CN114177153B - 一种利鲁唑口崩片及其制备方法 - Google Patents
一种利鲁唑口崩片及其制备方法 Download PDFInfo
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- CN114177153B CN114177153B CN202111558040.4A CN202111558040A CN114177153B CN 114177153 B CN114177153 B CN 114177153B CN 202111558040 A CN202111558040 A CN 202111558040A CN 114177153 B CN114177153 B CN 114177153B
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- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 title claims abstract description 69
- 229960004181 riluzole Drugs 0.000 title claims abstract description 66
- 239000006191 orally-disintegrating tablet Substances 0.000 title claims abstract description 53
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- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
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- 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 claims description 2
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Abstract
本发明属于药物制剂领域,具体涉及一种利鲁唑口崩片及其制备方法。所述利鲁唑口崩片包含2‑氨基‑6‑三氟甲氧基苯并噻唑5份、填充剂70‑120份、崩解剂60‑100份、稳定剂2‑25份、矫味剂40‑60份。本发明通过优选崩解剂、稳定剂等辅料,优化制备工艺,缩短了崩解时限,增加了口崩片的韧性,使得药片不易脆碎,方便运输,降低了有关物质含量,提高了药物的稳定性。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种利鲁唑口崩片及其制备方法。
背景技术
利鲁唑,化学名称为2-氨基-6-三氟甲氧基苯并噻唑,是一种苯并噻唑衍生物,可阻断中枢神经系统中的谷氨酸能神经传递。1995年,美国FDA批准利鲁唑作为第一种治疗ALS的药物。尽管利鲁唑在临床实践中大都是安全和耐受性良好的,但其在ALS中的疗效有限,仅延长了2-3个月的无气管造口术生存期。而陆续有研究者通过临床试验研究表明利鲁唑治疗可使患者中位生存期达到6个月到19个月,这比上述所说的2-3个月要长得多,因此利鲁唑对ALS的治疗效益还是非常可观的。
患有肌萎缩侧索硬化的病人大多有肌肉萎缩、吞咽困难、讲话困难等症状,普通的片剂或胶囊剂等服用药物顺应性差,口崩片则适合于这类吞咽困难的患者、不能主动或不配合用药的患者服用。
但是利鲁唑药物本身具有一些局限性,例如在水中的溶解度极低、口腔适口性差、稳定性依赖于pH、直接给予会刺激口腔粘膜产生麻木感等缺点,所以要将利鲁唑制成口崩片需要解决上述问题。
中国专利CN101390854A公开了一种含有利鲁唑的药用组合物,包含活性成分利鲁唑和水溶性填充剂和水不溶性填充剂、粘合剂、崩解剂、润滑剂、矫味剂,其主要是通过改进填充剂和优选崩解剂,增加利鲁唑的溶出度,并未解决稳定性和刺激口腔黏膜的问题。
中国专利CN111821289 A公开了一种利鲁唑口崩片及其制备方法,由利鲁唑、碳酸氢钠、填充剂、崩解剂、润滑剂、矫味剂制备而成。但是该专利未对所述口崩片为对稳定性进行控制,不能保证用药安全。
因此上述缺陷的解决是本领域技术人员需要研究的。
发明内容
为克服现有技术的不足,本发明提供了一种利鲁唑口崩片,通过优选崩解剂、稳定剂等辅料,优化制备工艺,缩短了崩解时限,增加了口崩片的韧性,使得药片不易脆碎,方便运输,降低了有关物质含量,提高了药物的稳定性,改善了服药口感,适口性更好。
具体而言,本发明的技术方案如下:
本发明提供了一种利鲁唑口崩片,以重量比计算,包含:
优选的,
进一步的,
所述填充剂为微晶纤维素、淀粉、预胶化淀粉、蔗糖、碳酸氢钠、磷酸氢钙、乳糖、β-环糊精、甘露醇中的一种或多种,优选为微晶纤维素或微晶纤维素与上述其他填充剂的混合物。
所述崩解剂为交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠中的一种和糖胺聚糖的混合物,优选为,交联聚维酮和糖胺聚糖。
尤其是,所述交联聚维酮和糖胺聚糖的重量比为2-4:1时,能够有效缩短崩解时限,并且糖胺聚糖亲水性强,有一定的粘性和润滑作用,可以增加口崩片的硬度和韧度,不易脆碎。
所述稳定剂为没食子酸或/和玉米黄素。
所述矫味剂为甘露醇、阿斯巴甜、赤藓糖醇中的一种。
本发明的第二个目的在于提供一种制备上述利鲁唑口崩片的方法,包括以下步骤:
(1)将2-氨基-6-三氟甲氧基苯并噻唑与矫味剂混合,共同进行微粉化处理;
(2)向步骤(1)的得到的混合物中加入微粉化的填充剂、崩解剂、稳定剂,混合;
(3)向步骤(2)所得混合物中加入适量乙酸-乙酸钠缓冲溶液进行软化处理,挤出,压制成片。
进一步的,所述缓冲溶液的pH范围为4.0-.5.5,pH范围为4.0-.5.5的乙酸-乙酸钠缓冲溶液可以帮助降低有关物质含量,辅助稳定剂提高药物稳定性,另一方面,溶液的加入可以辅助糖胺聚糖激发胶性,增加药片韧性。
与现有技术相比,本发明的有益效果在于:
(1)本发明通过优选崩解剂的种类,尤其是糖胺聚糖的加入,并优化糖胺聚糖和其他崩解剂的比例,明显缩短了崩解时限、缩短药物在口腔中的停留时间,起效迅速,另外,糖胺聚糖的加入,还增加了口崩片的韧性,使得药片不易脆碎,提高了药物质量,方便运输。
(2)本发明通过优选稳定剂、优选pH缓冲溶液及其pH值范围,解决了利鲁唑口崩片有关物质含量高的问题,提高药物稳定性。
(3)本发明通过优化制备工艺,将原、辅料预先进行微粉化处理,克服了药物有沙砾感的问题;通过将利鲁唑先与矫味剂混合进行微粉化的方法,解决了药物口感苦涩、入口麻木的问题,改善服药体验,适口性更好。
具体实施方式
为了使本发明的目的、技术方案更加清楚明白,以下结合实施例,对本发明做进一步的说明,但是本发明的保护范围并不限于这些实施例,实施例仅用于解释本发明。本领域技术人员应该理解的是,凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
实施例1利鲁唑口崩片(1000片)
处方:
制备方法:
(1)将处方量的2-氨基-6-三氟甲氧基苯并噻唑与矫味剂混合,共同进行微粉化处理,备用;
(2)向步骤(1)的得到的混合物中加入微粉化的填充剂、崩解剂、稳定剂,混合;
(3)向步骤(2)所得混合物中加入80ml pH为5.0的乙酸-乙酸钠缓冲溶液进行软化处理,挤出,压制成片。
实施例2利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例3利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例4利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例5利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例6利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例7利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例8利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例9利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例9利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例10利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例11利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例12利鲁唑口崩片(1000片)
制备方法:同实施例1。
实施例13利鲁唑口崩片(1000片)
制备方法:
(1)将处方量的2-氨基-6-三氟甲氧基苯并噻唑与矫味剂混合,共同进行微粉化处理,备用;
(2)向步骤(1)的得到的混合物中加入微粉化的填充剂、崩解剂、稳定剂,混合;
(3)向步骤(2)所得混合物中加入50ml pH为5.5的乙酸-乙酸钠缓冲溶液进行软化处理,挤出,压制成片。
实施例14利鲁唑口崩片(1000片)
制备方法:
(1)将处方量的2-氨基-6-三氟甲氧基苯并噻唑与矫味剂混合,共同进行微粉化处理,备用;
(2)向步骤(1)的得到的混合物中加入微粉化的填充剂、崩解剂、稳定剂,混合;
(3)向步骤(2)所得混合物中加入100ml pH为4.0的乙酸-乙酸钠缓冲溶液进行软化处理,挤出,压制成片。
对比实施例1利鲁唑口崩片(1000片)
制备方法:同实施例1。
对比实施例2利鲁唑口崩片(1000片)
处方:
制备方法:同实施例1。
对比实施例3利鲁唑口崩片(1000片)
处方:
制备方法:同实施例1。
对比实施例4利鲁唑口崩片(1000片)
处方:
制备方法:
(1)将处方量的2-氨基-6-三氟甲氧基苯并噻唑与矫味剂混合,共同进行微粉化处理,备用;
(2)向步骤(1)的得到的混合物中加入微粉化的填充剂、崩解剂,混合;
(3)向步骤(2)所得混合物中加入50ml pH为5.5的乙酸-乙酸钠缓冲溶液进行软化处理,挤出,压制成片。
对比实施例5利鲁唑口崩片(1000片)
制备方法:同实施例1。
对比实施例6利鲁唑口崩片(1000片)
制备方法:
(1)将处方量的2-氨基-6-三氟甲氧基苯并噻唑与矫味剂混合,过筛,备用;
(2)向步骤(1)的得到的混合物中加入过筛后的填充剂、崩解剂、稳定剂,混合;
(3)向步骤(2)所得混合物中加入50ml pH为5.5的乙酸-乙酸钠缓冲溶液进行软化处理,挤出,压制成片。
对比实施例7利鲁唑口崩片(1000片)
制备方法:
(1)将处方量的2-氨基-6-三氟甲氧基苯并噻唑、各辅料分别进行微粉化处理,备用;
(2)向步骤(1)的得到的2-氨基-6-三氟甲氧基苯并噻唑加入填充剂、崩解剂、稳定剂、矫味剂,混合;
(3)向步骤(2)所得混合物中加入50ml pH为5.5的乙酸-乙酸钠缓冲溶液进行软化处理,挤出,压制成片。
对比实施例8利鲁唑口崩片(1000片)
制备方法:
(1)将处方量的2-氨基-6-三氟甲氧基苯并噻唑与矫味剂混合,共同进行微粉化处理,备用;
(2)向步骤(1)的得到的混合物中加入微粉化的填充剂、崩解剂、稳定剂,混合;
(3)向步骤(2)所得混合物中加入50ml pH为6.0的乙酸-乙酸钠缓冲溶液进行软化处理,挤出,压制成片。
验证实施例
一、基本参量检查实验
1.脆碎度检查
照《中国药典》2020年版片剂脆碎度检查法(通则0923)检查。
取若干片,使其总重约为6.5g。用吹风机吹去片剂脱落的粉末,精密称重,置圆筒中,转动100次。取出,同法除去粉末,精密称重,减失重量不得过1%,且不得检出断裂、龟裂及粉碎的片。本试验一般仅作1次。如减失重量超过1%时,应复测2次,3次的平均减失重量不得过1%,并不得检出断裂、龟裂及粉碎的片。
2.崩解时限检查
照《中国药典》2020年版崩解时限检查法(通则0921)检查。
取本品1片,置上述不锈钢管中进行检查,应在60秒内全部崩解并通过筛网,如有少量轻质上漂或黏附于不锈钢管内壁或筛网,但无硬心者,可作符合规定论。重复测定6片,均应符合规定。如有1片不符合规定,应另取6片复试,均应符合规定。
表1实施例与对比实施例利鲁唑口崩片基本参量
由表1可知,本发明实施例制备的利鲁唑口崩片口感好,无沙砾感,无苦涩麻木感,硬度高,不易脆碎,崩解时限短,可以快速崩解,减少药物在口中融化时间,服药体验感好。
二、稳定性实验
1.有关物质含量
照高效液相色谱法(通则0512)测定。
供试品溶液:取本品细粉适量,加流动相使利鲁唑溶解并稀释制成每1ml中约含利鲁唑0.5mg的溶液,滤过,取续滤液。
对照溶液:精密量取供试品溶液1ml,置100ml量瓶中,用流动相稀释至刻度,摇匀。
色谱条件:用十八烷基硅烷键合硅胶为填充剂;以甲醇-水(70:30)为流动相;检测波长为221nm;进样体积10μl。
系统适用性要求:理论板数按利鲁唑峰计算不低于2000。
测定法:精密量取供试品溶液与对照溶液,分别注入液相色谱仪,记录色谱图至主成分峰保留时间的3倍。
限度:供试品溶液色谱图中如有杂质峰,单个杂质峰面积不得大于对照溶液主峰面积的0.5倍(0.5%),各杂质峰面积的和不得大于对照溶液主峰面积(1.0%)。
(加速试验条件:温度40℃±2%,相对湿度:75%±5%)
2.含量检测
照紫外-可见分光光度法(通则0401)测定。
供试品溶液:取本品20片,精密称定,研细,精密称取细粉适量(约相当于利鲁唑50mg),置250ml量瓶中,加0.1mol/L盐酸溶液使利鲁唑溶解(必要时超声)并稀释至刻度,摇匀,滤过,精密量取续滤液5ml,置100ml量瓶中,用0.1mol/L盐酸溶液稀释至刻度,摇匀。
对照品溶液:取利鲁唑对照品适量,精密称定,加0.1mol/L盐酸溶液溶解并定量稀释制成每1ml中约含10μg的溶液。
测定法:取供试品溶液与对照品溶液,在254nm的波长处分别测定吸光度,计算。
(加速试验条件:温度40℃±2%,相对湿度:75%±5%)
表2实施例与对比实施例利鲁唑口崩片含量与有关物质含量
由表2可知,本发明实施例制备的利鲁唑口崩片稳定性高,在加速试验0天时有关物质含量低,加速实验6个月时有关物质含量变化较小,稳定高。
Claims (7)
2.根据权利要求1所述的利鲁唑口崩片,其特征在于,所述填充剂为微晶纤维素、淀粉、预胶化淀粉、蔗糖、碳酸氢钠、磷酸氢钙、乳糖、β-环糊精、甘露醇中的一种或多种。
3.根据权利要求1所述的利鲁唑口崩片,其特征在于,所述崩解剂为交联聚维酮和糖胺聚糖。
4.根据权利要求3所述的利鲁唑口崩片,其特征在于,所述交联聚维酮和糖胺聚糖的重量比为2-4:1。
5.根据权利要求1所述的利鲁唑口崩片,其特征在于,所述稳定剂为没食子酸或/和玉米黄素。
6.根据权利要求1所述的利鲁唑口崩片,其特征在于,所述矫味剂为甘露醇、阿斯巴甜、赤藓糖醇中的一种。
7.根据权利要求1所述的利鲁唑口崩片,其特征在于,所述缓冲溶液的pH范围为4.0-.5.5。
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