CN109200018A - 含有奈妥吡坦的微乳制剂 - Google Patents
含有奈妥吡坦的微乳制剂 Download PDFInfo
- Publication number
- CN109200018A CN109200018A CN201710535433.0A CN201710535433A CN109200018A CN 109200018 A CN109200018 A CN 109200018A CN 201710535433 A CN201710535433 A CN 201710535433A CN 109200018 A CN109200018 A CN 109200018A
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- CN
- China
- Prior art keywords
- injection
- fat emulsion
- smooth
- appropriate pyrrole
- fat
- 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.)
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Abstract
本发明属于药物制剂领域，具体涉及一种含有奈妥吡坦的注射用脂肪乳剂，及制备上述制剂的方法。
Description
技术领域
本发明属于医药制剂技术领域，具体涉及一种含有奈妥吡坦的微乳制剂及其制备方法，还涉及由奈妥吡坦和帕洛诺司琼组合的微乳制剂及其制备方法。
背景技术
神经激肽1(NK-1，P物质)为哺乳动物体内存在的一种十一肽，参与调节多种炎性病症，包括偏头痛，类风湿性关节炎，哮喘和炎症性肠炎，呕吐，以及帕金森氏病、焦虑和抑郁等中枢神经系统疾病。
有文献报道，NK-1受体拮抗剂可以用于治疗下列疾病：疼痛，头痛(特别是偏头痛)，阿尔茨海默氏病，多发性硬化，吗啡戒断症状减弱，心血管病变，水肿(如由热损伤引起的水肿)，慢性炎性疾病(如类风湿性关节炎)，哮喘/支气管功能亢进和其他呼吸道疾病(包括过敏性鼻炎)，炎性消化道疾病(包括溃疡性结肠炎和局限性回肠炎)，眼损害和炎性眼疾病(《速激肽受体和速激肽受体拮抗剂》，J.Auton.Pharmacol.，13：23-93(1993))。研究发现，NK-1受体拮抗剂还可以用于治疗晕运病和诱导产生的呕吐反应。
奈妥吡坦，如式1所示，是一种NK-1受体的高选择性拮抗剂，临床证实能够有效预防癌症化疗急性期和延迟期产生的恶心和呕吐。
2014年，FDA批准了由奈妥吡坦和帕洛诺司琼组成的口服胶囊制剂，用于预防伴随癌症化疗的初始和重复疗程的急性和延迟恶心和呕吐，商品名为Akyneo。
肿瘤是一种严重威胁人类生命及生活质量的疾病，化疗是一种肿瘤治疗的常规手段，而75％以上的化疗患者会出现恶心或呕吐的症状。对于严重呕吐的患者，口服给药给患者带来很大的不遍，并且药物的吸收与生物利用度也大大降低，因此，有必要开发一种注射剂型，改善患者的依从性，提高药物的生物利用度。
目前，已有文献报道的奈妥吡坦制剂，均为口服剂型，尚未出现有关注射制剂的报道。例如，US8951969记载了包含奈妥吡坦和帕洛诺司琼的口服软胶囊。US6719996记载了奈妥吡坦具有较低的口服生物利用度并且在极性和/或非极性介质中溶解度差，为了解决这一问题，开发了奈妥吡坦的自乳化药物递送系统，包括药物，可食用脂质基质和可食用乳化剂。 CN105708799记载了一种纳米结构脂质载体口服药物组合物，包括药物，固态脂质材料，液态脂质材料，脂溶性乳化剂，水溶性乳化剂和水性溶剂，通过将难溶性药物制成相应的纳米级的剂型来提高药物稳定性和生物利用度。
奈妥吡坦属于难溶性药物，而脂肪乳作为难溶性药物的良好载体，主要以脂肪油为软基质，将药物溶解在脂肪油里，通过磷脂乳化作用将其包裹于磷脂膜包封的乳球中，通过乳球的包裹和保护作用，可延缓药物的水解、氧化，提高药物稳定性和延长药物作用时间。但如果难溶性药物在脂肪油中溶解度和稳定性差，则无法制备出能够长期储存，适合工业化生产的脂肪乳剂。研究发现，奈妥吡坦在脂肪油具有极差的溶解性和稳定性，不易制成稳定的脂肪乳剂。
但是，本发明人制备出一种含有奈妥吡坦的微乳注射制剂，不仅能够克服口服给药的缺陷制备成注射剂型，改善了患者的依从性，并且奈妥吡坦在制备获得的微乳剂中，还具有显著改善的溶解度和生物利用度，令人意外的是，在制备和储存过程中还表现出高稳定性。
发明内容
本发明的目的是提供一种溶解度改善的，稳定的、具有延长的保质期的奈妥吡坦微乳制剂。本发明的另一目的是提供上述奈妥吡坦微乳制剂的制备方法。
本发明是通过以下技术方案实现的：
一种注射用脂肪乳剂，包含奈妥吡坦，注射用油，乳化剂，助溶剂，PH调节剂和水，所述注射用油选自中等脂肪链长度的甘油三酯，并且奈妥吡坦溶解在中等脂肪链长度的甘油三酯中。
在一实施例中，本发明的注射用脂肪乳剂不含有大豆油。
在一实施例中，本发明注射用脂肪乳剂中包含0.1～1g的奈妥吡坦。
在一实施例中，本发明注射用脂肪乳剂中的乳化剂选自磷脂酰胆碱，泊洛沙姆，聚氧乙烯蓖麻油，聚山梨酯80中的一种或多种，优选自大豆磷脂酰胆碱或蛋黄磷脂酰胆碱。
在一实施例中，本发明注射用脂肪乳剂中的助溶剂选自油酸，油酸钠，丙三醇，1，2-丙二醇，聚乙二醇或乙醇中的一种或多种。
在一实施例中，本发明注射用脂肪乳剂中注射用油与奈妥吡坦的重量比为60:1～10:1，优选自60:1，50:1，40:1，30:1，25:1，24:1，20:1，15:1，或10:1。
在一实施例中，本发明注射用脂肪乳剂中乳化剂与奈妥吡坦的重量比为10:1～1:1，优选自10:1，9:1，8:1，7:1，6:1，5:1，4:1，3:1，2.4:1，2:1，1.2:1，或1:1。
在一实施例中，本发明注射用脂肪乳剂中助溶剂与奈妥吡坦的重量比为10:1～1:2，优选 自10:1，9:1，8:1，7:1，6:1，5:1，4:1，3:1，2:1，1:1或1:2。
在一实施例中，本发明注射用脂肪乳剂中的PH调节剂选自氢氧化钠，氢氧化钾，氢氧化镁，碳酸钠，碳酸钾或其混合物。
在另一实施例中，本发明注射用脂肪乳剂的PH范围是6～10，优选8.5-9.5。
在另一实施例中，本发明注射用脂肪乳剂中，进一步包含抗氧剂。
在一优选实施例中，本发明注射用脂肪乳剂中抗氧剂选自丁基羟基茴香醚(BHA)、2,6-二叔丁基对甲苯酚(BHT)或α-生育酚中的一种或多种。
在另一实施例中，本发明注射用脂肪乳剂中，进一步包含保护剂。
在一优选实施例中，本发明注射用脂肪乳剂中保护剂选自甘油，蔗糖，海藻糖，葡萄糖，木糖醇，甘露醇，氨基酸中的一种或多种，优先选用甘油。
在一实施例中，本发明注射用脂肪乳剂中，进一步包含5-HT3受体拮抗剂或其可药用盐，所述5-HT3受体拮抗剂或其可药用盐溶解在脂肪乳剂的水相中。
在另一实施例中，本发明注射用脂肪乳剂中的5-HT3受体拮抗剂选自昂旦司琼，格拉司琼，托烷司琼，雷莫司琼，朵拉司琼或帕洛诺司琼。
在一优选实施例中，本发明注射用脂肪乳剂中包含0.56～1.12mg的盐酸帕洛诺司琼。
在另一实施例中，本发明注射用脂肪乳剂中，进一步包含包含稳定剂，所述稳定剂选自乙二胺四乙酸二钠或乙二胺四乙酸钙钠。
本发明还提供了一种制备奈妥吡坦注射用脂肪乳剂的方法，
a)将奈妥吡坦，注射用油，助溶剂，乳化剂混合，获得油相；
b)将水，PH调节剂混合，获得水相；
c)将油相和水相混合，获得初乳；
d)初乳在10000-30000psi压力下高压均质2-5pass，获得终乳；
e)终乳灭菌获得脂肪乳剂。
在一实施例中，本发明提供的制备注射用脂肪乳剂的方法，终乳灭菌是经过0.2μm滤膜过滤除菌或者高压湿热灭菌。
在一实施例中，本发明提供的制备注射用脂肪乳剂的方法，在步骤b)中，进一步包括将5-HT3受体拮抗剂或其可药用盐混合在水相中。
在另一实施例中，本发明提供的制备注射用脂肪乳剂的方法，其中5-HT3受体拮抗剂选自昂旦司琼，格拉司琼，托烷司琼，雷莫司琼，朵拉司琼或帕洛诺司琼。
本发明中5-HT3受体拮抗剂的可药用盐表示保留母体化合物的生物有效性和性质的那些盐。其中与酸成盐是指，通过母体化合物的游离碱与无机酸或有机酸的反应而得。无机酸包 括但不限于盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等。有机酸包括但不限于甲酸、乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、苯甲酸、吡啶甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、三氟甲磺酸、四氟硼酸、六氟磷酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
本发明还提供了脂肪乳剂用于预防伴随癌症化疗的初始和重复疗程的急性和延迟恶心和呕吐的方法，包括将治疗量的上述脂肪乳剂给予需要治疗的患者的步骤，可以经非口服途径给药，优选静脉给药。
具体实施方式
下面将结合实施例对本发明作进一步说明，可以使本领域技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1奈妥吡坦在注射用油中的溶解度试验
室温下，取600mg奈妥吡坦与20mL注射用油混合，使混合液呈过饱和状态，室温搅拌过夜。次日，将浑浊溶液离心或过0.2μm滤膜得到上清液，使用HPLC测定上清液中药物含量，得到药物在各注射用油种类中的溶解度，结果见表1。
表1奈妥吡坦在注射用油中的溶解度
| 注射用油种类 | 溶解度(mg/mL) |
| 大豆油 | 3.65 |
| 中链甘油三酯(MCT) | 18.50 |
| 大豆油：中链甘油三酯＝1:1(V/V) | 14.44 |
实施例2奈妥吡坦在注射用油中的稳定性试验
取实施例1中制得的中链甘油三酯和大豆油的饱和奈妥吡坦溶液10mL，进行分装(每瓶2mL)，充氮气后封口放于60℃恒温箱，使用HPLC测定哥时间点奈妥吡坦含量，考察药物在不同注射用油种类中的稳定性，结果见表2。
表2奈妥吡坦在注射用油中的稳定性
综合实施例1和2的结果，可以看出，奈妥吡坦在中链甘油三酯中不仅具有显著改善的溶解度，还具有令人意外的高稳定性。
实施例3脂肪乳剂中助溶剂的选择
脂肪乳剂的载药量较小，为了获得足够的载药量，临床输注量较高。而在实际使用中，过多的输注量无论对生产成本还是患者的依从性都是一种挑战，为了尽可能减少输注量，常常在脂肪乳剂中增加助溶剂。因此，本发明人考察了油酸(OA)和乙醇等助溶剂对奈妥吡坦在脂肪乳剂中溶解度的影响，结果见表3。
表3助溶剂对奈妥吡坦在脂肪乳剂中溶解度的影响
| 溶剂 | 溶解度(mg/mL) |
| MCT+1％油酸 | 31.1 |
| MCT+3％油酸 | 43.9 |
| MCT+5％油酸 | 57.0 |
| MCT+10％油酸 | 83.7 |
| MCT+5％乙醇 | 48.0 |
| MCT+10％乙醇 | 71.0 |
| MCT+20％乙醇 | 85.5 |
| MCT+30％乙醇 | 110.6 |
| MCT+1％油酸+5％乙醇 | 51.2 |
| MCT+3％油酸+5％乙醇 | 67.8 |
| MCT+3％油酸+10％乙醇 | 81.2 |
| MCT+3％油酸+20％乙醇 | 96.7 |
| MCT+3％油酸+30％乙醇 | 119.6 |
结论：乙醇，油酸或乙醇和油酸的混合物均可以明显增加奈妥吡坦在MCT中的溶解度。
实施例4：脂肪乳剂中抗氧化剂的选择
本发明人还考察了不同抗氧化剂对脂肪乳剂稳定性的影响。我们考察了不同条件下，2,6-二叔丁基对甲苯酚(BHT)，和α-生育酚(VE)对脂肪乳剂稳定性的影响，结果见表5和表6。
表4抗氧化剂对奈妥吡坦在脂肪乳剂中稳定性的影响(40℃条件下)
表5抗氧化剂对奈妥吡坦在脂肪乳剂中稳定性的影响(60℃条件下)
实施例5奈妥吡坦脂肪乳剂的制备
处方
表6
| 处方1 | 处方2 | 处方3 | 处方4 | 处方5 | 处方6 | |
| 奈妥吡坦 | 0.2g | 0.50g | 0.50g | 0.50g | 0.50g | 1g |
| 乙醇 | - | - | 1g | 1g | 3g | 3g |
| MCT | 12g | 12g | 10g | 10g | 10g | 10g |
| 蛋黄卵磷脂E80 | 1.20g | 1.20g | 1.20g | 1.20g | 1.20g | 1.20g |
| 油酸 | - | 0.30g | 0.03g | - | - | 0.03g |
| 甘油 | 2.25g | 2.25g | 2.25g | 2.25g | 2.25g | 2.25g |
| VE | - | 0.03g | 0.03g | - | - | - |
| 水 | 至100mL | 至100mL | 至100mL | 至100mL | 至100mL | 至100mL |
| pH范围 | 8.5-9.5 | 8.5-9.5 | 8.5-9.5 | 8.5-9.5 | 8.5-9.5 | 8.5-9.5 |
制备方法
在70℃条件下，将注射用油，助溶剂，乳化剂混合，加热到70℃使乳化剂溶解，随后加入奈妥吡坦，获得油相；在70℃条件下，将甘油和注射用水混合，获得水相；油相和水相混合，剪切乳化机剪切，获得初乳；将初乳高压均质机中，10000-30000psi压力下均质2-5遍；用注射用水定容至100mL，用0.2M NaOH调节pH值为8.5-9.5；将样品分装，充氮，封口，121℃灭菌12min，获得奈妥吡坦脂肪乳剂。对不同处方的脂肪乳剂进行质量评价，结果见表8.
表7不同处方奈妥吡坦脂肪乳剂灭菌前后质量评价
实施例6：奈妥吡坦/盐酸帕洛诺司琼复方脂肪乳剂的制备
处方
表8
| 处方7 | 处方8 | 处方9 | 处方10 | 处方11 | |
| 奈妥吡坦 | - | 0.2g | 0.5g | 0.5g | 0.5g |
| 乙醇 | - | - | 3g | - | 3g |
| MCT | 10g | 12g | 10g | 12g | 10g |
| E80 | 1.20g | 1.20g | 1.20g | 1.20g | 1.20g |
| 油酸 | - | - | - | 0.30g | 0.30g |
| 甘油 | 2.25g | 2.25g | 2.25g | 2.25g | 2.25g |
| EDTA-2Na | 0.05g | 0.05g | 0.05g | 0.05g | 0.05g |
| 盐酸帕洛诺司琼 | 0.85mg | 0.85mg | 0.85mg | 0.85mg | 0.85mg |
| 水 | 至100mL | 至100mL | 至100mL | 至100mL | 至100mL |
| pH | 8.5-9.5 | 8.5-9.5 | 8.5-9.5 | 8.5-9.5 | 8.5-9.5 |
制备方法
在70℃条件下，将注射用油，助溶剂，乳化剂混合，加热到70℃使乳化剂溶解，随后加入奈妥吡坦，获得油相；在70℃条件下，将盐酸怕洛诺司琼，稳定剂，甘油和注射用水混合，获得水相；油相和水相混合，剪切乳化机剪切，获得初乳；将初乳高压均质机中，10000-30000psi压力下均质2-5遍；用注射用水定容至100mL，用0.2M NaOH调节pH值为8.5-9.5；将样品分装，充氮，封口，121℃灭菌12min，获得奈妥吡坦/盐酸帕洛诺司琼脂肪乳剂。对不同处方的脂肪乳剂进行质量评价，结果见表10.
表9不同处方奈妥吡坦/盐酸帕洛诺司琼复方脂肪乳剂质量评价
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本+发明的保护范围。
Claims (17)
1.一种注射用脂肪乳剂，包含奈妥吡坦，注射用油，乳化剂，助溶剂，PH调节剂和水，所述注射用油选自中等脂肪链长度的甘油三酯，奈妥吡坦溶解在中等脂肪链长度的甘油三酯中。
2.如权利要求1所述的注射用脂肪乳剂，其中包含0.1～1g的奈妥吡坦。
3.如权利要求1所述的注射用脂肪乳剂，其中乳化剂选自磷脂酰胆碱，泊洛沙姆，聚氧乙烯蓖麻油，聚山梨酯80中的一种或多种，优选自大豆磷脂酰胆碱或蛋黄磷脂酰胆碱。
4.如权利要求1所述的注射用脂肪乳剂，其中助溶剂选自油酸，油酸钠，丙三醇，1，2-丙二醇，聚乙二醇或乙醇中的一种或多种。
5.如权利要求1所述的注射用脂肪乳剂，其中注射用油与奈妥吡坦的重量比为60:1～10:1，优选自60:1，50:1，40:1，30:1，25:1，24:1，20:1，15:1，或10:1。
6.如权利要求1所述的注射用脂肪乳剂，其中乳化剂与奈妥吡坦的重量比为10:1～1:1，优选自10:1，9:1，8:1，7:1，6:1，5:1，4:1，3:1，2.4:1，2:1，1.2:1，或1:1。
7.如权利要求1所述的注射用脂肪乳剂，其中助溶剂与奈妥吡坦的重量比为10:1～1:2。
8.如权利要求1所述的注射用脂肪乳剂，进一步包含抗氧剂。
9.如权利要求9所述的注射用脂肪乳剂，其中抗氧剂选自丁基羟基茴香醚(BHA)、2,6-二叔丁基对甲苯酚(BHT)或α-生育酚中的一种或多种。
10.如权利要求1-9中任意一项所述的注射用脂肪乳剂，进一步包含5-HT3受体拮抗剂或其可药用盐，所述5-HT3受体拮抗剂或其可药用盐溶解在脂肪乳剂的水相中。
11.如权利要求10所述的注射用脂肪乳剂，其中5-HT3受体拮抗剂选自昂旦司琼，格拉司琼，托烷司琼，雷莫司琼，朵拉司琼或帕洛诺司琼。
12.如权利要求10所述的注射用脂肪乳剂，其中包含0.56～1.12mg的盐酸帕洛诺司琼。
13.如权利要求10所述的注射用脂肪乳剂，进一步包含稳定剂，所述稳定剂选自乙二胺四乙酸二钠或乙二胺四乙酸钙钠。
14.一种制备注射用脂肪乳剂的方法，
a)将奈妥吡坦，注射用油，助溶剂，乳化剂混合，获得油相；
b)将水，PH调节剂等水相成分混合，获得水相；
c)将油相和水相混合，获得初乳；
d)初乳在10000-30000psi压力下高压均质2-5pass，获得终乳；
e)终乳灭菌获得脂肪乳剂。
15.如权利要求14所述的制备注射用脂肪乳剂的方法，终乳灭菌是经过0.2μm滤膜过滤除菌或者高压湿热灭菌。
16.如权利要求14所述的制备注射用脂肪乳剂的方法，在步骤b)中，进一步包括将5-HT3受体拮抗剂或其可药用盐混合在水相中。
17.如权利要求16所述的制备注射用脂肪乳剂的方法，其中5-HT3受体拮抗剂选自昂旦司琼，格拉司琼，托烷司琼，雷莫司琼，朵拉司琼或帕洛诺司琼。
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Application publication date: 20190115 |
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