 包裝成安期或小臞並密封》 Β.笛帕徽索IV»釋劃里l.Oig/赢1 K 方(密度-1 〇fl g*/*〗): 0 · 2 g麗 lOOil 或 103. (請先閲讀背面之注意事項再填寫本頁j .裝. ..IT. 注射用水> USP 鳙ft lOOil或100g· 程序: 1. 嫫充1·(ϊ·1±0.01·1至各5*1鉛玻璃小瓶,密封 2. 离壓蒸氣滅0而建成無ΟΚ C.富帕徽索IV溶液里lig/il (鼸配) 配方(密度-1.035 gm/ml ): 成份 數· 霤粕徽索IV濃编_ ® 2·β/·1 1·1 IV雷帕徽索稀釋剛 1 il 線 經濟部中央樣隼局貝工消费合作社印製 -2 - 經濟部中央橾準局貝工消费合作社印製 Α7 Β7 五、發明説明(Γ) 程序: 1. 将lil霣帕tt索IVjR缩爾里2·Κ/·1使用良好無篇技術 注入含1«1 IV雷帕徽索稀譯麵小板内《 2. 震瘙至生成笛清溶液。 3 .於使用期内投藥β 實例2 雷帕徽索注射配方之製備(2·β/·1) Α.笛帕徽案IV囊鐮贿呈4 ·β/·1於丙二酵之製備 配方(密度-1 .〇36g/il): 成份 m m 霣帕撤素β 100% 0.4gi 丙二醇,USP 鳙最 100*1 或 103 . 6g· 程序: 1. 稱量《帕徽素至遽當校準之容罌β: B o D A7 _B7__ V. Description of the invention (々) 10 · 8 / · 1 FK50B in polyoxyethylated tenseed oil (HCO-efl, interfacial activity _) and _ solution. IWK noodles must be released in brute water or Portuguese and must be cast in a round of 1 to 2 hours. People from Shen Zhen unexpectedly discovered that the medical and medical acceptability of thunder »emblem cable injection water soluble can be obtained by using the surface active surface for the use of malonase to dissolve the patina and divide it into thunder« emblem cable The two-part system of the M and water release standard is to be used as a single-component formula, and it is a better injection solution due to tissue tolerance. In addition, it is possible to avoid mixing other diluent ingredients. "In the words of the present invention, the pamusol injection formulation is extremely suitable for large-volume injection and infusion. One of the examples of the present invention is a kind of water-based threshing powder ft. Injection injection, including the concentration of threshing oxaloxin and malonase & the liquid solution including water, which is a release agent solution * pending, apply The invention of man is an aqueous solution of thujamycin for injection, which comprises 40 to 75V% dipaxisol in saccharine, which is from 0.25 mg / il to 8ig / d. The surface of the box includes a diluted M solution combination of water, wherein the dilute translation surface accounts for 60 to 25V% of the combination solution and the concentration of rapamycin in the combination barren solution is provided by 0.1 · β / · 1 to 4 · β / · 1 鲔 鼷. The preferred dipamusol aqueous solution for injection is from 40 to 60V of the combined solution of the dilute cocoon-solubilized solution. The dilute solution is preferably water, but it also includes a small amount such as 1β% volume ratio or other solvents such as propylene醪 β The preferred injection dangpao 橐 solution of this kind in the present invention is cysteine ft. In malonase-concentrated epilepsy. The range is from 0.5ig / il to 4 g / al. · It is more preferable that the concentration of Pa Huisu in malondiamine embroidery is not less than 0.6 · β / · 1 to 3.3 · β / · 1β. The paper size of the present invention is preferably used in China. Homeless Strings (CNS) A4 Specification (2I0X297 mm) I --------- ^ ------ 1T ------ ^ i; please read the notes on the back first (Fill in this page again.) A7 B7_ Printed by the Consumers' Cooperative of the Shiyang Central Bureau of the Ministry of Economic Affairs. V. Description of the Invention (4) The aqueous solution of rapamycin for injection is the concentration of palmoxol in the combination solution provided by 0.2 5 g / 1 to 2 g / 1 range, and β--40V96 of malonase in the combined solution * Root palsy This is the same as the present invention, especially for injection "Paralunin aqueous solution includes 40 to 60% Rich meal emblemin in the concentrated sickle solution of malonic acid, The concentration of Parsignin ranges from 0.5 · β / · 1 to 4ag / «l, including the water ϋ Μ 禳 solution combination, where the dilution _ accounts for 60 to 40V% of the combination solution and The capsules obtained from the combination solution are provided in the range of 0.225ig / * l to 2ag / ai. The present invention also provides a large-scale injection of the aforementioned injectable palladium hydrolysate, in which the concentration of rapamycin in the injectable lysate is preferably provided in the range of D.25 · β / · 1 to 2_g / al _ · A second aspect of the present invention is an aqueous solution for injection of emblems, which includes a solution of Xuepa Huisuo malonase and water, in which water accounts for 40 to 75V96 of the fatigue and rapa emblem. The concentration of tincture is provided in the range of 0_l «g / il to 4 · β / · 1. The preferred injection thunder solution of this invention in this invention is the cysteine solution in which the rapazine solution is in solution. In the range of 0.25 · £ / · 1 to lig / il · «S outside is also preferred, in which water accounts for 60 to 40 ¥% of the solution. The present invention also provides a sacral embroidery solution containing threshing glutamin, which is used as a solution for dipping before injection, and has a concentration of palladium at 0.1 · 8 / · 1. Zhifan's Shenye; the capsule preparation lysate includes the standard of Paparin Codex II _ in the range of 0.2 5μ / · 1 to 8 · β / · 1; the diluted banyan solution includes water, and the thick edible solution I » The ratio is provided for the use of the Chinese National Standard (CNS) A4 specification (2 丨 0X297 mm > ---------- # ------ 1T ----- -0 i Please read the precautions on the back before filling out this page) Central Government Bureau of the Ministry of Economic Affairs I Industrial Consumer Cooperatives Seal A7 B7 V. Invention Description (r) 40: β〇 to 75: 2 5 When the production of Pa Hui Suo Jing is concentrated, including the addition of rapahuimin to C2 and hydration to the resulting solution, such a process is thrown into the chamber to fill it, and then dissolved in a B-wise way to filter out surface.鳙 Li brewing _ 纗 _ solution entropy is filled into the bait and then sealed by the method known as "root sickle injection of rain sacrifice preparation process, filling and sealing operations in all logic filters __ conditions" product mine Pa Hui cable embroidery M best cold dip commission storage "When the Pa Qiu cable quietly thinning _ strip milling system including) (quantity 酿 _ brewed water 瑱 charge small, after the small employment seal and Eliminate the vapor of the reaction · When the finished product of the emblem solution diluted Μ solution can be stored in the room waterfall or cold noodles · The process of formulating the final injection recipe includes injecting a copy of rapa emblem 鼸In the small plate of intravenous release agent, the size of the solution should be adjusted within about 1 minute or until the perfusion is completed. The use period of the postpain injection solution should be adjusted within the indicated period of use. The post-dissolution can be suspected to be a colorless period. The use period can be up to 4 hours, but it is preferably at most 1 hour. Β Medical malonase is easily obtained from various commercial sources. Therefore, the present invention also provides a A method for preparing an aqueous solution of palmensin for injection, which comprises mixing 40 to 75 ¥% thunder_huisuo in succinimide solution of malondisulfonate From 0.25 · β / · 1 to 8 | ^ / «1 of the norms> The code includes water dilute road fluid, in which the release of South accounted for 60 to 25V% of the combined swim fluid; therefore, rapamectin is soluble in injection The concentration of tritium is provided in the country of 0.1 · β / · 1 to 4ig / al. The following examples further illustrate the implementation of this S.M. (Mm) IIIIIIIII Order-Line C, please read the note on the back, and then fill out this page) ^ Δ38586 α7 Β7 V. Description of the invention (Yellow Example 1 Window-Paper Emblem Injection S Party Preparation (lag / · 1 ) VIII. Meal emblem 1? Falci 2 | g / Bl in the preparation of malonase gg formula (density -1 · 〇3 β g / 1 >: when paroxin β 100% propylene glycol, WSP Procedures for setting: 1. Weigh the egg crust and paraffin to the calibration container. 2. Use malonase to adjust the volume to i〇 "i. 3. Mix until a homogeneous solution is obtained. 4. Sugar-free" Filtration Solution " 。 5. Packed into a safe period or small 臞 and sealed "Β. Dipa emblem cable IV» release l.Oig / win 1 K square (density -1 〇fl g * / *〗): 0 · 2 g Li lOOil Or 103. (Please read the notes on the back before filling in this page j. Packing ..IT. Water for injection > USP 鳙 ft 100il or 100g · Procedure: 1. Filling 1 · (ϊ · 1 ± 0.01 · 1 to 5 * 1 lead glass vials, sealed 2. Isolation under pressure 0 And lig / il formula (density-1.035 gm / ml) in ΟΚ C. Fupa Huisuo IV solution was built: number of ingredients · glutinous Huisei IV concentrated _ ® 2 · β / · 1 1 · 1 IV Lepas emblem dilution 1 il line Printed by the Shellfish Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs-2-Printed by the Shellfish Consumer Cooperative of the Central Bureau of Economic Affairs of the Ministry of Economy Α7 Β7 V. Description of the invention (Γ) Procedure: 1 Inject lil 霣 pat TT IVjR 尔 2, and KI / · 1 into a small plate containing 1 «1 IV rapa visor thin noodle translation plate using a good non-textual technique. 2. Shake until the dilute solution is generated. 3. Dosing β during the use period. Example 2 Preparation of rapafil injection formula (2 · β / · 1) Α. Dipa emblem IV sacrifice formula 4 · β / · 1 in malonase (Density-1.036g / il): Ingredients mm 霣 Patoxin β 100% 0.4gi propylene glycol, USP 鳙 up to 100 * 1 or 103.6g · Procedure: 1. Weigh "Paxillin to 遽 when calibration Tolerant beta

2. 使用丙二酵躕轚譏積至100· U 3. 潺合至生成均勻溶液# 4 .無_邊濾溶液》 5.包裝成安瓿或小覼金密封β Β.雷帕徽索IV!» _ _呈2 ·β/·1 成扮 · » 丙二 B , USP 10al 注射用水,WSP 適量 1〇0·1 程序: 1.丙二酵置於邃當容罌内》 -9 - 本紙張尺度逍用中國國家標準(CNS ) Α4规格(210Χ297公釐) -----------餐------ΐτ------^ • - (請先聞讀背面之注意Ϋ項再填寫本頁) 鲤濟部中央橾準局負工消费合作社印製 0 . 6gi 100·1 或 103.egi A7 B7 五、發明説明(沒) 2. 以注射用水謂轚髓稹至100·1Φ 3. 混合至生成均勻溶掖, 4 .焦醣8濾裢掖〇 5. 包裝〇 6. 离壓蒸#(滅0建成無》« C.雷MflimiV稀鞾麵呈4 ·β/_1(調配) 配方(密度-1 . 0 3 5 eB/ml > : 成份 •量 雷帕徽素IV濃编劃@ 4 _β/«】 1雇1 IV1T帕徽索稀释_ 1 ·ι 程序: 1_将111當帕徽橐IV囊编痛呈2·β/·1使用良好無_技術 注入含1·1 1¥霤粕徽索|»鞾薄小級内β 2. 震蠕至生成灌淸濬液β 3. 於使用期内投麵》 寶佣3 雷帕徽索注射Κ方之_備<3Μ/·1) Α.雷帕徽索IV濃鐮_呈β·β/·1於丙二酵之》備 配方{密度-1 .0 36g/il> : 雷帕徽素β 10096 丙二B , USP 適置 程序: 1.稱量當帕徽索至濂當校準之赛罌 -10 - 本紙張尺度逍用中國國家橾準(〇阽)八4規格(210><297公釐> (請先閲讀背面之注意事項再填寫本頁) .裝· 訂 線 *^4385 8 6 Α7 Β7 五、發明説明(9 ) 2. 使用丙二霽圆整讎積至100»1。 3. 混合至生成均勻溶液。 4. _醣》濾溶掖β 5. 包装成安明或小雇並密封。 徽索 IV 稀 呈 3 lg/*l 配方(密度-1,〇〇 s<«l ): 成份 霞量― 丙二 _ , USP 1 Oil 注射用水,USP 逋· 100·1或1β〇8· 程序: 1. 丙二醇置於鳊當容《内。2. Use malonase to accumulate to 100 · U 3. Combine to produce a homogeneous solution # 4. Without _ side filter solution 5. Packed in ampules or small gold seal β Β. 莱帕 徽 索 IV! »_ _Cheng 2 · β / · 1 Chengzhuang ·» Methyldiamine B, USP 10al Water for injection, WSP amount 100 · 1 Procedure: 1. Malondiase is placed in 邃 Dangrongyan》 -9-This paper Standard Chinese Standard (CNS) Α4 specification (210 × 297 mm) ----------- Meal ------ ΐτ ------ ^ •-(Please read the back first (Please note this item and fill in this page again.) Printed by the Consumers' Cooperative of the Central Bureau of Quasi-Ministry of Finance and Economics of the People's Republic of China. 0.6gi 100 · 1 or 103.egi A7 B7 V. Description of the invention (none) To 100 · 1Φ 3. Mix until a homogeneous solution is formed, 4. Caramel 8 filter 〇5. Packaging 〇6. 压 压 蒸 # (extinguish 0 completed without "« C. Ray MflimiV thin noodles are 4 · β / _1 (Mixing) Formula (density-1.0 0 5 5 eB / ml >: Ingredients • Quantitative Rapaparin IV Concentration Plan @ 4 _β / «] 1 Employment 1 IV1T Paxil Dilution _ 1 · ι Procedure : 1_ will be 111 when Pa Hui 橐 IV capsule compilation pain is 2 · β / · 1 using good no _ technology injection containing 1.1 · 1 1 溜 meal emblem cable | »鞾 小小Intra-level β 2. Shake to the formation of irrigation and dredging fluid β 3. During the use period, Bao Mai 3 Rapahuisuo injection K Fangzhi _ preparation < 3Μ / · 1) Α. Rapahuisuo IV Concentrated sickle_ presents β · β / · 1 to malonase. Prepared formula {density-1.06g / il >: rapavin β 10096 malondi B, USP Applicable procedure: 1. Weighing Dangpa Emblem to dangdang calibration match opium-10-This paper size is in accordance with China National Standard (〇 阽) 8 4 specifications (210 > < 297 mm >) (Please read the precautions on the back before filling this page ) .Packing and Threading * ^ 4385 8 6 Α7 Β7 V. Description of the Invention (9) 2. Use the propylene diamine to round the product to 100 »1. 3. Mix until a uniform solution is produced. 4. _ 糖》 filtration掖 β 5. Packaged in a safe or small size and sealed. Emblem IV dilute 3 lg / * l formula (density-〇〇s < «l): composition amount-Ⅱ-USP 1 Oil water for injection , USP 逋 · 100 · 1 or 1β〇8 · Procedure: 1. Propylene glycol is placed in 鳊 Dongrong 《.

2. 以注射用水調轚釀積至100IU 3. 混合至生成均勻溶液。 4 皤通濾溶液e 5 .包裝。 e.离壓無氣緘K連成無 C.富帕徽素IV稀釋Μ里3 ig/al(謂配} 配方(密度-1.035 gm/ml ): 成份 · · 經濟部中央橾準局貝工消费合作社印製 (請先閲讀背面之注意事項再填寫本頁) 霣帕濃编爾® 111 IVff帕徽素稀鬌爾 1 ai 程序: 1.将1·1言帕濃鐮爾里6ig/al使用良好無醻技術 注入含1·1 IV雷帕徽素稀鬌爾小瓶内》 -11 - 本紙張尺度遑用中國國家標率(CNS ) Α4规格(210Χ297公釐) 經濟部中央棣準局貝工消费合作社印製 _B7_ 五、發明説明('。) 2. 震篷至生成澄淸溶液, 3. 於使用期内投蕖# 實例4 雷帕徽索注射配方之91備(4·β/·1) Α.雷帕徽索1?灞纗_£β·β/·1於丙二β之製備 配方(密度-1.〇36g/il ): 成份 營 S 帕徽素 ® 100% 0 . 8κ· 丙二酵,USP 逋最 10(ί·1 或 103.6g· 程序: 1. 稱《霣帕徽素至逋當校準之容器。2. Adjust the volume to 100IU with water for injection. 3. Mix until a homogeneous solution is formed. 4 皤 filter solution e 5. Packaging. e. Depressurization without air pressure, K continuous without C. Fupahuixin IV diluted Μ 3 ig / al (predicated) formula (density -1.035 gm / ml): Ingredients Printed by the Consumer Cooperative (please read the precautions on the back before filling this page) 霣 Paranoel ® 111 IVff Parvoline Diluter 1 ai Procedure: 1. Put 1.1 words Parnell in 6ig / al Injected into a vial containing 1.1 rapamycin, using a good technology. -11-This paper uses China National Standard (CNS) Α4 size (210 × 297 mm). Printed by the Industrial and Commercial Cooperatives_B7_ V. Description of the invention ('.) 2. Shake the awning to produce a solution of Cheng Zhi, 3. Invest in the period of use # Example 4 91 of the preparation of Rapahui injection (4 · β / · 1) Α. Reparaline 1? 灞 纗 _ £ β · β / · 1 in the preparation of malonyl β (density -1.036g / il): Ingredients Camperin ® 100% 0. 8κ · malonase, USP 逋 10 (ί · 1 or 103.6g ·) Procedure: 1. Weigh the "palladium to the calibration container."

2. 使用丙二酵讖整積至UIOiU 3. 混合至生成均勻溶液。 4. 無騸過濾溶液β 5. 包裝成安明或小級並密封β Β.雷粕徽索IV稀轉靖呈4 *£/·1 成松 丙二酵,USP 注射用水,BSP 程序: 1. 丙二酵置於適當容罌内。2. Use malonase to accumulate to UIOiU 3. Mix until a homogeneous solution is formed. 4. Filtration-free filtered solution β 5. Packed in a safe or small grade and sealed β β. Ray meal emblem IV dilute to Jingcheng 4 * £ / · 1 into pine malonase, USP water for injection, BSP procedures: 1. C The second leaven is placed in a suitable container.

2. 以注射用水讕整鑤積至IOOiU 3. 混合至生成均勻溶掖。 4. 無阐_濾溶液。 -12 - 本紙張尺度逋用中國國家標準(CNS ) A4规格(210X297公釐) ----------餐------ΪΤ------^ (請先閲讀背面之注意事項再填寫本頁) 10顧1 100疆1或 100g· 鱅 A7 B7 五、發明説明(d ) 5. 包裝。 6. 离懕蒸氣滅醣速成無 C.雷帕徽素IV稀釋莆呈4 ig/il(鼴配> K 方(密度-1.035 抓/|»1 ): 成i 數量 雷柏徽索ΐνϋ總剤@ 8〇g/<nl 1*1 IV霣帕徽索稀釋_ 111 程序: 1.將1·1當帕徽素IV濃繡麵里8ig/»l使用良好嫵_技術 注入含1«1 IV當Μ徽素稀釋麵小級内。 2.S搖至生成澄淸溶液》 3.於使用期内投_ β ---1 — -----裝------訂------線 (請先«.讀背面之注意Ϋ項再填寫本頁) 經濟部中央標準局員工消費合作社印裝 -13 本紙張尺度逋用中國國家標率(CNS > A4说格(210X297公釐)2. Mix with water for injection to 100iU. 3. Mix until a uniform solution is formed. 4. No solution_filter solution. -12-This paper uses China National Standard (CNS) A4 size (210X297 mm) ---------- Meal -------- ΪΤ ------ ^ (Please read first Note on the back, please fill out this page again) 10Gu 1 100 Xinjiang 1 or 100g · 鱅 A7 B7 V. Description of the invention (d) 5. Packaging. 6. Isolate the steam and destroy sugar quickly without C. Rapain IV diluted 莆 is 4 ig / il (鼹 > K square (density -1.035 grab / | »1): into i quantity Leibo emblem cable ΐνϋ total 8 @ 8〇g / &n; nl 1 * 1 IV 霣 Parsignin Dilution _ 111 Procedure: 1. Put 1.1 · Paliparin IV concentrated embroidery surface 8ig / »l using good 妩 _ technology to inject 1« 1 IV is within the small scale of the M-muxil dilution surface. 2. S shake to produce a clear water solution. 3. Put _ β --- 1 — ------------- Order --- ----- line (please «. Read the note on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -13 This paper standard uses the Chinese national standard (CNS > A4 Say (210X297 mm)

Claims (1)

A8 B8 C8 D8A8 B8 C8 D8 經濟部中央標隼局男工消費合作社印裝 第8310S922號「水ί注射用之雷帕儆素翳藥組成物,其 産物及製法」專利案 (97年1月修正) 杰申請專利範圍 1. 一種水性注射用雷帕黴素醫藥組成物,基本上不含非 離子界面活性劑,傜經由下述方法獲得,該方法特_ 為將4 0至7 5體積%之雷帕徽素於丙二醇瀑縮劑溶液 (其雷帕滅素濃度於0.25 oig/ml至8fflg/isl範圍)與含 水之稀釋劑溶液相混合,其中稀釋劑佔組合溶液之60 至25體積百分比;使得於注射溶液内雷帕徽素漫度範 圍為0.1 iss/inl至4 mg/ml,且濃縮劑對稀釋劑之比像 於48:60至75:25體積百分率之範圍。 2. 如申請專利範圍第1項之水性注射用雷帕徽素醫藥, 其中該雷帕徽素於丙二醇之濃縮劑溶掖占注射溶液之 40至60證積%。 3. 如申請專利範圍第1項之水性注射用雷帕徵素醫藥組 成物,其中該雷帕徽素於丙二醇濃縮劑之濃度傜於 0,5iDg/iB丨至4mg/nl之範圍内。 4 .如申請專利範圍第1項之水性注射用雷帕徽素翳藥組 成物,偽獲自將40至60體稹%之雷帕徽素於丙二醇濃 縮劑溶液(其雷帕徽素濃度於0.5 nig/nil至4mg/n!l範 圍)與含水之稀澤劑溶液相混合,其中稀釋劑佔組合 溶掖之f50至40體積百分比;使得於注射溶液内雷帕徽 -1 - n^i ϊ—^— 1 n^i In c ^^^1 i I «In \J -¾. Te (請先閔讀背面之注意事項再填寫本頁) 本紙張尺度適用中國K家揉準(CNS ) A4规格(210X297公釐) 經濟部中央標率局負工消費合作社印裂 A8 Be C8 D8六、申請專利範圍 素襟度範圍為0.25 ntg/ml至2 ing/nil。 5. 如申謓專利範圍第4項之水性庄射用雷帕锹素醫蕖組 成物,其中該雷帕徽素於丙二醇之濃縮劑溶液占注射 溶液之4 0至5 0體積炻^ 6. 如申請專利範圍第4項之水性注射用雷帕徽素醫藥組 成物,其中該雷帕徽茉於丙二醇濃縮劑之濃度偽於 0.6 fflg/m'i至 3,3iDg/nil之範圍内。 7,如申請專利範圍第4項之水性注射用雷帕徽素翳藥組 成物,其中該雷帕徽素於注射溶液之濃度係於0.5mg/ mi至1.5fflg/i0l之範圍内。 8. 如申諳專利範圍第1項之水性注射用雷帕徽素醫藥組 成物,其供大劑量注射用且其中該雷帕徽素於注射溶 液之濃度係於0.25ms/rai至2 usg/ni丨之範圍内。 9. 一種水性注射用雷帕徽素醫藥組成物,包括雷帕徽素 於丙二醇及水之溶液,其中水占溶掖之40至7 5體積%及 雷帕徽素於組成物之濃度偽於0,lmg/ni!至4ms/ni丨之範 圍内。 1 0 · —種呈組合製劑且包括含耷雷帕潘[素之濃縮劑溶液與 稀釋劑之産品,可珙於靜脈注射前混合以獲得具有雷 帕徽素濃度於至4lDg/iBl範圍之溶液;該濃縮 劑溶液基本上由0,25aig/ml至8nis/m丨範圍之雷帕徽素 於丙二醇中組成;該稀釋割溶液包含水,濃縮劑對稀 -2* _:ί—.------^-- (請先閱讀背面之注意事項再填寫本頁) 、1Τ 本紙ft尺度逍用中囷國家梂率(CNS ) Α4说格(2!〇Χ29?公釐) 經濟部中央標準局更工消費合作社印装 …::· O' p; A8 cs D8六、申請專利範圍 釋劑之比偽由40:60至75:2 5體積百分率之範圍。 11. 如申請專利範圍第10項之産品,其中該濃縮劑對稀釋 劑之比傜於60: 40至40: 60體積百分率之範圍内。 12. 如申請專利範圍第1Θ或11項之産品,其中該雷帕徽素 於丙二醇濃綿劑之濃度俱於0.5mg/ml至4rag/ral之範圍 内。 13. 如申請專利範圍第10項之産品,供大劑量注射用且其 中該雷帕徵素濃縮劑與稀釋劑混合後雷帕徽素濃度傺 於0.25atg/:D!至2rag/ml之範圍内。 14. 如申請專利範圍第10項之産品,呈組合製劑供於靜脈 注射前混合獲得具有雷帕徽素濃度於0.1mg/ml至4ϋΐε/ ml範圍之溶液;該濃縮劑溶液基本上由之0.5ms/ral至 4 b S / s 1範圍之雷帕徽素於丙二醇中組成;該稀釋劑溶 液包含水,濃縮劑對稀釋劑之比傷於由4 0 : 6 0至6 0 : 40體積百分率之範圍。 15. —種製備水性注射用雷帕徽素溶液之方法,包括混合 4 0至7 5體積%雷帕徽素於丙二醇之濃縮劑溶掖(雷帕 激素濃度於0.25ing/nl至8mg/!Dl之範圍内)與包含水之 稀釋劑溶液,其中稀釋劑占組合溶液之6Θ至25體積% :因此雷帕礅素於注射溶液之濃度傜於0.1mS/Djl至 4aig/s丨之範圍内。 1 6,如申請專利範圍第1 5項之方法,其中該雷帕激素於丙 m S - 1 i a^m - - 1 ϋ^—----- I ^^^1 1^1 ^1J 3 、v5 (請先閲讀背面之注意事項再填寫本頁) 本纸張尺度遑用十國國家橾率(CNS)A4说格(2!OX297公釐) A8 B8 C8 D8 々、申請專利範圍 二醇之濃縮劑溶液占注射溶液之4 0至6 0體積%。 17.如申請專利範圍第15或16項之方法,其中該雷帕徽素 於丙二醇濃縮劑之濃度偽於0.5nig/iiil至4®g/ral之範圍 内。 13,如申請專利範圍第15項之方法,包括混合40至60體積 炻雷帕徽素於丙二醇之濃縮劑溶掖(雷帕徽素濃度於 0,5π^/πί至4nig/nil之範圍内)與包含水之稀釋劑溶液, 其中稀釋劑占組合溶液之6 8至4 0體積% ;因此雷帕擻 素於注射溶液之濃度係於0.25nig/nil至2 rag/sil之範圍 内。 ----HH ^^^1 - - - - - =1 ! --—II ^^^1 ϋ. » W3. 言 (請先閱讀背面之注意事項再填寫本頁) 經濟部中央標率局貝工消妒合作社印策 本紙張尺度適用中《8家#準(CNS) A4说格(2丨0X297公釐) 申請曰期 案 -號 \〇 類 別 (以上各棚由本局填註) Α4 C4 438:*86 ||蜃專利説明書(畔1·正〉 發明 一、新型名稱 中文 水性注射用之雷帕徽素醫藥組成物,其產品及製法 英文 An aqueous, injectable rapamycin pharTnaceutical composition^ its product and a process for preparing thereof 姓 名 國 籍 鼯伯特Ρ *瓦拉尼斯 Robert P.Varanis 湯姆斯W ♦里納德 Thomas W. Leonard 装 發明 創作β 美國 美國 住、居所 1. 美國紐约12921S5辛9753線路9號 2. 美國北卡羅萊纳州威明頓南里夫歐克公園 路2201號 訂 姓 名 (名稱) 美國家庭産品股份有限公司 Anerican Hose Products Corporation 經濟部十央樣準局貝工消费合作社印製 線 三、申請人 國 籍 住、居所 (事務所) 代表人i 姓 名 美國 美國纽潭西州07940-0874曼迪森5吉拉德農埸 依岡E *貝格 Egon E. Berg 本紙張尺度適用中囷國家標準(CNS ) A4規格(210X297公釐) *?43β586 Α5 Β5 四 、中丈發明摘要(發明之名稱: 水性注射用之雷帕徽素醫藥組成物*其產品及製法 此麻掲示一種注射用雷帕徽素水溶掖,包括40至75V% 霉粕徽素於丙二酵之瀑缩铕溶掖,笛柏徽索鷇度於由 0.25g/ll至,8ag/l之範歯,舆包括水之稀釋爾溶液組 合,其中該稀釋劑占組合溶掖之60至25V%及雷帕微素 於組合溶液之濃度偽於O.lng/Bl至之範圍β 英文發明摘要(發明之名稱:⑭ aqueous, injectable rap咖ycin pharmaceutical composition its product and a process for preparing thereof Disclosed herein is an aqueous, injectable rapamycin solution comprising 40 to 75 volume percent of a concentrate solution of rapamycin in propylene glycol, at concentrations of rapamycin ranging from 0.25 mg/ml to 8 mg/ml, in combination with a diluent solution comprising water, wherein the diluent comprises 60 to 25 volume percent of the combined solution and the concentration of rapamycin in the combined solution ranges from 0.1 mg/ml to 4 mg/ml 本紙張尺度適用中國國家椟準(CNS ) Μ規格(210X297公餐) ----r----.------t------ir------0 (請先閲讀背面之注意事項再填寫本頁各欄) A8 B8 C8 D8No. 8310S922 “Rapaparin peony composition for water injection, its product and its manufacturing method” patent case (revised in January 1997). Patent application scope 1. An aqueous rapamycin pharmaceutical composition for injection, which basically does not contain a non-ionic surfactant, is obtained by the following method, which specifically comprises 40 to 75% by volume of rapamycin in propylene glycol waterfall. The shrinkage solution (with a rapamectin concentration in the range of 0.25 oig / ml to 8fflg / isl) is mixed with an aqueous diluent solution, wherein the diluent accounts for 60 to 25 volume percent of the combined solution; The diffusion range of Huixin is 0.1 iss / inl to 4 mg / ml, and the ratio of the concentrate to the diluent is in the range of 48:60 to 75:25 volume percentage. 2. For example, the application of rapamycin for water injection in item 1 of the patent scope, wherein the concentration of the rapamycin in propylene glycol is 40 to 60% of the injection solution. 3. The pharmaceutical composition of aqueous rapamycin for injection according to item 1 of the patent application scope, wherein the concentration of the rapamycin in the propylene glycol concentrate is in the range of 0,5 iDg / iB 丨 to 4 mg / nl. 4. If the rapamectin peony composition for aqueous injection is used in item 1 of the scope of patent application, 40 to 60% of rapamycin in propylene glycol concentrate solution (whose concentration of rapamycin is 0.5 nig / nil to 4 mg / n! L range) mixed with an aqueous diluent solution, in which the diluent accounts for f50 to 40 volume percent of the combined solvent; so that the rapa emblem-1-n ^ i in the injection solution ϊ — ^ — 1 n ^ i In c ^^^ 1 i I «In \ J -¾. Te (please read the notes on the back before filling out this page) This paper size is applicable to Chinese K family standards (CNS) A4 specification (210X297mm) A8 Be C8 D8 printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 6. Application scope of patents The prime range is from 0.25 ntg / ml to 2 ing / nil. 5. For example, the rapamycin medicinal composition for water-based shots in the patent application item 4, wherein the concentration solution of the rapamycin in propylene glycol occupies 40 to 50 volumes of the injection solution. ^ 6. For example, the pharmaceutical composition of aqueous rapamycin for injection in item 4 of the scope of the patent application, wherein the concentration of the rapamycin in the propylene glycol concentrate is in the range of 0.6 fflg / m'i to 3,3iDg / nil. 7. The aqueous rapamycin peony composition for injection according to item 4 of the application, wherein the concentration of the rapamycin in the injection solution is in the range of 0.5 mg / mi to 1.5 fflg / i0l. 8. The pharmaceutical composition of aqueous rapamycin for injection as described in item 1 of the patent application, which is for high-dose injection, and wherein the concentration of the rapamycin in the injection solution is 0.25ms / rai to 2 usg / within the range of ni 丨. 9. An aqueous pharmaceutical composition of rapamycin for injection, comprising a solution of rapamycin in propylene glycol and water, wherein water accounts for 40 to 75% by volume of the dissolved lysate and the concentration of rapamycin in the composition is pseudo 0, lmg / ni! To 4ms / ni 丨. 1 · · A product containing a combination of rapapan [concentrate solution and diluent containing rapapanin] can be mixed before intravenous injection to obtain a solution with a concentration of rapamectin of up to 4lDg / iBl ; The concentrate solution is basically composed of rapavin in the range of 0,25 aig / ml to 8nis / m 丨 in propylene glycol; the dilute cutting solution contains water, and the concentrate is diluted -2 * _: ί —.-- ---- ^-(Please read the notes on the back before filling out this page), 1T paper ft scale free use China National Standard (CNS) Α4 grid (2! 〇 × 29? Mm) Central Ministry of Economic Affairs Standards Bureau Printing of Industrial Cooperative Cooperatives ... :: · O 'p; A8 cs D8 VI. Patent application scope The ratio of release agent is from 40:60 to 75: 2 5 volume percentage range. 11. For a product in the scope of claim 10, wherein the ratio of the concentrate to the diluent is in the range of 60: 40 to 40: 60 volume percentage. 12. If the product of the scope of patent application No. 1Θ or 11 is applied, the concentration of the rapamycin in the propylene glycol thickening agent is in the range of 0.5 mg / ml to 4 rag / ral. 13. If the product in the scope of patent application is No. 10, it is intended for high-dose injection and the concentration of rapamycin after the rapaphyllin concentrate and diluent is in the range of 0.25 atg /: D! To 2rag / ml. Inside. 14. For the product in the scope of patent application No. 10, a combination preparation is prepared for intravenous injection to obtain a solution having a concentration of rapamectin in the range of 0.1 mg / ml to 4 / ε / ml; the concentrate solution is basically 0.5 The composition of rapamycin in the range of ms / ral to 4 b S / s 1 in propylene glycol; the diluent solution contains water, and the ratio of the concentrate to the diluent is from 40:60 to 60:40 volume percentage Range. 15. A method for preparing an aqueous solution of rapamycin for injection, comprising mixing a concentration of 40 to 75% by volume of rapamycin in propylene glycol (a concentration of rapa hormone of 0.25ing / nl to 8mg /! Within the range of Dl) and a diluent solution containing water, wherein the diluent accounts for 6Θ to 25% by volume of the combined solution: Therefore, the concentration of rapamycin in the injection solution is within the range of 0.1 mS / Djl to 4 aig / s. . 16. The method according to item 15 of the scope of patent application, wherein the rapa hormone is at propyl m S-1 ia ^ m--1 ϋ ^ ------ I ^^^ 1 1 ^ 1 ^ 1J 3 、 V5 (Please read the notes on the back before filling in this page) This paper size uses 10 countries' national standard (CNS) A4 scale (2! OX297 mm) A8 B8 C8 D8 申请, patent application scope diol The concentrate solution accounts for 40 to 60% by volume of the injection solution. 17. The method according to claim 15 or 16, wherein the concentration of the rapafaline in the propylene glycol concentrate is in the range of 0.5nig / iiil to 4 g / ral. 13. The method according to item 15 of the scope of patent application, which comprises mixing 40 to 60 volumes of rapamycin in a propylene glycol concentrate solubilizer (the concentration of rapamycin is in the range of 0,5π ^ / πί to 4nig / nil). ) And a diluent solution containing water, wherein the diluent accounts for 68 to 40% by volume of the combined solution; therefore, the concentration of rapamycin in the injection solution is in the range of 0.25 nig / nil to 2 rag / sil. ---- HH ^^^ 1-----= 1! --- II ^^^ 1 ϋ. »W3. (Please read the notes on the back before filling this page) Central Standards Bureau, Ministry of Economic Affairs Beigong Anti-jealousy Cooperative Co., Ltd. The paper standard is applicable to "8 companies # 准 (CNS) A4 格格 (2 丨 0X297 mm) Application date-No. \ 〇 category (the above sheds are filled in by this bureau) Α4 C4 438: * 86 || 蜃 Patent Specification (Pan 1. Zheng) Invention One, New Name Chinese Rapaparin Pharmaceutical Composition for Aqueous Injection, Its Product and Preparation Method English An aqueous, injectable rapamycin pharTnaceutical composition ^ its product and a process for preparing its name Nationality Robert P. Varanis Robert P. Varanis Tom W. Leonard Thomas W. Leonard Pretend to invent and create β United States American residence and residence 1. New York, USA 12921S5 Xin 9753 Line 9 2. Name (Name), 2201 South Oakville Park Road, South Reeve, Wilmington, North Carolina, USA Anerican Hose Products Corporation Printed Line by the Shell Department Consumer Cooperative, Department of Economics, Ten Central Samples Bureau III. Applicant's nationality, residence (office) Representative i Name New York, U.S.A. 07940-0874, Mandison, 5 Giladnon, Reigan E * Berg, Egon E. Berg This paper is applicable to the countries of Central Europe Standard (CNS) A4 specification (210X297 mm) *? 43β586 Α5 B5 IV. Abstract of Zhongzhang Invention (Name of the invention: Rapaparin pharmaceutical composition for aqueous injection * Its product and preparation method This mochi shows a kind of injection mine Palmitoin soluble in water, including 40 to 75V% mold meal, soluble in maltase in the waterfall shrinkage, and dibo emblem in the range from 0.25g / ll to 8ag / l, including water The diluent solution combination, wherein the diluent accounts for 60 to 25V% of the combined solution and the concentration of rapamycin in the combined solution is in the range of 0.1 ng / Bl to β English Abstract of Invention (Name of the Invention: ⑭ aqueous , injectable rapCaycin pharmaceutical composition its product and a process for preparing thereof Disclosed here is an aqueous, injectable rapamycin solution comprising 40 to 75 volume percent of a concentrate solution of rapamycin in propylene glycol, at concentrations of rapamycin ranging from 0.25 mg / ml to 8 mg / ml, in combination with a diluent solution comprising water, hereinafter the diluent includes 60 to 25 volume percent of the combined solution and the concentration of rapamycin in the combined solution ranges from 0.1 mg / ml to 4 mg / ml This paper size is applicable to China National Standard (CNS) M specifications (210X297 meals) ---- r ----.------ t ----- -ir ------ 0 (Please read the notes on the back before filling in the columns on this page) A8 B8 C8 D8 經濟部中央標隼局男工消費合作社印裝 第8310S922號「水ί注射用之雷帕儆素翳藥組成物,其 産物及製法」專利案 (97年1月修正) 杰申請專利範圍 1. 一種水性注射用雷帕黴素醫藥組成物,基本上不含非 離子界面活性劑,傜經由下述方法獲得,該方法特_ 為將4 0至7 5體積%之雷帕徽素於丙二醇瀑縮劑溶液 (其雷帕滅素濃度於0.25 oig/ml至8fflg/isl範圍)與含 水之稀釋劑溶液相混合,其中稀釋劑佔組合溶液之60 至25體積百分比;使得於注射溶液内雷帕徽素漫度範 圍為0.1 iss/inl至4 mg/ml,且濃縮劑對稀釋劑之比像 於48:60至75:25體積百分率之範圍。 2. 如申請專利範圍第1項之水性注射用雷帕徽素醫藥, 其中該雷帕徽素於丙二醇之濃縮劑溶掖占注射溶液之 40至60證積%。 3. 如申請專利範圍第1項之水性注射用雷帕徵素醫藥組 成物,其中該雷帕徽素於丙二醇濃縮劑之濃度傜於 0,5iDg/iB丨至4mg/nl之範圍内。 4 .如申請專利範圍第1項之水性注射用雷帕徽素翳藥組 成物,偽獲自將40至60體稹%之雷帕徽素於丙二醇濃 縮劑溶液(其雷帕徽素濃度於0.5 nig/nil至4mg/n!l範 圍)與含水之稀澤劑溶液相混合,其中稀釋劑佔組合 溶掖之f50至40體積百分比;使得於注射溶液内雷帕徽 -1 - n^i ϊ—^— 1 n^i In c ^^^1 i I «In \J -¾. Te (請先閔讀背面之注意事項再填寫本頁) 本紙張尺度適用中國K家揉準(CNS ) A4规格(210X297公釐)No. 8310S922 “Rapaparin peony composition for water injection, its product and its manufacturing method” patent case (revised in January 1997). Patent application scope 1. An aqueous rapamycin pharmaceutical composition for injection, which basically does not contain a non-ionic surfactant, is obtained by the following method, which specifically comprises 40 to 75% by volume of rapamycin in propylene glycol waterfall. The shrinkage solution (with a rapamectin concentration in the range of 0.25 oig / ml to 8fflg / isl) is mixed with an aqueous diluent solution, wherein the diluent accounts for 60 to 25 volume percent of the combined solution; The diffusion range of Huixin is 0.1 iss / inl to 4 mg / ml, and the ratio of the concentrate to the diluent is in the range of 48:60 to 75:25 volume percentage. 2. For example, the application of rapamycin for water injection in item 1 of the patent scope, wherein the concentration of the rapamycin in propylene glycol is 40 to 60% of the injection solution. 3. The pharmaceutical composition of aqueous rapamycin for injection according to item 1 of the patent application scope, wherein the concentration of the rapamycin in the propylene glycol concentrate is in the range of 0,5 iDg / iB 丨 to 4 mg / nl. 4. If the rapamectin peony composition for aqueous injection is used in item 1 of the scope of patent application, 40 to 60% of rapamycin in propylene glycol concentrate solution (whose concentration of rapamycin is 0.5 nig / nil to 4 mg / n! L range) mixed with an aqueous diluent solution, in which the diluent accounts for f50 to 40 volume percent of the combined solvent; so that the rapa emblem-1-n ^ i in the injection solution ϊ — ^ — 1 n ^ i In c ^^^ 1 i I «In \ J -¾. Te (please read the notes on the back before filling out this page) This paper size is applicable to Chinese K family standards (CNS) A4 specifications (210X297 mm)
TW83108922A 1993-09-30 1994-09-26 An aqueous, injectable rapamycin pharmaceutical composition its product and a process for preparing thereof TW438586B (en)

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JP2001253824A (en) * 2000-03-14 2001-09-18 Mitsukazu Matsumoto Formulated agent for local injection
EP1553940B1 (en) * 2002-07-30 2008-02-13 Wyeth Parenteral formulations containing a rapamycin hydroxyester
CA2574664C (en) * 2004-07-30 2013-01-15 Novartis Ag Compound formulations of 2-amino-1,3-propanediol compounds
CN1919194A (en) * 2006-08-17 2007-02-28 刘瑜玲 Liquid composition of sirolimus
CN109431997B (en) * 2018-12-20 2021-06-04 武汉科福新药有限责任公司 Local rapamycin injection and preparation method thereof

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IL111008A (en) 1999-10-28
CN1109748A (en) 1995-10-11
IL111008A0 (en) 1994-11-28
BR9403945A (en) 1995-06-13
CA2133180A1 (en) 1995-03-31
JP3584064B2 (en) 2004-11-04
JPH07196507A (en) 1995-08-01

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