CN111150703A - 一种澄清丙泊酚注射液及其制备方法 - Google Patents
一种澄清丙泊酚注射液及其制备方法 Download PDFInfo
- Publication number
- CN111150703A CN111150703A CN201811316623.4A CN201811316623A CN111150703A CN 111150703 A CN111150703 A CN 111150703A CN 201811316623 A CN201811316623 A CN 201811316623A CN 111150703 A CN111150703 A CN 111150703A
- Authority
- CN
- China
- Prior art keywords
- injection
- propofol
- cyclodextrin
- sodium bicarbonate
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 229960004134 propofol Drugs 0.000 title claims abstract description 103
- 238000002347 injection Methods 0.000 title claims abstract description 80
- 239000007924 injection Substances 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 28
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000008215 water for injection Substances 0.000 claims abstract description 18
- 239000003381 stabilizer Substances 0.000 claims abstract description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 50
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- 238000003756 stirring Methods 0.000 claims description 30
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 28
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000011049 filling Methods 0.000 claims description 11
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 239000001569 carbon dioxide Substances 0.000 claims description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
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- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
本发明涉及一种澄清丙泊酚注射液及其制备方法,该注射液包括以下组分:丙泊酚、环糊精、稳定剂、pH调节剂和注射用水,该注射液的pH值为6‑9,优选为7‑8.5。本发明的注射液可在线过滤,辅料种类少、用量低,游离丙泊酚浓度低、便于储存、稳定性好。
Description
技术领域
本发明属于医药技术领域,具体涉及一种澄清丙泊酚注射液及其制备方法。
背景技术
丙泊酚作为一种临床常用静脉麻醉药以其起效快、作用时间短、代谢快、安全性高的特点得到了广泛的应用。市售丙泊酚乳剂包括注射乳剂、中长链脂肪乳和长链脂肪乳制剂。这类制剂存在成分复杂、易于染菌、大概率出现注射疼痛,辅料大豆油和花生油易致敏等缺陷,对患者机体造成了严重影响。开发一种不使用乳剂作为辅料的丙泊酚注射液能降低患者的用药风险。
现有技术中的药用辅料种类繁多,不溶性药物也很多,但并没有一种辅料能解决所有药物存在的难溶缺陷。脂肪乳、脂质体、脂微球、纳米粒、白蛋白等技术都曾用于开发丙泊酚注射剂。
从1993年至今,国际专利PCT/GB/00737、WO/2003/06324、W/O/2004/108113、WO/2007/052295、WO/2012/104730和美国专利7138387、7034013、9006215等十余篇环糊精用于澄清丙泊酚注射液制备的专利文献被公开,但这些专利存在环糊精用量高,不易过滤,制备时间长易染菌,pH过高,存放不易等缺陷。
2011年的一份临床研究显示(Anesthesia&Analgesia 2011;113:738-41,CrystalB.Wallentine et al.)磺丁基醚-β-环糊精应用于丙泊酚注射液时游离丙泊酚浓度过高,降低疼痛效果不明显。环糊精用于制备澄清丙泊酚注射液的尝试陷入停滞。迄今为止,未有低游离丙泊酚浓度的澄清丙泊酚注射液研制成功。
发明内容
为了制备出低游离丙泊酚浓度的澄清丙泊酚注射液,我们通过对α-环糊精、β-环糊精、γ-环糊精及它们各自的衍生物进行筛选,优选出使用羟丙基-β-环糊精和磺丁基醚-β-环糊精的实验方案。经过大量辅料的尝试,最终我们成功制备了低游离丙泊酚浓度的澄清丙泊酚注射液。
本发明的一个目的在于,提供一种澄清丙泊酚注射液。该注射液特征:澄清、辅料用量低、游离丙泊酚浓度低、稳定性好、可在线过滤。
本发明的另一个目的在于,提供一种丙泊酚注射液的制备方法。
本发明的上述特征采用如下技术方案来实现。
一方面,本发明提供一种澄清丙泊酚注射液,该注射液包括以下组分:丙泊酚、环糊精、稳定剂、pH调节剂和注射用水,该注射液的pH值为6-9,优选为7-8.5。
优选地,所述环糊精选自羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟丙基-磺丁基醚-β-环糊精、甘露糖基-β-环糊精和半乳糖基-β-环糊精中的一种或多种;优选为羟丙基-β-环糊精或磺丁基醚-β-环糊精。
优选地,所述稳定剂选自药学上可以接受的碱或酸,包括但不局限于碳酸氢钠、碳酸氢钾、氢氧化钠、乳酸钠、磷酸氢钠、柠檬酸钠、乙酸钠、乙酸铵、碳酸氢铵、碳酸氢钾、磷酸、乳酸、柠檬酸、乙酸、盐酸和二氧化碳中的一种或多种,优选为碳酸氢钠。
优选地,所述pH调节剂选自药学上可以接受的碱或酸,包括但不局限于碳酸氢钠、氢氧化钠、盐酸和二氧化碳。
优选地,在所述注射液中,以重量百分含量计,所述丙泊酚的量为0.5%-2%(w/v),优选为1%(w/v)。
优选地,在所述注射液中,以重量百分含量计,所述环糊精的量为10%-30%(w/v),优选为12%-25%(w/v)。
优选地,在所述注射液中,以重量百分含量计,所述稳定剂的量为0.001-1.0%(w/v),优选为0.01-1.0%(w/v),更优选为0.01-0.5%(w/v)。
在所述注射液中,所述pH调节剂的量以将所述注射液调整至合适的pH值为准。
优选地,所述注射液中,游离丙泊酚的含量不高于50μg/mL,优选不高于35μg/mL,最优选不高于30μg/mL。
优选地,所述注射液还进一步包括防腐剂、抗氧剂、抑菌剂和渗透调节剂中的一种或多种。这些防腐剂、抗氧剂、抑菌剂,比如EDTA、亚硫酸氢钠、维生素C、半胱氨酸等常用试剂,可由制剂人员根据工艺需求相应增减。
在一个优选的实施方案中,本发明提供一种丙泊酚注射液,该注射液包括丙泊酚、磺丁基醚-β-环糊精、碳酸氢钠,除碳酸氢钠以外的pH调节剂和注射用水,该注射液的pH值为6-9,优选为7-8.5;
优选地,在所述注射液中,以重量百分含量计,所述丙泊酚的量为1%(w/v);
优选地,在所述注射液中,以重量百分含量计,所述磺丁基醚-β-环糊精的量为12%-25%(w/v)。
优选地,所述注射液中,以重量百分含量计,所述碳酸氢钠的量为0.01-1.0%(w/v)。
优选地,所述注射液中,所述除碳酸氢钠以外的pH调节剂为氢氧化钠、盐酸、二氧化碳。
本发明的丙泊酚注射液与现有环糊精类制剂相比具有更低的游离丙泊酚浓度。具体而言,CyDex公司的文件显示丙泊酚与环糊精组合物中游离丙泊酚浓度约为50-80μg/mL,而在本发明中,游离丙泊酚在水相中浓度约为30μg/mL。
本发明中碳酸氢钠作为稳定剂,稳定剂的作用为:①低环糊精用量时制剂存放过程中保持澄清透明无油滴;②降低水相中游离丙泊酚的浓度。
本发明的特征还在于,尽量降低碳酸氢钠的用量,并将pH值和碳酸氢钠的用量尽量控制在适宜大容量输液的安全范围。
本发明使用较低量的碳酸氢钠(约0.5mg/mL),达到了降低疼痛及注射安全的效果。
本发明的丙泊酚注射用方便存储、稳定性好,在25℃下存储6个月,未见主药析出形成油滴,主药丙泊酚的含量不低于99.5%。
另一方面,本发明提供一种上述丙泊酚注射液的制备方法,该制备方法包括如下步骤:取处方量的环糊精(优选磺丁基醚-β-环糊精)和稳定剂(优选为碳酸氢钠)加入注射用水中,溶解后,通入惰性气体,加入丙泊酚,搅拌,pH调节剂调节pH值,过滤,惰性气体保护下封装即得。
优选地,所述惰性气体为氮气,用于降低氧含量。
在本发明中,使用环糊精,例如磺丁基醚-β-环糊精包合难溶于水的丙泊酚,在磺丁基醚-β-环糊精超过22g后,游离丙泊酚浓度不再随环糊精的量上升而显著降低。碳酸氢钠的加入降低了游离丙泊酚的浓度,并降低了环糊精的用量。
本发明的丙泊酚注射液采用以下方法使稳定性提高:
1)用环糊精,例如磺丁基醚-β-环糊精装载丙泊酚,减少丙泊酚与氧化剂的接触;
2)在无菌氮气氛围下制剂并封装;
3)丙泊酚在强碱环境下更容易被氧化,碳酸氢钠作为稳定剂,降低了制剂过程中局部碱性过大造成质量下降的风险;
4)本发明还使用了pH调节剂,将pH控制在7-8.5之间,以降低大量输入高pH溶液造成的患者酸碱平衡破坏。
在一个优选的技术方案中,本发明的丙泊酚注射液的处方如下:
制备方法:
室温下,取磺丁基醚-β-环糊精16g,碳酸氢钠0.001~0.5g,加注射用水50mL,搅拌溶解后,溶液中通氮气排除溶解氧,在氮气氛围下,加入1000mg的丙泊酚,搅拌2-6小时,调节pH为6~9,加水至100mL,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存。
在一个更优选的技术方案中,本发明的丙泊酚注射液的处方如下:
制备方法:室温下,取磺丁基醚-β-环糊精16.0g,碳酸氢钠0.05g,加注射用水50mL,搅拌溶解后,溶液中通氮气,排除溶解氧,在氮气氛围下,加入1000mg的丙泊酚,搅拌2-6小时,调节pH值为6~9,加水至100mL,搅拌均匀,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存。
本发明在环糊精溶液中注入氮气,驱走溶剂体系中的溶解氧;加入稳定剂,尽量减少水相中游离的丙泊酚,减少长期存放出现主药析出形成油滴的概率;提高环糊精包合率,进一步包合丙泊酚,降低游离丙泊酚浓度。
与现有技术相比较,本申请至少存在以下有益的技术效果:
本发明将环糊精、丙泊酚和碳酸氢钠组合制剂,显著降低了游离丙泊酚浓度,降低了丙泊酚与环糊精组合的注射剂的注射疼痛的风险,对注射疼痛发生的频度与烈度有可预见性的缓解作用。
在已有的环糊精专利中,本专利产品具有辅料用量低、肾毒性小,溶血作用小等优点。
本发明中的碳酸氢钠浓度在0.5mg/mL左右,显著降低了诱发正常人产生严重碱中毒、低钾血症、低钙血症的可能性,极大提高了安全性。
本发明的注射液为透明的,便于给药之前通过视觉检查。可使用在线微生物过滤器给药。
本发明避免使用工艺要求复杂,过敏风险较大的大豆油和卵磷脂等辅料,扩大了丙泊酚注射液的适用人群,降低了丙泊酚注射剂辅料致敏风险。
本发明的注射液不含有利于微生物成长的脂质,在长期给药中也能降低微生物感染风险。
本发明的注射液不包含磷脂。因此,磷脂血药浓度不受胃肠道外给予所述组合物的影响,对花生、大豆等过敏的患者也可使用。
本发明的注射液对甘油三酯的清除不引起任何变化,不会引起脂质代谢紊乱。
附图说明
图1为依据实施例2制备样品核磁共振氢谱放大图;
图2为依据实施例9制备样品核磁共振氢谱放大图。
具体实施方式
为进一步阐述本发明,以下通过稳定性好、储存方便、低注射疼痛的新型丙泊酚注射剂的制备实施例对本发明作进一步的详细描述。
以下实施例中使用的制剂丙泊酚含量检测方法和游离丙泊酚浓度的测定方法如下:
制剂丙泊酚含量检测方法:
精密吸取丙泊酚注射液适量置于容量瓶中,加入色谱纯甲醇至刻度,混匀,离心,取上清,按含量测定项下色谱条件HPLC法测定制剂中丙泊酚总浓度;
色谱条件:色谱柱:C18 4.6×250mm,5μm;流动相:甲醇-水(80:20);检测波长:280nm;流速:1mL/min;柱温:25℃。
游离丙泊酚浓度的测定方法:
将处方量的注射用水替换为重水,进行注射剂的制备。
核磁共振氢谱条件:采用zg30脉冲序列在恒温(25℃)下获取1H-NMR谱。谱宽(SWH):8000Hz,射频中心频率(OIP):Hz,采样点数(TD):32K,采样时间(AQ):4.09s,弛豫时间(D1):20s,采样次数(NS):64。
计算含量是以酚羟基对位上的一个质子引起的吸收峰面积(A1/n1)和游离丙泊酚基团上同一位置的质子引起的吸收峰面积(A2/n2)进行比较,然后按下式计算样品与该杂质的相对百分含量:样品的相对百分含量={(A1/n1)/〔(A1/n1)+(A2/n2)〕}×100%式中,n1,n2是指定基团的质子数。
实施例1~8
室温下,取处方量的磺丁基醚-β-环糊精,相应处方量的碳酸氢钠,加注射用水50mL,搅拌溶解后,溶液中通氮气,排除溶解氧,在氮气氛围下,加入1000mg的丙泊酚,搅拌2-6小时,调节pH值为6-9,加水至100mL,搅拌均匀,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存。其中各实施例中原料的用量及获得的注射液的外观及游离丙泊酚的浓度见表1所示。
图1列出了依据实施例2制备样品核磁共振氢谱放大图。
实施例9~10
参照Cydex公司的专利,具体参见US7034013的实施例1、2来制备实施例9-10。图2列出了依据实施例9制备样品核磁共振氢谱放大图。
其中各实施例中原料的用量及获得的注射液的外观及游离丙泊酚的浓度见表1所示。
表1
由实施例1~10可见,碳酸氢钠高于1%(w/v)时,制剂轻微发黄,稳定性不佳,碳酸氢钠低于0.01%(w/v),制剂乳浊。比较实施例9和实施例10,提高磺丁基醚-β-环糊精的浓度,不能显著降低游离丙泊酚的浓度。
在不含碳酸氢钠的实施例8-10中,磺丁基醚-β-环糊精为16g时,静置后有油滴漂浮在液面上,说明环糊精未有效包合丙泊酚,磺丁基醚-β-环糊精为22g时溶液澄清,说明至少需要22g磺丁基醚-β-环糊精才能有效包合丙泊酚。磺丁基醚-β-环糊精为30g时溶液澄清,但游离丙泊酚浓度没有显著降低。相比较,在使用适量碳酸氢钠的处方中,游离丙泊酚的含量显著降低,磺丁基醚-β-环糊精和碳酸氢钠的用量也更少。
实施例11
室温下,取磺丁基醚-β-环糊精18.0g,柠檬酸钠100mg,加注射用水50mL,搅拌溶解后,溶液中通氮气,排除溶解氧,在氮气氛围下,加入1000mg的丙泊酚,搅拌2-6小时,调节pH值至6-9,加水至100mL,搅拌均匀,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存,测游离丙泊酚浓度为37.3μg/mL。
实施例12
室温下,取磺丁基醚-β-环糊精18.0g,葡甲胺100mg,加注射用水50mL,搅拌溶解后,溶液中通氮气,排除溶解氧,在氮气氛围下,加入1000mg的丙泊酚,搅拌2-6小时,调节pH值至6-9,加水至100mL,搅拌均匀,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存,测游离丙泊酚浓度为36.6μg/mL。
实施例13
室温下,取磺丁基醚-β-环糊精18.0g,碳酸氢铵100mg,加注射用水50mL,搅拌溶解后,溶液中通氮气,排除溶解氧,在氮气氛围下,加入1000mg的丙泊酚,搅拌2-6小时,调节pH值至6-9,加水至100mL,搅拌均匀,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存,测游离丙泊酚浓度为35.2μg/mL。
实施例14
室温下,取磺丁基醚-β-环糊精20.0g,乙酸铵100mg,加注射用水50mL,搅拌溶解后,溶液中通氮气,排除溶解氧,在氮气氛围下,加入1000mg的丙泊酚,搅拌2-6小时,调节pH值至6-9,加水至100mL,搅拌均匀,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存,测游离丙泊酚浓度为38.7μg/mL。
实施例15
室温下,取磺丁基醚-β-环糊精10.0g,磷酸氢钠50mg,加注射用水50mL,搅拌溶解后,溶液中通氮气,排除溶解氧,在氮气氛围下,加入500mg的丙泊酚,搅拌2-6小时,调节pH值至6-9,加水至100mL,搅拌均匀,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存,测游离丙泊酚浓度为33.7μg/mL。
实施例16
室温下,取磺丁基醚-β-环糊精20.0g,乳酸钠100mg,加注射用水50mL,搅拌溶解后,溶液中通氮气,排除溶解氧,在氮气氛围下,加入1000mg的丙泊酚,搅拌2-6小时,调节pH值至6-9,加水至100mL,搅拌均匀,0.22μm过滤除菌,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存,测游离丙泊酚浓度为36.1μg/mL。
对比例1
取丙泊酚市售注射液得普利麻19mL,加入1mL的5%碳酸氢钠,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存,计算得碳酸氢钠终浓度为0.25%。
对比例2
取丙泊酚市售注射液得普利麻15mL,加入5mL5%碳酸氢钠注射液,装入透明无菌安瓿瓶中,无菌氮气驱尽空气封装,在25℃下保存,计算的碳酸氢钠终浓度为1.25%。
实施例17丙泊酚注射剂稳定性考察
以实施例1-3处方、对比例1-2制备样品,进行考察,放置于40℃,避光环境中,不同时间点下,测定各项稳定性相关数据如表2所示。由表2可见,本发明的丙泊酚注射剂稳定性良好。
表2
为了进一步考察稳定性,以实施例2处方制备样品,进行考察,放置于25℃,避光环境中,不同时间点下,测定各项稳定性相关数据见表3所示。
表3
由碳酸氢钠注射液说明书可知,临床治疗代谢性酸中毒的应用浓度为1.4%~8%。专利US8546453中表明碳酸氢钠终浓度接近1.4%方能降低注射疼痛,低浓度碳酸氢钠(0.25%)不能降低注射疼痛。但长时间的输注该乳剂会大大提高人体内碳酸氢盐的浓度,极可能打破病人的酸碱平衡,引起病人不适。本发明极大降低了碳酸氢钠终浓度,具有更好的安全性。
Claims (9)
1.一种澄清丙泊酚注射液,该注射液包括以下组分:丙泊酚、环糊精、稳定剂、pH调节剂和注射用水,该注射液的pH值为6-9,优选为7-8.5。
2.根据权利要求1所述的丙泊酚注射液,其中,所述环糊精选自羟丙基-β-环糊精、磺丁基醚-β-环糊精、羟丙基-磺丁基醚-β-环糊精、甘露糖基-β-环糊精和半乳糖基-β-环糊精中的一种或多种;优选为羟丙基-β-环糊精或磺丁基醚-β-环糊精。
3.根据权利要求1或2所述的丙泊酚注射液,其中,所述稳定剂选自药学上可以接受的碱或酸,包括但不局限于碳酸氢钠、碳酸氢钾、氢氧化钠、乳酸钠、磷酸氢钠、柠檬酸钠、乙酸钠、乙酸铵、碳酸氢铵、碳酸氢钾、磷酸、乳酸、柠檬酸、乙酸、盐酸和二氧化碳中的一种或多种;优选为碳酸氢钠;
优选地,所述pH调节剂选自药学上可以接受的碱或酸,包括但不局限于碳酸氢钠、氢氧化钠、盐酸和二氧化碳。
4.根据权利要求1至3中任一项所述的丙泊酚注射液,其中,在所述注射液中,以重量百分含量计,所述丙泊酚的量为0.5%-2%(w/v),优选为1%(w/v);
优选地,在所述注射液中,以重量百分含量计,所述环糊精的量为10%-30%(w/v),优选为12%-25%(w/v)。
5.根据权利要求1至4中任一项所述的丙泊酚注射液,其中,所述注射液中,以重量百分含量计,所述稳定剂的量为0.001-1.0%(w/v),优选为0.01-1.0%(w/v),更优选为0.01-0.5%(w/v)。
6.根据权利要求1至5中任一项所述的丙泊酚注射液,其中,所述注射液中,游离丙泊酚的含量不高于50μg/mL,优选为不高于35μg/mL,最优选为不高于30μg/mL。
7.根据权利要求1至6中任一项所述的丙泊酚注射液,其中,所述注射液还进一步包括防腐剂、抗氧剂、抑菌剂、渗透调节剂中的一种或多种,所述防腐剂例如为EDTA,所述抗氧剂例如为亚硫酸氢钠,所述抑菌剂例如为维生素C。
8.一种澄清丙泊酚注射液,该注射液包括丙泊酚、磺丁基醚-β-环糊精、碳酸氢钠,除碳酸氢钠以外的pH调节剂和注射用水,该注射液的pH值为6-9,优选为7-8.5;
优选地,在所述注射液中,以重量百分比计,所述丙泊酚的量为0.5%-2%(w/v),优选为1%(w/v);
优选地,在所述注射液中,以重量百分比计,所述磺丁基醚-β-环糊精的量为10%-30%(w/v),优选为12-25%(w/v);
优选地,所述注射液中,以重量百分含量计,所述除碳酸氢钠以外的碳酸氢钠的量为0.001-1.0%(w/v),优选为0.01-1.0%(w/v),更优选为0.01-0.5%(w/v);
优选地,所述除碳酸氢钠以外的pH调节剂选自药学上可以接受的碱或酸,包括但不局限于碳酸氢钠、氢氧化钠、盐酸、二氧化碳。
9.一种权利要求1至8中任一项所述的丙泊酚注射液的制备方法,该制备方法包括如下步骤:
取处方量的环糊精和稳定剂加入注射用水中,溶解后,通入惰性气体,加入丙泊酚,搅拌,pH调节剂调节pH值,过滤,即得;
优选地,所述惰性气体为氮气;
更优选地,所述制备方法包括在注射用水中先加入碳酸氢钠和磺丁基醚-β-环糊精,溶解后,通入惰性气体如氮气,加入丙泊酚,搅拌至悬浮的丙泊酚油滴消失,此时继续搅拌2-6小时,pH调节剂调节pH值,过滤,充氮,即得。
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