CN115463101B - 一种稳定的多替拉韦钠片及其制备方法 - Google Patents
一种稳定的多替拉韦钠片及其制备方法 Download PDFInfo
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- 239000011734 sodium Substances 0.000 title claims abstract description 44
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 44
- 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 title claims abstract description 41
- 229960000980 entecavir Drugs 0.000 title claims abstract description 26
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000000725 suspension Substances 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 7
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- 239000002245 particle Substances 0.000 claims abstract description 7
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 239000011248 coating agent Substances 0.000 claims abstract description 5
- 238000000576 coating method Methods 0.000 claims abstract description 5
- 238000005550 wet granulation Methods 0.000 claims abstract description 5
- 229940083542 sodium Drugs 0.000 claims description 28
- 229920002472 Starch Polymers 0.000 claims description 13
- 239000008107 starch Substances 0.000 claims description 13
- 235000019698 starch Nutrition 0.000 claims description 13
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 9
- 229930195725 Mannitol Natural products 0.000 claims description 9
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 9
- 239000000594 mannitol Substances 0.000 claims description 9
- 235000010355 mannitol Nutrition 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- 229960001855 mannitol Drugs 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 229940069328 povidone Drugs 0.000 claims description 7
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 13
- 239000000463 material Substances 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
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- 230000000052 comparative effect Effects 0.000 description 7
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- 241000725303 Human immunodeficiency virus Species 0.000 description 3
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- UGWJRRXTMKRYNK-VSLILLSYSA-M dolutegravir sodium Chemical compound [Na+].C([C@@H]1OCC[C@H](N1C(=O)C1=C([O-])C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F UGWJRRXTMKRYNK-VSLILLSYSA-M 0.000 description 3
- MCRNHLQVPJEMSQ-UHFFFAOYSA-N C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] Chemical compound C(C=CC(=O)O)(=O)O.C(CCCCCCCCCCCCCCCCC)[Na] MCRNHLQVPJEMSQ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
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- 238000009501 film coating Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
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- 229940124321 AIDS medicine Drugs 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 108010002459 HIV Integrase Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010061833 Integrases Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
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- 239000002850 integrase inhibitor Substances 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
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- 238000005070 sampling Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 229940014075 tivicay Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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Abstract
本发明涉及医药制剂技术领域,提出了一种稳定的多替拉韦钠片及其制备方法,所述制备方法包括以下步骤:S1、将多替拉韦钠分散于pH为7‑12的水溶液中,得到混悬液;S2、将辅料置于湿法制粒机中,加入混悬液进行湿法制粒;S3、干燥;S4、将干燥的颗粒与外加崩解剂、润滑剂混合均匀;S5、压片、包衣。通过上述技术方案,解决了现有技术中的多替拉韦钠片的稳定性受环境温湿度影响导致溶出降低问题。
Description
技术领域
本发明涉及医药制剂技术领域,具体的,涉及一种稳定的多替拉韦钠片及其制备方法。
背景技术
多替拉韦钠(Dolutegravir sodium)是葛兰素史克/ViiV研发的一款抗艾滋病药物,属于整合酶抑制剂。2013年8月12日,多替拉韦以其钠盐(Dolutegravir sodium)为唯一活性成分的口服片剂获美国FDA批准上市(商品名为Tivicay),其结构式如下:
多替拉韦通过与整合酶活性位点结合并阻碍HIV复制周期中关键的逆转录病毒脱氧核糖核酸(DNA)整合链转移步骤而抑制HIV整合酶。常用于治疗人类免疫缺陷病毒(HIV)感染的成人和年满12岁的儿童患者。已在全球100多个国家获批,并被大部分国际性治疗指南推荐为初治艾滋病病人联合治疗方案的一线首选治疗药物。
多替拉韦钠属于BCSⅡ类药物,在pH1.0~pH6.8的生理pH内,药物的溶解度均小于50ug/mL属于低溶解性药物,制备的片剂在稳定性期间受环境温湿度的影响,原料的溶解性下降,溶出降低,影响产品的临床应用效果,是本领域技术人员难以解决的技术难题。
发明内容
本发明提出一种稳定的多替拉韦钠片及其制备方法,解决了现有技术中的多替拉韦钠片的稳定性受环境温湿度影响导致溶出降低问题。
本发明的技术方案如下:
一种稳定的多替拉韦钠片的制备方法,包括以下步骤:
S1、将多替拉韦钠分散于pH为7-12的水溶液中,得到混悬液;
S2、将辅料置于湿法制粒机中,加入混悬液进行湿法制粒;
S3、干燥;
S4、将干燥的颗粒与外加崩解剂、润滑剂混合均匀;
S5、压片、包衣。
作为进一步的技术方案,所述pH为8-10。
作为进一步的技术方案,所述辅料包括稀释剂、内加崩解剂;
所述稀释剂包括甘露醇、微晶纤维素、乳糖、磷酸氢钙、碳酸钙中的一种或多种。
作为进一步的技术方案,所述内加崩解剂和外加崩解剂均选自羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠、淀粉、低取代羟丙基纤维素中的一种或多种。
作为进一步的技术方案,润滑剂包括硬脂富马酸钠、硬脂酸镁、硬脂酸、滑石粉中的一种或多种。
作为进一步的技术方案,所述外加崩解剂占总片重的比例为1%~10%,优选的为2%~8%;所述润滑剂占总片重的比例为1%~10%,优选的为2%~8%。
作为进一步的技术方案,所述步骤S2中辅料经过40目筛预处理。
作为进一步的技术方案,所述步骤S3中干燥具体为60℃~90℃的进风温度下干燥至水分小于3%。
本发明还提出一种如所述的稳定的多替拉韦钠片的制备方法得到的多替拉韦钠片。
作为进一步的技术方案,所述的多替拉韦钠片,包含20-60mg的多替拉韦钠。
本发明的有益效果为:
1、本发明通过不断的研究,发现采用湿法制粒工艺制备,将多替拉韦钠通过混悬液的方式加入,并调节混悬液的pH至微碱性能够提高API的溶解度,从而使其在稳定性期间原料的溶解性不变,保证了溶出水平不受影响。通过本发明制得的多替拉韦钠片的溶出在加速40℃+75%RH条件下放置6个月,产品的溶出未出现显著下降,解决了本品在稳定性期间的溶出降低的技术难题。
具体实施方式
下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都涉及本发明保护的范围。
实施例1
一种多替拉韦钠片:
S1、将表1中处方量的甘露醇、微晶纤维素、羧甲淀粉钠、聚维酮分别过40目筛,除去结块;
S2、将多替拉韦钠于pH为8.5的氢氧化钠水溶液中分散均匀,得到混悬液;
S3、将S1的物料置于湿法制粒机中,缓慢加入混悬液进行湿法制粒;
S4、将制得的颗粒在沸腾干燥机内,控制进风温度60℃~90℃下,干燥至水分小于3%;
S5、将干燥的颗粒与外加羧甲淀粉钠、硬脂富马酸钠混合均匀;
S6、将S5中总混后的物料采用高速压片机压制成片;
S7、采用胃溶型包衣粉将S6中片芯进行薄膜包衣。
实施例2
与实施例1相比,处方量相同,不同的是步骤S2中的pH为7.5,其他与实施例1相同。
实施例3
与实施例1相比,处方量相同,不同的是步骤S2中的pH为9.5,其他与实施例1相同。
实施例4
与实施例1相比,处方量相同,不同的是步骤S2中的pH为11.5,其他与实施例1相同。
实施例5
与实施例1相比,处方量相同,不同的是步骤S2中的pH为8,其他与实施例1相同。
实施例6
与实施例1相比,处方量相同,不同的是步骤S2中的pH为9,其他与实施例1相同。
实施例7
与实施例1相比,处方量相同,不同的是步骤S2中的pH为10,其他与实施例1相同。
实施例8
将实施例1中的甘露醇替换为等量的乳糖,聚维酮替换为等量的低取代羟丙基纤维素,其他与实施例1相同。
实施例9
与实施例1相比,处方量不同,其他与实施例1相同。
对比例1
处方如表1所示,制备方法如下:
S1、将处方量的多替拉韦钠、甘露醇、微晶纤维素、羧甲淀粉钠、聚维酮分别过40目筛,除去结块;
S2、将S1中物料加入至湿法制粒机中,缓慢加入水,湿法制粒;
S3、将制得的颗粒在沸腾干燥机内,控制进风温度60℃~90℃下,干燥至水分小于3%;
S4、将干燥的颗粒与外加羧甲淀粉钠、硬脂富马酸钠混合均匀;
S5、将S4中总混后的物料采用高速压片机压制成片;
S6、采用胃溶型包衣粉将S5中片芯进行薄膜包衣。
表1实施例1处方量
组成 | 实施例1/mg | 对比例1/mg | 实施例9/mg |
多替拉韦钠 | 52.6 | 52.6 | 52.6 |
微晶纤维素 | 90.0 | 90.0 | 60.0 |
甘露醇 | 130.4 | 130.4 | 160.4 |
聚维酮 | 18.0 | 18.0 | 18.0 |
羧甲淀粉钠 | 9.0 | 9.0 | 9.0 |
碱性水溶液 | 75 | 75 | 65 |
外加羧甲淀粉钠 | 6.0 | 6.0 | 6.0 |
外加硬脂富马酸钠 | 6.0 | 6.0 | 6.0 |
将实施例和对比例得到的产品按照市售包装进行包装,并在40℃+75%RH的环境下放置6个月。加速试验过程中,检测产品的溶出度。溶出方法:照溶出度测定法(中国药典2020版二部附录XC第二法),使用900ml pH6.8含0.25%SDS w/v的磷酸盐缓冲液作为溶出介质,设置转速为50转/min,在30min取样,检测产品中多替拉韦钠的溶出量。实验结果如表2所示。
表2实施例及对比例样品在加速试验过程中的溶出度变化
样品 | 0天 | 加速1月 | 加速2月 | 加速3月 | 加速6月 |
实施例1 | 98 | 98 | 98 | 97 | 98 |
实施例2 | 95 | 93 | 92 | 92 | 90 |
实施例3 | 96 | 95 | 95 | 96 | 95 |
实施例4 | 96 | 93 | 93 | 91 | 90 |
实施例5 | 98 | 98 | 97 | 97 | 98 |
实施例6 | 99 | 99 | 98 | 97 | 99 |
实施例7 | 98 | 99 | 99 | 99 | 99 |
实施例8 | 94 | 94 | 93 | 93 | 94 |
实施例9 | 96 | 93 | 93 | 93 | 93 |
对比例1 | 96 | 93 | 91 | 87 | 83 |
与对比例1相比,实施例得到的片剂解决了产品在储存期间的溶出下降问题,大大提升产品的稳定性,更有利于产品发挥临床效力。实施例8中改变了辅料,实施例9中改变辅料的加入量,相比于实施例1溶出水平降低,但相比于对比例1储存期间稳定性仍然较高。
以上仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (4)
1.一种稳定的多替拉韦钠片的制备方法,其特征在于,包括以下步骤:
S1、将多替拉韦钠分散于pH为8-10的水溶液中,得到混悬液;
S2、将微晶纤维素、甘露醇、聚维酮、羧甲淀粉钠置于湿法制粒机中,加入混悬液进行湿法制粒;
S3、干燥;
S4、将干燥的颗粒与外加羧甲淀粉钠、外加硬脂富马酸钠混合均匀;
S5、压片、包衣;
每片多替拉韦钠片的处方组成为:多替拉韦钠52.6mg、微晶纤维素90.0mg、甘露醇130.4mg、聚维酮18.0mg、羧甲淀粉钠9.0mg、外加羧甲淀粉钠6.0mg、外加硬脂富马酸钠6.0mg。
2.根据权利要求1所述的一种稳定的多替拉韦钠片的制备方法,其特征在于,所述步骤S2中微晶纤维素、甘露醇、聚维酮、羧甲淀粉钠经过40目筛预处理。
3.根据权利要求1所述的一种稳定的多替拉韦钠片的制备方法,其特征在于,所述步骤S3中干燥具体为60℃~90℃的进风温度下干燥至水分小于3%。
4.一种如权利要求1-3任意一项所述的稳定的多替拉韦钠片的制备方法得到的多替拉韦钠片。
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