CN1976682A - 用于延时和控制释放药物活性成分的微粒口服盖仑制剂 - Google Patents
用于延时和控制释放药物活性成分的微粒口服盖仑制剂 Download PDFInfo
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- CN1976682A CN1976682A CNA2005800117230A CN200580011723A CN1976682A CN 1976682 A CN1976682 A CN 1976682A CN A2005800117230 A CNA2005800117230 A CN A2005800117230A CN 200580011723 A CN200580011723 A CN 200580011723A CN 1976682 A CN1976682 A CN 1976682A
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Abstract
本发明涉及用于延时和控制释放活性成分的微粒系统，其中所述的活性成分在体内的吸收窗基本限于胃肠道的上部，该系统规定用于口服给药。本发明的目的是提供一种借助“时间依赖”和“pH依赖”释放的双重机理来确保活性成分可靠释放的系统。为实现此目的，本发明提供了一种多微囊口服盖仑制剂，其经过设计以保证疗效，其中活性成分的释放受双释放触发机理控制、即“时间触发”和“pH触发”机理。本发明的系统由含有活性成分核的微囊(200－600μm)组成，所述的活性成分核由含有亲水性聚合物A(EudradigitL)和疏水性化合物B(植物蜡、熔点＝40－90℃)的膜(最多占40wt％)包覆，B/A为0.2到1.5。这些微囊具有如下的体外溶解特性：在pH恒定1.4的条件下，可观察到具有1到5小时的延迟期，随后释放活性成分，且从pH1.4变化成pH6.8导致活性成分在体外没有延迟期地释放。
Description
本申请是申请号为No.10/492,129的部分连续申请，后者为2002年10月9日提交的国际申请号为PCT/FR02/03443的国际申请的国家阶段，并要求了2001年10月9日提交的申请号为FR01/12999的权利，上述申请均被合并作为参考。
技术领域
本发明涉及用于延时和控制释放一种或多种活性成分AP的微粒系统领域，旨在用于口服给药。
背景技术
本发明中所指的活性成分是那些吸收作用基本限于结肠上游的胃肠道上部(回肠结上游)，并且代表了大部分药物活性的成分。
更确切地说，本发明涉及用于延时和控制释放的微粒盖仑制剂，其中控释阶段通过双重机理而被确实无误地触发：在胃里停留一段时间之后触发的“时间依赖性”释放，和当颗粒进入小肠时由于PH变化而触发的“PH依赖性”释放，这种“PH依赖性”释放没有延迟期。本发明的微粒是含有至少一种活性成分(AP)-不包括培哚普利-的微囊，其粒径为100到1200微米，并各自被包上薄膜，从而允许活性成分的延时和控制释放。
用于活性成分的延时和控制释放的系统在需要时特别有用，出于时间生物学的原因，需要活性成分在每天的确切时间被“生物吸收”，以便与昼夜节律周期合拍。这种方式适于癌症或高血压的治疗，抗炎药物的给药或糖尿病治疗中对血糖的调节。例如，使活性成分在一大清早被生物吸收，以便确保患者醒来时已经得到治疗，而不必强迫他过早醒来，这将是有利的。为此，患者在例如每天晚餐之后摄取盖仑制剂系统，就能够延时释放活性成分。
然而，药剂师承担的首要原则是确保处方药物能够被患者吸收。因此，就延时释放剂型来说，完全保证活性成分在规定的时间释放以便得到治疗效果是最关键的。现在，人们必须注意到，延时释放剂型不能完全确保活性成分在指定的时间后释放。在这种释放对患者来说非常致命时，例如在心血管疾病或糖尿病的治疗中，这个问题将变得非常严重。
事实上，用肠衣聚合物层包衣活性成分可以方便地获得延时释放剂型，所述的肠衣聚合物例如是甲基丙烯酸/甲基丙烯酸甲酯共聚物EUDRAGITL。这类肠衣已知在胃的酸性PH条件下具有低的渗透性，并且当PH增加到接近于小肠中主要的PH值时溶解，从而释放活性成分。然而，胃PH条件和胃排空时间的个体内和个体间差异不能确保活性成分在给定的时间后能够被释放出来。
单纯的“时间依赖性”延时释放系统，即，在胃肠道停留一定时间之后触发活性成分的释放系统，是不能令人满意的。事实上，由于胃停留时间的个体内和个体间的差异，活性成分可能是在其过了吸收窗之后才得以释放，而对于大部分活性成分来说，最佳吸收窗位于胃肠道的上部。因此生物吸收度可能非常低，甚至是零。
因此，用于延时和控制释放活性成分的盖仑制剂特别有利，其可以借助活性成分释放双重触发机理来确保活性成分的释放：在胃中经过一段受控时间之后触发“时间依赖”释放，无需PH变化，和当盖仑制剂剂型进入肠时通过PH增加而触发“PH依赖”释放。这两种活性成分释放触发因素，以连续的方式，使得盖仑制剂系统在使用时具有高度的可靠性。因此能够在预设的延迟期之后保证活性成分的释放，即使PH的变化没有作为触发机制介入，即，即使盖仑制剂没有从胃进入肠。
为使活性成分吸收的个体间差异最小化，必须考虑人的胃肠道的生理条件来调整活性成分释放进入胃之前的延迟期。根据Davis等人的J.ofControlled Release，2，27-38(1985)的公知结果，制剂的胃停留时间是及其不定的，约为0.5到10小时。因此，使用盖仑制剂是特别有利的，其在规定的0.5-10小时时限内的恒定延迟期之后将活性成分释放入胃中，以使药物作用时间在不同的个体中是相同的，甚至对相同个体而言的某日与往后的日子也是相同的。
此外，为优化吸收主要限于胃肠道上部的活性成分的生物利用度，如果“PH依赖”释放入肠是在没有延迟期限的前提下进行，其将是有利的，因为反之则活性成分将不能在其吸收窗内释放，结果是患者得不到治疗。
这种系统的另一个独特优点是，通过将其与用于立即释放活性成分的盖仑制剂混合，或者通过将其与另一种用于延时和控制释放活性成分的盖仑制剂混合，将呈现若干个活性成分释放波(一种活性成分或若干种相同或不同的活性成分)的释放特征，或者通过适当调整不同的分数来确保恒定的活性成分血浆浓度水平。
另一优点是，延时和控制释放剂型由多个直径低于2000微米的微囊组成。事实上，这种剂型是将活性成分的给药剂量分散在大量的微囊中(对500mg剂量来说通常是10,000个)，因此具有下列内在优点：
●微囊在胃肠道上部的停留时间得以延长，从而增加了活性成分经过吸收窗的时间并且由此最大化活性成分的生物利用度。
●使用具有不同的延时和控制释放特征的微囊混合物，可以产生显示若干释放波的释放特征，或通过适当调节不同分数，确保活性成分恒定血浆浓度水平的释放特征。
●由于在这种情形下，发生在大量微粒数目上的排空具有统计学上更多的可重现性，因此降低了对胃排空可变性的敏感性。
●避免了使组织与高剂量的活性成分接触--剂量堆积。每个微囊实际仅含有很少量的活性成分。这消除了由于侵蚀性活性成分的局部浓度过量造成组织损伤的风险。
●在这些“多微囊”系统中可以将含有一种或多种活性成分的数种盖仑制剂(立即释放和/或延时释放和/或延缓释放)合并。
●这些微囊可以以小药囊、胶囊或片剂的形式存在。如果活性成分剂量较高(500mg或更高)，单片剂型太大以至于不容易吞服。因而，具有用于活性成分延时和控制释放的微粒剂型是特别有价值的，本领域的技术人员可以按崩解片或小药囊来配制。
最后，还需要包在微囊外的包衣膜是薄的。事实上，厚的包衣会造成如下数个不利的后果：
(a)盖仑制剂中的赋形剂的质量分数太大，使得药物的质量太大以至于不容易吞服，因此最后造成危害治疗成功的顺应性问题；和
(b)微囊需要花费非常长的时间来制造。
总之，用于活性成分延时和控制释放的微粒口服盖仑制剂将因此而特别有价值，其同时具有下列特性：
●活性成分的释放可以分两条途径触发：
●当颗粒在胃中的停留时间超过5小时，通过依赖于时间来释放，也称为“时间依赖”释放；
●通过依赖于PH的改变来释放，也称为“PH依赖”释放，这种释放当系统进入肠并且PH增加时便立即开始而没有延迟期；这两种活性成分释放因素，以连续的方式，保证活性成分在预设的延迟期之后释放，即便PH变化没有作为触发机制介入；
●由多个包覆活性成分的小微囊组成；以及
●限制了包衣用赋形剂的质量分数。
活性成分的延时或控制释放已经成为很多研究的主题。
PCT专利申请WO-A-96/11675描述了用于医疗和/或营养的活性成分口服给药的微囊，其粒径小于或等于1000μm。这些微囊由用包衣材料包衣的颗粒组成，其中所述的包衣材料由成膜聚合物衍生物(乙基纤维素)、疏水增塑剂(蓖麻油)、表面活性剂和/或滑润剂(硬脂酸镁)和含氮聚合物(聚乙烯吡咯烷酮：PVP)组成。这些微囊的特征还在于它们能够在小肠中长时间停留(至少5小时)，因而允许活性成分在较长时期内得到吸收，该时期长于活性成分在小肠中的天然运转时间。
上述专利申请中的微囊不能提供针对“时间依赖型”和“PH依赖型”触发活性成分的延时和控制释放的特别问题的解决方案。
专利申请FR-A-00 14876描述了用于治疗II型糖尿病的药物，该药物中含有数千粒抗高血糖微囊(二甲双胍)，每个微囊由含有至少一种抗高血糖物质的内核和包在核上的包衣膜(例如硬脂酸和乙基纤维素)组成，包衣膜允许抗高血糖药在体内延时释放。这些微囊的粒径为50到1000μm。
上述专利申请FR-A-00 14876中没有指出如何获得具有“时间依赖型”和“PH依赖型”触发活性成分的延时和控制释放。
欧洲专利申请EP-A-0 609 961公开了口服的吗啡颗粒，对其而言活性成分的控释随PH增加而加速。
这些颗粒由以下成分组成：
-糖核(φ＝100到1700μm)
-包有一层与粘合剂(PVP或羟丙基甲基纤维素：HPMC)结合的活性成分，
-和基于以下成分的外部包封物：
◆不依赖于PH的不溶性聚合物(乙基纤维素或甲基丙烯酸酯/甲基丙烯酸铵共聚物：EUDRAGITRS或RL)，
◆在酸性PH下不溶性的肠衣聚合物(甲基丙烯酸/甲基丙烯酸甲酯共聚物：EUDRAGITL)，
◆在酸性PH下部分溶解的组分(聚乙二醇、PVP、HPMC、聚乙烯醇：PVA)，
◆任选的增塑剂(邻苯二甲酸二乙酯)
◆以及任选地，填充剂(滑石)。
活性成分的质量分数为，例如41％、38％和29％，且外部包封物的质量分数为例如14.1％、25.1％和12.3％(按重量计)。
活性成分的释放发生在任何PH下并随PH从1.2变化至7.5而增加。因此它是用于延缓释放而非延时释放的剂型。
H.YOSHINO的出版在Current status on targeted drug delivery to TheGI tract里的题为“Design and evaluation of time-controlled release systemsfor site-specific oral drug delivery drug delivery to The GI tract”的文章，Capsugel图书馆，Symp.Ser.，Short Hills 22/04，London 6/05，Tokyo14/05，pp185-190，(1993)，描述了用于延时和控制释放的多颗粒口服盖仑制剂系统，该系统通过有机酸和通过在GIT中的停留时间来引发。该系统由1000μm的微囊构成，所述的微囊由中性糖核和甲基丙烯酸酯/甲基丙烯酸铵共聚物(EUDRAGITRS)的外层组成，所述的中性糖核包有一层与有机酸(琥珀酸)混合的活性成分。据描述，有机酸允许在延迟阶段后对活性成分进行快速释放。这种有机酸由经过肠衣外层而进入微囊的水来运输。之后，其作用方向是改变包衣的渗透性，以使活性成分从微囊中快速扩散出来。这种与活性成分紧密接触的酸的存在对后者是不利的。
专利US-B-6,033,687描述了由两种类型的基于地尔硫卓的颗粒(φ＝1.4mm)，即具有短延迟期的颗粒和具有长延迟期的颗粒的混合物组成的制剂。释放分布特征在PH＝1时测定。这些颗粒含有：
中性糖核(φ＝0.5到1.5mm)
一层与粘合剂(羟丙基纤维素、羧甲基纤维素、乙基纤维素、聚乙烯吡咯烷酮、藻朊酸盐、EUDRAGIT)相结合的地尔硫卓，
在具有短延迟期的颗粒中，包衣的质量分数占12.3％，而在具有长延迟期的颗粒中，包衣的质量分数占30.3％。然而，这种技术对低于30％的膜包衣率不能提供长的延迟期。而且，鉴于胃停留时间的个体内和个体间不定性，这种“时间依赖型”延时释放系统可能在活性成分已经过吸收窗后才将其释放。这导致生物利用度的损失。
专利EP-B-0 263 083描述了微囊包衣组合物，该组合物能提供零级的和可再现的活性成分释放特征。这种包衣组合物由以下成分的混合物组成：
-硬化性聚合物，以保证包衣的机械强度，可能的例子是乙基纤维素或甲基丙烯酸共聚物(EUDRAGITE，L，S或RS)，
-亲脂性化合物，例如硬脂酸或石蜡，
-和滑石。
这种包衣组合物在微囊中存在的量为例如15到35％重量。硬化性聚合物/亲脂性化合物的比例在实施例4和5中分别为例如44％和42％。
所获得的特征是没有可变时间的延迟期。所述专利既没有教导也没有提及如何获得在延迟期结束时触发和/或通过PH变化的延时和控制释放的特征。
专利申请WO-A-01/58424 A1公开了用肠衣包衣的“漂浮”微囊，所述肠衣基于例如EUDRAGITL、硬脂酸镁、滑石和诸如癸二酸二丁酯的增塑剂。该包衣可以被包封在基于脱乙酰壳聚糖的“生物粘附”膜内。与每种肠衣一样，专利文献WO-A-01/58424中的肠衣的目的是“PH依赖型”释放而不是“时间依赖型”释放和“PH依赖型”释放的结合。此外，所述专利申请中的图1-3显示了“PH依赖型”释放的简单目标实现得非常不完美，因为在两个小时内仅在恒定的性PH下释放了最多20％的活性成分。至于所述专利申请中描述的漂浮在胃中的颗粒，它们的胃停留时间据描述有所增加，所增加的程度大到使人甚至担心缺少任何“PH触发型”释放。最后，由于活性成分是反常漏入尾部的，因而释放是按照无控方式进行的。
欧洲专利申请EP-A-1 101 490涉及一种能够将活性成分释放入大肠且更具体为结肠中的药物制剂。该制剂可以由含有内核和包衣的片剂和颗粒组成。
所述发明所要解决的技术问题是提出一种能够允许医药物质在小肠下部、升结肠、横结肠或大肠下部的靶位释放的药物剂型。假设在胃中的平均停留时间是5小时，并且平均还需2小时到达小肠的下部，而EP-A-1101 490的制剂设计成医药物质在模拟胃部的酸性条件下不能被5小时内释放，并且于模拟肠PH条件的流体中，在至少2小时的延迟期之后才能被释放(特别参见EP-A-1 101 490的权利要求7)。
因此，显然这种目的在于使医药物质在肠下部(结肠)吸收的系统不适合主要在胃肠道上部吸收的医药物质。此外，欧洲专利申请EP-A-1 101 490的系统没有作出借助如下双触发机理进行活性成分释放的措施：
-在恒定的规定的延迟期后释放入胃，其中所述的规定的延迟期在0.5-10小时的时限内(“时间依赖型”机理)，
-和在进入肠之后没有延迟期地释放(“PH依赖型”机理)。
最后，EP-A-1 101 490的制剂没有解决胃停留时间的个体间或个体内的不定性。
由此，现有技术中不包括盖仑制剂系统，其是借助如下双释放机理来延迟和确保活性成分的释放优选在胃肠道上部被吸收：
-在胃中经延迟期后的“时间依赖性”释放，该延迟期的特征在于恒定的给定延迟期，在0.5-10小时的时限内，
-和没有延迟期地“PH依赖型”释放。
发明内容
鉴于现有技术的状况，本发明的一个基本目的是提供新的多微粒盖仑制剂系统，用于基本在胃肠道上部被吸收的活性成分口服给药，该系统是延时和控制释放型，通过双重的“时间依赖性”和“PH依赖型”机理确保活性成分的确定的释放，从而保证所述系统的治疗效果。这两种活性成分释放触发因素以连续的方式，保证活性成分在预设的延迟期之后释放，即使PH的变化没有作为触发机制介入。
本发明的一个基本目的是提供由多个微囊构成的盖仑制剂，这种盖仑制剂剂型通过在PH 1.4下按照具有0.5-10小时可调整的给定期限的延迟期的延时释放特征释放活性成分，接着开始无延迟期的释放阶段，以避开胃排空的个体间和个体内可变性。
本发明的一个基本目的是提供由多个微囊构成的盖仑制剂，这种盖仑制剂在一方面，可以按照在PH1.4下以具有0.5-10小时恒定给定延迟期的延时释放特征，并按照0.25-35小时的释放半衰期t1/2来释放活性成分，在另一方面，当PH从1.4变化至6.8时，可以无延迟期地并且以0.25-20小时的释放半衰期t1/2来释放活性成分。
本发明的一个基本目的是当PH从1.4变化至6.8时，本发明能够得到控制。
本发明的一个基本目的是提供由大量微囊、例如数千数量级的微囊组成的盖仑制剂，这种多数量可以从统计学上确保活性成分在整个胃肠道中运转动力学的良好再现性，结果是使生物利用度得到更好控制并因此得到更好的疗效。
本发明的一个基本目的是提供由多个包衣微囊构成的盖仑制剂，其避免使用大量的包衣剂，包衣剂的质量分数与单片形式的质量分数相差不大。
本发明的一个基本目的是提供由多个包衣微囊构成的药物剂型，活性成分可以容易吞服的形式存在，即小药囊(sachet)或崩解片。
本发明的一个基本目的是提供由多个包衣微囊构成的药物剂型，可以将数种不同的活性成分混合。
本发明的另一个目的是提供由多个包衣微囊构成的药物剂型，其中所述的包衣微囊均含有中性内核。
在设定上述目的后，为保证主要在胃肠道上部吸收的活性成分确实无误地释放和保证药物活性成分具有良好的生物吸收度，本发明者成功地研发了多微囊盖仑制剂体系，该体系：
-保证活性成分在其吸收窗中得以吸收，所述吸收窗主要限定于胃肠道上部；
-从而保证这种系统或这种盖仑制剂的确定疗效；
-并具有活性成分释放双重触发的基本特征。
与迄今已知的活性成分控释系统相比，这代表了很大的进步，在已知的活性成分控释系统中，活性成分通过单一因素触发，即对一些系统来说通过胃肠道的停留时间而对另一些系统来说是通过PH的变化。
因此，满足上面所述目标的本发明涉及用于延时和控制释放至少一种活性成分-不包括培哚普利(perindopril)-的微粒口服盖仑制剂，其中这种活性成分的体内吸收窗基本限于胃肠道的上部，
所述的剂型经过设计，通过保证其在体内吸收而保证其疗效，
其中：
-活性成分的释放受两种不同触发机理控制，一种基于PH变化而另一种允许在胃中经过预设的停留时间后释放活性成分，
-其体外的溶解行为(按照欧洲药典第三版，标题为“固体口服剂型的溶解测试”中所示的内容测定：在SINK条件下进行II型溶解试验，保持在37℃且在100rpm下搅拌)如下：
-在1.4恒定PH下，溶解特征包括具有小于或等于5小时期限的延迟期，
-且在延迟期中，从PH 1.4变化至PH 6.8导致无延迟期的释放阶段的开始；
其中溶解特征包括1-5小时期限的延迟期；
其中，该剂型包含“储库”微囊，所述的“储库”微囊含有至少一种活性成分-不包括培哚普利-这些微囊属于下述类型：
◆由活性成分的颗粒组成，其中颗粒各自包覆至少一层膜，这个包衣膜由复合材料组成，所述的复合材料：
○含有：
●至少一种亲水性聚合物A，其带有在中性PH下离子化的基团，
●和至少一种疏水性化合物B；
○且所占的质量分数(％按重量计，基于微囊的总重量)≤40％；
◆并且直径低于2000微米，
这些微囊的包衣膜由基于A和B的复合物组成，其中：
重量比B/A为0.45到1.0，
且疏水性化合物B选自在固态时结晶的产品，其熔点TfB≥40℃，优选TfB≥50℃。
有利地，微囊的直径为200到800微米，B/A为0.5到1.0，且疏水性化合物B选自在固态时结晶的产物，具有熔点TfB，40℃≤TfB≤90℃。
根据本发明的一个优选特征，亲水性聚合物A选自：
-(甲基)丙烯酸/(甲基)丙烯酸烷基(例如甲基)酯共聚物(EUDRAGITS或L)及其混合物；
-纤维素衍生物，优选醋酸纤维素和/或邻苯二甲酸纤维素、邻苯二甲酸羟丙基甲基纤维素和乙酸羟丙基甲基纤维素和/或琥珀酸羟丙基甲基纤维素；
-及其混合物。
更优选地，化合物B选自如下产物：
-植物蜡，单独或混合物使用；
-氢化植物油，单独或混合物使用；
-甘油与至少一种脂肪酸的至少一种单酯和至少一种二酯和/或至少一种三酯的混合物；
-及它们的混合物。
根据本发明的最优选实施例，微囊包衣膜的化合物B选自以下商品名(商标)的产品：Dynasan(氢化棕榈油)、Cutina(氢化蓖麻油)、Hydrobase(氢化豆油)、Dub(氢化豆油)、Castorwax(氢化蓖麻油)、Croduret(氢化蓖麻油)、Carbowax、Compritol(山嵛酸甘油酯)、Sterotex(氢化棉子油)、Lubritab(氢化棉子油)、Apifil(蜜蜡黄)、Akofme(氢化棉子油)、Softisan(氢化棕榈油)、Hydrocote(氢化豆油)、Livopol(氢化豆油)、Super Hartolan(羊毛脂)、MGLA(无水乳脂)、Corona(羊毛脂)、Protalan(羊毛脂)、Akosoft(栓剂基质，硬脂)、Akosol(栓剂基质，硬脂)、Cremao(栓剂基质，硬脂)、Massupol(栓剂基质，硬脂)、Novata(栓剂基质，硬脂)、Suppocire(栓剂基质，硬脂)、Wecobee(栓剂基质，硬脂)、Witepsol(栓剂基质，硬脂)、Coronet、Lanol、Lanolin、Incromega(Omega 3)、Estaram(栓剂基质，硬脂)、Estol、Suppoweiss(栓剂基质，硬脂)、Gelucire(聚乙二醇月桂酸甘油酯(laurylmacrogolglycerides))、Precirol(硬脂酸棕榈酸甘油酯)、Emulcire(鲸蜡醇)、Plurol diisostearique(二异硬脂酸聚甘油酯)、Geleol(硬脂酸甘油酯)、Hydrineet Monthyle；以及以下号码的添加剂：E901、E907、E903及其混合物；以及它们的混合物。
实践中，该化合物可以选自下列商品名(商标)的产品：Dynasan P60、Dynasan 116、Dynasan 118、Cutina HR、Hydrobase 66-68、Dub、Compritol888、Sterotex NF、Lubritab以及它们的混合物。
根据本发明的重要实施例，微囊包衣膜不含滑石。
优选的聚合物A是(甲基)丙烯酸/(甲基)丙烯酸烷基(例如甲基)酯共聚物。这些共聚物，例如是ROHM PHARMA POLYMERS以注册商标名EUDRAGITL和S系列(例如，EUDRAGITL100、S100、L30D-55和L100-55)，市售的产品，是在pH值高于胃中所遇到pH时可溶于含水介质的阴离子肠衣共聚物。
根据本发明另一个优选的特征，化合物B选自下列产物：
-植物腊，单独或混合使用，如以商标DYNASANP60和DYNASAN116市售的产品，及其他；
-氢化植物油，单独或混合物使用，优选选自氢化棉子油、氢化豆油、氢化棕榈油及其混合物；
-甘油与至少一种脂肪酸、优选山嵛酸，的单酯和/或二酯和/或三酯单独或混合使用；
-以及它们的混合物。
在胃中经过预定停留时间后，无需PH变化的活性成分释放触发机理，具体由通过控制微囊的水合率和/或微囊中一种或多种组分的溶解率引发。例如，并且不限与此，微囊的水合可以受如下因素的控制：
○在微囊中，亲水性产品的存在使得调节渗透压或者引起微囊膨胀成为可能；
○包衣膜水渗透性的调节；
○在包衣膜中产生微孔；
○或甚至包衣膜中的化合物的水合或溶解。
本发明用于延时和控制释放活性成分的多微囊盖仑制剂系统的一个决定性优点在于，它牵涉体内触发活性成分释放使其进入胃肠道的两个因素，即：
-在胃中的停留时间：“时间触发”释放，
-和PH的变化，“PH触发”释放。
这两个活性成分释放触发因素是连续式的，因此使得盖仑制剂系统在使用时具有高度的可靠性。从而保证在预设的延迟期后释放活性成分，即使PH的变化没有作为触发机制介入。个体的可变性问题也因此得以解决，通过对意图治疗性能相适应的预定时间生物学现象的观察，保证了含有这种盖仑制剂系统的药物疗效。
另外，在本发明中活性成分的吸收窗被认为是限于胃肠道上部的情形中，如果用于延时释放、并随后控制释放的剂型由多个微囊组成，则特别有利。事实上，对这种剂型而言，活性成分的给药剂量分散在大量的微囊中(对500mg剂量来说典型地是10000个)，因而具有如下本质性优点：
●微囊在胃肠道上部的停留时间可以得到延长，从而增加了活性成分经过吸收窗的时间，并且因此最大化活性成分的生物利用度。
●使用具有不同延时和控制释放分布特征的微囊的混合物，可以产生呈现数个活性成分释放波的释放特征，或者通过适当调节不同因素来确保恒定血浆活性成分浓度的释放特征。
●由于这种情形下，发生在大量颗粒数量上的排空在统计学上更具有可重现性，因而降低了胃排空的可变性。
●避免了组织与高剂量活性成分的接触--剂量堆积。每个微囊实际仅含有很少量活性成分。这消除了由于侵蚀性活性成分局部浓度过量造成组织损伤的风险。
●这些微囊能以小药囊、明胶胶囊或片剂的形式存在。如果活性成分的剂量较高(500mg或更高)，单片剂型太大以至于不容易吞服。因而，用于活性成分延时和控制释放的微粒剂型是特别有价值的，本领域的技术人员可以按崩解片或小药囊来配制。
本发明的多微囊盖仑制剂系统可能确保借助两个触发因素将活性成分延时和控制释放至GIT中，并且由此避开了胃排空条件的个体间和个体内可变性，同时又是经济上可行的且容易摄取(优化顺应性)。
根据优选实施方案的一个特别有利的特征，在恒定pH 1-4下，延迟期后的控释期应当符合：释放50wt％活性成分的释放时间(t1/2)定义如下(以小时计)：
0.25≤t1/2≤35
优选0.5≤t1/2≤20
实践中，在恒定pH1.4下体外活性成分释放特征的释放阶段具有可调的释放半衰期。
根据优选实施方案的另一个有价值的特征，从pH 1.4变化至pH 6.8后的不带延迟期的释放期应当符合：释放50wt％活性成分的释放时间(t1/2)定义如下(以小时计)：
0.25≤t1/2≤20
优选0.5≤t1/2≤15
优选地，本发明的微囊含有单层复合包衣膜AB。这样可以简化它们的制备并且限制包衣的比率。
优选地，将活性成分沉积在直径为200到800微米、优选200到600微米的中性核上。
不限制于此，亲水性中性核可以含有蔗糖和/或葡萄糖和/或乳糖，或者它可由纤维素微球组成。
有利地，除基本成分A和B外，微囊包衣还可以含有其它本领域技术人员已知的常规辅料，特别是：
■着色剂；
■增塑剂，例如癸二酸二丁酯；
■亲水性化合物，例如纤维素及其衍生物或聚乙烯吡咯烷酮及其衍生物；
■以及它们的混合物。
以本领域技术人员已知的技术来沉积活性成分是有利的，例如在流化空气床中使用喷雾技术，喷雾到直径为200到800微米、优选200到600微米的中性核上。
从数量方面讲，单层包衣剂占微囊重量的最多40％，优选最多30％。这样的包衣限制率使得可以生产出均含有高剂量活性成分的盖仑制剂单位，同时又不会超过不允许吞咽的大小。这样可以只改进治疗的依顺性及治疗的成功性。
从定性方面，本发明微囊的活性成分基本在胃肠道的上部吸收并且有利的选自以下活性物质家族中的一种：抗溃疡剂，抗糖尿病药，抗凝剂，抗凝血剂(antithrombics)，降脂血剂，抗心律不齐药，血管舒张剂，抗心绞痛剂，抗高血压药，血管保护剂，致育促进剂，分娩引产物和抑制物，避孕药，抗生素，抗真茵素，抗病毒药，抗癌剂，抗炎剂，镇痛药，抗癫痫药，抗震颤麻痹药，神经弛缓剂，安眠药，抗焦虑药，精神兴奋剂，抗偏头痛药，抗抑郁剂，镇咳剂，抗组胺剂和抗变态反应剂。
还可以参考专利申请EP-A-0 609 961第4-8页中所列的活性成分。
优选地，活性成分选自以下化合物：二甲双胍，乙酰水杨酸，阿莫西林，己酮可可碱，哌唑嗪，阿昔洛韦，硝苯地平，地尔硫卓，萘普生，布洛芬，氟苯布洛芬，酮基布洛芬，苯氧布洛芬，吲哚美辛，双氯酚酸，双苯噻酸，戊酸雌二醇，美多洛尔，舒必利，卡托普利，西咪替丁，叠氮胸苷，尼卡地平，特非那丁，阿替洛尔，沙丁胺醇，卡马西平，雷尼替丁，依那普利，辛代他汀(simvastatin)，氟西汀，阿普唑仑，法莫替丁，丙氧乌苷，泛西洛维，螺内酯，5-氮杂胞苷(5-asa)，奎尼丁，吗啡，喷他佐辛，对乙酰氨基酚，奥美拉唑，甲氧氯普胺及其混合物。
本发明的微粒口服盖仑制剂的剂型可以是片剂(有利地，为分散在口中的片剂)，粉剂或胶囊。
上述的微囊可以用于制造各种活性成分的新颖的药物或膳食制剂，使其具有最佳化的治疗或膳食性能特征，并且最好以片剂形式，优选崩解片，更优选在口中分散的片剂、粉剂或胶囊剂型呈现。
这些微囊全部具有更高的价值，因为它们还完全经生物体的耐受，特别是经胃的耐受，并且还可以容易且经济地获得。
本发明还涉及这些新的以原先结构存在的药物或膳食制剂，它们的外观和它们的组合物。这种药物或膳食制剂口服给药，优选每天单剂量给药。
应当指出的是，可以将释放动力学不同但都属于本发明框架特征内的至少两种类型的微囊，混合在一种和同一种胶囊、片剂或粉剂中。
还可以将本发明的微囊与确定量的可在生物体内立即利用的活性成分混合。
本发明还包括将含有不同活性成分的微囊混合。
另外，本发明的再一个目的是盖仑制剂(药物或膳食)系统，优选以片剂(优选崩解片，更优选在口中分散的片剂)、粉剂或胶囊的剂型，其特征在于该系统含有如上所述的微囊。
此外，本发明涉及如上所定义的微粒用于制备微粒口服盖仑制剂(药物或膳食)剂型中的用途，优选作为片剂，更优选是在口中分散的片剂、粉剂或胶囊的剂型。
最后，本发明还涉及治疗方法，其特征在于该方法包括，根据给定量摄取含有如上定义微囊的药物。
本发明将通过以下实施例的方式作更清楚地解释，以便获得对本发明的更好理解并且显示其在实施时的可变性和/或方式以及其不同的优点，这些实施例仅以举例说明性的目的而给出。
附图说明
-图1显示了实施例1的微囊在pH1.4下的体外释放特征：—●—，并以及在pH1.4下3小时之后从T＝3小时开始在pH6.8下：—□—，以溶解的二甲双胍的重量％(％D)计，作为时间T(以小时计)的函数；
-图2显示了实施例2的微囊在pH1.4下的体外释放特征：—●—，以及在pH1.4下2小时之后从T＝2小时开始在pH6.8下：—□—，以阿昔洛韦的重量％(％D)计，作为时间T(以小时计)的函数；
-图3显示了实施例3的微囊在pH1.4下的体外释放特征：—■—，以及在pH6.8下：—□—，以二甲双胍的重量％(％D)计，作为时间T(以小时计)的函数。
具体实施方式
实施例1：制备允许双重机理延时和延缓释放盐酸二甲双胍的微囊
将75g盐酸二甲双胍(Chemsource)和75gPVP溶解于1350g异丙醇中。于GlattGPCG3喷雾包衣机中，将溶液喷在850g中性微球体(NP Pharm)上。
将93.3g氢化棕榈油(Hüls)(B)和140gEudragitL100(Rhm)(A)溶解于热的异丙醇中。B/A＝0.66。将溶液喷在700g前面制备的微粒上。膜的包衣条件是：入口温度：45℃，喷雾速率：8-12g/min，雾化压力：1.5巴。
将微囊根据药典在II型溶解试验中，于37℃下进行测试，同时在100rpm下搅拌，测试的介质如下：
a)pH1.4的HCL
b)pH1.4的HCL下3小时，然后是pH6.8的KH2PO4/NaOH缓冲介质。
释放特征见图1。
这些特征具有借助双重机理的延时及然后延缓释放的特征：2小时没有释放，接着在pH没有变化的情形下延缓释放，最后由于pH变化而加速释放。
实施例2：制备允许双重机理延时和延缓释放阿昔洛韦的微囊
将75g阿昔洛韦和75g聚乙烯吡咯烷酮PLASDONEK29/32溶解于833g异丙醇中。于GlattGPCG3喷雾包衣机中，将溶液喷在850g中性微球体(NP Pharm)上。
将93.3g氢化棕榈油(Hüls)(B)和140g EudragitL100(Rhm)(A)溶解于热的异丙醇中。B/A＝0.66。将溶液喷在700g前面制备的微粒上。膜的包衣条件是：入口温度：45℃，喷雾速率：8-12g/min，雾化压力：1.5巴。
将微囊根据药典在II型溶解试验中，于37℃下进行测试，同时在100rpm下搅拌，测试的介质如下：
c)pH1.4的HCl
d)pH1.4的HCl下3小时，然后是pH6.8的KH2PO4/NaOH缓冲介质。
释放特征见图2。
在pH1.4下所获得的阿昔洛韦的释放特征是借助双重机理的延时和延缓释放的特征。
实施例3：制备允许双重机理延时和延缓释放盐酸二甲双胍的微囊
将105g氢化棕榈油(Hüls)(B)、30g癸二酸二丁酯和165gEudragitL100(Rhm)(A)溶解于热的异丙醇中。B/A＝0.64。将溶液喷在700g二甲双胍颗粒(95.5％二甲双胍/4.5％PVP)上。膜的包衣条件是：入口温度：45℃，喷雾速率：8-12g/min，雾化压力：1.5巴。
将微囊根据药典在II型溶解试验中，于37℃下进行测试，同时在100rpm下搅拌，测试的介质如下：
e)pH 1.4的HCl
f)pH 6.8的KH2PO4/NaOH缓冲介质
释放特征见图3。
这些特征具有借助双重机理的延时及然后延缓释放的特征：在酸性pH下2小时没有释放，在中性pH下快速释放。
Claims (22)
1.一种微粒口服盖仑制剂，用于延时和控制释放至少一种活性成分-不包括培哚普利-这种活性成分具有基本限于胃肠道上部的体内吸收窗，
所述的剂型经过设计，通过保证其在体内吸收而保证其疗效，
其特征在于
-活性成分的释放受两种不同触发机理控制，一种基于PH变化且一种允许在胃中经过预设的停留时间后释放活性成分，
-其体外的溶解行为(按照欧洲药典第三版，标题为“固体口服剂型的溶解测试”中所示的内容测定：在SINK条件下进行II型溶解试验，保持在37℃且在100rpm下搅拌)如下：
-在1.4恒定PH下，溶解特征包括具有小于或等于5小时期限的延迟期，
-在延迟期中，从PH1.4变化至PH6.8导致无延迟期的释放阶段开始；
其中溶解特征包括1到5小时持续时间的延迟期；
其中，该剂型包含“储库”微囊，所述的“储库”微囊含有至少一种活性成分-不包括培哚普利-这些微囊为下述类型：
◆由活性成分的颗粒组成，各颗粒至少包覆一层膜，这种包覆膜由复合材料组成，所述的复合材料：
○含有：
●至少一种亲水性聚合物A，其带有在中性PH下离子化的基团，
●和至少一种疏水性化合物B；
○且所占的质量分数(％按重量计，基于微囊的总重量)≤40％；
◆并且直径低于2000微米，
这些微囊的包覆膜由基于A和B的合成物组成，其中：
重量比B/A为0.45到1.0，
且疏水性化合物B选自在固态时结晶的产物，并且熔点TfB≥40℃。
2.如权利要求1所述的盖仑制剂剂型，其中微囊的直径为200到800微米，重量比B/A为0.5到1.0，且疏水性化合物B选自在固态时结晶的产物，具有熔点TfB，40℃≤TfB≤90℃。
3.如权利要求1所述的盖仑制剂，其中亲水性聚合物A选自：
-(甲基)丙烯酸/(甲基)丙烯酸烷基(例如甲基)酯共聚物及其混合物；
-纤维素衍生物，优选醋酸纤维素和/或邻苯二甲酸纤维素、邻苯二甲酸羟丙基甲基纤维素和乙酸羟丙基甲基纤维素和/或琥珀酸羟丙基甲基纤维素；
-及其混合物。
4.如权利要求1所述的盖仑制剂，其中亲水性聚合物A选自：
-(甲基)丙烯酸/(甲基)丙烯酸甲基酯共聚物及其混合物；
-醋酸纤维素和/或邻苯二甲酸纤维素、邻苯二甲酸羟丙基甲基纤维素和乙酸羟丙基甲基纤维素和/或琥珀酸羟丙基甲基纤维素；
-及其混合物。
5.如权利要求1所述的盖仑制剂，其中化合物B选自如下产品：
-植物蜡，单独或与其他产品混合使用；
-氢化植物油，单独或与其他产品混合使用；
-甘油与至少一种脂肪酸的单酯和/或二酯和/或三酯，单独或与其他产物混合使用；
-及它们的混合物。
6.如权利要求1所述的盖仑制剂，其中化合物B选自如下产物：
-植物蜡，单独或与其他产物混合使用；
-氢化植物油，单独或与其他产物混合使用；
-甘油与至少一种脂肪酸的至少一种单酯和至少一种二酯和/或至少一种三酯的混合物；
-及它们的混合物。
7.如权利要求5或6所述的盖仑制剂，其中化合物B选自氢化棉子油、氢化豆油、氢化棕榈油、山嵛酸甘油酯、氢化蓖麻油、三硬酯酸甘油酯、三棕榈酸甘油酯、三肉豆蔻酸甘油酯、蜜蜡黄、栓剂基质或硬脂、无水乳脂肪、羊毛脂、棕榈酰硬脂酰甘油酯、硬脂酸甘油酯、聚乙二醇月桂酸甘油酯、鲸蜡醇、二异硬脂酸聚甘油酯、二甘醇一硬脂酸酯、单硬脂酸乙二醇酯、Omega3以及上述物质的任意混合物。
8.如权利要求5或6所述的盖仑制剂，其中化合物B选自氢化棉子油、氢化豆油、氢化棕榈油、山嵛酸甘油酯、氢化蓖麻油、三硬酯酸甘油酯、三棕榈酸甘油酯、三肉豆蔻酸甘油酯以及上述物质的任意混合物。
9.如权利要求1所述的盖仑制剂，其中化合物B选自以下商品名(商标)的产品：Dynasan、Cutina、Hydrobase、Dub、Castorwax、Croduret、Compritol、Sterotex、Lubritab、Apifil、Akofine、Softtisan、Hydrocote、Livopol、Super Hartolan、MGLA、Corona、Protalan、Akosoft、Akosol、Cremao、Massupol、Novata、Suppocire、Wecobee、Witepsol、Lanolin、Incromega、Estaram、Suppoweiss、Gelucire、Precirol、Emulcire、Pluroldiisostearique、Geleol、Hydrine et Monthyle；以及以下号码的添加剂：E901、E907、E903及其混合物；以及上述物质的混合物。
10.如权利要求1所述的盖仑制剂，其中化合物B选自以下商品名(商标)的产品：Dynasan P60、Dynasan 114、Dynasan116、Dynasan118、CutinaHR、Hydrobase 66-68、Dub HPH、Compritol 888、Sterotex NF、SterotexK、Lubritab及其混合物。
11.如权利要求1所述的盖仑制剂，其中微囊体的包覆膜不含滑石。
12.如权利要求1所述的盖仑制剂，其中在恒定pH 1-4下，延迟期后的控释期应当符合：释放50wt％活性成分的释放时间(t1/2)定义如下(小时)：
0.25≤t1/2≤35。
13.如权利要求1所述的盖仑制剂，其特征在于，pH 1.4变化至pH 6.8后不带延迟期的释放期应当符合：释放50wt％活性成分的释放时间(t1/2)定义如下(小时)：
0.25≤t1/2≤20
14.如权利要求1所述的盖仑制剂，其中微囊含有单层复合包衣膜AB。
15.如权利要求1所述的盖仑制剂，其中活性成分沉积在直径为200到800微米的中性核上。
16.如权利要求1所述的盖仑制剂，其中该中性核含有蔗糖和/或乳糖和/或葡萄糖。
17.如权利要求16所述的盖仑制剂，其中该中性核是纤维素微球。
18.如权利要求1所述的盖仑制剂，其中所用的活性成分属于以下活性物质家族中的至少一种：抗溃疡剂，抗糖尿病药，抗凝剂，抗凝血剂，降脂血剂，抗心律不齐药，血管舒张剂，抗心绞痛剂，抗高血压药，血管保护剂，致育促进剂，分娩引产物和抑制物，避孕药，抗生素，抗真菌素，抗病毒药，抗癌剂，抗炎剂，镇痛药，抗癫痫药，抗震颤麻痹药，精神抑制剂，安眠药，抗焦虑药，精神兴奋剂，抗偏头痛药，抗抑郁剂，镇咳剂，抗组胺剂和抗变态反应剂。
19.如权利要求18所述的盖仑制剂，其中所述的活性成分选自以下化合物：阿莫西林，二甲双胍，乙酰水杨酸，己酮可可碱，哌唑嗪，阿昔洛韦，硝苯地平，地尔硫卓，萘普生，布洛芬，氟苯布洛芬，酮基布洛芬，苯氧布洛芬，吲哚美辛，双氯酚酸，双苯噻酸，戊酸雌二醇，美多洛尔，舒必利，卡托普利，西咪替丁，叠氮胸苷，尼卡地平，特非那丁，阿替洛尔，沙丁胺醇，卡马西平，雷尼替丁，依那普利，辛代他汀，氟西汀，阿普唑仑，法莫替丁，丙氧鸟苷，泛西洛维，螺内酯，5-氮杂胞苷，奎尼丁，吗啡，喷他佐辛，对乙酰氨基酚，奥美拉唑，甲氧氯普胺及其混合物。
20.如权利要求1所述的盖仑制剂，其特征在于它是片剂、粉剂或明胶胶囊的形式。
21.如权利要求1所述的微囊在制备作为片剂的微粒口服盖仑制剂中的应用。
22.如权利要求1或20所述的盖仑制剂，其特征在于它是在口中分散的片剂。
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| US10/826,690 US8101209B2 (en) | 2001-10-09 | 2004-04-19 | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
| US10/826,690 | 2004-04-19 |
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-
2004
- 2004-04-19 US US10/826,690 patent/US8101209B2/en active Active
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2005
- 2005-04-19 CA CA002563689A patent/CA2563689A1/en not_active Abandoned
- 2005-04-19 JP JP2007508876A patent/JP2007532689A/ja not_active Withdrawn
- 2005-04-19 CN CNA2005800117230A patent/CN1976682A/zh active Pending
- 2005-04-19 WO PCT/EP2005/005551 patent/WO2005099671A2/en active Application Filing
- 2005-04-19 EP EP05742904A patent/EP1744729A2/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112791046A (zh) * | 2021-01-22 | 2021-05-14 | 杭州汉达医药科技有限公司 | 一种具儿童安全保护功能的药物制剂和使用方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| US8101209B2 (en) | 2012-01-24 |
| US20040234601A1 (en) | 2004-11-25 |
| WO2005099671A3 (en) | 2006-06-08 |
| CA2563689A1 (en) | 2005-10-27 |
| EP1744729A2 (en) | 2007-01-24 |
| JP2007532689A (ja) | 2007-11-15 |
| WO2005099671A2 (en) | 2005-10-27 |
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