CN107157945B - 一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法 - Google Patents
一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法 Download PDFInfo
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明涉及一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法，本发明采用内外加入崩解剂法解决了片剂崩解和溶出缓慢的问题。该δ受体激动剂为4‑{（αR）‑α‑[(2S,5R)‑4‑（3‑氟苄基）‑2,5‑二甲基‑1‑哌嗪基]‑（3‑羟基苄基）}‑（4’‑甲基哌啶基）‑苯甲酰胺。通过对崩解剂和崩解剂加入方法的筛选，使该片剂的崩解时限小于5分钟，实现药物在胃液中迅速释放，快速起效。
Description
技术领域
本发明属化学制药领域，具体涉及一种4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐片剂及其制备方法。
技术背景
随着经济的快速发展和生活的节奏加快，抑郁症已经成为一种常见病、多发病。随之，市场上涌现出如选择性5-羟色胺再摄取抑制剂类、三环类抗抑郁药、氨基酮类抗抑郁药等不同类型的抗抑郁药物。上述药物虽有效，但用药过程中会产生不同程度的嗜睡、思维紊乱、性功能障碍等副作用，且起效慢。现有抑郁症治疗药物主要有以下几大类，
1)传统的单胺氧化酶抑制剂类药物例如苯乙肼、异卡波肼、苯环丙胺等非选择性，不可逆的单胺氧化酶抑制剂；
2)吗氯贝胺、托洛沙酮等可逆性单胺氧化酶抑制剂；
3)三环类和四环类等单胺再摄取抑制剂；
4)选择性5-羟色胺-再摄取抑制剂；
5)选择性去甲肾上腺素再摄取抑制剂；
6)5-羟色胺和去甲肾上腺素再摄取双重抑制剂；
7)α2受体拮抗剂和去甲肾上腺素再摄取双重抑制剂；
8)5-HT/NE/DA三重再摄取抑制剂；
9)天然药物与中草药。
4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺能够选择性激动阿片受体的δ-受体亚型发挥抗抑郁作用，作用于新的靶点，有望解决现有抗抑郁药物存在的上述问题。阿片受体有三个亚型：μ-受体、δ-受体、κ-受体。用δ-受体和μ-受体缺陷型转基因小鼠的研究结果表明:δ-受体在抗抑郁方面的阳性作用，而μ-受体在改变行为学活动上表现为阴性作用。啡肽酶抑制剂RB101通过FST试验表明该类化合物具有抗抑郁作用，而δ-阿片类受体拮抗剂纳屈吲哚则可逆转RB101的抗抑郁作用。啡肽类δ-受体激动剂SNC80和(+)BW373U86在FST中单次给药后抗抑郁效果明显。临床上所有抗抑郁药物均己证实了强迫游泳实验(FST)的可靠性。研究发现，与本文所述结构相近的化合物与δ-受体均有较强的亲和力。发明专利CN200810058495.8中提到该化合物的动物实验数据优于目前世界上广泛使用的抗忧郁症药物，如美国Lilly公司的Prozac(氟洛西汀是一种选择性5-羟色胺再回收抑制剂SSRIs类药物)，GSK公司的Wellbutrin，百忧解SERI类药物等。大鼠强迫游泳实验表明该药见效快，仅单次给药就可见明显效果，而目前的常用抗抑郁症药物往往需要1-2周方可见效。
研究发现，游离碱在室温水中的溶解度低于0.09ug/ml，在室温模拟胃液中溶解度约3.0mg/ml，在室温模拟肠液中小于0.1mg/ml。而该化合物的二盐酸盐在上述条件下均能表现出显著的溶解度改善作用。其二盐酸盐较游离碱具有更好的水溶性，有利于口服吸收。如公知的，口服给药是患者较为容易接受的用药方式，对于抑郁症患者更是如此。口服制剂，尤其是片剂能够提高患者的依从性，确保患者按要求服药。
本发明提供了一种通过内外加崩解剂的办法，制备4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐速释片，具有服药方便、起效迅速、工艺简便的优点。
发明内容
本发明提供一种4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐的片剂，具有崩解迅速，溶出快速的优点。
本发明的另一个目的是提供一种工艺稳定的4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐片剂的制备方法。
本发明通过以下技术方案实现：
一种新型阿片δ受体激动剂盐酸盐的片剂,该片剂含有生理有效量的4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐，以及必要的药学上适用的赋形剂。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐的重量百分比为5％-40％。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述药学上适用的赋形剂选自填充剂、崩解剂、助流剂和润滑剂之中几种的混合物。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述填充剂选自淀粉、可压性淀粉、糊精、蔗糖、乳糖、果糖、葡糖糖、木糖醇、甘露醇、微晶纤维素、碳酸钙、磷酸氢钙、硫酸钙、氧化镁、氢氧化铝、羧甲基纤维素钙、羧甲基纤维素钠中的一种或几种。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、低取代羟丙基甲基纤维素中的一种或几种。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述崩解剂用量占片剂的重量百分比为2％-15％。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述助流剂选胶体二氧化硅、粉状纤维素、三硅酸镁、滑石粉中的一种或几种。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述润滑剂选自硬脂酸、硬脂酸钙、硬脂酸镁、硬脂酸锌、滑石粉、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、十二烷基硫酸镁、聚乙二醇、硬脂基富马酸钠中的一种或几种。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，该速释片的制备方法为：
(1)将4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐与填充剂、崩解剂混合均匀；
(2)以水溶液制粒，干燥整粒；
(3)加入部分填充剂、崩解剂、助流剂及润滑剂，混合均匀；
(4)压片，即可。
缩略语
API Active Pharmaceutical Ingredient 活性药物成分
5-HT 5-hydroxytryptamine 5-羟色胺
DA Dopamine 多巴胺
NE Norepinephrine 去甲肾上腺素
FST forced swim test 强迫游泳实验
PVPPXL Polyvinylpolypyrrolidone cross-linked XL交联聚乙烯吡咯烷酮XL
HPC-EF Hydroxypropyl cellulose EF 羟乙基纤维素EF
具体实施方式
以下通过具体的实施例对发明做进一步详细的说明。正如本领域技术人员所应知道的，本发明中所表述的实施方案和实施例仅以举例的目的提供，并不构成对具体技术方案中赋形剂的选择、组合物的制备方法，以及组合物的用途的限制。
实施例1
纯水湿法制粒，然后外加下列物料
制备：将4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐与其余赋形剂、粘合剂、崩解剂混合均匀。以水溶液制粒，干燥整粒。加入崩解剂、填充剂、助流剂及润滑剂，混合均匀。压片。取6片照中国药典2015版附录崩解时限测定项下方法测定，所得片剂平均崩解时间为4.83min。
实施例2
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为5min。
实施例3
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为1min。
实施例4
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为1min。
实施例5
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为9.5min。
实施例6
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为12min。
测试例
测定4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐体外溶出度。
(1)溶出度检测方法
色谱条件色谱柱:Waters-C18(4.6mm×250mm，5μm)；流动相：磷酸盐缓冲液(pH3.5)：甲醇(25∶75)；流速：1.0mL/min；进样量5μL；检测波长：220nm；柱温40℃。
取实施例1、2及实施例3、4片剂各6片，置溶出杯中，以0.1mol/L盐酸溶液500ml作为溶出介质，转速为50转/分，依法操作，HPLC法测定每片溶出量。
(2)溶出度试验结果显示：照溶出度测定法(中国药典2015版二部附录XC第二法)，依法操作，HPLC法测定每片溶出量，结果为30min内实施例1、2、3片剂的溶出百分率大于85％，在30min内实施例4片剂的溶出百分率大于80％，所有实施例在60min内基本全部溶出。结果见表1、表2。
表1实施例1、实施例2溶出度结果
表2实施例3、实施例4溶出度结果
Claims (4)
1.一种新型阿片δ受体激动剂盐酸盐的片剂，该片剂含有重量百分比为22.8％-40％的生理有效量的4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐，以及药学上适用的赋形剂，其中所述赋形剂由乳糖重量占比为18％～37.2％、微晶纤维素重量占比为23％～48％、交联羧甲基纤维素钠重量占比为1％～5％、PVPP XL重量占比为1％～10％、微粉硅胶重量占比为0.5％和硬脂酸镁重量占比为0.5％、聚维酮重量占比为4％或HPC EF重量占比为3％组成。
2.如权利要求1所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述崩解剂交联羧甲基纤维素钠和PVPP XL，以内外加法添加使用。
3.如权利要求1所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述的微晶纤维素，外加占比为所使用微晶纤维素总量的3/23～2/7为制粒后加入。
4.如权利要求1-3任一项所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，该片剂的制备方法为：
(1)将4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐与乳糖、微晶纤维素、交联羧甲基纤维素钠、聚维酮或HPC EF混合均匀；
(2)以水溶液制粒，干燥整粒；
(3)加入微晶纤维素、PVPP XL、微粉硅胶及硬脂酸镁，混合均匀；
(4)压片，即可。
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| CN106491545A (zh) * | 2016-09-22 | 2017-03-15 | 万特制药(海南)有限公司 | 盐酸氟西汀口崩片及其制备方法 |
| CN106588874A (zh) * | 2016-11-21 | 2017-04-26 | 云南省药物研究所 | 一种三芳基二甲基哌嗪二盐酸盐的多晶型物及其制备方法和应用 |
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