CN113398079B - 一种注射用氟达拉滨冻干粉 - Google Patents
一种注射用氟达拉滨冻干粉 Download PDFInfo
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- CN113398079B CN113398079B CN202010183298.XA CN202010183298A CN113398079B CN 113398079 B CN113398079 B CN 113398079B CN 202010183298 A CN202010183298 A CN 202010183298A CN 113398079 B CN113398079 B CN 113398079B
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- fludarabine
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- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 title claims abstract description 97
- 229960000390 fludarabine Drugs 0.000 title claims abstract description 52
- 238000002347 injection Methods 0.000 title claims abstract description 21
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- 239000000843 powder Substances 0.000 title claims abstract description 21
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims abstract description 21
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- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 16
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- A61K31/13—Amines
- A61K31/133—Amines having hydroxy groups, e.g. sphingosine
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- 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
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- 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
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Abstract
本发明属于医药技术领域,具体公开了一种注射用氟达拉滨冻干粉制剂。本发明所述冻干粉制剂包括氟达拉滨和pH调节剂,以氨丁三醇作为pH调节剂,氨丁三醇用于治疗急性呼吸性、代谢性酸血症;不仅可以作为酸碱平衡调节剂来提高氟达拉滨的溶解度,还可以降低患有尿素血症的风险。本发明以乙二胺作为辅助酸碱调节剂,制剂稳定性得到了显著的提高。本发明所得到的制剂辅料种类少,制剂更安全,制备工艺简单,适合扩大生产。
Description
技术领域
本发明属于医药技术领域,具体涉及一种注射用氟达拉滨冻干粉制剂。
背景技术
磷酸氟达拉滨作为抗病毒药阿糖腺苷的氟化核苷酸类似物,可相对地抵抗腺嘌呤脱氨基酶的脱氨基作用。磷酸氟达拉滨是一种抗肿瘤药,用于慢性淋巴细胞性白血病的治疗。磷酸氟达拉滨在体内被快速地去磷酸化成为2F-ara-A,后者可以被细胞摄取,然后被细胞内的脱氧胞苷激酶磷酸化后成为有活性的三磷酸盐2F-ara-ATP。该代谢产物可以通过抑制核糖核酸还原酶、DNA聚合酶α、DNA引物酶和DNA连接酶的活性从而抑制DNA的合成。此外还可以部分抑制RNA聚合酶Ⅱ的活性从而减少蛋白的合成。
US2004006041公开了一种磷酸氟达拉滨注射液,该注射液由磷酸氟达拉滨、碱及水组成,该磷酸氟达拉滨注射液的pH范围在5.5~7.1之间。虽然该发明通过控制注射液的pH,增强了注射液在短暂的高温环境中的稳定性,但是该注射液的稳定性仍有待提高。
CN103040855A公开了一种磷酸氟达拉滨粉针剂,赋形剂选自甘露醇或山梨醇,磷酸氟达拉滨为晶体化合物,但需要将磷酸氟达拉滨转晶,转晶过程用到了有机溶剂,工艺复杂,且容易造成制剂中溶剂的残留。
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CN102552175A公开了一种注射用磷酸氟达拉滨冻干制剂及其制备方法,赋性剂为乳糖、甘露醇、葡萄糖、氯化钠和甘氨酸中的一种或多种,该制剂的杂质含量较高,稳定性较差。
以上现有技术均是针对磷酸氟达拉滨开发的制剂,然而,磷酸氟达拉滨的酸性较高,其在酸性条件下不稳定,需要加入氢氧化钠调节pH,氢氧化钠用量非常大,生产较为复杂,且加入的氢氧化钠和磷酸反应,生产大量的磷酸的钠盐,这样给患者带来一定的用药隐患。使用磷酸氟达拉滨治疗的患者中有肿瘤溶解综合征的报道,这一合并症可包括高尿酸血症、高磷酸血症、低钙血症、代谢性酸中毒、高钾血症、血尿、尿酸结晶尿症和肾衰。对于高磷酸血症,发明人考虑可能与磷酸氟达拉滨的磷酸盐有关,故很有必要开发氟达拉滨的制剂。
CN1617713A公开了一种快速释放活性成分的口服氟达拉滨高纯制剂,该片剂包含1-100mg纯度大于99.19%的活性成分氟达拉滨,以及单水合乳糖,胶态二氧化硅,微晶纤维素,交联羧甲基纤维素钠和硬脂酸镁。
目前尚无关于氟达拉滨的冻干制剂,需要提供一种稳定的氟达拉滨制剂来丰富临床应用。
发明内容
现有关于磷酸氟达拉滨的制剂产品中,由于磷酸氟达拉滨酸性较高,均采用氢氧化钠调节pH,需要大量高浓度的氢氧化钠溶液,生产较为复杂。
具体而言,本发明的技术方案如下:
一种注射用氟达拉滨冻干粉,包括氟达拉滨和pH调节剂。
优选地,所述pH调节剂为氨丁三醇。
优选地,所述冻干粉中氟达拉滨与氨丁三醇的重量比为1:0.1~0.4。
进一步优选地,所述冻干粉中氟达拉滨与氨丁三醇的重量比为1:0.1~0.3。
更进一步优选地,所述冻干粉中氟达拉滨与氨丁三醇的重量比为1:0.2。
优选地,所述pH调节剂还包括乙二胺、碳酸钠、碳酸氢钠或醋酸钠中的一种。
进一步优选地,所述pH调节剂还包括乙二胺或碳酸钠。
更进一步优选地,所述pH调节剂为氨丁三醇和乙二胺的混合物。
优选地,所述氟达拉滨与乙二胺的重量比为1:0.02~0.1。
进一步优选,所述氟达拉滨与乙二胺的重量比为1:0.04~0.08。
更进一步地,所述氟达拉滨与乙二胺的重量比为1:0.06。
一种所述注射用氟达拉滨冻干粉的制备方法,包括如下步骤:将pH调节剂溶解到注射用水中,形成溶液,然后加入活性成分氟达拉滨,搅拌溶解,所得溶液经过微孔滤膜过滤两次,分装后冷冻干燥,即得氟达拉滨冻干粉。
具体地,所述制备方法包括如下步骤:将处方量的pH调节剂溶解到注射用水中形成溶液,然后向溶液中加入处方量的活性成分氟达拉滨,搅拌溶解,所得溶液经过0.2μm的微孔滤膜过滤两次,灌装,将冻干机板层预先降温至-45℃以下,将灌装样品半加胶塞,将样品放入冻干机内冻干,样品冻干结束后,真空下压紧胶塞,放掉冻干机内的真空,取出样品,外轧铝盖,即得氟达拉滨冻干制剂。
需要说明的是,本发明对冷冻干燥步骤没有特别限制,本领域常规的冷冻干燥方法或现有技术公开的冷冻干燥方法均可用于本发明。
与现有技术相比,本发明所得到的注射用氟达拉滨冻干粉以氨丁三醇作为pH调节剂,氨丁三醇适用于治疗急性呼吸性、代谢性酸血症,不仅可以作为酸碱平衡调节剂来提高氟达拉滨的溶解度,还可以降低尿素血症的风险。同时,本发明以乙二胺作为辅助酸碱调节剂,制剂稳定性得到了显著的提高。本发明所得到的制剂辅料种类少,制剂更安全,制备工艺简单,适合扩大生产。
具体实施方式
以下实施例进一步描述本发明,应当理解的是,实施例仅用于例证的目的,不用来限制本发明的保护范围,同时本领域技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
实施例1
制备工艺:将处方量的氨丁三醇、乙二胺溶解到注射用水中形成溶液,然后向溶液中加入处方量的活性成分氟达拉滨,搅拌溶解,所得溶液经过0.2μm的微孔滤膜过滤两次,灌装,将冻干机板层预先降温至-45℃以下,将灌装样品半加胶塞,将样品放入冻干机内冻干,样品冻干结束后,真空下压紧胶塞,放掉冻干机内的真空,取出样品,外轧铝盖,即得氟达拉滨冻干制剂。
实施例2
制备工艺:将处方量的氨丁三醇、乙二胺溶解到注射用水中形成溶液,然后向溶液中加入处方量的活性成分氟达拉滨,搅拌溶解,所得溶液经过0.2μm的微孔滤膜过滤两次,灌装,将冻干机板层预先降温至-45℃以下,将灌装样品半加胶塞,将样品放入冻干机内冻干,样品冻干结束后,真空下压紧胶塞,放掉冻干机内的真空,取出样品,外轧铝盖,即得氟达拉滨冻干制剂。
实施例3
制备工艺:将处方量的氨丁三醇、乙二胺溶解到注射用水中形成溶液,然后向溶液中加入处方量的活性成分氟达拉滨,搅拌溶解,所得溶液经过0.2μm的微孔滤膜过滤两次,灌装,将冻干机板层预先降温至-45℃以下,将灌装样品半加胶塞,将样品放入冻干机内冻干,样品冻干结束后,真空下压紧胶塞,放掉冻干机内的真空,取出样品,外轧铝盖,即得氟达拉滨冻干制剂。
实施例4
制备工艺:将处方量的氨丁三醇、乙二胺溶解到注射用水中形成溶液,然后向溶液中加入处方量的活性成分氟达拉滨,搅拌溶解,所得溶液经过0.2μm的微孔滤膜过滤两次,灌装,将冻干机板层预先降温至-45℃以下,将灌装样品半加胶塞,将样品放入冻干机内冻干,样品冻干结束后,真空下压紧胶塞,放掉冻干机内的真空,取出样品,外轧铝盖,即得氟达拉滨冻干制剂。
实施例5
制备工艺:将处方量的氨丁三醇、碳酸钠溶解到注射用水中形成溶液,然后向溶液中加入处方量的活性成分氟达拉滨,搅拌溶解,所得溶液经过0.2μm的微孔滤膜过滤两次,灌装,将冻干机板层预先降温至-45℃以下,将灌装样品半加胶塞,将样品放入冻干机内冻干,样品冻干结束后,真空下压紧胶塞,放掉冻干机内的真空,取出样品,外轧铝盖,即得氟达拉滨冻干制剂。
实施例6
氟达拉滨 37g
氨丁三醇 7.4g
注射用水 2000mL
制备工艺:将处方量的氨丁三醇溶解到注射用水中形成溶液,然后向溶液中加入处方量的活性成分氟达拉滨,搅拌溶解,所得溶液经过0.2μm的微孔滤膜过滤两次,灌装,将冻干机板层预先降温至-45℃以下,将灌装样品半加胶塞,将样品放入冻干机内冻干,样品冻干结束后,真空下压紧胶塞,放掉冻干机内的真空,取出样品,外轧铝盖,即得氟达拉滨冻干制剂。
实施例7
制备工艺:将处方量的氨丁三醇、乙二胺溶解到注射用水中形成溶液,然后向溶液中加入处方量的活性成分氟达拉滨,搅拌溶解,所得溶液经过0.2μm的微孔滤膜过滤两次,灌装,将冻干机板层预先降温至-45℃以下,将灌装样品半加胶塞,将样品放入冻干机内冻干,样品冻干结束后,真空下压紧胶塞,放掉冻干机内的真空,取出样品,外轧铝盖,即得氟达拉滨冻干制剂。
对比实施例1
制备工艺:
于配液罐中加入注射用水1530mL,配液罐温度为10℃,再加入50g磷酸氟达拉滨,充分搅拌后,加入适量5mol/L氢氧化钠溶液并搅拌,直至磷酸福达拉滨完全溶解;再加入40g甘露醇,搅拌使药液成澄明溶液;用5mol/L氢氧化钠溶液调节药液pH值至7.7加注射用水270mL,混匀。
向澄明溶液中加入活性炭5.4g,搅拌吸附30分钟后,用0.45μm微孔滤膜采用边脱碳边循环的方式过滤脱碳、0.2μm滤膜一次除菌过滤及0.2μm滤膜二次终端除菌过滤,所得滤液至药液瓶内,供灌装待用。
滤液分装,每瓶含有磷酸氟达拉滨25mg,半加塞,放入冻干机中进行冷冻干燥,冷冻干燥分为预冻、一次干燥和二次干燥三个阶段;
预冻阶段:将隔板温度以将隔板温度以0.5℃/min的速度降至-3℃,保温0.5小时,再以0.72℃/min的速度降至-30℃,停止降温,保温1小时,缓慢升温至-5℃,保温1小时,再以0.72℃/min的速度降温至-45℃,继续保温4小时,抽真空至箱内真空度达10pa;
一次干燥阶段:隔板温度采用阶梯式升温,升温-保温交替进行,每升温10分钟,接着保温5分钟,升温的速率为0.34℃/min,待升温至-3℃时,继续保温4小时。
二次干燥阶段:将隔板温度以0.55℃/min的速度升至18℃,保温1小时,隔板继续以0.2℃/min的速度升至40℃,待二次干燥中的制品的温度达35℃后,继续保温3小时。整个冻干过程结束,全压塞,检测合格后出箱。
对比实施例2
磷酸氟达拉滨 5g
注射用水 100mL
制备工艺:称取微粉化获得的75~100μm的磷酸氟达拉滨粉末5g,加入注射用水100mL,使用氢氧化钠调节pH值至7.2~8.2,搅拌使其完全溶解,每支1mL灌装于10mL西林瓶中。冻干机板层降温至-45℃,灌装结束后将西林瓶放入冻干机,保温4h。将板层温度升温到-8℃,保温2h后将板层降温到-40℃,继续保温3h。将板层在8~12h内升温到15℃;在40℃保温10h后,冲入氮气压塞,取出轧盖包装即得。
对比实施例3
磷酸氟达拉滨 50g
乳糖 50g
注射用水 1200mL
制备工艺:称取处方量的乳糖,加入1200mL注射用水,搅拌使其全溶,按照1.0%(g/L)加入活性炭,于25℃下搅拌吸附15min,加入磷酸氟达拉滨,用0.1mol/L的氢氧化钠溶液或0.1mol/L磷酸溶液调节溶液pH为7.5后继续搅拌使全部溶解并混合均匀。所得溶液依次经0.45μm、0.22μm微孔滤膜过滤,对所得半成品滤液进行检验合格后进行灌装,将灌装并半封盖的半成品置于冻干机箱内的隔板上进行预冻,并使半成品在0.7小时内达到预冻温度-37℃,达到预冻温度后保温2小时,干燥箱内的真空度达到13Pa时,关闭制冷箱开关,打开冷阱制冷,并保持冷阱温度-48℃,隔板温度-22℃,升华干燥10小时;之后进行在干燥,在干燥阶段温度为25℃,再干燥时间10小时,进行无菌密封、轧盖、经质检合格后包装,即得注射用磷酸氟达拉滨。
对比实施例4
磷酸氟达拉滨 500g
甘露醇 500g
注射用水 40Kg
制备工艺:将磷酸氟达拉滨及甘露醇配制罐中,加注射用水至40Kg,搅拌,用0.1mol/L磷酸溶液和0.1mol/L氢氧化钠溶液调节pH7.7使之完全溶解,并继续搅拌使混合均匀;
无菌过滤、分装:
将磷酸氟达拉滨溶液经微孔滤膜过滤至无菌室内,按4mL/支的装量分装于西林瓶中,半加塞;
真空冷冻干燥:
a.预冻:将分装好的磷酸氟达拉滨药液置冻干机内,分阶段进行预冻,
第一阶段,设定前箱温度为-10℃,保温70分钟,
第二阶段,10分钟内将前箱温度降低至-40℃以下,保温120分钟使磷酸氟达拉滨药液完全冻结;
b.后箱制冷:利用压缩机对后箱冷阱制冷,并保持后箱冷阱温度为-45℃~-55℃;
c.干燥:开启真空泵和中隔阀,开始升温升华干燥,每小时升温1.1℃,最后干燥温度为35℃,持续3小时,至关闭中隔阀前箱真空无显著变化后,压塞,出箱,用铝塑组合盖轧口,经质检合格后包装,即得供注射用的磷酸氟达拉滨组合物。
对比实施例5
磷酸氟达拉滨转晶制备:
(1)按照水:丙酮:乙醇的体积比为5:1:1配置混合溶剂,按照每升混合溶剂加入80g磷酸氟达拉滨固体的比例配置溶液,加热至45℃,搅拌至完全溶解;
(2)在50℃条件下减压蒸馏,当混合溶剂的体积减少至20%时,停止减压蒸馏,将混合溶剂降温至1℃,降温速度为2℃/min;静置养晶5小时;得到晶体后过滤,真空干燥4小时,得到的磷酸氟达拉滨的白色结晶性粉末。
磷酸氟达拉滨 50mg
山梨醇 50g
氯化钠 5mg
制备工艺:
(1)称取处方量的磷酸氟达拉滨、氯化钠和山梨醇;
(2)于配液罐中加入80%全液量的注射用水,加入处方量的山梨醇和氯化钠,搅拌至完全溶解,再加入处方量的磷酸氟达拉滨,充分搅拌后加入0.2mol/L的氢氧化钠溶液调节溶液的pH值为6.5~7.5;
(3)加入0.01%g/mL的药用活性炭,搅拌吸附20分钟,经0.45μm微孔滤膜过滤除炭,滤液加注射用水至全量,充分搅匀,配制好的溶液经0.22μm的微孔滤膜进行终端过滤除菌,得滤液;
(4)将滤液装入到注射剂瓶中,低温冷冻干燥,得到冻干粉针;其中所述的低温冷冻干燥过程为:
a.冻结期
将隔板温度以0.5℃/min的速度降至-3℃,保温0.5小时,再以0.72℃/min的速度降至-45℃;冷冻4小时;
b.升华期
药品冻结后,将冷凝器的温度控制在-45℃,对整个系统抽真空,真空度低于15Pa,升温的速率为0.35℃/min;待温度升至-1℃时,继续保温5小时;
c.干燥期
控制温度和真空度,将隔板温度以0.6℃/min的速度升温至20~30℃,保温5~7小时,检查合格后全压塞,出箱即得。
验证实施例:
取上述实施例1-7及对比例1-5的样品,分别置于温度60℃、相对湿度RH75%±5%条件下进行加速试验6个月。并对含量及有关物质等指标进行考察,具体检查方法及考察结果如下:
1、有关物质测定:参照中国药典2015年版四部通则0512高效液相色谱法的规定进行测定。
色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂;以甲醇-0.01mol/L磷酸二氢钾溶液(6:94)为流动相;检测波长为260nm。按色谱条件进行试验,去灵敏度测试用溶液20μL注入液相色谱仪,调节检测灵敏度,使主成分峰高于基线噪音的比不得小于10;取系统适用性溶液20μL液相色谱仪,阿糖异鸟苷磷酸盐峰(相对保留时间约为0.26)与异鸟嘌呤峰(相对保留时间约为0.34)的分离度不小于2(注:改检测波长为292nm,杂质阿糖异鸟苷磷酸盐与异鸟嘌呤的峰会明显增加,可确定阿糖异鸟苷磷酸盐与异鸟嘌呤峰);另取对照品溶液,连续进样5次,其峰面积测量值的相对标准偏差应不得大于2.0%。
系统适用性溶液:取磷酸氟达拉滨10mg,精密称定,置10mL量瓶中,加0.1mol/L盐酸溶液适量使溶解并稀释至刻度,80℃水浴加热15分钟,摇匀,作为系统适用性溶液。
对照品溶液:取磷酸氟达拉滨对照品适量,精密称定,加流动相溶解并定量稀释成每1mL中约含20μg的溶液,摇匀,作为对照品溶液。
灵敏度测试用溶液:精密量取对照品溶液5mL,置200mL量瓶中,用流动相稀释至刻度,摇匀,作为灵敏度测试用溶液。
供试品溶液取实施例1-7及对比例1-5中的样品各5瓶,每瓶加水2mL使溶解,5瓶均移至(用流动相荡洗小瓶)同一250mL量瓶中,用流动相稀释至刻度,摇匀,作为供试品溶液。
测定法:精密量取供试品溶液20μL,注入液相色谱仪,记录色谱图至主成分保留时间的4.5倍。
2、含量测定
参照中国药典2015年版四部0512高效液相测定的规范进行。
色谱条件与系统适用性试验用十八烷基硅烷键合硅胶为填充剂;以甲醇-0.01mol/L磷酸二氢钾溶液(6:94)为流动相;检测波长为260nm;理论塔板数按磷酸氟达拉滨峰计算应不低于2500。
测定法:取实施例1-7及对比实施例1-5所得的样品各5瓶,每瓶加水2mL使溶解,5瓶样品移至同一250mL量瓶中(用流动相荡洗小瓶),用流动相稀释至刻度,摇匀,精密量取2mL,置100mL量瓶,用流动相稀释至刻度,摇匀,精密量取20μL,注入液相色谱仪,记录色谱图;另精密称取磷酸氟达拉滨对照品适量,用流动相溶解制成每1mL中约含20μg的溶液,同法测定,外标法以峰面积计算含量。各实施例及对比例样品的加速试验结果见表1。
表1实施例1-7及对比例1-5加速试验结果
Claims (5)
1.一种注射用氟达拉滨冻干粉,其特征在于,所述冻干粉由氟达拉滨和pH调节剂组成;所述pH调节剂为氨丁三醇;氟达拉滨和氨丁三醇的重量比为1:0.1~0.4。
2.一种注射用氟达拉滨冻干粉,其特征在于,所述冻干粉由氟达拉滨和pH调节剂组成;所述pH调节剂为氨丁三醇和乙二胺;氟达拉滨和氨丁三醇的重量比为1:0.1~0.4,氟达拉滨与乙二胺的重量比为1:0.02~0.1。
3.根据权利要求1或2所述的冻干粉,其特征在于,氟达拉滨和氨丁三醇的重量比为1:0.1~0.3。
4.根据权利要求2所述的冻干粉,其特征在于,氟达拉滨与乙二胺的重量比为1:0.04~0.08。
5.一种权利要求1-4任一项所述冻干粉的制备方法,其特征在于,包括如下步骤:将pH调节剂溶解到注射用水中,形成溶液,然后加入活性成分氟达拉滨,搅拌溶解,所得溶液经过微孔滤膜过滤两次,分装后冷冻干燥,即得氟达拉滨冻干粉。
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