CN1511026A - 加波沙朵颗粒制剂 - Google Patents
加波沙朵颗粒制剂 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/00—Medicinal preparations characterised by special physical form
- 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
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Abstract
本发明涉及含有酸加成盐形式的加波沙朵的颗粒状产品,用于其制备的熔化制粒方法,以及由所述加波沙朵颗粒状产品制备的固体药物单位剂型。
Description
本发明涉及含有加波沙朵的颗粒状产品,用于其制备的熔化制粒方法,以及由所述颗粒产品制备的固体药物单位剂型。
发明背景
固体、成型的药物单位剂型例如片剂是通过将粉末或小颗粒形式的干燥成分压缩而制备的。用于片剂压缩的方法和赋形剂是本领域众所周知的。用于特定制剂的药物赋形剂的选择在很大程度上取决于包括活性成分的压片特性在内的活性成分的物理/化学特性。
用于制片的可再现定量配料要求所有的干燥成分具有良好的流动性。在某些情况下,如果活性成分具有良有好流动性,通过该成分的直接压缩就可制备片剂。然而,在很多情况下,如果活性物质的粒径很小,活性物质就会粘结从而具有不良的流动性。为了确保最理想的流动性和保证化合物的均匀混合物,一般通过将活性成分单独或者与填充剂或其它常规片剂成分一起制粒来制备活性混合物和赋形剂的附聚物。
一种这样的制粒方法是“湿法”制粒法。使用这种方法,是把干燥固体(活性成分、粘合剂等)混合,并用水或另外的润湿剂(例如醇)将其湿润,湿润的固体形成附聚物或颗粒。继续进行混和直至达到所要求的均匀粒径,随后把颗粒产品干燥。
该“湿法”制粒方法被广泛地应用于其中水可以用作润湿剂的粉末或精细颗粒的制粒。具有以下结构式:
的化合物加波沙朵是一种颇有价值的催眠药。该化合物被认为对于治疗睡眠障碍具有特别的价值(US专利5929,065)。在活性成分是酸性反应加成盐、特别是盐酸盐形式的加波沙朵的情况下,湿法制粒技术就存在很多问题。对于其它酸性反应盐例如氢溴酸盐,预计也会存在类似的问题。
可以用含有玉米淀粉、乳糖、交联羧甲基纤维素钠和羟丙基纤维素的加波沙朵盐酸盐的湿颗粒制片而不存在技术问题。然而,在加工该产品时发现,压片设备发生腐蚀。压片设备的一些部件是由钢和铁制造的,在颗粒与设备接触几个小时后就能发现这些部件的腐蚀。在该腐蚀过程中,由于加波沙朵盐酸盐水溶液的低pH值,三价铁离子就从设备中释放出。或许,加波沙朵还能够与三价铁离子形成可能有颜色的络合物。
由于大多数压片设备具有含铁部件,所以在压片过程中完全避免铁是不可能的。
本发明所描述的制备方法正是着眼于上述问题的解决。通过使用无水赋形剂和使用无水粘合剂的熔化制粒法可以将水加以避免。
发明目的
本发明的目的是提供含有加波沙朵盐酸盐的颗粒制剂,该颗粒制剂可用于制备含有加波沙朵盐酸盐的在贮藏状态下稳定的固体、成型药物单位剂型。提供具有合适的释放特性的加波沙朵盐酸盐的颗粒制剂也是本发明的目的。
发明概述
本发明特别包括下列单独或组合的方面:
颗粒状产品,其中含有活性成分加波沙朵,以及除活性成分之外可以呈颗粒状产品形式的其它成分。固体药物单位剂型通常包含各种其它的常规赋形剂例如另外的填充剂、粘合剂、崩解剂,和任选少量润滑剂、着色剂和甜味剂。
赋形剂的选择在很大程度上取决于活性成分的物理/化学特性,包括活性成分的压片特性和最终组合物的稳定性。
适用于制备本发明固体单位剂型的填充剂包括糖(山梨醇、甘露醇、葡萄糖、蔗糖)、乳糖、磷酸钙、淀粉、玉米淀粉、改性淀粉、微晶纤维素、硫酸钙、碳酸钙。填充剂应当是无水,且优选不吸湿的。
在本发明的优选实施方案中,使用玉米淀粉或磷酸钙,或者联合使用玉米淀粉与磷酸钙。
可以将填充剂在制粒后加到颗粒产品中或与之混合,或者可以将填充剂与活性成分一起制粒或者这两种情况都包括。
崩解剂包括羟乙酸淀粉钠、交联羧甲基纤维素钠、聚维酮、低取代的羟丙基纤维素、改性淀粉、预凝胶化淀粉和天然淀粉。
润滑剂的实例包括硬脂酸金属盐(硬脂酸镁、硬脂酸钙、硬脂酸钠)、硬脂酸、蜡、氢化植物油、滑石粉、胶态二氧化硅和苯甲酸钠。
优选地,所述赋形剂是无水且不吸湿的。
熔化颗粒状产品包含
a)5-40%的亲水性熔化粘合剂,
b)0-90%的填充剂,和
c)作为游离碱、作为水合物或作为其可药用酸加成盐的加波沙朵。
适宜地,熔化颗粒状产品含有50-90%的填充剂。
用于本发明颗粒状产品的合适的填充剂包括糖(山梨醇、甘露醇、葡萄糖、蔗糖)、磷酸钙(磷酸氢钙、磷酸钙和无水磷酸钙)、淀粉、改性淀粉、微晶纤维素、硫酸钙和碳酸钙。
在本发明的优选实施方案中,与加波沙朵的可药用盐一起形成颗粒的填充剂是无水磷酸钙。在另外的优选实施方案中,该填充剂是无水磷酸钙和玉米淀粉的混合物。
适宜地,亲水性熔化粘合剂以5-30%或10-20%的量,或者更优选地以大约10-15%的量加入。最优选地,当填充剂是CaHPO4时,亲水性熔化粘合剂以10-12%的量加入。
在本发明的一个实施方案中,该亲水性熔化粘合剂是式HO-(CH2CH2O)n-H所示的聚乙二醇,其可以以各种不同的平均分子量使用。平均分子量为1000-10000的PEG适合于制备本发明颗粒产品。PEG3000(平均分子量大约为3000的PEG)的熔化范围是48-54℃;PEG4000的熔化范围是50-58℃,PEG6000的熔化范围是55-63℃,PEG8000的熔化范围是60-63℃。
其它聚醚二醇例如聚丙二醇、聚乙二醇酯或酸以及聚氧化丙烯、聚氧化乙烯和它们的共聚物也可用作亲水性熔化粘合剂。
在本发明的一个优选方案中,该熔化粘合剂是PEG6000。
活性成分以最高达颗粒状产品的50%的适当量存在于颗粒状产品中。在本发明的优选实施方案中,活性成分的量在30%以下,并且优选为2-25%。在最优选的实施方案中,活性成分的量为3-10%。上面的所有百分比皆按活性化合物计算,并且在本文中是这样使用,%意指%(w/w)。
本发明还涉及制备含有加波沙朵可药用盐的颗粒状产品的方法,包括将干燥成分混合,同时将其加热至亲水性熔化粘合剂熔点以上的温度,然后实施机械加工直至形成均匀的颗粒状产品。优选地,组分在一个步骤中制粒,改步骤从总量的所有成分开始。如有润滑剂,则在临压片之前将其加入。
当制粒剂为PEG6000时,制粒操作的适宜温度为60-85℃。制粒可以在装配有混合装置的转鼓、流动床或适于进行制粒的可引入热的任何其它装置中进行。
将制粒剂与其它成分(即活性成分和填充剂)在加热之前干混合。或者,将制粒剂熔化,并连续地加入或喷雾到其它成分的搅拌混合物中。
将制粒混合物加热以使制粒剂基本上熔化,其后继续加热并进行机械加工或搅拌直至达到所要求的粒径。将该颗粒状产品冷却至制粒剂熔点以下的温度。为了获得均匀的颗粒,可以在加热和冷却的整个过程持续搅拌或运转颗粒状产品。
或者,制粒可在流动床设备上进行。使用此技术时,将熔化的制粒剂加到流动床的其它组分中。在该技术的一个具体实施方案中,将该制粒剂喷雾到流动床中。流动床熔化制粒也可以像DE 21 27 683所描述的那样进行。
在最后的实施方案中,本发明包括含有熔化颗粒状产品的组合物,所述熔化颗粒状产品含有加波沙朵和常规药物赋形剂。
在本发明的优选实施方案中,本发明组合物呈固体、成型药物单位剂型,即片剂的形式。在本发明的一个实施方案中,片剂是通过直接压缩制得的。
固体而成型的药物单位剂型可以用压制片剂的常规方法和装置来制备。
药物单位剂型可任选用本领域已知的技术和本领域已知的包衣剂包衣。用市售的薄膜包衣悬浮液可获得良好的效果。
以下通过实施例对本发明进行举例说明。然而,这些实施例只是用来举例说明本发明,不应当理解为是对本发明的限制。
实施例1
制备含有加波沙朵盐酸盐作为活性成分的熔化颗粒状产品,并压制含有5mg活性成分的200mg片剂。
制粒成分:
活性成分 15.75g(3.15%)
聚乙二醇6000 58.4g(11.68%)
无水磷酸氢钙 412.4g(82.47%)
在流动床中熔化制粒:
将流动床的入口空气温度设定为90℃。在流动床中把磷酸氢钙与加波沙朵和PEG6000合并在一起并混合。在达到PEG的熔点后,将该工序继续进行3-5分钟,同时将温度升至65-80℃。将颗粒状产品冷却,并让其通过1mm的网筛。
在高速剪切混合机中熔化制粒:
把包有热套层的高速剪切混合机的温度调整器设定在80℃。将磷酸氢钙与加波沙朵和PEG6000在混合机中合并在一起,并以1200rpm的转速混合直至测量到马达的峰值功率消耗。继续以800rpm混和2-4分钟,同时让温度升至60-75℃。将颗粒产品冷却,并让其通过1mm的网筛。
筛析
几何重量平均直径(dgw): 100-250μm
几何标准偏差(Sg): 2-3
片剂成分:
熔化颗粒 500g(97.3%)
交联羧甲基纤维素钠 10.3g(2%)
硬脂酸镁 3.6g(0.7%)
硬脂酸镁通过0.2mm的网筛。将加波沙朵熔化颗粒与交联羧甲基纤维素钠混合。加入硬脂酸镁并混合。将所得组合物加到装配有5.5×8mm椭圆冲孔的Korch PH 106压片机中,并将该混合物压成具有200mg的芯的片剂。
实施例2
下面的实验以与上面类似的方式进行:
活性成分 5%
PEG6000 14.6%
玉米淀粉 77.7%
交联羧甲基纤维素钠 2%
硬脂酸镁 0.7%
实施例3
活性成分 4.2%
PEG6000 10.5%
无水CaHPO4 30.3%
玉米淀粉 30.3%
微晶纤维素 20%
羟乙酸淀粉钠 4%
硬脂酸镁 0.7%
通过上述方法形成的片剂的实验显示,没有发现设备的侵蚀现象,并且片剂在贮藏状态下是非常稳定的。同样,该片剂的溶解时间是令人满意的。
Claims (17)
1.含有作为游离碱、作为水合物或作为其可药用酸加成盐的加沙朵以及赋形剂和填充剂的熔化颗粒状产品。
2.权利要求1的颗粒状产品,其中加波沙朵的可药用盐为盐酸盐。
3.权利要求1-2任一项的颗粒状产品,其中填充剂主要由CaHPO4组成。
4.权利要求1-2任一项的颗粒状产品,其中填充剂主要由玉米淀粉组成。
5.权利要求1-2任一项的颗粒状产品,其中填充剂是玉米淀粉和CaHPO4的组合。
6.权利要求1-5任一项的颗粒状产品,其中制粒是在聚乙二醇存在下进行的。
7.权利要求6的颗粒状产品,其中亲水性熔化粘合剂是平均分子量为约1000-10000的聚乙二醇。
8.权利要求6-7任一项的颗粒状产品,其中亲水性熔化粘合剂是平均分子量为约3000-8000的聚乙二醇。
9.权利要求6-8任一项的颗粒状产品,其中亲水性熔化粘合剂为PEG6000。
10.权利要求6-9任一项的颗粒状产品,其中PEG的含量为10-25%。
11.制备权利要求1-10任一项的颗粒状产品的方法,包括将含有
a)熔点为40℃-100℃的亲水性粘合剂,
b)0-90%的填充剂和
c)作为游离碱、作为水合物或作为其可药用加成盐的加波沙朵的混合物加热并机械加工至亲水性熔化粘合剂熔点以上的温度,直至形成均匀的颗粒产品。
12.权利要求11的方法,其中亲水性粘合剂的熔化温度为60℃-85℃。
13.权利要求1-12任一项的熔化颗粒状产品,所述产品可通过下述方法获得:将含有
a)熔点为40℃-100℃的亲水性粘合剂,
b)0-90%的填充剂和
c)作为游离碱、作为水合物或作为其可药用加成盐的加波沙朵
的混合物加热并机械加工至亲水性熔化粘合剂熔点以上的温度,
直至形成均匀的颗粒产品。
14.权利要求13的熔化颗粒状产品,所述产品可通过下述方法获得:将含有熔点为60℃-85℃的亲水性粘合剂的混合物加热并机械加工。
15.包含权利要求1-10或13-14任一项的熔化颗粒状产品和常规药物赋形剂的组合物。
16.权利要求15的组合物,其中所述组合物呈固体、成型药物单位剂型的形式。
17.权利要求16的固体、成型药物单位剂型,其中所述剂型是包衣的。
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PL1641456T3 (pl) | 2003-06-25 | 2010-08-31 | H Lundbeck As | Gaboksadol do leczenia depresji i innych zaburzeń afektywnych |
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US8022084B2 (en) | 2005-01-28 | 2011-09-20 | H. Lundbeck A/S | Polymorphic forms of a GABAA agonist |
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