CN1222075A - 双面凸的迅速崩解剂型 - Google Patents
双面凸的迅速崩解剂型 Download PDFInfo
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- CN1222075A CN1222075A CN97195603A CN97195603A CN1222075A CN 1222075 A CN1222075 A CN 1222075A CN 97195603 A CN97195603 A CN 97195603A CN 97195603 A CN97195603 A CN 97195603A CN 1222075 A CN1222075 A CN 1222075A
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Abstract
本发明涉及具有对称顶部和底部表面的双面凸药片形状的固体迅速崩解剂型的制造方法,及由其所取得的剂型。
Description
本发明涉及具有对称顶部和底部表面的双面凸药片形状的固体迅速崩解剂型的制造方法,及由其所取得的剂型。
由GB-A-1,548,022(US-4,305,502)已知装填以预定量活性成分的固体迅速崩解剂型。此固体剂型包括一种承载活性成分的多孔网状基体材料,此基体材料由水溶性或水分散性载体材料所组成。固体剂型由该基体材料和活性成分的冷冻溶液或冷冻悬浮液加以冷冻干燥而制得。
已开发出用冷冻干燥制备剂型的各种改良法。GB-A-2,111,423和US-4,371,561公开了以此类方法制备遇水迅速崩解的固体剂型,其中基体材料网状物承载了预定量的活性成分,特别是药物。此类剂型可供许多用途,特别是欲将活性成分以预定单位份量投予、配药或于不同状态的利用。例如,某些以溶液或悬浮液形式使用但以此形式运送或贮存有困难或危险的活性成分,可被转变成一种固体型式,它可被使用者加到含水介质中而产生内含预定量活性成分的所需溶液或分散液。此外,此活性成分可为一种试剂,它可被加到已知数量的含水液体中产生例如可用于化学分析的标准化液体组合物。再有,该活性成分可为一种诊断性化合物,可将其加到生物样品(如血液、尿)中,从而允许我们测定样品中所存在的特别成分的数量。然而,该活性成分优选为一种人类或兽医使用的药物。迅速溶解固体药物剂型特别适于口服。当经口服时,它们通常在口中迅速崩解(如,一或两秒钟内),因而此剂型为特别便于人类或动物服用药物的方法。此类剂型可用于代替传统的药片、丸剂或胶囊,特别是对于难于吞下这些传统剂型的患者(人类和动物等)。
US-4,642,903教示一种使用传统的冷冻干燥技术制备冷冻干燥泡沫剂形的操作程序,该技术可制成迅速溶解制剂剂型。
WO-93/23017提出传统的冷冻干燥方法的固有问题,即在冷冻干燥产品中缺乏均匀的孔隙。冷冻干燥产品中的均匀孔隙对于其的装填安慰药或具有活性成分的未装填剂型是至关重要的。WO-93/23017涉及到一种剂型的制法,该剂形可避免断裂和回熔,具有充足的强度及隙率且表现出迅速溶解的性能。
制备在口中迅速崩解固体剂型的另外方法,即固体状态溶解技术揭示于US-5,039,540、US-A-5,215,756、US-A-5,330,764和US-5,298,261中。
GB-2,119,246涉及使用具有侧壁或由底部向外岔开且在组合物表面制成至少5℃角度壁的模具,制备固体剂型的方法。当将这类下方装填的模具冷冻干燥时,则可取得甚至更厚的固体成型物品,且因此比由垂直底部之侧壁下方装填塑模所取得的物品更为平坦。
先有技术所提供的固体剂型用于提供预定量的活性成分。由于此类产品的投药伴随着许多危险,故必须将其适当地包装,如在泡体包装物中,且对其赋予一种同一性。
按先有技术方法所制备的固体迅速崩解剂型的包装,特别是在大量的工业规模上,乃伴随着若干的特殊问题。首先,此类剂型的易脆性严重地限制了其可能的运输及装卸方法。结果,任何降低固体迅速崩解剂型易脆性的方法将由于减缓了制造上的限制而极大地增加了其工业上的可用性。第二个问题直接涉及到按先有技术方法所制得的固体迅速崩解剂型的形状,这就是剂型顶部和底部的表面经常是不对称的。通常底部是垂直于剂型之侧壁或壁多少平坦的表面,然而顶部表面为内凹或平坦的,视塑模装填程度而定。顶部和底部不同的剂型,其缺点在于可能在装填入泡体包装物前必须进行使剂型定向的步骤(此工序包括探知各种单个剂形的方位,并选择且处于不希望方向上的剂形并使其倒转)。
本发明提供一种解决上述所有问题的方法,这包括将对称的凸面顶部和底部表面赋予固体迅速崩解剂型。首先,这导致在侧壁或壁和顶部或底部表面间具有较不尖锐角度的剂型,从而降低剂型的易脆性。对称性进一步总味着剂型一旦由其塑模移出时,其底部和顶部不再有任何不同。双面凸形状还有利于使剂型可通过缓和的振荡而轻易地以其凸面表面之一躺平排列。此外,不论在制造和包装的过程中或者于其后,都可由患者或服用剂型人士较容易地将其拾起。
依据本发明制备的固体剂型之双面凸形状,亦可用于将本方法与其他先有技术剂型加以区别,因此有助于预防医生、药剂师或最终使用者患者对于装填在双面凸形状剂型上的医药品的服用上的错误。
于附图中:
图1示出由上方观察0.5毫升(比例5∶1)的卵形(椭圆)塑模,且图2和3显示出图1塑模的两个横切面;
图4显示出由上方观察1.0毫升(比例5∶1)的小帽状(扁圆)塑模,而图5和6显示出图4塑模的两个横切面;
图7显示出上方观察0.5毫升(比例5∶1)的具有弯曲壁角的正方形塑模,而图8和9示出该塑模的两个横切面;且
图10显示出图1的卵形塑模以及由其中所取得的相应的双凸面固体剂型。
图11显示出圆形塑模以及由其中所取得的相应的双面凸固体剂型。
本发明涉及到包括了多孔网状基体成形材料的固体迅速崩解剂型的制造方法,该方法包括:
一以预定量的包括基体成形材料的含水组合物过度充填塑模,使得于塑模顶部产生凸弯月面;
一令塑模中的含水组成物冰冻;且
一将冷冻的组合物进行冷冻干燥或通过固体状态溶解作用而除去溶剂,从而留下多孔网状的基体成形材料;
本方法的特征在于,塑模底部表面的形状是顶部冷冻弯月面形状的镜像,镜平面平行于塑模边缘所界定的平面,因而产生剂形的形状为具有对称顶部和底部表面的双面凸药片。
含水组合物亦可经任何传统的冷却过程予以冷冻。例如,可以通过将含水组合物在与所欲剂型大小和形状相当的预成形塑模中进行配合然后令此塑模于冷冻托架上或于冷冻室中冷却而被冷冻。另外,可令内含混合液的塑模于冷冻通道中通过冷的气体或蒸汽流,比如液氮流。在一个优选的冷冻方法中,令组合物通过已注入液氮的冷冻通道,液氮汽化并导致所产生的气态氮通过此组合物。另一将塑模中含水组合物冷冻的方法是将塑模用干冰围住直到含水组合物结冻。
由冷冻溶液或悬浮液中除去溶剂的最为熟知的方法是冷冻干燥,它包括在真空下升华溶剂而令混合液脱除溶剂。若需要,于升华步骤进行前可将冷冻的组合物贮存于冷藏库中。升华作用可通过在冷冻干燥机中,将塑模中的冷冻组合物进行减压而进行,且视需要,可运用加热控制以助升华。压力可低于4mmHg(533 Pa),比如低于0.3mmHg(40Pa),例如0.1至0.2mmHg(13.3至26.6 Pa)甚至低于0.05mmHg(6.7Pa)。冷冻干燥机中的起始温度例如可高至60℃,且此温度随着冷冻组合物温度的升高而降低(如至40℃)。各种方法和改良法叙述于说明书刚开始的参考文献中。亦可将冷冻组合物于冷冻干燥前由塑模移出。
剂型也可通过由冷冻样品中除去固体溶剂的固体状态溶解法而制得。在此不太传统的方法中,将一种或多种基体成形剂溶解于或分散于第一溶剂中,然后冻结并随之在高于或在第二溶剂固化点的温度下及低于或在第一溶剂固化点的温度下与第二溶剂接触。固化状态中的第一溶剂与第二溶剂实质上为易混合的,而基体成形剂为实质上不溶于第二溶剂的。因此第一溶剂实质上由固化基体中被除去,产生实质上无第一溶剂的固体基体。典型地,第一溶剂为水且第二溶剂为乙醇。
按照本发明的方法所取得的双凸面剂型可被制成各种尺寸。塑模的体积通常在300至2,000mm3(0.3至2毫升)的范围,而剂型的体积在350至2,500 mm3(0.35至2.5毫升)的范围。塑模的体积优选在350至800 mm3(0.35至0.8毫升)的范围,而剂型的体积优选在450至1,000mm3(0.45至1毫升)的范围。换言之,过度充填或者塑模上方凸弯月面的体积可高达塑模本身体积的30%。概言之,该过度充填将为塑模体积的20%至我26%的范围。此外,过度充填的程度、凸弯月面的大小受含水组合物与形成塑模边缘材料间接触角度及含水组合物的表面张力所限制。重要的是应注意到过度充填愈大,则凸表面弯曲度愈高。进而这就使易脆性的降低和装卸性能的改善两者变为最大。
塑模的最大深度一般在3.4至6mm的范围;或者说塑模中冷冻组合物的最大厚度一般在5.0至8.5mm的范围。此最大距离为沿着垂直于塑模边缘轴线所测量的距离,而且通过塑模顶部弯月面的最高点和塑模底的最低点。更低的值通常不被优选,因为得到的剂型将薄至使其强度经常为不足,而厚度更大经常是不希望的,因为难于有效地将所有溶剂由此类冷冻组合物中除去,特别是当使用冷冻干燥除去溶剂时。
由塑模边缘所界定的表面面积典型为100至500mm2范围内,且呈圆的形状。由于降低了易脆性,此圆的形状有助于剂型的机械强度。
该圆的形状可为圆形、椭圆形、长椭圆形、扁圆形或多边形,若后者内角290°则较佳具有圆形壁角。
塑模例如可以是比如在一个金属板(如铝板)上的凹窝。此板上可含有一个以上的凹窝,每个凹窝的尺寸与形状与所需制品的尺寸相当。但此塑模亦可压于薄膜材料的薄片上。该薄膜材料可含有一个以上的凹窝。此薄膜材料可类似于包装制药片及类似药剂型式所使用的传统泡体包装物。例如,薄膜材料可由热塑性材料经热成形形成的凹窝而制成。优选的薄膜材料为加入滑石的聚丙烯薄膜或聚氯乙烯薄膜。亦可使用薄膜材料的层合物如聚氯乙烯/聚偏二氯乙烯、聚氯乙烯/聚四氟乙烯或聚氯乙烯/聚偏二氯乙烯/聚丙烯。
当使用冷冻干燥时,可优选使基体材料溶液在带涂层或衬里的塑模中冷冻,以易于脱出冻结的材料。优选的塑模为由加入滑石粉的聚丙烯薄片所制成的热成形杯,可任选地将接触含水组合物的表面上烘焙以聚硅氧烷/甲基硅氧烷层而予以硅氧烷化。
塑模底部的轮廓和体积可按如下方法确定。将具有所需体积且具有平坦底部(平行于塑模边缘)及所需弯曲形状的第一塑模用可制备最终剂型的水溶液过度充填至所需程度,通过冷冻及除去溶剂加工成剂形。弯月面的体积可由加入塑模的体积减去塑模体积而确定,或另外由数个描述弯月面顶部表面的方程式而计算体积。此类方式包括将剂型沿着一个或以几个对称平面切断,测量该对称平面与弯月面的顶部表面交叉的横切线并确定描述该切线的方程式。如果可确实地假设椭圆足以描述此类切线,测定主轴及次轴即可轻易地提供各方程式所需的参数。弯月面顶部表面与各种对称平面(沿着其乃作成横切面)的切线方程式随后可用于推演描述弯月面顶部表面的方程式,并使用已知的积分方法计算弯月面的体积。取得此类资料,可令人计算出塑模需要如何改造以产生双面凸对称剂型。例如,可计算最初塑模的深度需要减少至何种程度以使得塑模的体积可因弯月面的体积,及随后在塑模底部加入顶部弯月面的镜像后而得到以减小。此步骤可以保证凸面底部具有最终使用的顶部弯月面的形状和体积。然后将计算所得的数据提供给塑模制造商使得可在金属中成形凸面形状塑模。
含水组合物可为各种型式如溶液、悬浮液、分散液、乳状液、泡沫体。此领域专业人士可辨识出制备各者所可采用的方法。优选使用水作为被冷冻和脱除溶剂的组合物中的溶剂。若欲改善组合物任何成分的溶解性、分散性或湿润性,则亦可使用附加的助溶剂(如酒精)。
该剂型包括多孔的网状基体成形材料,它包括:
ⅰ)水溶性、可水合性凝胶或成泡材料,
ⅱ)凝胶或成泡材料的硬化剂,以及选择性地,
ⅲ)一种或几种氨基酸。
适当的水溶性、可水合性凝胶或成泡材料包括蛋白质材料如明胶、明胶A、明胶B、流体明胶、改性流体明胶、明胶衍生物、白蛋白、大豆纤维蛋白、小麦和欧车前种子蛋白、马铃薯蛋白、木瓜蛋白酶;磷脂类如凝集层蛋卵磷脂、或卵磷脂;树胶如阿拉伯树胶、瓜耳树胶、洋菜胶、刺槐豆胶、呫树胶;黄蓍胶;多醣类如藻酸盐(聚甘露糖醛酸)、脱乙酰壳多糖、角叉菜胶、葡聚糖、糊精、麦芽精(麦芽糊精)、果胶(聚半乳糖醛酸)、微晶纤维素、玉米浆固体、蒟蒻粉、米粉、小麦麸蛋白;合成聚合物如聚乙烯基吡咯烷酮、羧甲基纤维素钠、羟基乙酸淀粉钠、羟乙基纤维素;和多肽/蛋白质或多醣配合物如明胶-阿拉伯胶配合物,各为单独或以组合。
适当的硬化剂包括单醣类、直线和环状低聚糖和多醣类,如甘露糖醇、木糖醇、山梨糖醇、葡萄糖、果糖、蔗糖、乳糖、麦芽糖、半乳糖、海藻糖;环状糖类如环糊精如3-环糊精和2-羟丙基-β-环糊精;葡聚糖、糊精;还包括无机物质如磷酸钠、氯化钠、硅酸镁铝、三硅酸镁、天然粘土、或它们的组合。优选的硬化剂为甘露糖醇。
适当的氨基酸具有2至12个碳原子,如甘氨酸、L-丙氨酸、L-天冬氨酸、L谷氨酸、L-羟基脯氨酸、L-异亮氨酸、L-亮氨酸、L-苯基丙氨酸、或其组合。甘氨酸是优选的氨基酸。含有甘氨酸作为基体形成体之一的剂型具有数个优点:于含水介质中快速溶解并崩散、宜人风味和口感、营养价值、低卡路里含量且非生龋性。特别重要的是此类剂型可以以最低的断裂或回熔被制成,而且其具有均匀的孔隙率及充足的操作强度,即在正常制造和储运条件下可抵抗崩解或破碎。后者性质有助后装填方法的可行性,用这种方法在安慰剂或未装填剂形上装填活性成分。
优选的基体成形剂包括制药级明胶类、果胶类(非水解、部分水解或经水解)、甘氨酸和山梨糖醇。基体成形剂的特优组合包括明胶、甘氨酸和山梨糖醇。
下列段落中所述百分比和比率均为重量比。
制备基体所用材料的溶液成分或分散液可含有0.1%至15%重量的凝胶或泡体成形材料,特别为1%至5%,更优选为1.2%至3%。它可再含有0.5%至10%,特别为0.8%至2.5%重量的氨基酸及0.5%至10%,特别为1%至4%的硬化剂,其余部分可为后述的溶剂和次要成分。
此些材料间的比率可在特定范围内变化。特别为氨基酸总量相对于水溶性、可水合性凝胶或泡体成形材料的重量比为1∶1至1∶3。优选的比率为1.5∶1。水溶性、可水合性凝胶或泡体成形材料相对于硬化剂的重量比为2∶1至1∶2。优选的比率为1.5∶2。
典型地,非溶剂成分总量相对于含水组合物中水分的重量比为约1∶9至1∶33,特别为约1∶13至1∶30的范围内,例如约1∶20。
固体迅速溶解剂型可有许多用途,特别用于欲将活性成分以预定单位份量投予、配药或于不同状态的利用中。活性成分特别是人类或兽医用药物。
在固体迅速溶解剂型中所使用的活性成分可以涂糖衣的形式存在。例如,它可以以颗粒型式存在,而活性成分的颗粒可用适当的糖衣剂涂上糖衣,使其在稀释剂、悬浮剂或口部或其他粘膜腔的含水环境、或其他可溶解或破坏该活性成分的环境条件过程中受到保护。此糖衣材料可选自本质为亲水性或斥水性的天然或合成聚合物或其他的斥水性材料如脂肪酸、甘油酯、三酸甘油酯及其混合物。以此方式,活性或生物活性剂的味道可被遮蔽,同时允许固体剂型在接触生理性稀释剂时迅速溶解。依据本发明可包糖衣的苦味活性成分例子包括扑热息痛、布洛芬、氯苯那敏顺丁烯二酸盐、假麻黄碱、右旋甲氧甲基吗啡喃、西沙比利、哌双咪酮、雷丝哌酮。制药应用包括具有粘膜吸附性或预定以控制速率供给药物的剂型;预定在眼中、阴道、直肠及其他体孔中供给药物的剂量单位;预定取代液体配方的固体剂型;再溶解(再组成)后用于局部涂敷的干燥加药制剂;局部涂敷用的加药单位或片状制剂;表现出感官不良性能药物的更可口剂型制剂;将药物以口服给药的方式给予难以吞下药片或胶囊人士的剂型。
次要成分如营养物类、维生素类、其他活性成分、增甜剂类、调味剂类、色剂类、表面活性剂类、防腐剂类、抗氧化剂类、粘度增强剂类、矿物类、诊断剂类、肥料类和杀昆虫剂类,亦可混合至剂型的配方中。
制成溶液或悬浮液的剂型还可含有前述的次要成分。可加入树胶或聚丙烯酸聚合物及其盐类(亦被称为碳聚物或羧乙烯基聚合物、如CarbopolTM)以增加粘度、或将混合物的成分保持于悬浮态。
本发明还提供经前述任一方法所取得的双面凸、固体迅速崩解剂型。
依本发明方法所制得的双面凸药片的崩解速度完全或至少大部分取决于所选择的基体成形剂、其浓度和固化作用/脱溶剂化作用过程的条件。特别是,下述例子中所述尺寸的剂型将迅速地溶解或分散,例如,少于大约10秒且通常更快,如少于约5秒钟到或甚至更少,比如1至2秒之间。
剂型在水中在比如少于10秒钟内迅速地分散。测定剂型的崩解时间以决定其是否可使用如英国药典(1980,第Ⅱ册,附录ⅫA)所述的标准药片崩散装置用水充分迅速地崩解,但是要用不锈钢40目筛代替标准的2.00毫米铁丝网筛。将样品产品置入保持于水表面上的干燥管中。开启装置并将样品于20℃下浸入水中。样品应分散在液体表面上,且任何固体残渣应于10秒内,优选在5秒内,理想在1至2秒内通过40目筛。
本发明进一步以下列实施例予以阐明,其中活性成分为药剂。应明了依据本发明的方法及由其所得的剂型可应用于其他许多类型的活性成分。实验部分
界定依据本发明凸面塑模的若干必须参数表示在下表中1中。列出下列参数:
Vt:剂型体积
Sc:塑模边缘所界定的表面
Hc:垂直于Sc的塑模侧壁高度
Hm:弯月面高度(也为塑模凸面底部的深度)
Ht:剂型总高度=Hc+2Hm
曲线1(2):界定描述弯月面顶部表面沿着一个对称平面与第一(第二)相交横切面交叉的椭圆曲线的主轴及次轴值
Vc:以Sc×Hc所得塑模部分的体积
Vm:以(Vt-Vc)/2所得的弯月面或塑模凸面底部的体积
正方形药片示于图7、扁圆形药片示于图4、卵形药片示于图1和图10,且圆形药片示于图11。
表1
参数/形状 | 正方形药片 | 扁圆形药片 |
Vt=VolumetotalSc=SurfacecenterHc=HeightcenterHm=HeightmeniscusHt=Heighttotal曲线1曲线2Vc=Volumecenter=Sc×HcVm=Volumemeniscus=(Vt-Vc)/2 | 500mm3长度=11mm圆角=1.4mm面积=119.8mm32.00mm1.80mm(90%)5.60mm主轴=11mm次轴=3.6mm主轴=14.4mm次轴=3.6mm239.6mm3(47.9%)130.2mm3(26%) | 1,000mm3长度=20mm圆端r=5mm面积=178.54mm22.70mm2.20mm(81.5%)7.10mm主轴=20mm次轴=4.4mm主轴=10mm次轴=4.4mm482.06mm3(48.2%)258.97mm3(25.8%) |
表1(续)
参数/形状 | 卵形药片 | 弯曲药片 |
Vt=VolumetotalSc=SurfacecenterHc=HeightcenterHm=HeightmeniscusHt=Heighttotal曲线1曲线2Vc=Volumecenter=Sc×HcVm=Volumemeniscus=(Vt-Vc)/2 | 500mm3长度=17mm圆角=93mm面积=124.17mm22.25mm1.75mm(77.8%)5.75mm主轴=17mm次轴=3.5mm主轴=9.3mm次轴=3.5mm279.39mm3(55.9%)110.31mm3(22.1%) | 1,000mm3r=8.4mm面积=221.67mm22.34mm1.85mm(79.1%)6.53mm16.8mm3.7mm16.8mm3.7mm518.71mm3(51.2%)240.65mm3(24.1%) |
Claims (24)
1.一种制造包括多孔网状基体成形材料的固体迅速崩解剂型的方法,该方法包括:
-以预定量的包括基体成形材料的含水组合物过度充填塑模,使得于塑模顶部产生凸弯月面;
-令塑模中的含水组成物冰冻;且
-将冷冻的组合物进行冷冻干燥或通过固体状态溶解作用而除去溶剂,从而留下多孔网状的基体成形材料;本方法的特征在于塑模底部表面的形状是顶部冷冻弯月面形状的镜像,镜平面平行于塑模边缘所界定的平面,因而产生剂形的形状为具有对称顶部和底部表面的双面凸药片。
2.如权利要求1的方法,其中塑模体积在300至2,000mm3(0.3至2毫升)的范围,而剂型体积在350至2,500mm3(0.35至2.5毫升)的范围。
3.如权利要求2的方法,其中塑模体积在350至800mm3(0.35至0.8毫升)的范围,而剂型体积在450至1,000mm3(0.45至1毫升)的范围。
4.如权利要求1的方法,其中塑模的最大深度在3.4至6mm的范围;或者塑模中冷冻组合物的最大厚度在5.0至8.5mm的范围。
5.如权利要求1的方法,其中塑模边缘所界定的表面面积在在100至500mm2的范围,且具有圆形形状。
6.如权利要求5的方法,其中该圆形形状为圆形、椭圆形、长椭圆形、扁圆形或多边形,若后者内角290°则为具有圆角。
7.如权利要求1的方法,其中塑模为一种在薄膜塑胶材料薄片中或在金属板上的凹窝。
8.如权利要求7的方法,其中塑模为一种聚丙烯薄片的热成型杯,其表面选择性地被硅氧烷化。
9.如权利要求1的方法,其中含水组合物呈溶液、悬浮液、分散液、乳状液、或泡体型式。
10.如权利要求9的方法,其中基体成形材料包括:
ⅰ)水溶性、可水合性凝胶或泡体成形材料,
ⅱ)凝胶或泡体成形材料的硬化剂,以及选择性地,
ⅲ)一种或多种氨基酸。
11.如权利要求10的方法,其中凝胶或泡体成形材料为蛋白质材料如明胶、明胶A、明胶B、流体明胶、改性流体明胶、明胶衍生物、白蛋白、大豆纤维蛋白、小麦和欧车前种子蛋白、马铃薯蛋白、木瓜蛋白酶;磷脂类如凝集层蛋卵磷脂、或卵磷脂;树胶如阿拉伯树胶、瓜耳树胶、洋菜胶、刺槐豆胶、呫树胶;黄蓍胶;多醣类如藻酸盐(聚甘露糖醛酸)、脱乙酰壳多糖、角叉菜胶、葡聚糖、糊精、麦芽精(麦芽糊精)、果胶(聚半乳糖醛酸)、微晶状纤维素、玉米浆固体、蒟蒻粉、米粉、小麦麸蛋白;合成聚合物如聚乙烯吡咯烷酮、羧甲基纤维素钠、羟基乙酸淀粉钠、羟乙基纤维素;和多肽/蛋白质或多醣配合物如明胶-阿拉伯胶配合物,各为单独或以组合。
12.如权利要求12的方法,其中硬化材料为单醣、直线或环状低聚醣、多醣、或无机物质、或其组合。
13.如权利要求12的方法,其中硬化材料为甘露糖醇、木糖醇、山梨糖醇、葡萄糖、果糖、蔗糖、乳糖、麦芽糖、半乳糖、海藻糖;环状糖选自β-环糊精和2-羟丙基β环糊精、葡聚糖、糊精、无机物质选自磷酸钠、氯化钠、硅酸镁铝、三硅酸镁、天然粘土、或其组合。
14.如权利要求10的方法,其中氨基酸为甘氨酸、L-天冬氨酸、L-谷氨酸、L-羟基脯氨酸、L异亮氨酸、L-苯基丙胺酸、或其组合。
15.如权利要求10的方法,其中基体成形材料包括:
ⅰ)0.1%至15%(w/w)的水溶性、可水合性凝胶或泡体成形材料;
ⅱ)0.5%至10%(w/w)的凝胶或泡体成形材料的硬化剂;以及选择性地;
ⅲ)0.5%至10%(w/w)的一种或几种氨基酸。
16.如权利要求1 5的方法,其中基体成形材料包括:
ⅰ)1.2%至3%(w/w)的水溶性、可水合性凝胶或泡体成形材料;
ⅱ)1%至4%(w/w)的凝胶或泡体成形材料的硬化剂;以及选择性地;
ⅲ)0.8%至2.5%(w/w)的一种或几种氨基酸。
17.如权利要求10的方法,其中氨基酸总量相对于水溶性、可水合性凝胶或泡体成形材料的重量比为1∶1至1∶3;水溶性可水合性凝胶或泡体成形材料相对于硬化剂的重量比为2∶1至1∶2;且非溶剂成分总量相对于含水组合物中水分的重量比为1∶9至1∶33。
18.如权利要求17的方法,其中氨基酸总量相对于水溶性、可水合性凝胶或泡体成形材料的重量比为1∶1.5;水溶性可水合性凝胶或泡体成形材料相对于硬化剂的重量比为1.5∶2;且非溶剂成分总量相对于含水组合物中水分的重量比为1∶13至1∶30。
19.如权利要求1的方法,其中含水组合物含有一种人类或兽医用的药物作为活性成分。
20.如权利要求19的方法,其中含水组合物还含有营养物类、维生素类、其他活性成分、增甜剂类、调味剂类、着色剂类、表面活性剂类、防腐剂类、抗氧化剂类、粘度增强剂类、矿物类、诊断剂类、肥料类或杀昆虫剂类。
21.如权利要求19的方法,其中药物为西沙比利〔(±)-顺-4-氨基-5-氯-N-〔1-〔3-(4-氟苯氧基)丙基〕-3-甲氧基-4-哌啶基〕-2-甲氧基-苄酰胺单水合物。
22.如权利要求1的方法,其中基体材料可于20℃下在10秒钟内被水所崩解。
23.可由权利要求1至22中任一项的方法得到的一种固体迅速崩解剂型。
24.在权利要求1至22中任一项方法中使用的薄膜塑性材料制成或金属制成的薄片,它包括以规则型式排列的多个塑模,其特征在于,各塑模底部表面的形状为顶部预定凸弯月面形状的镜像、镜平面平行于塑模边缘所界定的平面,因而该薄片适合于制备成形为具有对称顶部和底部表面的双凸药片剂型。
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US2025996P | 1996-06-17 | 1996-06-17 | |
US60/020,259 | 1996-06-17 | ||
CNB971956030A CN1191824C (zh) | 1996-06-17 | 1997-06-10 | 双面凸的迅速崩解剂型 |
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CN1191824C CN1191824C (zh) | 2005-03-09 |
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US (1) | US6224905B1 (zh) |
EP (1) | EP0910345B1 (zh) |
JP (1) | JP4371435B2 (zh) |
CN (1) | CN1191824C (zh) |
AT (1) | ATE213154T1 (zh) |
AU (1) | AU713062B2 (zh) |
BR (1) | BR9709829A (zh) |
CA (1) | CA2257303C (zh) |
CY (1) | CY2288B1 (zh) |
CZ (1) | CZ297261B6 (zh) |
DE (1) | DE69710460T2 (zh) |
DK (1) | DK0910345T3 (zh) |
EE (1) | EE03549B1 (zh) |
ES (1) | ES2172793T3 (zh) |
HK (1) | HK1019200A1 (zh) |
HU (1) | HU225819B1 (zh) |
IL (1) | IL127603A (zh) |
NO (1) | NO321510B1 (zh) |
NZ (1) | NZ332832A (zh) |
PL (1) | PL188231B1 (zh) |
PT (1) | PT910345E (zh) |
SI (1) | SI0910345T1 (zh) |
SK (1) | SK282868B6 (zh) |
TR (1) | TR199802616T2 (zh) |
TW (1) | TW402561B (zh) |
WO (1) | WO1997048383A1 (zh) |
ZA (1) | ZA975277B (zh) |
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Cited By (4)
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CN102413808A (zh) * | 2009-04-29 | 2012-04-11 | 英特威国际有限公司 | 形成片剂的方法和适于应用该方法的装置 |
CN102413808B (zh) * | 2009-04-29 | 2015-02-18 | 英特威国际有限公司 | 形成片剂的方法和适于应用该方法的装置 |
CN102462665A (zh) * | 2010-11-18 | 2012-05-23 | 董玲 | 冻干赋形制剂的制备方法 |
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