CN117243927A - 含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂及其制备方法 - Google Patents
含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂及其制备方法 Download PDFInfo
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- CN117243927A CN117243927A CN202311342409.7A CN202311342409A CN117243927A CN 117243927 A CN117243927 A CN 117243927A CN 202311342409 A CN202311342409 A CN 202311342409A CN 117243927 A CN117243927 A CN 117243927A
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
本发明公开了一种含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂及其制备方法。包含安全的用于掩味的功能性辅料,能达到安全有效的掩味效果,所占比例为1‑30%。本发明开发了一种能安全的解决盐酸卡利拉嗪苦味的口溶膜,用于解决患者藏药,并拥有制备工艺简单,能维持药物稳定的优点。
Description
技术领域
本发明属于药物领域,具体的,本发明涉及含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂及其制备方法。
背景技术
盐酸卡利拉嗪为非典型抗精神病药物,属于多巴胺D2、D3受体部分激动剂,主要用于治疗成人精神分裂症及双相躁狂症。盐酸卡利拉嗪(cariprazine hydrochloride)是一种D3/D2受体部分激动剂,优先结合D3受体,与传统精神类药物(单纯作用于D2)相比有优势(锥体外反应副作用发生率低、阴性症状的治疗)。
盐酸卡利拉嗪是一种白色到类白色粉末状物质,属于BCS II类的化合物,为低溶解度-高渗透性药物,化学式C21H32Cl2N4O·HCl,分子量大小为463.9g/mol,化学名为3-[4-[Chemicalbook2-[4-(2,3-二氯苯基)哌嗪-1-基]乙基]环己基]-1,1-二甲基脲,结构式如下所示:
近年来越来越多的精神类药物正在被开发成口溶膜剂型,其目的是为了解决患者的藏药现象。
全球首款口溶膜是2001年辉瑞公司旗下的口腔护理品牌李施德林推出的口气清新膜当时被时代周刊评为最佳发明。FDA评价其为“传统口服剂型中不可取代的新剂型”。口溶膜剂是一种具有释药迅速、给药方便、患者顺应好和用药安全等优势的新型固体制剂。口溶膜剂也没有常规口服制剂堵塞口腔或窒息的风险,同时保留了传统口服固体制剂的优势,包装轻便易携带、剂量准确,并且给药无需饮水送服和二次容器,适合用于治疗一些精神类疾病时患者由于不配合治疗导致的藏药或者吐出药物等行为有着不可替代的作用。
盐酸卡利拉嗪为治疗精神疾病的药物,患者在使用过程也存在藏药现象,故制备成口溶膜能很好的解决该问题。但盐酸卡利拉嗪是一种具有苦味的药物,制备成口溶膜后,药物在口腔内释放,苦味更加剧烈。而药物苦味的产生主要是由于其在口腔内溶解之后,通过味导素激活苦味受体蛋白或药物直接与苦味受体蛋白结合,经神经将苦味信号传递到味觉中枢,最终产生苦的感觉。而掩味技术则是通过添加矫味剂、添加苦味抑制剂或将药物进行包合等方法来抑制药物与苦味受体蛋白的结合,进而巧妙掩盖苦味。因而掩味技术对于药物,尤其是苦味药物来说是很有必要的,将药物原本的苦味进行掩盖,让患者服药时更加容易接受,进而提高服药的顺应性。
环糊精为现阶段常用的包合物之一,但是近年来环糊精存在重要不良反应的报道屡见不鲜,主要表现为环糊精有肾毒性,可引起肾小管远端空泡样病变,甚至肾小管细胞坏死。肾功能不全患者使用含环糊精药物时,易引起环糊精蓄积,增加肾脏毒性,进一步加重肾脏损害。
而淀粉是一种基本上无毒无刺激性的物质,被认为是安全的。直链淀粉和支链淀粉的分子其构象并不是笔直的,而是卷曲成螺旋形,只是支链淀粉的直链部分较短。直链淀粉和支链淀粉的空间结构决定了具有一定的包合作用,可以用于药物的包合研究。在Handbook of Pharmaceutical Excipients(Eighth edition)中提及淀粉是一种可食用的食品物质,被认为是一种食品成分,而不是食品添加剂,所以每日摄入量不受限制。因此,淀粉可应用于药物配方中作为一种包合物用于药物的掩味。
因此急需开发一种能安全的解决盐酸卡利拉嗪苦味的口溶膜,用于解决患者藏药,并拥有制备工艺简单,能维持药物稳定的优点。
发明内容
本发明提供一种含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂及其制备方法。
该含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂包含膜剂所必须的成膜剂、增塑剂;还具有增加药物活性物能更快在口腔中释放的润湿剂,用于改善气味的矫味剂及香精,使药物更容易被患者接受的色素,有安全且具有掩味的功能性辅料,以及包合剂。该药物被放置于口腔内能1分钟内崩解并释放药物,使得药物活性物能更快的起效。
本发明的溶膜制剂中,安全的包合剂的种类可以单一或者由多个安全的包合剂组成。
在一些实施方案中,包合剂选自玉米淀粉、马铃薯淀粉或大豆淀粉,或其组合。其原理为在水中,玉米或大豆中所含的直链淀粉分子链能够自动形成螺旋状,其螺旋外表面分布着许多羟基,能够与水分子相互作用形成氢键而亲水,相反,其螺旋的内表面疏水,从而与药物产生包合作用。
在一些实施例中所用淀粉的粒径:玉米淀粉为2-50μm,马铃薯淀粉为10-80μm,木薯淀粉为5-35μm,小麦淀粉为2-45μm。所用淀粉的粒径在成品中表现出无沙硕感,外观均一(图6和图7)。
本发明的口溶膜中,成膜剂的种类可以单一或者由多个成膜剂组成。
在一些实施方案中,成膜剂选自水溶性,水溶胀性,和/或水蚀性聚合物,例如(但不限于)纤维素衍生物(羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素等)、合成的高分子材料(PVA、PVP、PEO等)、其他(海藻酸钠、卡波姆、壳聚糖)等,或其组合。
本发明的口溶膜中,增塑剂的种类可以单一或者由多个增塑剂组成。
在一些实施方案中,增塑剂选自甘油、丙二醇、低分子量聚乙二醇、山梨酸、枸橼酸及其衍生物、膜中残留的水分等,或其组合。
本发明的口溶膜中,润湿剂的种类可以单一或者由多个润湿剂组成。
在一些实施方案中,润湿剂选自聚山梨酯60、聚山梨酯80、失水山梨醇脂肪酸酯20等,或其组合。其原理是通过分子中不同部分分别对于两相的亲和,使两相均将其看作本相的成分,分子排列在两相之间,使两相的表面相当于转入分子内部。从而降低表面张力。由于两相都将其看作本相的一个组分,就相当于两个相与润湿剂分子都没有形成界面,就相当于通过这种方式部分的消灭了两个相的界面,就降低了表面张力和表面自由能。
本发明的口溶膜中,矫味剂的种类可以单一或者由多个矫味剂组成。
在一些实施方案中,矫味剂选自葡萄糖、三氯蔗糖、甜蜜素、糖精等,或其组合。其原理为通过增加甜味来改善药物的味道。
本发明的口溶膜中,香精的种类可以单一或者由多个香精组成。
在一些实施方案中,香精选自天然和人工香料,例如薄荷香精、混合浆果香精以及苹果、梨、桃、草莓的水果香精等,或其组合。其原理是通过香精的味道来进行掩味或者增加香味,提高药物服用的顺应性。
本发明的口溶膜中,色素的种类可以单一或者由多个色素组成。
在一些实施方案中,色素选自天然和人工色素,例如白色、黄色、橙色、红色等,或其组合。其原理是通过色素改善药物的颜色,更符合人的食欲。
本发明的含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂的制备方法包括将药物活性物与包合物在溶剂中进行均质混合;加入除成膜剂的其他辅料均质混合;加入成膜剂进行搅拌混合;进行静置脱气处理;采用刮刀将膜液在离型膜(例如:涂二甲基硅油聚脂膜)上进行涂布;加热烘干产品;分切成所需的大小,采用遮光密封的内包材(例如:聚酯/铝/聚乙烯药用易揭复合膜)进行包装。
在一些实施例中,成品膜的厚度在30-75μm;或者30-100μm,或者30-150μm。
在一些实施方案中,药物活性组合物在物理上均匀的分布在成品膜中,是不可分离的。
在一些实施方案中,口溶膜被制备成在使用时将口溶膜放置在受试者的口腔中与舌头接触。
优选,含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂,其配方为每33.76g水中含有盐酸卡利拉嗪1-15%、玉米淀粉1-30%或马铃薯淀粉1-30%、甘油10-35%、羟丙甲纤维素E5030-80%、聚山梨酯0.5-5%g、三氯蔗糖1-10%、草莓香精1-10%。
本发明开发了一种能安全的解决盐酸卡利拉嗪苦味的口溶膜,用于解决患者藏药,并拥有制备工艺简单,能维持药物稳定的优点。
附图说明
图1:处方一显微镜底下的形态
图2:处方一加速一个月后显微镜底下的形态
图3:制备过程的流程图示意图。
图4:盐酸卡利拉嗪处方一加速一个月前后的溶出曲线对比
图5:盐酸卡利拉嗪处方一和处方二加速一个月后的含量变化情况
图6:玉米淀粉的粒径情况
图7:马铃薯淀粉的粒径情况
具体实施方式
已经包括以下实施例作为本领域的技术人员提供指导,以实施本公开主题的代表性实施方案。鉴于本公开和本领域技术人员的一般水平,本领域技术人员可以理解,以下实施例仅是示例性的,并且在不脱离本公开主题的范围的情况下可以采用许多改变,修改和变更。现结合本发明的实施例,对本发明作进一步说明。
实施例1:
(1)处方组成:
(2)制备方法(图3):
1)、将羟丙甲纤维素E50制备成质量分数20%的凝胶溶液备用;
2)、将盐酸卡利拉嗪和淀粉(玉米淀粉或马铃薯淀粉)在水中以10000rpm进行均质混合5min,使得淀粉能充分包合盐酸卡利拉嗪;
3)、在上述混悬液中加入甘油、聚山梨酯80、三氯蔗糖、草莓香精,以10000rpm进行均质混合5min,使得各物质均匀分散不聚团;
4)、加入20%羟丙甲纤维素E50凝胶溶液,进行搅拌混合;
5)、进行脱气处理;
6)、调整刮刀高度,进行涂布;
7)、调整烘干温度,烘干;
8)、收卷,并分切成品进行检测。
(3)检测结果:
崩解情况:
取各处方样品口溶膜各6片,采用釆用升降式崩解仪测定口溶膜崩解时限,测试方法如下:
在1L烧杯中加入1000ml纯化水,并加热至37±1℃。将口溶膜夹在蝶网上,并将蝶网固定在升降的金属支架末端,进行测试崩解情况:
机械性能检测:
将膜片裁成2cm*4cm的膜片于质构仪上检测机械性能情况:
成膜性、口感评价:
处方编号 | 处方一 | 处方二 | 处方三 | 处方四 |
成膜性 | 成膜性好 | 成膜性好 | 能成膜 | 成膜性好 |
口感 | 轻微苦味 | 轻微苦味 | 无苦味 | 味苦 |
上述实施例处方一、处方二、处方三和处方四的实验数据表明,本发明提供的盐酸卡利拉嗪口溶膜,具有成膜性能好、口感良好的优点;且制备工艺简单。
图1是处方一显微镜底下的形态。
实施例2:
采用德国美墨尔特的人工气候箱,将处方一的盐酸卡利拉嗪口溶膜放置在50.0℃的条件下加速一个月,加速实验前后的溶出曲线测定结果如下所示:
4.1仪器和设备
溶出试验仪(天津市天大天发科技有限公司,型号:RC1207DP)
高效液相色谱仪(安捷伦,型号:Agilent 1200)
4.2检测方法:
(1)采用溶出试验仪进行溶出曲线取样,采用桨碟法,取本品6片,在5min,10min、15min、30min、45min分别取样,过滤;
(2)采用高效液相色谱仪进行本品溶出量进行检测,结果如下所示:
取样时间 | 未加速样品 | 加速一个月后样品 |
5min | 67.40% | 68.73% |
10min | 89.88% | 90.23% |
15min | 92.76% | 93.73% |
30min | 95.01% | 94.29% |
45min | 95.04% | 95.07% |
上述实施例处方一在50℃下加速一个月前后的溶出实验数据表明,本发明提供的盐酸卡利拉嗪口溶膜,具有产品作用快且稳定的性能。
图2是处方一加速一个月后显微镜底下的形态。图4是盐酸卡利拉嗪处方一加速一个月前后的溶出曲线对比。
实施例3:
采用德国美墨尔特的人工气候箱,将处方一和处方二的盐酸卡利拉嗪口溶膜放置在50.0℃的条件下加速一个月,加速实验前后的含量测定结果如下所示:
含量变化情况:
时间 | 0天 | 30天 |
盐酸卡利拉嗪处方一 | 98% | 100% |
盐酸卡利拉嗪处方二 | 101% | 97% |
上述实施例处方一和处方二在50℃下加速一个月前后的含量数据表明,本发明提供的盐酸卡利拉嗪口溶膜,具有产品稳定的性能。图5是盐酸卡利拉嗪处方一和处方二加速一个月后的含量变化情况。
Claims (10)
1.一种含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂,其特征在于,包含安全的用于掩味的功能性辅料,能达到安全有效的掩味效果,所占比例为1-30%。
2.根据权利要求1所述的盐酸卡利拉嗪口溶膜制剂,其特征在于,包含膜剂所必须的成膜剂、增塑剂;还具有增加药物活性物能更快在口腔中释放的润湿剂,用于改善气味的矫味剂及香精,使药物更容易被患者接受的色素,有安全且具有掩味的功能性辅料,以及包合剂。
3.根据权利要求1所述的盐酸卡利拉嗪口溶膜制剂,其特征在于,所述的包合剂选自玉米淀粉、马铃薯淀粉或大豆淀粉,或其组合;优选,淀粉的粒径:玉米淀粉为2-50μm,马铃薯淀粉为10-80μm,木薯淀粉为5-35μm,小麦淀粉为2-45μm。
4.根据权利要求1所述的盐酸卡利拉嗪口溶膜制剂,其特征在于,所述的成膜剂选自水溶性,水溶胀性,和/或水蚀性聚合物,包括但不限于,纤维素衍生物,优选羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素等;合成的高分子材料,优选为PVA、PVP、PEO;或
海藻酸钠、卡波姆、壳聚糖。
5.根据权利要求1所述的盐酸卡利拉嗪口溶膜制剂,其特征在于,增塑剂选自甘油、丙二醇、低分子量聚乙二醇、山梨酸、枸橼酸及其衍生物、膜中残留的水分等,或其组。
6.根据权利要求1所述的盐酸卡利拉嗪口溶膜制剂,其特征在于,所述的润湿剂选自聚山梨酯60、聚山梨酯80、失水山梨醇脂肪酸酯20等,或其组合。
7.根据权利要求1所述的盐酸卡利拉嗪口溶膜制剂,其特征在于,矫味剂选自葡萄糖、三氯蔗糖、甜蜜素、糖精等,或其组合;香精选自天然和人工香料,例如薄荷香精、混合浆果香精以及苹果、梨、桃、草莓的水果香精等,或其组合,色素选自天然和人工色素,例如白色、黄色、橙色、红色等,或其组合,其原理是通过色素改善药物的颜色,更符合人的食欲。
8.根据权利要求1所述的盐酸卡利拉嗪口溶膜制剂,其特征在于,所述的含安全有效掩味剂的盐酸卡利拉嗪1-15%、玉米淀粉1-30%或马铃薯淀粉1-30%、甘油10-35%、羟丙甲纤维素E50 30-80%、聚山梨酯0.5-5%g、三氯蔗糖1-10%、草莓香精1-10%。
9.一种权利要求2所述的含安全有效掩味剂的盐酸卡利拉嗪口溶膜制剂的制备方法,其特征在于,包括将药物活性物与包合物在溶剂中进行均质混合;加入除成膜剂的其他辅料均质混合;加入成膜剂进行搅拌混合;进行静置脱气处理;采用刮刀将膜液在离型膜上进行涂布;加热烘干产品;分切成所需的大小,采用遮光密封的内包材进行包装。
10.根据权利要求9所述的制备方法,其特征在于,盐酸卡利拉嗪口溶膜制剂成品膜的厚度在30-75μm;或者30-100μm,或者30-150μm。
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