CN1159000C - 口腔释放*** - Google Patents

口腔释放*** Download PDF

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CN1159000C
CN1159000C CNB971945632A CN97194563A CN1159000C CN 1159000 C CN1159000 C CN 1159000C CN B971945632 A CNB971945632 A CN B971945632A CN 97194563 A CN97194563 A CN 97194563A CN 1159000 C CN1159000 C CN 1159000C
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K·温图拉斯
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Abstract

本发明涉及一种可缓慢侵蚀的锭剂形式的口腔释放***，它可延长活性物质释放到口腔粘膜的时间，例如长达15至90分钟。本发明锭剂表现出几乎零级的活性物质释放和舒适的口感特性。

Description

口腔释放***
本发明涉及一种缓慢侵蚀的、具有舒适感觉特性的锭剂，使用者在吮吸它时，口中有一种舒适感。当活性物质，特别是药物活性物质被加入到这种组合物中时，就得到以控制方式(例如：几乎为零级释放〕缓慢释放活性物质的口腔释放***(buccal delivery system)。
药物通过口腔粘膜释放是服用许多局部或***作用的活性成分的一种众所周知的和方便的途径。咀嚼片、锭剂和其它类似的口服剂型在市场上存在多年。这些未精炼药物形式通常由可溶性稀释物如蔗糖、乳糖、甘露醇、山梨醇和粘合剂构成。通常加入润滑剂、调味剂、增甜剂、味道调整剂和一种或多种活性物质，它们并不改进混合物药片特性。这些形式的药物一放在口中，在几秒钟内或至多十分钟内就比较快地溶化了，并把可溶的和不可溶的活性成分都释放到口腔中。
市场上存在的口香糖，经常被用来增加活性成分释放到口腔的时间，该时间可超过半小时。虽然这些剂型广泛和适用于几种药物例如氟化物补充物(fluoride supplement)、尼古丁等，但是它们的确也有缺点。一个主要缺点是通常味道在口中改变较快—经常是咀嚼几分钟后味道即改变—原因是咀嚼活动开始时存在的调味剂和增甜剂的迅速释放。而且口香糖不是一个完善的给药方式，并且一天数次长时间的咀嚼使人疲劳和不舒适。
本发明涉及一种新的口腔释放***，它可延长可溶的或不可溶的活性物质释放到口腔粘膜的时间。这种释放是以一种控制释放方式进行的，通常在15到90分钟甚至更长时间内进行。
本发明的口腔释放***的形式为缓慢侵蚀的锭剂，并且基本上由下列成分组成：(由下列成分形成的不溶性基质)
a)含量为组合物总量的50～99％(重量)的可溶性填料，
b)能够形成不溶性基质的不溶性成膜剂，
c)可溶胀的聚合物，
d)可有可无的活性物质，以及
e)可有可无的常用的助剂。
可采用的可溶性填料(a)例如是任何糖或不含糖的增甜剂，如麦芽糖醇、木糖醇、山梨醇、甘露醇、乳糖、葡萄糖、蔗糖或果糖，或其任意混合物，例如木糖醇和山梨醇的混合物如Xylisorb。可溶性填料(a)优选为麦芽糖醇、木糖醇、甘露醇、葡萄糖、果糖或其任意混合物。可溶性填料(a)更优选麦芽糖醇、木糖醇、甘露醇或其任意混合物；特别优选的是麦芽糖醇、木糖醇或其任意混合物。
可溶性填料(a)的量为组合物总量的50～95％(重量)，优选为55～95％(重量)，更优选为60～90％(重量)，尤其优选为70～90％(重量)，特别为80～90％(重量)。
可利用的能形成不溶性基质的不溶性成膜剂(b)例如可以是聚丙烯酸酯，包括丙烯酸和/或甲基丙烯酸的烷基酯、尤其是甲基和乙基酯以及取代的烷基酯如二甲氨基乙基酯的均聚物或共聚物，例如Roehm PharmaGmbH，Darmstadt(德国)的Eudragit产品，如EudragitS、EudragitNE、EudragitE或EudragitL。另外，不溶性成膜剂还包括例如：乙基纤维素，如FMC公司，Philadelphia(美国)的Aquacoat产品，如AquacoatECD 30；聚氯乙烯、乙酸纤维素、邻苯二甲酸乙酸纤维素或紫胶。上述物质的混合物也可用作不溶性成膜剂(b)。
不溶性成膜剂(b)优选为聚丙烯酸酯，尤其是水分散体形式的聚丙烯酸酯，例如EudragitNE30D。
不溶性成膜剂(b)的量通常为组合物总量的0.5～30％(重量)、优选为0.5～24％(重量)、更优选为3～10％(重量)。
在本发明的口腔释放***的生产中，能形成不溶性基质的不溶性成膜剂(b)例如可以以水分散体[假乳胶(Pseudolatex)]或非水分散体(利用有机溶剂)，或以水溶液或非水溶液，或固体的形式加以利用。
为避免任何可能的误解，这里所采用的成膜剂(b)不是用来形成膜或涂层，而是用来与其它成分完全混合而形成不溶性基质，即锭剂。
任何天然或合成得到的可溶胀的毒理学可接受的聚合物均可用作可溶胀聚合物(c)。合适的可溶胀聚合物(c)的实例包括：黄原胶，瓜耳胶，藻蛋白酸或其盐如藻酸钠，果胶，聚乙烯醇，多糖如葡聚糖，以及可溶胀的纤维素衍生物，如羧甲基纤维素的钠盐或钙盐(如Dow Chem，Midland(美国)的Methocel系列)、羟乙基纤维素(如Klucel)或羟丙基纤维素。上述物质的混合物也可作为可溶胀的聚合物(c)使用。
优选的可溶胀的聚合物(c)为黄原胶、瓜耳胶、藻蛋白酸或其盐如藻酸钠，以及可溶胀的纤维素衍生物如羧甲基纤维素的钠盐或钙盐、羟丙基甲基纤维素、羟乙基纤维素或羟丙基纤维素。
尤其优选的可溶胀聚合物(c)为黄原胶。
可溶胀聚合物(c)的量通常为组合物总量的0.5～30％(重量)，优选为0.5～24％(重量)，更优选为3～10％(重量)。
活性物质(d)例如为药物活性物质。它包括任何种类的可经口腔或通过口腔粘膜给药的药物活性物质。药物活性物质也可理解为包括例如用于戒烟的尼古丁及其盐和衍生物。可应用的药物活性物质种类，例如包括：尼古丁及其盐和衍生物，如尼古丁酒石酸盐或尼古丁polacrilex(含尼古丁的复合树脂，如含10或20％(wt)的尼古丁)，特别是尼古丁酒石酸盐；激素，如褪黑激素；氟化物补充物，如氟化钠或其它氟化物盐类；局部消毒剂，如氯苄羟乙胺、洗必太或洁尔灭；局部麻醉剂，如利多卡因、苯佐卡因、奴夫卡因或地布卡因；止痛和/或消炎药，例如乙酰水杨酸、双氯高灭酸、醋氨芬或布洛芬；抗酸药；止吐药；抗牙斑制剂；抗口腔溃疡制剂；H2-受体拮抗剂如呋喃硝胺或甲氰咪胍；含有细菌的制剂，特别是含有选自乳酸杆菌属和/或双歧杆菌的细菌的制剂；抗菌素、盐酸二乙胺苯丙酮、平喘药、制尿药、抗偏头痛制剂(antimigraine agents)、解痉药、镇静药、抗机能亢进药(antihyperactives)、镇定药、甲氧苄二胺、减充血剂(decongestants)、β-阻滞剂以及其组合制剂。
本领域公知的可选择性存在的常用助剂(e)包括润滑剂、调味剂、芳香剂、增甜剂、着色剂、缓冲剂、酸化剂、稀释剂、防腐剂、滑移剂如二氧化硅胶体等。
由于吮吸作用，本发明的口腔释放***允许锭剂在口中控制地侵蚀，同时伴有舒适的口感特性和活性成分的近似零级释放，不发生锭剂的崩解。“零级释放”是指释放-时间关系是线性的(见图1)。
如果口腔释放***仅是由可溶性填料(a)和不可溶的成膜剂(b)的混合物制成—没有可溶胀聚合物(c)—所得到的锭剂具有延长释放的特性，但是也有了令人讨厌的口感特性。尤其在吮吸过程中，这种不可溶的成膜剂在口中以一种具有令人讨厌的味道和粘稠的不可溶丝状物存在。
如果口腔释放***仅仅由可溶性填料(a)和可溶胀聚合物(c)组成的混合物来制成—没有不可溶的成膜剂(b)—通过压缩，所得到的锭剂具有延长释放的特性，但是造成在口中有令人讨厌的膨胀和胶凝感。而且这些锭剂在口中极易破裂，并且受吮吸的影响很大，这通常在吮吸锭剂后最初的10分钟内即变得明显。
相反，当吮吸本发明的锭剂时，可膨胀聚合物(c)仅在润湿的锭剂表面溶胀。可溶胀聚合物(c)(＝胶凝剂)的小片和不溶性成膜剂(b)一起从锭剂表面被侵蚀。被侵蚀的微粒(c)和(b)混和物在口中感觉不到。被侵蚀的锭剂的尺寸减少，但是在吮吸过程结束前一直保持它的形状。也就是说，被侵蚀的锭剂直至最后被完全侵蚀和溶化之前不会崩解。而且，如前所述，由锭剂的释放几乎是恒定的(零级释放)。这在对健康志愿者所作的吮吸试验中得到确认(见图1，尤其是配方1和2)。
根据所想要的释放情况，可调配得到在口中更慢或稍快地可侵蚀的本发明新型口服可溶胀药剂(参见图1，配方1和2)。如果增加不溶性成膜剂(b)(例如聚丙烯酸酯分散体)的量，和/或可溶胀聚合物(c)(例如黄原胶)的量，将得到侵蚀更慢的锭剂。
因此令人惊奇的是，发现三种基本成分(a)、(b)和(c)的混合物导致控制释放锭剂具有以下特性：(1)通过侵蚀和扩散从而改善延迟释放效果，(2)几乎为零级释放(见表1，配方1和2)，和(3)具有舒适的口感特性。
本发明的缓蚀的锭剂千万不要与硬糖(象“夹心糖”)混淆，硬糖是硬的，不溶胀并且通常包含象谷类糖浆一样的液化糖。
本发明的口腔释放***可通过几种不同的制作方法生产，例如通过：
(1)混合所有成分、并且接着压缩的传统湿造粒法，或者
(2)两阶段法，它包括：仅将其中的一些成分造粒阶段，然后是向外部相加入其它成分、例如活性物质(见配方1、2、3和5)的阶段，接着压缩，或者
(3)不需要造粒阶段的直接压缩方法(见配方4)。
上述所有方法最后都有一个共同的压缩步骤。因此从原理上讲，本发明锭剂优选通过成分(a)、(b)、(c)、(d)和(e)的混合物的压缩得到。
下述实施例解释、但不是以任何方式限制本发明。
配方1： 组成(1000片锭剂)
尼古丁酒石酸盐二水合物     3.07克
麦芽糖醇                   880.0克
碳酸氢钠                   20.0克
聚丙烯酸酯分散体30％       50.0克(干重)
黄原胶                     40.0克
无水二氧化硅胶体           15.0克
硬脂酸镁                   20.0克
制作方法：
在一个流动床(fluid bed)中混合麦芽糖醇、碳酸钠和2/3无水二氧化硅胶体。利用一逆流流动床造粒装置(contra-current fluid bedgranulation)将该混合物和聚丙烯酸酯分散体一起造粒。将干燥的微粒和尼古丁酒石酸盐、黄原胶以及剩余的1/3无水二氧化硅胶体和硬脂酸镁混合。压缩此混合物，得到质量为约1028mg的15mm的两面凸的圆形锭剂。
配方2： 组成(1000片锭剂)
尼古丁酒石酸盐二水合物      3.07克
麦芽糖醇                    880.0克
无水碳酸钠                    40.0克
聚丙烯酸酯分散体30％          70.0克(干重)
黄原胶                        60.0克
无水二氧化硅胶体              15.0克
薄荷                          30.0克
Levomenthol                   3.0克
糖精钠                        5.0克
硬脂酸镁                      20.0克
制作方法：
在一个流动床中将麦芽糖醇、无水碳酸钠和2/3无水二氧化硅胶体混合。利用一逆流流动床造粒装置将此混合物与聚丙烯酸酯分散体一起造粒。将这些干燥颗粒与尼古丁酒石酸盐、黄原胶、剩余的1/3无水二氧化硅胶体、Levomenthol、薄荷、糖精钠和硬脂酸镁混合。压缩此混合物，得到质量为约1126mg的15mm的两面凸的圆形锭剂。
配方3： 组成(1000片锭剂的)
尼古丁酒石酸盐的二水合物      3.07克
木糖醇                        880.0克
无水碳酸钠                    40.0克
聚丙烯酸酯分散体30％          50.0克(干重)
黄原胶                        40.0克
无水二氧化硅胶体              15.0克
肉桂调味剂                    15.0克
糖精钠                        5.0克
硬脂酸镁                      20.0克
制作方法：
在一个流动床中混合麦牙糖醇、无水碳酸钠和2/3无水二氧化硅胶体。利用一逆流流动床造粒装置将此混合物与聚丙烯酸酯分散体一起造粒。将这些干燥颗粒与尼古丁酒石酸盐、黄原胶、剩余1/3无水二氧化硅胶体、levomenthol、薄荷、糖精钠和硬脂酸镁混合。压缩此混合物，得到质量为约1068mg的15mm的两面凸的圆形锭剂。
配方4： 组成(1000片锭剂的)
尼古丁酒石酸盐的二水合物                    3.07克
Xylisorb(＝木糖醇和山梨醇之混合物)       850.0克
无水碳酸钠                                  40.0克
Eudragit S-100                           100.0克
黄原胶                                      40.0克
无水二氧化硅胶体                            5.0克
薄荷                                        30.0克
Levomenthol                                 3.0克
糖精钠                                      5.0克
硬脂酸镁                                    20.0克
制作方法：
将除硬脂酸镁以外的所有成分混合，并且通过一个装有孔径大小为0.63mm筛网的Frewitt进行过筛。加入硬酯酸镁并混合5分钟。压缩此混合物，得到质量为约1096mg的15mm的两面凸的圆形锭剂。
配方5： 组成(1000片锭剂的)
尼古丁酒石酸盐二水合物               3.07克
麦芽糖醇                             880.0克
碳酸钠                               10.0克
碳酸氢钠                             20.0克
聚丙烯酸酯分散体30％                 50.0克(干重)
黄原胶                               40.0克
无水二氧化硅胶体                     15.0克
Levomenthol                          3.0克
薄荷油                               5.0克
天冬酰苯丙酸甲酯                   10.0克
硬脂酸镁                           20.0克
制作方法：
在一个流动床(fluid bed)中将麦芽糖醇、碳酸钠、碳酸氢钠和2/3无水二氧化硅胶体混合。利用一逆流流动床造粒装置将此混合物与聚丙烯酸酯分散体一起造粒。将这些干燥颗粒与尼古丁酒石酸盐、黄原胶、剩余1/3无水二氧化硅胶体、硬脂酸镁、levomenthol、薄荷油和天冬酰苯丙酸甲酯混合。压缩此混合物，得到质量为约1056mg的15mm的两面凸的圆形锭剂。

Claims (7)

1.一种可缓慢侵蚀的锭剂，它基本上由以下成分组成：
(a)含量为组合物总量的50～95％wt的可溶性填料，该可溶性填料选自麦芽糖醇、木糖醇及其任意混合物；
(b)能形成不溶性基质的不溶性成膜剂，该不溶性成膜剂为聚丙烯酸酯。
(c)可溶胀的聚合物，该聚合物是黄原胶；
(d)可选的活性物质，以及
(e)可选的常用助剂。
2.如权利要求1所述的锭剂，其中所述可溶性填料(a)的量为组合物总量的50～95wt％。
3.如权利要求1所述的锭剂，其中所述可溶性填料(a)的量为组合物总量的70～95wt％。
4.如权利要求1所述的锭剂，其中所述可溶性填料(a)的量为组合物总量的80～95wt％。
5.如权利要求1或2所述的锭剂，其中存在所述成分(d)，并且表示它是至少一种能够经口或通过口腔粘膜给药的药物活性物质。
6.如权利要求5所述的锭剂，其中所述成份(d)是尼古丁或其盐或其衍生物。
7.如权利要求5中所述的锭剂，其中所述成份(d)是尼古丁酒石酸盐。
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ATE247951T1 (de) 2003-09-15
AU2891997A (en) 1997-12-05
TR199802305T2 (xx) 2002-06-21
WO1997042941A2 (en) 1997-11-20
NO321608B1 (no) 2006-06-12
CY2497B1 (en) 2005-09-02
CA2251623C (en) 2006-12-19
ZA974077B (en) 1997-11-24
CN1218395A (zh) 1999-06-02
PT906089E (pt) 2004-01-30
RU2192245C2 (ru) 2002-11-10
CZ298212B6 (cs) 2007-07-25
WO1997042941A3 (en) 1997-12-24
JP2000504028A (ja) 2000-04-04
EP0906089A2 (en) 1999-04-07
US6183775B1 (en) 2001-02-06
CZ365998A3 (cs) 1999-02-17
PL187242B1 (pl) 2004-06-30
DK0906089T3 (da) 2003-12-08
CA2251623A1 (en) 1997-11-20
HU224035B1 (hu) 2005-05-30
BR9709452B1 (pt) 2008-11-18
JP3707798B2 (ja) 2005-10-19
BR9709452A (pt) 1999-08-10
EP0906089B1 (en) 2003-08-27
HUP9903658A3 (en) 2000-04-28
DE69724424T2 (de) 2004-06-24
NO984773L (no) 1998-10-13
NO984773D0 (no) 1998-10-13
DE69724424D1 (de) 2003-10-02
PL329744A1 (en) 1999-04-12
ES2206709T3 (es) 2004-05-16
HK1019199A1 (en) 2000-01-28
HUP9903658A2 (hu) 2000-03-28

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