CN1310613A - 快速崩解固体制剂 - Google Patents
快速崩解固体制剂 Download PDFInfo
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- CN1310613A CN1310613A CN99808969A CN99808969A CN1310613A CN 1310613 A CN1310613 A CN 1310613A CN 99808969 A CN99808969 A CN 99808969A CN 99808969 A CN99808969 A CN 99808969A CN 1310613 A CN1310613 A CN 1310613A
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Abstract
本发明涉及一种可快速崩解固体制剂,其中含有(ⅰ)药学活性成分,(ⅱ)糖和(ⅲ)具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素。该快速崩解固体制剂具有快速崩解性,适当的强度且无粗糙感。
Description
技术领域
本发明涉及在存在唾液的口腔内、在少量水中或在胃内具有快速崩解性的固体制剂,具体涉及用作口腔内可崩解固体制剂的可快速崩解固体制剂。
背景技术
人们希望开发出一种口腔内可崩解固体制剂,它们可易于在不用水的条件下对老年人或儿童给药。作为公开了此类制剂的背景技术,譬如有下列现有技术。
JP-A-9-48726公开了一种通过以可模压方式湿润制备的口腔内可快速崩解制剂。它含有药物和可在模压和干燥后保持形状的材料。此类材料例如是糖、糖醇和水溶性聚合物材料。
JP-A-9-71523公开了一种含有药物、结晶纤维素、低取代羟丙基纤维素和润滑剂的片剂。它在口腔中具有快速崩解性。
EP-A839526公开了含有药学活性成分、赤藓醇、结晶纤维素和崩解剂的固体药物制剂。
然而,这些背景技术没有说明本发明的(ⅰ)药学活性成分,(ⅱ)糖和(ⅲ)具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素。
发明公开
希望开发出一种在存在唾液的口腔内、在少量水中或在胃内具有快速崩解性的可快速崩解固体制剂,其具有适当的强度(硬度)以在制备过程和分配中不被损坏,并且不再具有粗糙度。
本发明涉及:
(1)可快速崩解固体制剂,其中含有(ⅰ)药学活性成分,(ⅱ)糖和(ⅲ)具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素;
(2)上述(1)的制剂,其是口腔内可快速崩解固体制剂;
(3)上述(1)或(2)的制剂,其是片剂;
(4)上述(1)的制剂,其中所述糖是糖醇;
(5)上述(4)的制剂,其中糖醇是甘露糖醇或赤藓醇;
(6)上述(1)的制剂,其中糖的用量是5-97重量份/100重量份固体制剂;
(7)上述(1)的制剂,其中具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素的用量是3-50重量份/100重量份的固体制剂;
(8)上述(1)的制剂,其中药学活性成分是兰索拉唑;
(9)上述(1)的制剂,其中药学活性成分是伏格列波糖;
(10)上述(1)的制剂,其中药学活性成分是盐酸马尼地平;
(11)上述(1)的制剂,其中药学活性成分是盐酸吡格列酮;
(12)上述(1)的制剂,其中药学活性成分是西拉克西替坎德沙坦(candesartan celexetil);
(13)上述(3)的制剂,其含有微细颗粒;
(14)上述(13)的制剂,其中药学活性成分含在微细颗粒中;
(15)上述(14)的制剂,其中(ⅰ)糖和(ⅱ)具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素含在固体制剂中但与微细颗粒分开;
(16)上述(15)的制剂,其中糖的用量是5-97重量份/100重量份的除微细颗粒之外的固体制剂剩余部分;
(17)上述(15)的制剂,其中具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素的用量是3-50重量份/100重量份的除微细颗粒之外的固体制剂剩余部分;
(18)具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素在制备含有药学活性成分和糖的可快速崩解固体制剂中的用途;和
(19)一种提高含有药学活性成分和糖的固体制剂的快速崩解性的方法,其特征在于其中包含具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素。
1)药学活性成分
本发明所用的药学活性成分是任何状态,如固体、粉状、结晶、油性和溶液状态。此类药学活性成分例如是一种或多种选自下列的成分,例如滋补剂、退热-止痛-抗炎剂、精神病治疗药、抗焦虑药、抗抑郁药、催眠镇静药、解痉剂、中枢神经药、脑代谢改善剂、脑循环改善药、抗癫痫药、拟交感神经药、胃肠药物、抗酸剂、溃疡病治疗药、镇咳-祛痰药、止吐剂、呼吸促进剂、支气管扩张药、抗变态反应药、齿颊药、抗组胺药、强心剂、抗心律失常药、利尿剂、抗高血压药、血管收缩药、冠状血管舒张药、外周血管舒张药、抗低血脂药、利胆药、抗生素、化疗药、抗糖尿病药、骨质疏松症治疗药、风湿病治疗药、骨骼肌弛缓药、抗眩晕药、激素、生物碱麻醉药、磺胺类药物、治痛风药、凝血抑制剂、抗肿瘤剂、早老性痴呆治疗药等。
作为滋补剂,例如:维生素,如维生素A、维生素D、维生素E(如醋酸d-α-生育酚等)、维生素B1(如联苯甲酰硫胺、盐酸呋喃硫胺等)、维生素B2(如核黄素四丁酯等)、维生素B6(如盐酸吡哆醇等)、维生素C(如抗坏血酸、L-抗坏血酸钠等)和维生素B12(如醋酸羟钴胺、氰钴胺等);矿物质,如钙、镁、铁等;蛋白质,氨基酸,低聚糖,生药等。
作为退热剂-止痛剂-抗炎剂,例如阿斯匹林、乙酰氨基酚、乙柳酰胺、布洛芬、盐酸苯海拉明、马来酸dl-氯苯吡胺、磷酸双氢可待因、那可丁、盐酸甲基麻黄碱、苯丙醇胺盐酸盐、咖啡因、无水咖啡因、锯齿肽酶、氯化溶菌酶、托芬那酸、甲灭酸、双氯高灭酸钠、氟芬那酸、水杨酰胺、氨基比林、酮洛芬、吲哚美辛、布可隆、镇痛新等。
作为精神病治疗药,例如氯丙嗪、利血平等。
作为抗焦虑药,例如阿普唑仑、利眠宁、地西泮等。
作为抗抑郁药,例如丙咪嗪、盐酸马普替林、苯丙胺等。
作为催眠镇静药,例如舒乐安定、硝基安定、安定、哌拉平、苯巴比妥钠等。
作为解痉剂,例如氢溴酸东茛菪硷、盐酸苯海拉明、盐酸罂粟硷等。
作为中枢神经药,例如胞磷胆碱等。
作为脑代谢改善剂,例如盐酸甲氯芬酯等。
作为脑循环改善药,例如长春西汀等。
作为抗癫痫药,例如苯妥英、卡马西平等。
作为拟交感神经药,例如盐酸异丙肾上腺素等。
作为胃肠药,例如胃消化药如淀粉酶、含糖胃蛋白酶、东茛菪属提取物、纤维素酶AP3、脂肪酶AP和桂皮油;肠道疾病治疗药如盐酸小檗硷、耐乳酸杆菌、双歧乳酸杆菌。
作为抗酸剂,例如碳酸镁、碳酸氢钠、硅酸镁铝、合成水化碳酸氢氧化镁铝、沉淀碳酸钙、氧化镁等。
作为溃疡病治疗药,例如兰索拉唑、奥美拉唑、雷贝拉唑、泮托拉唑、法莫替丁、西咪替丁、盐酸雷尼替丁等。
作为镇咳剂-祛痰药,例如盐酸氯哌啶、氢溴酸美沙芬、茶硷、愈创木酚磺酸钾、愈创木酚甘油醚(guaiafenesin)等。
作为止吐剂,例如盐酸地芬尼多、胃复安等。
作为呼吸促进剂,例如酒石酸烯丙左吗喃等。
作为支气管扩张药,例如茶硷、硫酸沙丁胺醇等。
作为抗变态反应药,例如氨来占司、塞曲司特等。
作为齿颊药,例如土霉素、醋酸曲安缩松、盐酸洗必太、利多卡因等。
作为抗组胺药,例如盐酸苯海拉明、异丙嗪、盐酸氮异丙嗪、马来酸d1-氯苯吡胺等。
作为强心剂,例如咖啡因、地高辛等。
作为抗心律失常药,例如盐酸普鲁卡因胺、盐酸普萘洛尔、吲哚洛尔等。
作为利尿剂,例如异山梨醇、速尿、噻嗪类如HCTZ等。
作为抗高血压药,例如盐酸地拉普利、卡托普利、溴化六烃季铵、盐酸肼、盐酸柳胺苄心定、盐酸马尼地平、西拉克西替坎德沙坦(candesartancilexetil)、甲基多巴、氯沙坦、缬沙坦、依普沙坦(eprosartan)、依布沙坦(irbesartan)、他索沙坦(tasosartan)、替米沙坦等。
作为血管收缩药,例如苯福林盐酸盐等。
作为冠状血管舒张药,例如盐酸卡波孟、吗多明、盐酸维拉帕米等。
作为外周血管舒张药,例如桂利嗪等。
作为抗低血脂药,例如西伐他汀(cerivastatin)钠、辛伐他汀、帕伐他汀钠等。
作为利胆药,例如脱氢胆酸、三乙丁酮等。
作为抗生素,例如头孢烯类,如头孢氨苄、头孢氯、阿莫西林、氮卓脒青霉素双酯盐酸盐、盐酸海克西替头孢替安、头孢羟氨苄、头孢克肟、匹伏西头孢托仑(cefditoren pivoxil)、匹伏西头孢特仑(cefteram pivoxyl)、匹伏西头孢泊肟(cefpodoxime proxetil)、头孢替安二盐酸盐、头孢唑兰盐酸盐、头孢甲肟半盐酸盐、头孢磺啶钠;合成杀菌剂如氨苄青霉素、环己西林、磺苄青霉素钠、萘啶酮酸、依诺沙星;单菌霉素类如卡鲁莫南钠;青霉烯类;碳青霉烯类等。
作为化疗药,例如磺胺甲噻唑、盐酸磺胺甲噻唑、噻唑砜等。
作为抗糖尿病药,例如甲苯磺丁脲、伏格列波糖、盐酸吡格列酮、优降糖、troglitazone、马来酸曲格列酮、阿卡波糖、米格列醇、乙格列酯等。
作为骨质疏松症治疗药,例如异丙氧黄酮等。
作为骨骼肌弛缓药,例如美索巴莫等。
作为抗眩晕药,例如盐酸美其敏、茶苯海明等。
作为风湿病治疗药,例如甲氨蝶呤、布西拉明等。
作为激素,例如碘甲腺氨酸钠、磷酸地塞米松钠、泼尼松龙、异乙诺酮、醋酸亮丙瑞林等。
作为生物碱麻醉药,例如阿片、盐酸吗啡、吐根、盐酸羟可酮、盐酸阿片生物碱、盐酸可卡因等。
作为磺胺类药物,例如磺酰胺、磺胺二甲异嘧啶、磺胺甲噻唑等。
作为治痛风药,例如别嘌醇、秋水仙碱等。
作为凝血抑制剂,例如双香豆素等。
作为抗肿瘤剂,例如5-氟尿嘧啶、尿嘧啶、丝裂霉素等。
作为早老性痴呆病治疗药,例如艾地苯醌、长春西汀等。
在上述药学活性成分中,优选采用滋补剂、退热-止痛-抗炎剂、催眠镇静药、中枢神经药、胃肠药物、溃疡病治疗药、镇咳-祛痰药、抗变态反应药、抗心律失常药、利尿剂、抗高血压药、血管收缩药、冠状血管舒张药、抗低血脂药、抗糖尿病药、骨质疏松症治疗药、骨骼肌弛缓药、抗眩晕药等。
在本发明中,优选的药学活性成分是溃疡病治疗药如兰索拉唑;抗糖尿病药如伏格列波糖和盐酸吡格列酮;抗高血压药如盐酸马尼地平和西拉克西替坎德沙坦等。
两种或多种药学活性成分可以任选地以混合物应用在本发明的可快速崩解固体制剂中。
药学活性成分可任选地利用药物治疗和食品领域中常用的稀释剂稀释。此外,为掩蔽药学活性成分的苦味还可以任选地处理。
上述药学活性成分的用量例如对每100重量份的固体制剂是0.01至70重量份,优选0.02至50重量份,更优选0.05至30重量份。
2)糖
作为本发明所用的糖类,例如糖、淀粉糖、乳糖、蜂蜜和糖醇。此类糖任选地以它们具有适当比例的混合物应用。
作为糖,例如蔗糖、偶合糖、果糖-低聚糖、巴糖。
作为淀粉糖,例如葡萄糖、麦芽糖、糖粉、淀粉糖浆、左旋糖和果糖等。
作为乳糖,例如乳糖、异构化乳糖(乳果糖),还原乳糖(乳糖醇)等。
作为蜂蜜,例如多种常食用的蜂蜜。
作为糖醇,例如山梨糖醇、甘露糖醇、麦芽糖醇、还原淀粉糖、木糖醇、还原巴糖、赤藓醇等。赤藓醇是一种任选使用的组分,它一般是以葡萄糖作为起始物料用酵母通过发酵制备且粒度至多为50目。此类赤藓醇市场上可买到[例如由Nikken Chemicals Co.Ltd.(日本)]。
优选上述糖类是水溶性糖类。水溶性糖类是指当将1g糖加入水中且随后在20℃下在30分钟内通过每5分钟剧烈搅拌30秒使糖溶解时至多需要30ml水的任何水溶性糖。
在本发明中,优选糖是糖醇,更优选是甘露糖醇或赤藓醇。
为了获得足够的制剂强度和足够快速的崩解性,在固体制剂不含有微细颗粒的情况下糖的用量对每100重量份的固体制剂是5至97重量份,优选10至90重量份。另一方面,在固体制剂含有微细颗粒的情况下,糖的用量对每100重量份除微细颗粒之外的固体制剂剩余部分是5至97重量份,优选10至90重量份。
例如,在固体制剂不含有微细颗粒的情况下,甘露糖醇或赤藓醇的用量通常是5至90%(重量),优选10至80%(重量),更优选20至80%(重量),特别优选50至80%(重量),以固体制剂总重量计。另一方面,在固体制剂含有微细颗粒时,甘露糖醇或赤藓醇的用量通常是5至90%(重量),优选10至80%(重量),更优选20至80%(重量),尤其优选50至80%(重量),以除微细颗粒之外的固体制剂剩余部分重量为基准计。
3)具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素(L-HPC)
3-1)L-HPC的制备
本发明中所用的“具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素(此后任选称作L-HPC)”可以按照已知方法,如JP-B-57-53100或其类似方法制备。
首先,含有游离碱的碱性纤维素与氧化丙烯反应得到含有游离碱的低取代羟丙基纤维素粗品。
具体地说,例如,将原料浆如木浆和棉壳(cotton leader)浸渍在浓度为10-50%的氢氧化钠水溶液中并且加压,得到NaOH/纤维素的比例为0.1至1.2(重量比例)的碱性纤维素。随后,通过在20-90℃和搅拌下所得碱性纤维素和氧化丙烯反应2-8小时可获得含有游离碱的低取代羟丙基纤维素粗品。氧化丙烯的用量应使预期的低取代羟丙基纤维素中羟丙氧基的含量等于或大于5%(重量)至小于7%(重量)。
将含有游离碱的低取代羟丙基纤维素粗品分散在含有5-80%用于中和全部碱所需要的酸的水或热水中,并且将一部分含有游离碱的低取代羟丙基纤维素溶解在其中。此外,加入酸以中和剩余的碱。
中和后,按照常规方法进行加工,如排水、干燥和研磨,得到预期的低取代羟丙基纤维素。
3-2)L-HPC的性质
本发明中所用的L-HPC的粒径是,例如平均粒径5-60μm。优选平均粒径是10-40μm。
在上述范围内,在采用具有较大粒径(如,L-HPC的平均粒径是26-40μm)L-HPC的情况中,可以制备具有优良崩解性的药物制剂。另一方面,在采用具有较小粒径(例如,L-HPC的平均粒径为10-25μm)L-HPC的情况中,可以制备制剂强度优良的药物制剂。
所以,根据预期药物制剂的特征可对L-HPC的粒径进行选择。
为了获得足够的制剂强度和足够快速的崩解性,在所述固体制剂不含有微细颗粒的情况下,本发明的L-HPC的用量对每100重量份的固体制剂是3至50重量份,优选5至40重量份。另一方面,在固体制剂含有微细颗粒的情况中,本发明中的L-HPC的用量对每100重量份的除微细颗粒之外的固体颗粒剩余部分是3至50重量份,优选5至40重量份。
如上所述,通过采用L-HPC,从而可以提高含有药学活性成分和糖的固体制剂的快速崩解性,特别是口腔内快速崩解性。
4)剂型
本发明的可快速崩解固体制剂的剂型例如是片剂、颗粒剂、微细颗粒剂等,优选如片剂。在可快速崩解片剂如口腔内可快速崩解片剂和水中可崩解片剂中,优选口腔内可崩解片剂。
5)其他组分
除非干扰制剂的快速崩解性(特别是在口腔内的快速崩解性)或强度,本发明的可快速崩解固体制剂可进一步含有多种普通剂型制剂制备中常用的的添加剂。此类添加剂的用量为用于制备普通剂型制剂的常规用量。此类添加剂例如是粘合剂、酸、起泡剂、人造甜味剂、矫味剂、润滑剂、着色剂、稳定剂、赋形剂、崩解剂等。
上述粘合剂例如是羟丙基纤维素、羟丙基甲基纤维素、结晶纤维素、预胶凝淀粉、聚乙烯吡咯烷酮、阿拉伯胶粉、明胶、茁霉多糖等。上述两种或多种粘合剂可以以指定配比混合应用。应用结晶纤维素作为粘合剂可提供具有更佳制剂强度且保持口腔内优良快速崩解性的固体制剂。作为结晶纤维素,也包括微晶纤维素。“结晶纤维素”包括具有部分α-纤维素解聚的精制纤维素。作为结晶纤维素,如CEOLUS KG 801、Avicel PH 101、Avicel PH102、Avicel PH 301、Avicel PH 302、Avicel RC-A591 NF(结晶纤维素羧甲醚纤维素钠)、Avicel RC-591(结晶纤维素·羧甲醚纤维素钠)等是具体实例。其中,优选采用称作可高度模压结晶纤维素的CEOLUS KG 801。此类结晶纤维素任选地以适当比例混合物应用。此类结晶纤维素可从市场上购得(Asahi Chemical Industry Co.Ltd.(日本)生产)。在所述固体制剂不含有微细颗粒的情况下,所述结晶纤维素的用量对每100重量份的固体制剂是1至50重量份,优选2至40重量份,更优选2至20重量份。另一方面,在固体制剂含有微细颗粒的情况下,所述结晶纤维素的用量对每100重量份的除微细颗粒之外的固体颗粒剩余部分是1至50重量份,优选2至40重量份,更优选2至20重量份。
作为酸类,例如柠檬酸、酒石酸、苹果酸等。
作为起泡剂,例如碳酸氢钠等。
作为人造甜味剂,例如糖精钠、甘草酸二钾、天门冬氨酯、蛇菊素(stevia)、索马丁等。
作为矫味剂,例如柠檬、酸柠檬、柑橘、薄荷醇、草莓等。
作为润滑剂,例如硬脂酸镁、蔗糖脂肪酸酯、聚乙二醇、滑石粉、硬脂酸等。应用聚乙二醇作为润滑剂得到稳定的固体制剂,其药学活性成分随时间的分解作用受到控制。此时,在所述固体制剂不含有微细颗粒的情况中,聚乙二醇的用量对每100重量份的固体制剂是0.01至10重量份,优选0.1至5重量份。另一方面,在固体制剂含有微细颗粒的情况下,聚乙二醇的用量对每100重量份的除微细颗粒之外的固体颗粒剩余部分是0.01至10重量份,优选0.1至5重量份。
作为着色剂,例如多种食品着色剂如食品5号黄、食品2号红、食品2号蓝等;食品色淀,红氧化铁等。
作为稳定剂,例如,在药学活性成分为碱性的情况下是碱性物质,而且在酸性药学活性成分的情况下是酸性物质。
作为赋形剂,例如乳糖、蔗糖、D-甘露糖醇、淀粉、玉米淀粉、结晶纤维素、轻质硅酐、二氧化钛等。
作为崩解剂,例如称作高级崩解剂的崩解剂如交联聚乙烯吡咯烷酮(crospovidone)[ISP Inc.(美国),BASF(德国)制造]、交联羧甲醚纤维素(croscarmellose)钠[FMC-Asahi Cheimical Industry Co.Ltd.(日本)]、羧甲醚纤维素钙[Gotoku Chemical(Yakuhin),(日本)];羟丙基纤维素;低取代羟丙基纤维素;羧甲基淀粉钠[Matsutani Chemical Co.,Ltd.(日本)];玉米淀粉等。其中,优选采用交联聚乙烯吡咯烷酮。所述两种或多种崩解剂任选地以其适当比例混合物应用。
作为交联聚乙烯吡咯烷酮,可以利用任何交联均聚物如1-乙烯基-2-吡咯烷酮均聚物,并且可采用分子量至少为1000000的交联聚乙烯聚吡咯烷酮。市售的聚乙烯吡咯烷酮例如是交联聚乙烯吡咯烷酮Kollidone CL[BASF生产(德国)],Polypladone XL、Polyplasdone XL-10[ISP Inc.生产,(美国)],聚乙烯吡咯烷酮PVPP,1-乙烯基-2-吡咯烷酮均聚物等。
两种或多种的上述崩解剂可以是具有指定比例的混合物。例如(ⅰ)单独的交联聚乙烯吡咯烷酮,或(ⅱ)优选交联聚乙烯聚吡咯烷酮和另一种崩解剂。
在所述固体制剂不含有微细颗粒的情况下,此类崩解剂的用量对每100重量份的固体制剂是0.1-20重量份,优选1-10重量份,更优选3-7重量份。另一方面,在固体制剂含有微细颗粒的情况下,此类崩解剂的用量对每100重量份的除微细颗粒之外的固体颗粒剩余部分是0.1-20重量份,优选1-10重量份,更优选3-7重量份。
5-1)剂型,尤其是含酸不稳定的药学活性成分的剂型所用的其他组分
在药学活性成分是酸不稳定成分如兰索拉唑、奥美拉唑、雷贝拉唑、泮托拉唑等的情况下,优选加入碱性无机盐以使该固体制剂中的药学活性成分稳定。
“碱性无机盐”包括,例如钠、钾、镁和/或钙的碱性无机盐,优选镁和/或钙的碱性无机盐。其中,优选镁的碱性无机盐。
钠的碱性无机盐包括,例如碳酸钠、碳酸氢钠、磷酸钠、磷酸氢钠等。
钾的碱性无机盐包括,例如碳酸钾、碳酸氢钾、磷酸钾、磷酸氢钾、碳酸钾钠等。
镁的碱性无机盐包括,例如重质碳酸镁、碳酸镁、氧化镁、氢氧化镁、硅酸铝酸镁、硅酸铝酸镁、硅酸镁、铝酸镁、合成水滑石[Mg6Al2(OH)16·CO3·4H2O]、氢氧化铝镁[2.5MgO·Al2O3·xH2O]等。其中,优选重质碳酸镁、碳酸镁、氧化镁和氢氧化镁等。
钙的碱性无机盐包括,例如沉淀碳酸钙、氢氧化钙等。
“碱性无机盐”的优选实例是镁的碱性无机盐,并且更优选的实例包括重质碳酸镁、碳酸镁、氧化镁、氢氧化镁等。
当是1%水溶液或悬浮液的形式时,所述镁或钙的碱性无机盐等具有碱性pH(不小于7)。
两种或更多种的上述碱性无机盐(优选镁的碱性无机盐,钙的碱性无机盐等)可以以指定比例的混合物应用。碱性无机盐的用量适宜根据碱性无机盐的种类进行选择,例如0.3至200重量份,优选1-100重量份,更优选10-50重量份,尤其是20-40重量份,以药学活性成分为基准计。
6)含有微细颗粒的剂型(例如片剂)
如上所述,本发明的可快速崩解制剂可以以任何固体剂型,例如片剂、颗粒剂、微细颗粒剂等应用。在片剂的情况下,所述片剂可含有微细颗粒。微细颗粒可含有药学活性成分。通过常规方法或其类似方法可以制备这些剂型。
7)含有核芯的微细颗粒
所述微细颗粒含有核芯,该核芯与药学活性成分结合或与之分开。作为核芯,例如(1)含有结晶纤维素和乳糖的球形颗粒产物[例如100-200μm且含有结晶纤维素(3份)和乳糖(7份)的球形颗粒产物(Nonpareil 105(商品名),Freund lndustrial Co.,Ltd.(日本)制造,150-250μm且含有结晶纤维素(3份)和乳糖(7份)的球形颗粒产物(Nonpareil NP-7:3(商品名),Freund Industrial Co.,Ltd.(日本)制造,150-250μm且含有结晶纤维素(5份)和乳糖(5份)的球形颗粒产物(Nonpareil NP-5:5(商品名),Freund Industrial Co.,Ltd.(日本)制造,等等],(2)例如150-250μm且含有结晶纤维素的球形颗粒产物[Avicel SP(商品名),Asahi Chemical Industry Co.Ltd.(日本)制造,等等]。
在采用核芯的情况下,核芯任选地被药学活性成分等包衣,并且通过熟知方法进一步包衣以掩蔽味道和/或气味和/或用于提供肠溶性或缓释性质。在此类情况下,所述核芯形成含有药学活性成分的微细颗粒。在此情况中作为包衣剂可例如是:肠溶包衣聚合物(例如邻苯二甲酸乙酸纤维素)(CAP)、甲基丙烯酸酯共聚物L、甲基丙烯酸酯共聚物LD(Eudragit L30D-55(商品名;Rohm GmbH(德国)制造)),甲基丙烯酸酯共聚物S,邻苯二甲酸羟丙基甲基纤维素,琥珀酸乙酸羟甲基纤维素,琥珀酸乙酸羟丙基甲基纤维素,KolllCoat MAE30DP(商品名;BASF(德国)制造),Polyquid PA-30(商品名;Sanyokasei(日本)制造),羧甲基乙基纤维素,紫胶,甲基丙烯酸酯共聚物[例如Eudragi NE30D(商品名),Eudragit RL30D(商品名),EudragitRS30D(商品名)等]、柠檬酸三乙酯,聚乙二醇,乙酰基化一甘油酯,甘油三乙酸酯,蓖麻油等);胃溶聚合物(例如聚乙烯醇缩醛二乙基氨基乙酸酯,甲基丙烯酸氨基烷基酯共聚物等),水溶性聚合物(例如羟丙基纤维素,羟丙基甲基纤维素等),微溶性聚合物(例如乙基纤维素,甲基丙烯酸氨基烷基酯共聚物RS,丙烯酸乙酯·甲基丙烯酸甲酯共聚物等),蜡等。一种或多种包衣剂是以混合物应用。
7-1)微细颗粒的制备
本发明中的“微细颗粒”可以通过已知制粒方法制备。
所述“制粒方法”包括,例如滚动制粒法(例如离心滚动制粒法等),流化床制粒法(例如滚动流化床制粒法,流化制粒法等),搅拌制粒法等。其中,优选流化床制粒法,更优选滚动流化床制粒法。
“滚动制粒法”的具体实例包括一种利用“CF设备”(Freund IndustrialCo.,Ltd.(日本)制造)等的方法。“滚动流化床制粒法”的具体例子包括采用“SPIR-A-FLOW”,“multi plex”(Powrex Corp.制造(日本)),“New-Marumerizer”(Fuji Paudal Co.,Ltd.制造(日本))等的方法。应根据制粒机的类型适当选择混合物喷雾的方法,所述喷雾方法可例如是顶部喷雾法、底部喷雾法、切向喷雾法等任一种。其中,优选切向喷雾法。
本发明中的“微细颗粒”可以通过常规包衣方法或其类似方法,利用任何其他组分包括活性组分和其他组分进行包衣。例如,在药学活性成分是酸不稳定的生理活性物质的情况中,使用的一种方法包括用酸不稳定生理活性成分将含有结晶纤维素和乳糖的核芯包衣。
例如,采用JP-A-5-92918(包衣法)所述的方法,其中包括用酸不稳定生理活性物质将含有结晶纤维素和乳糖的核芯包衣,如果需要,联合应用碱性无机盐、粘合剂、润滑剂、赋形剂、水溶性聚合物等(此后,可以简称为“包衣层”)。例如,采用一种方法,该方法包括用酸不稳定生理活性物质和碱性无机盐将核芯包衣,且随后用粘合剂、润滑剂、赋形剂、水溶性聚合物等包衣。
7-2)微细颗粒核芯的性质
“核芯”的平均粒径等于或小于250μm,优选50-250μm,更优选100-250μm,尤其优选100-200μm。具有上述平均粒径的“核芯”包括:所有通过#50筛(300μm)的颗粒,其中等于或少于5%w/w的总数保留在#60筛(250μm)上的颗粒,和其中等于或少于10%w/w的总数通过#282筛(53μm)的颗粒。“核芯”的比体积等于或小于5ml/g,优选等于或小于3ml/g。
“核芯”的例子包括:
(1)含有结晶纤维素和乳糖的球形颗粒产物,(2)150-250μm且含有结晶纤维素的球形颗粒产物[Avicel SP, Asahi Chemical Co.Ltd.(日本)制造],(3)50-250μm且含有乳糖(9份)和淀粉(1份)的搅拌颗粒产物,(4)分类为球形颗粒的等于或小于250μm且含有微晶纤维素的微粒,如JP-A-61-213201所述,(5)一种加工产物,例如通过喷雾或熔融制粒法形成的蜡球,(6)一种加工产物,例如含有油成分的明胶珠,(7)硅酸钙,(8)淀粉,(9)多孔颗粒,例如壳多糖、纤维素、壳聚糖等,和(10)松散产物,例如砂糖、结晶乳糖或氯化钠,和它们的加工的产物。此外,这些核芯可以按照已知研磨方法或制粒方法制备,并且筛分制成具有预定粒径的颗粒。
上述“含有结晶纤维素和乳糖的球形颗粒产物”包括,例如(ⅰ)100-200μm且含有结晶纤维素(3份)和乳糖(7份)的球形颗粒产物[例如,Nonpareil 105(70-140)(粒径100-200μm),Freund Industrial Co.,Ltd.(日本)制造],(ⅱ)150-250μm且含有结晶纤维素(3份)和乳糖(7份)的球形颗粒产物[例如,Nonpareil NP-7:3,Freund Industrial Co.,Ltd.(日本)制造],(ⅲ)100-200μm且含有结晶纤维素(4.5份)和乳糖(5.5份)的球形颗粒产物[例如,Nonpareil105T(70-140)(粒径100-200μm),Freund Industrial Co.,Ltd.(日本)制造],(ⅳ)150-250μm且含有结晶纤维素(5份)和乳糖(5份)的球形颗粒产物[例如,Nonpareil NP-5:5 Freund Industrial Co.,Ltd.(日本)制造],等等。
为了制备具有良好溶解作用且保持适当强度的药物制剂,所述“核芯”包括,例如优选含有结晶纤维素和乳糖的球形颗粒产物,更优选含有结晶纤维素和乳糖且所含乳糖占全部固体制剂的50%(重量)或以上的球形颗粒产物。其中,优选含有40-50%(重量)结晶纤维素和50-60%(重量)乳糖的核芯。
作为本发明中使用的“核芯”,优选采用含有结晶纤维素和乳糖的球形颗粒产物,更优选粒径为100-200μm且含有结晶纤维素(4.5份)和乳糖(5.5份)的球形颗粒产物。
所述“核芯”可以含有药学活性物质,如上述药学活性成分。另外,“核芯”可以不含有生理活性物质,因为可通过含有生理活性物质的包衣层来控制生理活性物质的释放。
除了粉状核芯以外,“核芯”优选是尽可能均匀的球形,以便减少包衣的不规则性。
“包衣层”和“核芯”的比例可以选择在能够控制生理活性物质的溶解作用和组合物粒度的范围内,例如通常是50至400重量份,以100重量份的核芯为基准计。
7-3)微细颗粒的包衣方法
包衣可以由多层构成。多层中的至少一层必须含有生理活性物质。可适合选择多层的组合,例如不含有活性成分的包衣层、基质包衣层和构成包衣层的肠溶包衣层。
在“核芯”包衣的情况中,例如上述生理活性物质和水溶性聚合物可以以其混合物应用。混合物可以是溶液或分散体,并且可以利用有机溶剂如水或乙醇或其混合物来制备。
混合物中水溶性聚合物的浓度根据生理活性物质和添加剂的比例而改变,并且通常是固体制剂总量的0.1至50%(重量),优选0.5至10%(重量),以便使核芯保持生理活性物质的粘合强度且维持混合物的粘度,从而不降低可加工性。
当包衣层包括多个层时,通过选择水溶性聚合物的含量比例或粘度,或通过用生理活性物质和其他添加剂的比例不同的混合物连续包衣,可以连续或逐级改变生理活性物质在各层中的浓度。在上述情况中,可以用混合物包衣,混合物中水溶性聚合物的含量比例不在0.1至50%(重量)的范围内,但只要包衣层中总共含有0.1至50%(重量)的水溶性聚合物。此外,在按照已知方法形成惰性包衣中,包衣层任选地含有一些层,由此惰性层可阻隔含有生理活性物质的各层。
另外,在相容性不适宜的两种或多种生理活性物质的情况中,核芯可以用结合或分开的各种混合物进行包衣。
将上述包衣材料干燥,并且通过筛子,得到具有均匀尺寸的“组合物”。因为组合物的形式一般取决于核芯,所以可以获得粗糙球形的微细颗粒。可以利用筛子,例如#50圆形筛子(300μm)。通过选择通过#50圆形筛子的那些颗粒得到所述组合物。
本发明中的“微细颗粒”可以按照与上述制粒方法相同的方法来制备,例如一种包括用肠溶包衣包被组合物的方法,从而保护生理活性物质或赋予肠溶性。如果必要,用肠溶包衣层包被的组合物可以进一步用水溶性糖醇包衣,优选甘露糖醇包衣。在这种情况中,含有微细颗粒的口腔内可崩解片剂的强度得以提高。
“肠溶包衣层”适宜是厚度为20-70μm,优选30-50μm且包被在含生理活性物质的组合物整个表面的包衣层。所以,组合物的粒径越小,整个微细颗粒中肠溶包衣层的百分重量越高。在本发明的微细颗粒中,“肠溶包衣层”占微细颗粒总量的30-70%(重量),优选50-70%(重量)。
“肠溶包衣层”任选地由多层(例如2或3层)构成。例如,采用一种方法,该方法包括用具有聚乙二醇的肠溶包衣层包被组合物,并且随后用具有柠檬酸三乙酯的肠溶包衣层包被,此后用具有聚乙二醇的肠溶包衣层包被。
8)可快速崩解固体制剂的制备
按照药物制剂领域中的常规方法或其类似方法可以制备本发明的可快速崩解固体制剂。此类方法例如是下述方法,包括将药学活性成分、糖和具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素混合,如果需要可在混合之前加入水,模压,并且随后根据需要进行干燥。然而,本发明的可快速崩解的固体制剂也可以不用水制备。
8-1)可快速崩解片剂的制备
为了制备口腔内可崩解片剂,通过采用适当的组分可应用常规模压方法或其类似方法,所述组分选自包括微细颗粒的上述组分。
对于具有包衣核芯的微细颗粒的口腔内可崩解片剂,优选方法的实例包括:
(ⅰ)用生理活性物质和赋形剂将含有结晶纤维素和乳糖的核芯包衣,随后用含有水溶性聚合物的包衣层包封,得到组合物,
(ⅱ)用具有聚乙二醇的肠溶包衣层包被所得组合物,并且随后用具有柠檬酸三乙酯的肠溶包衣层包被,和进而用甘露糖醇包衣,得到微细颗粒;和
(ⅲ)将所得微细颗粒与添加剂混合,随后模压。
当固体制剂是片剂,尤其是口腔内可崩解片剂时,模压操作例如可以利用单冲中压片机[Kikusui Seisakusho(日本)]或旋转压片机[KikusuiSeisakusho(日本)]采用0.5至3ton/cm2,优选1至2ton/cm2的压力进行压片。
可以利用任何技术进行干燥操作,例如真空干燥,流化床干燥和用于干燥普通药物制剂的类似方法干燥。
通过任何常规混合工技术混合、捏和、制粒等进行混合操作。混合操作采用设备例如是竖式制粒机VG10[Powrex Corp.(日本)制造],通用捏合机[Hata Iron works Co.Ltd.(日本)制造],流化床制粒机LAB-1和FD-2S[PowrexCorp.(日本)制造],离心流化包衣制粒机MP-10、MP-400[Powrex Corp.(日本)制造]等进行。
在本说明书中,“包衣”也是指除在被包衣目标(例如核芯)的整个表面包衣以外的部分包衣和粘附或吸附。
“球形”也是指除了球形以外具有弯曲表面的形状,例如具有椭圆形截面的形状,和茄形和液滴性的形状。
“平均粒径”是指基于体积分布的正中直径(正中直径:得自累积分布的50%粒径),除非另外说明。其可以通过例如激光衍射粒子分布测量法测定。具体例如Raiser衍射分析仪,型号:HEROS RODOS[商品名;Sympatec(德国)制造]。
在本发明中,“微细颗粒”具有的平均粒径等于或小于约400μm,以便在口腔内感觉不到粗糙。优选的微细颗粒的平均粒径是300-400μm。
除了上述“微细颗粒”的平均粒径以外,对于最大粒度,粒径基本上等于或小于425μm,并且优选基本上等于或小于400μm。优选的粒径基本上是300-425μm,更优选300-400μm。
在“粒径基本上等于或小于425μm”和“粒径基本上等于或小于400μm”中所用的词语“基本上”是指所述颗粒可以包含少量(等于或小于约5%重量)粒径不在上述范围内的颗粒,包括不可避免的污染颗粒。
“组合物”可以含有水溶性聚合物,上述粘合剂、润滑剂、赋形剂和常用作药物材料的类似物质。此类水溶性聚合物、粘合剂、润滑剂和赋形剂的用量选自在制备普通剂型制剂中所用的常规用量。
“水溶性聚合物”包括,例如:可溶于乙醇的水溶性聚合物(即乙醇溶性水溶性聚合物),如纤维素类衍生物(如羟丙基纤维素,在下文中可称作“HPC”),聚乙烯吡咯烷酮等;不溶于乙醇的水溶性聚合物(即乙醇不溶性水溶性聚合物),如纤维素类衍生物(如羟丙基结晶纤维素,其在下文中可称作“HPMC”,甲基纤维素,羧甲基纤维素钠等),聚丙烯酸钠,聚乙烯醇,藻酸钠,和瓜尔胶等。
当采用此类水溶性聚合物时,通过应用乙醇溶性水溶性聚合物和乙醇不溶性水溶性聚合物的混合物或通过应用某些具有不同粘度的水溶性聚合物的混合物来控制药物(生理活性物质)的溶解。
在本发明中,“水溶性聚合物”优选是纤维素类衍生物如HPC、HPMC、甲基纤维素和聚乙烯醇。更优选是纤维素类衍生物如HPC、HPMC。
“HPC”含有例如约53.4至77.5%(重量),更优选约60-70%(重量)的羟丙氧基。2%(重量)的HPC水溶液在20℃下的粘度一般是约1-150000cps(厘泊)。作为上述HPC,可采用日本药典中定义的羟丙基纤维素。此后,HPC的所有粘度是在20℃的2%(重量)值。
“HPMC”是通过甲氧基和羟丙氧基相连的混合醚。HPMC中甲氧基的含量例如是约19-30%(重量)。羟丙氧基的含量例如是约4-12%(重量)。在20℃2%(重量)HPMC的水溶液的粘度通常是约1至40000厘沲。此类HPMC可以采用日本药典定义的羟丙基甲基纤维素2208,日本药典定义的羟丙基甲基纤维素2906,日本药典定义的羟丙基甲基纤维素2910等。羟丙基纤维素(类)可以单独使用或以两种或多种的混合物使用。
水溶性聚合物如HPC和/或HPMC的含量一般是约0.1至50%(重量),优选约1-30%(重量),以含有生理活性物质的“组合物”的总量计,从而控制含有生理活性物质的组合物中生理活性物质的溶解作用并且维持高含量的生理活性物质。
在本发明中,“微细颗粒”可含有例如氧化钛作为掩蔽剂。
本发明的“口腔内可崩解片剂”的直径是约5至20mm,优选约7-15mm,更优选约8-13mm。
“口腔内可崩解片剂”任选地在片剂内可不含有润滑剂。
当本发明的“微细颗粒”应用于除口腔内可崩解片剂以外的片剂时,片剂的直径是约5至10mm,优选约5-8mm。当本发明的微细颗粒用于胶囊时,胶囊的尺寸优选是#2或小于#2胶囊。
9)可快速崩解固体制剂的性质
由此所得的本发明的可快速崩解固体制剂在口腔、水或胃内具有快速崩解性或溶解性,和适当的制剂强度。此外,改进了本发明可快速崩解固体制剂的粉质口感并且无粗糙感。
9-1)崩解时间
本发明的可快速崩解固体制剂的口腔内崩解时间(在颊唾液作用下对于健康成年男子或女子制剂完全崩解所用的时间)通常是5至50秒,优选5至40秒,更优选5至35秒。
本发明的可快速崩解固体制剂在胃内的崩解时间(对于健康成年男子或女子制剂完全崩解所用的时间)比普通制剂如普通片短。
本发明的可快速崩解固体制剂在水中的崩解时间通常是5至40秒,优选5至30秒,更优选5至25秒。
9-2)制剂的强度
本发明的可快速崩解固体制剂的强度(用片剂硬度检验器测定)通常是2至20kg,优选4至15kg。
9-3)给药方式
本发明的可快速崩解固体制剂尤其适宜于口腔内可崩解片剂并且可以不用水或用水的条件下给药。
作为给药方法,有(1)一种给药方法是用少量水,或不用水而用口腔内的唾液溶解或崩解,不吞咽药物,或(2)一种给药方法用水吞咽药物。另外,可以用水溶解或崩解片剂给药。
本发明的“口腔内可崩解片剂”适用于(a)其中不允许用水给药的情况,(b)向难以吞咽片剂的患者给药的情况,或(c)向那些如果是普通片剂则畏惧梗塞在喉部的老年或儿童给药的情况。
本发明的可快速崩解固体制剂可安全地口腔内给药于哺乳动物,如小鼠、大鼠、兔、猫、狗、牛、马、猴、人等。
9-4)剂量和具体实施方案
所述可快速崩解固体制剂的剂量根据药学活性成分、对象、疾病类型等改变,选择的剂量应使药学活性成分的剂量可以是有效量。
在上述情况(a)中,口腔内可崩解片剂适用于解热剂、镇痛药、抗炎药、抗焦虑药、镇咳祛痰药、抗运动病药、预防和制疗晕车的药物等。
在上述情况(b)中,口腔内可崩解片剂优选用于预防和/或治疗高血压、高脂血症、糖尿病、支气管哮喘、脑血管疾病等。
9-4-1)兰索拉唑
例如,当兰索拉唑用作药学活性成分时,本发明的可快速崩解固体制剂适用于治疗和预防消化性溃疡(如胃溃疡、十二指肠溃疡、吻合处溃疡、Zollinger-Ellison综合征)、胃炎、反射性食管炎等;根除幽门螺旋菌;抑制由消化性溃疡引起的上胃肠道出血,急性应激性溃疡和出血性胃炎;抑制由侵袭性应激(例如增强护理或脑血管疾病、头部损伤、多种器官衰竭、需要特别护理的大面积烧伤后大规模手术压迫引起的应激)引起的上胃肠道出血,治疗和预防非甾类抗炎药引起的溃疡;治疗和预防胃酸过多和术后应激引起的溃疡;麻醉前给药等。兰索拉唑对每个成年人(体重60kg)的给药剂量是0.5至1500mg/天,优选5至150mg/天。
9-4-2)伏格列波糖
当用伏格列波糖作为药学活性成分时,本发明的可快速崩解固体制剂用于治疗和预防肥胖、肥胖症、脂血症、糖尿病等。伏格列波糖对于每个成人(体重60kg)的给药剂量是0.01至30mg/天,优选0.1至3mg/天。可快速崩解固体制剂可以每天给药1次,或每天分开给药2至3次。
9-4-3)马尼地平·HCl
当用盐酸马尼地平作为药学活性成分时,本发明的可快速崩解固体制剂用于治疗和预防循环系统疾病如高血压、局部缺血性心脏病(例如心绞痛、心肌梗塞等),中枢和外周循环疾病(例如脑梗塞,瞬时性局部缺血发作、肾动脉收缩等)等。盐酸马尼地平对于每个成人(体重60kg)的给药剂量是1至200mg/天,优选10至20mg/天。可快速崩解固体制剂通常每天在早餐之后给药1次。
9-4-4)吡格列酮·HCl
当用盐酸吡格列酮作为药学活性成分时,本发明的可快速崩解固体制剂用作耐胰岛素改善药等,并且用于治疗和预防糖尿病。盐酸吡格列酮对于每个成人(体重60kg)的给药剂量是7.5至60mg/天,优选15至45mg/天。可快速崩解固体制剂可以每天给药1次,或每天分开给药2至3次。
9-4-5)西拉克西替坎德沙坦(candesartan celexetil)
另外,当用西拉克西替坎德沙坦作为药学活性成分时,本发明的可快速崩解固体制剂适用于治疗和预防高血压、心脏病、脑中风、肾病等。西拉克西替坎德沙坦对于每个成人(体重60kg)的给药剂量是1至50mg/天,优选2至30mg/天。
实施本发明的最佳方式
本发明通过下列参照实施例、实施例和试验实施例更具体地说明。应理解本发明不限定在这些实施例。
除非另外具体指出,下文的“%”是指重量百分比。
另外,羟丙氧基的含量是按照日本药典(例如第13版)描述的方法测定。片剂的物理性质(硬度和崩解时间)按照下列试验方法测定。
(1)硬度试验
采用片剂硬度检测仪[Toyama Sangyo Co.Ltd.(日本)制造]进行测定。试验进行10次且用平均值表示。
(2)口腔内崩解时间
测定片剂仅在口腔内唾液的作用下完全崩解或溶解的时间。
实施例
参照实施例1
通过将木浆浸渍在49%氢氧化钠的水溶液中且随后压制得到含有24.1%NaOH,1.7%Na2CO3,42.9%纤维素,31.8%H2O的碱性纤维素。反应器中加入100重量份碱性纤维素。随后,进行氮气置换。置换后,在反应器中加入5重量份的氧化丙烯并且在40℃搅拌下反应1小时,在50℃下反应1小时和在70℃下1小时,得到103重量份的反应物。
另一方面,向捏合机中加入2.5重量份65℃的热水和0.13重量份冰醋酸(中和所需当量的40%(重量),起始中和酸)并且其中分散1重量份的上述所得碱性纤维素。随后,将温度调节在30℃以溶解一部分反应物,和加入0.20重量份冰醋酸(中和所需的剩余当量,完全中和酸)以提供一种含有一部分溶解和一部分沉积物的经加工纤维产物。
所得产物用80℃的热水洗涤,排水,干燥,用高级滚动冲击研磨机研磨,用100目筛子筛分,得到低取代羟丙基纤维素LH-33(羟丙氧基的含量:5.8%(重量),平均粒径:17.8μm)的粉末。
参照实施例2
按照与参照实施例1相同的方法得到低取代羟丙基纤维素LH-23的粉末,其具有略大的平均粒径(羟丙基的含量:5.7%(重量),平均粒径:30.8μm)
实施例1
(1)具有核芯的粉末的制备
向离心流化包衣制粒机[Powrex Corp.(日本)制造,MP-10]加入900gNonpareil 105(商品名)(粒径:100-200μm)。分别将入口气体温度和出口气温度控制在70℃和30℃,用组成如下的喷雾液,按照切向喷雾法以22g/分钟的喷雾速率喷涂Nonpareil。随后干燥10分钟。所得颗粒经#60圆形筛(250μm)和#100圆形筛(150μm)筛分,得到2186g具有核芯的粉末(150-250μm)。
[喷雾液]
兰索拉唑 927g
碳酸镁 309g
低取代羟丙基纤维素LH-32 154.7g
(羟丙基的含量:8.8%重量)
(平均粒径:17.57μm)
羟丙基纤维素(SSL型) 309g
纯水 3955g
(2)具有核芯的底层薄膜包衣粉末的制备
向离心流化包衣制粒机[Powrex Corp.(日本)制造,MP-10]加入2040g的上述具有核芯的粉末。分别将入口气体温度和出口气体温度控制在75℃和40℃,按照切向喷雾法以13g/分钟的喷雾速率喷涂组成如下的预制的底层薄膜包衣液。得到2145g具有核芯的底层薄膜包衣粉末。
[底层包衣液]
羟丙基甲基纤维素 264g
(2910型,粘度:3厘沲)
纯水 5016g
(3)具有核芯的肠溶包衣粉末的制备
向离心流化包衣制粒机[Powrex Corp.(日本)制造,MP-10]加入1710g上述具有核芯的底层薄膜包衣粉末。分别将入口气体温度和出口气体温度控制在70℃和40℃,按照切向喷雾法以19g/分钟的喷雾速率喷涂组成如下的预制的肠溶薄膜包衣液。随后干燥7分钟。所得颗粒经#420圆形筛(355μm)和#80圆形筛(177μm)筛分,得到2393g具有核芯的粉末(177-355μm)。
[肠溶薄膜包衣液]
Eudragit L30D-55 5016.4g
Eudragit NE30D 559.0g
柠檬酸三乙酯 333.7g
一硬脂酸甘油酯 106.5g
吐温80 34.8g
氧化铁红 1.8g
纯水 2547.1g
(4)具有核芯的甘露糖醇外涂层的肠溶包衣粉末的制备
向离心流化包衣制粒机[Powrex Corp.(日本)制造,MP-10]加入600g上述具有核芯的肠溶包衣粉末。分别将入口气体温度和出口气体温度控制在65℃和32℃,按照切向喷雾法以11g/分钟的喷雾速率喷涂组成如下的预制的薄膜包衣液。随后,干燥7分钟。得到617g具有核芯的外涂层肠溶包衣粉末。
[薄膜包衣液]
甘露糖醇33g
纯水297g
(5)甘露糖醇粒化粉末的制备
向流化床制粒机[Powrex Corp.(日本)制造,LAB-1]加入800g甘露糖醇[Merck Japan Co.,Ltd.制造]。并且在喷雾315g纯水的同时进行制粒。干燥颗粒得到727.3g粒化粉末。
(6)混合粉末的制备
向105g上述具有核芯的外涂层肠溶包衣粉末中加入97.3g的上述甘露糖醇粒化粉末、15.0g的低取代羟丙基纤维素LH-33(羟丙氧基的含量:5.8%(重量),平均粒径:17.8μm)、22.5g的结晶纤维素[CEOLUS KG-801(商品名),Asahi Chemical Industry Co.,Ltd.(日本)制造]、7.5g交联聚乙烯吡咯烷酮、1.5g的无水柠檬酸、0.45g的天冬甜素和0.75g硬脂酸镁,它们在一个袋中混合得到混合粉末。
(7)口腔内可崩解片剂的制备
通过冲击锤(15R,直径11mm)利用旋转式压片机以1.5ton/cm2的制片压力将250mg的上述混合粉末压片,得到各重500mg的片剂。
所得各片剂的硬度和口腔内崩解时间分别是5.0kg和30秒。
实施例2
(1)具有核芯的颗粒的制备
向离心流化包衣制粒机[Powrex Corp.(日本)制造,MP-10(Ⅱ型)]加入900gNonpareil 105(商品名)(粒径:100-200μm)。分别将入口气体温度和加料温度控制在65℃和约30℃,通过喷涂预制的组成如下的喷雾液(bulkliquid),按照切向喷雾法以22g/分钟的喷雾速率喷涂Nonpareil。当喷雾达到5661g喷雾液的给定用量时停止喷雾操作,随后在制粒机中干燥8分钟。所得颗粒经#42圆形筛(350μm)和#100圆形筛(150μm)筛分,得到2074g具有核芯的颗粒。
喷雾液:
兰索拉唑 1080g
碳酸镁 360g
低取代羟丙基纤维素LH-32 180g
(羟丙基的含量:8.8%重量)
羟丙基纤维素(SSL型) 360g
纯水 4680g
(2)具有核芯的底层薄膜包衣颗粒的制备
向离心流化包衣制粒机[Powrex Corp.(日本)制造,MP-10(Ⅱ型)]加入2074g上述具有核芯的颗粒。分别将入口气体温度和加料温度控制在78℃和约40℃,按照切向喷雾法以22g/分钟的喷雾速率喷涂组成如下的预制的底层包衣液。当喷雾达到1980g喷雾液的给定用量时停止喷雾操作,随后在制粒机中干燥9分钟。所得颗粒经#42圆形筛(350μm)和#100圆形筛(150μm)筛分,得到2555g具有核芯的底层薄膜包衣颗粒。
底层包衣液:
羟丙基甲基纤维素 252g
(2910型;粘度:3厘沲)
氧化钛(TiO2) 108g
灭菌滑石粉(商品名) 108g
[Matsumura Sangyo Co.,Ltd.(日本)制造]
低取代羟丙基纤维素LH-32 180g
(羟丙氧基含量:8.8%重量)
甘露糖醇 252g
纯水 3600g
(3)具有核芯的肠溶包衣颗粒的制备
向离心流化包衣制粒机[Powrex Corp.(日本)制造,MP-10(Ⅱ型)]加入1320g上述具有核芯的底层薄膜包衣粉末。分别将入口气体温度和加料温度控制在80℃和约42℃,按照切向喷雾法以22g/分钟的喷雾速率喷涂组成如下的预制的肠溶薄膜包衣液(A)。喷雾达到给定量1638g的肠溶薄膜包衣液。
肠溶薄膜包衣液(A):
Eudragit L30D-55 1219.2g
Eudragit NE30D 134.4g
聚乙二醇6000 40.8g
一硬脂酸甘油酯 24.0g
吐温80 7.2g
氧化铁 0.24g
氧化铁(黄色) 0.24g
无水柠檬酸 0.48g
纯水 1693g
此后,分别将入口气体温度和加料温度控制在76℃和约42℃,按照切向喷雾法以22g/分钟的喷雾速率喷涂组成如下的预制的肠溶薄膜包衣液(B)。喷雾达到给定量6552g的肠溶薄膜包衣液。
肠溶薄膜包衣液(B):
Eudragit L30D-55 4032g
Eudragit NE30D 447.8g
柠檬酸三乙酯 269.3g
一硬脂酸甘油酯 86.4g
吐温80 25.9g
氧化铁 0.86g
氧化铁(黄色) 0.86g
无水柠檬酸 0.72g
纯水 2624g
此后,分别将入口气体温度和加料温度控制在80℃和约42℃,按照切向喷雾法以22g/分钟的喷雾速率喷涂组成如上的预制肠溶薄膜包衣液(A)。喷雾达到给定量819g的肠溶薄膜包衣液。
(4)具有核芯的肠溶包衣且甘露糖醇包衣的颗粒的制备
(3)后,在分别将入口气体温度和加料温度控制在85℃和约35℃的,利用离心流化包衣制粒机[Powrex Corp.(日本)制造,MP-10(Ⅱ型)]按照切向喷雾法以22g/分钟的喷雾速率喷涂组成如下的预制的薄膜包衣液。当喷雾达到882g喷雾液的特定用量时停止喷雾操作,随后在制粒机中干燥10分钟。所得颗粒经#35圆形筛(420μm)和#60圆形筛(250μm)过筛,得到1964g具有核芯的肠溶包衣且甘露糖醇包衣的颗粒。
所得颗粒的平均粒径为333.7μm。
薄膜包衣液:甘露糖醇 180g
纯水 1080g
(5)混合粉末的制备
向270g的上述具有核芯的肠溶包衣和甘露糖醇包衣颗粒中加入204.0g的甘露糖醇、30g的低取代羟丙基纤维素LH-33(羟丙氧基的含量:5.8%(重量))、30g结晶纤维素[CEOLUS KG-801(商品名),Asahi ChemicalIndustry Co.,Ltd.(日本)制造]、15g交联聚乙烯吡咯烷酮、3g的无水柠檬酸、9g的天冬甜素、6g硬脂酸镁和3g矫味剂[STRAWBERRYDURAROME(商品名),Nihon Filmenich Co.,Ltd.(日本)制造],它们在一个袋中混合得到混合粉末。
(6)口腔内可崩解片剂的制备
利用装有具有倾斜边缘直径为13mm的冲击锤的Autograph(商品名;压力测量设备)以1.5ton/cm2的制片压力将570mg的上述混合粉末压片,得到各重570mg的片剂。
所得各片剂的硬度和口腔内崩解时间分别是2.6kg和20秒。
所得片剂的抗酸性为3.5%。
实施例3
向流化床制粒机[Powrex Corp.(日本)制造,LAB-1]加入0.6g伏格列波糖、410.4g赤藓醇[Nikken Chemicals Co.,Ltd.(日本)制造]、30g低取代羟丙基纤维素LH-33(羟丙氧基的含量:5.8%(重量),平均粒径:17.8μm)、30.0g CEOLUS KG-801[Asahi Chemical Industry Co.,Ltd.(日本)制造]、30g交联聚乙烯吡咯烷酮、6.0g的无水柠檬酸和1.2g的天冬甜素,并且在喷雾纯水的同时制粒。干燥后,掺入1.8g的硬脂酸镁。通过冲击锤(具有倾斜边缘,直径为10mm)、利用旋转式压片机以1.0ton/cm2的制片压力将所得粉末压片,得到各重300mg的片剂。
所得各片剂的硬度和口腔内崩解时间分别是10.7kg和26秒。
实施例4
向流化床制粒机[Powrex Corp.(日本)制造,LAB-1]加入0.6g的伏格列波糖、440.4g赤藓醇[Nikken Chemicals Co.,Ltd.(日本)制造]、120.0g的低取代羟丙基纤维素LH-33(羟丙氧基的含量:5.8%(重量),平均粒径:17.8μm)、30.0g的交联聚乙烯吡咯烷酮、6.0g的无水柠檬酸和1.2g的天冬甜素,并且在喷雾纯水的同时制粒。干燥后,掺入1.8g的硬脂酸镁。通过冲击锤(具有倾斜边缘,直径为10mm)、利用旋转式压片机以1.0ton/cm2的制片压力将所得粉末压片,得到各重300mg的片剂。
所得各片剂的硬度和口腔内崩解时间分别是7.1kg和20秒。
实施例5
向流化床制粒机[Powrex Corp.(日本)制造,LAB-1]加入0.4g的伏格列波糖、470.6g赤藓醇[Nikken Chemicals Co.,Ltd.(日本)制造]、120.0g的低取代羟丙基纤维素LH-33(羟丙氧基的含量:5.7%(重量),平均粒径:30.8μm)、6.0g的无水柠檬酸和1.2g的天冬甜素,并且在喷雾纯水的同时制粒。干燥后,掺入1.8g的硬脂酸镁。通过冲击锤(具有倾斜边缘,直径为10mm)、利用旋转式压片机以1.25ton/cm2的制片压力将所得粉末压片,得到各重300mg的片剂。
所得各片剂的硬度和口腔内崩解时间分别是4.5kg和23秒。
实施例6
向流化床制粒机[Powrex Corp.(日本)制造,LAB-1]加入0.4g的伏格列波糖、470.6g甘露糖醇[Merck Japan Co.,Ltd.制造]、120.0g的低取代羟丙基纤维素LH-23(羟丙氧基的含量:5.7%(重量),平均粒径:30.8μm)、6.0g的无水柠檬酸和1.2g的天冬甜素,并且在喷雾纯水的同时制粒。干燥后,掺入1.8g的硬脂酸镁。通过冲击锤(具有倾斜边缘,直径为10mm)、利用旋转式压片机以1.25ton/cm2的制片压力将所得粉末压片,得到各重300mg的片剂。
所得各片剂的硬度和口腔内崩解时间分别是4.3kg和27秒。
实施例7
向流化床制粒机[Powrex Corp.(日本)制造,LAB-1]加入40.0g的盐酸马尼地平、460.94g赤藓醇[Nikken Chemicals Co.,Ltd.(日本)制造]、60.0g的低取代羟丙基纤维素LH-33(羟丙氧基的含量:5.8%(重量),平均粒径:17.8μm)、30.0g的聚交联乙烯吡咯烷酮、6.0g的无水柠檬酸和1.2g的天冬甜素,并且在喷雾其中溶解有0.06g黄色氧化铁的纯水的同时制粒。干燥后,掺入1.8g的硬脂酸镁。通过冲击锤(具有倾斜边缘,直径为10mm)、利用旋转式压片机以1.0ton/cm2的制片压力将所得粉末压片,得到各重300mg的片剂。
所得各片剂的硬度和口腔内崩解时间分别是6.0kg和21秒。
试验实施例1
向4位女人分别给药低取代羟丙基纤维素LH-30(羟丙氧基的含量:14.6%(重量),平均粒径:17.26μm),LH-31(羟丙氧基的含量:11.0%(重量),平均粒径:18.18μm),LH-32(羟丙氧基的含量:8.8%(重量),平均粒径:17.57μm)和LH-33(羟丙氧基的含量:5.8%(重量),平均粒径:17.8μm),并且评价溶解度和口感。
试验结果如[表1]所示:
[表1]低取代羟丙基纤维素 试验对象 评价
LH-30 4/4 在口腔内难以溶解
LH-31 4/4 在口腔内溶解,粉质口感
LH-32 4/4 在口腔内溶解,粉质口感
KH-33 4/4 在口腔内溶解,无粉质口感
如[表1]所示,对于含有5.8%(重量)羟丙氧基的低取代羟丙基纤维素LH-33的情况,其中改善了溶解度和粉质口感,并且不再有粗糙感。
试验实施例2
按照下列方式利用低取代羟丙基纤维素LH-30(羟丙氧基的含量:14.6%(重量),平均粒径:17.26μm),LH-31(羟丙氧基的含量:11.0%(重量),平均粒径:18.18μm),LH-32(羟丙氧基的含量:8.8%(重量),平均粒径:17.57μm)和LH-33(羟丙氧基的含量:5.8%(重量),平均粒径:17.8μm)制备片剂。
向流化床制粒机[Powrex Corp.(日本)制造,LAB-1]加入398.5g赤藓糖[Nikken Chemicals Co.,Ltd.(日本)制造]和100g的低取代羟丙基纤维素,并且在喷雾纯水的同时进行制粒。干燥后,掺入1.5g硬脂酸镁。通过冲击锤(具有倾斜边缘,直径为10mm)、利用旋转式压片机以1.0ton/cm2的制片压力将所得粉末压片,得到各重300mg的片剂。
分别将所得片剂给药于4名女人,评价溶解度和口感。
结果如[表2]所示。
[表2]低取代羟丙基纤维素 试验对象 评价
LH-30 4/4 在口腔内不溶解
LH-31 4/4 在口腔内不溶解
LH-32 4/4 在口腔内感觉粘着,溶解后仍有粉质口感
KH-33 4/4 在口腔内快速溶解,轻微粉质口感
如[表2]所示,对于含有5.8%(重量)羟丙氧基的低取代羟丙基纤维素LH-33的情况,其中改善了溶解度和粉质口感,并且不再有粗糙感。
发明效果
本发明的可快速崩解固体制剂适用于治疗和预防多种疾病,尤其是作为可口腔内快速崩解的固体制剂,该制剂不用水就可给药于老年人或儿童,因为该制剂具有优良的崩解性和溶解度。其在胃内的崩解性也得以改进。
而且,所述可快速崩解固体制剂具有良好的长时间稳定性,因为该制剂具有适当的强度。
此外,本发明的可快速崩解固体制剂改善了溶解度和粉质口感,并且不粗糙。
Claims (19)
1.一种可快速崩解固体制剂,其中含有(ⅰ)药学活性成分,(ⅱ)糖和(ⅲ)具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素。
2.权利要求1的制剂,其是口腔内可快速崩解固体制剂。
3.权利要求1或2的制剂,其是片剂。
4.权利要求1的制剂,其中所述糖是糖醇。
5.权利要求4的制剂,其中糖醇是甘露糖醇或赤藓醇。
6.权利要求1的制剂,其中糖的用量是5至97重量份/100重量份固体制剂。
7.权利要求1的制剂,其中具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素的用量是3至50重量份/100重量份的固体制剂。
8.权利要求1的制剂,其中药学活性成分是兰索拉唑。
9.权利要求1的制剂,其中药学活性成分是伏格列波糖。
10.权利要求1的制剂,其中药学活性成分是盐酸马尼地平。
11.权利要求1的制剂,其中药学活性成分是盐酸吡格列酮。
12.权利要求1的制剂,其中药学活性成分是西拉克西替坎德沙坦。
13.权利要求3的制剂,其含有微细颗粒。
14.权利要求13的制剂,其中药学活性成分含在该固体制剂的微细颗粒中。
15.权利要求14的制剂,其中(ⅰ)糖和(ⅱ)具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素含在固体制剂中但与微细颗粒分开。
16.权利要求15的制剂,其中糖的用量是5至97重量份/100重量份的除微细颗粒之外的固体制剂剩余部分。
17.权利要求15的制剂,其中具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素的用量是3至50重量份/100重量份的除微细颗粒之外的固体制剂剩余部分。
18.具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素在制备含有药学活性成分和糖的可快速崩解固体制剂中的用途。
19.一种提高含有药学活性成分和糖的固体制剂的快速崩解性的方法,其特征在于其中包含具有等于或大于5%(重量)至小于7%(重量)羟丙氧基的低取代羟丙基纤维素。
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1999
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Cited By (3)
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CN1321629C (zh) * | 2002-02-15 | 2007-06-20 | 大塚制药株式会社 | 具有改善的压片特性的片剂及其生产方法 |
CN101534792B (zh) * | 2006-08-04 | 2013-02-20 | 爱的发 | 包含氧可酮的粒剂和口腔崩解片剂 |
CN102379854A (zh) * | 2010-08-31 | 2012-03-21 | 扬子江药业集团北京海燕药业有限公司 | 盐酸马尼地平口服速释制剂及其制备方法 |
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