CN1158999C - 具有单一核心的控释口服片剂 - Google Patents

具有单一核心的控释口服片剂 Download PDF

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CN1158999C
CN1158999C CNB998064343A CN99806434A CN1158999C CN 1158999 C CN1158999 C CN 1158999C CN B998064343 A CNB998064343 A CN B998064343A CN 99806434 A CN99806434 A CN 99806434A CN 1158999 C CN1158999 C CN 1158999C
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郑秋秋
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陈志明
冉史帝夫
周约瑟
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Abstract

一种抗高血糖药控释片剂，它不含膨胀聚合物，而包含一个含抗高血糖药的核心、一个包围该核心的半渗透性薄膜涂覆物及至少一个该薄膜内的通道。

Description

具有单一核心的控释口服片剂
技术领域
本发明涉及关于含有一抗高血糖药的控释单位剂量配方。更特别地，本发明是关于一种含有双胍(biguanide)例如二甲双胍(metformin)或丁福明(buformin)或其医药上可接受的盐类的口服剂型，其医药上可接受的盐类为例如二甲双胍氢氯化物或二甲双胍盐类，在美国专利案第3,957,853及4,080,472号中有描述，其内容以参考方式并于本文。
背景技术
在现有技术中，已使用许多技术来提供控制的及延长释放的医药剂型，以维持药物治疗的血清含量且使因患者顺从性缺乏所造成药物剂量遗漏的影响降至最小。
现有技术为具有一个由半渗透薄膜包围的渗透活性药核心的延长释放片剂。这些片剂的作用是通过液体例如胃液或肠液渗透过包覆的薄膜且溶解活性成分，以使该活性成分释放通过一包覆薄膜中的通道(passageway)，或者若该活性成分在渗透液体中不可溶时，可通过膨胀剂例如水凝胶可促使其通过该通道。这些渗透性片剂系统的一些代表性实例可见于美国专利案和3,485,770，3.916,899，4,034,758，4,077,407及4,783,337号中。美国专利案第3,952,741号教示一种渗透性装置，其中在半渗透性薄膜内已发展出足够的压力而在薄膜的脆弱部分上使薄膜胀破或破裂之后，该活性剂立即由该薄膜所包围的核心中释放出来。
在上述引用的专利案中所叙述的基本渗透性装置已随时间而改良，以尝试提供活性成分翻译的较佳控制。举例而言，美国专利案第4,777,049及4,851,229号叙述一种渗透性剂型，其包含一个包围核心的半渗透壁，该核心包括一种活性成分以及一种调节剂，其中该调节剂使活性成分以脉冲(pulsed)方式释放通过半渗透薄膜中的一通道。进一步的改良包括包围活性核心的半透膜的改变，例如改变形成该薄膜成分的比例，见于美国专利案第5,178,867，4,522,625号中。或者增加包围活性核心的涂覆物数量，见于美国专利案第5,650,170及4,892,739号中。
虽然针对控释或缓释组合物及特别是针对渗透剂型的大量研究已进行，但是极少研究在使用抗高血糖药控释或缓释组合物的领域中进行。
对于使用抗高血糖药例如二甲双胍氢氯化物的控释或缓释配方的有限研究局限于抗高血糖药以及一膨胀剂或胶凝剂的组合，以控制药物自剂型中释放。此有限的研究的例示是由WO96/08243中及商业上可购自Bristol-Myers Squibb Co.的含有盐酸二甲双胍的GLUCOPHAGE产品所示。
在第五十版的Physician′s Desk Reference，copyright 1996，p.753中记载食物会减少GLUCOPHAGE剂型所传送的二甲双胍的吸收程度且轻微延缓其吸收。与在禁食情况下施用相似的片剂比较，此食物造成的减少已显示在施用含有850毫克的盐酸二甲双胍的单一的GLUCOPHAGE片剂后，血浆中有约40％较低的峰浓度及25％较低的AUC以及达到血浆峰浓度有35分钟的延长时间。
发明内容
本发明的一个目的在于提供一种抗高血糖的控释或缓释配方，其中药物的生物可吸收性不会由于食物的存在而降低。
本发明的另一个目的在于提供一种不使用膨胀剂聚合物的抗高血糖药控释或缓释配方。
本发明的另一个在于对需要治疗的动物或人提供12至24小时的抗高血糖药控释或缓释配方，其可提供连续及非脉冲式(non-pulsating)治疗量的抗高血糖药。
本发明的另外一个目的在于提供一种抗高血糖药控释或缓释配方，其可在施用后约8至12小时得到血浆峰浓度含量。
本发明的再一个目的在于提供一种仅具有均质渗透核心的控释或缓释医药片剂，其中该渗透核心成分可用常规片剂压制技术制得。
前述目标由一种控释剂型来达到，该剂型包含：
(a)一个核心，其包含：
(i)50-98％双胍类药；
(ii)0-40％粘合剂；及
(iii)0-20％吸收增进剂；
(b)包围该核心的半透膜涂覆物，所述半透膜对于水及生物液体的通过具有可渗透性，而对所述抗高血糖药的通过不具可渗透性，所述涂覆物包含50-99％半渗透性聚合物，0-40％流动增进剂和0-25％塑化剂；以及
(c)使所述双胍类药得以释放的至少一个半透膜内的通道。
在所述核芯和半透膜之间还可以具有一层水溶性密封涂覆物。
本发明的剂型可提供12至24小时治疗量的抗高血糖药，且若与食物一同摄取时不会降低生物利用度。事实上，当本发明的控释剂型与食物一起施用时会观察到抗高血糖药的生物利用度有些微升高。在一个较佳具体实施例中，该剂型将每天施用一次，理想上与餐食一起或在餐后施用，且最佳是与晚餐一起或之后施用，并在一天中提供治疗量的药物，其血浆峰浓度于施用8至12小时后达到。
在此说明书中所使用的抗高血糖药一词系指有效控制或驾驭非胰岛素依赖性糖尿糖(NIDDM)的药物。较佳地，抗高血糖药为双胍，例如二甲双胍(metformin)或丁福明(buformin)或其医药上可接受的盐类如二甲双胍氢氯化物。
粘合剂可为任何公知的医药上可接受的粘合剂，例如聚乙烯吡咯烷酮，羟基丙基纤维素，羟基乙基纤维素，乙基纤维素，聚甲基羧酸酯，蜡质及类似物。上述粘合剂的混合物也可使用。较佳的粘合剂为具有水溶性的，例如平均分子量为25,000至3,000,000的聚乙烯吡咯烷酮。该粘合剂包含核心总重量的约0至约40％，较佳为核心总重量的约3至约15％。
该核心可选择性地包含吸收增进剂，该吸收增进剂可为本领域公知的任何形式的吸收增进剂，例如脂肪酸、表面活性剂、螯合剂、胆盐或其混合物。一些较佳的吸收增进剂的实例为脂肪酸，例如癸酸、油酸及其等单甘油酯；表面活性剂例如月桂基硫酸钠、牛磺胆酸钠及聚山梨酸酯80(polysorbate 80)，螫合剂例如柠檬酸、植酸、乙二胺四乙酸(EDTA)及乙二醇-二(β-胺基乙基醚)-N，N，N，N-四乙酸(EGTA)。该核心包含约0至20％的吸收增进剂(基于核心总重量)，最佳地为核心总重量的约2％至约10％。
本发明的核心包含抗高血糖药、较佳为医药上可接受的水溶性聚合物粘合剂以及吸收增进剂，该吸收增进剂较佳系藉由将核心成分进行湿式制粒且加入润滑剂将颗粒于一旋转压模上压缩为片剂而形成。该核心也可藉由将核心成分进行干式制粒且加入润滑剂将颗粒于一旋转压模上压缩为片剂或藉由直接压缩而形成。
该核心中也可加入其他公知的赋形剂，如润滑剂、颜料或染料。
该均质核心系被一个半透膜、较佳为一修饰的聚合物薄膜所涂覆而形成本发明的控释片剂。半透膜对于外来液体(例如水及生物液体)的通过具有可渗透性，而对核心中抗高血糖药的通过不具可渗透性。有效用于形成半透膜的物质为纤维素酯，纤维素二酯，纤维素三酯，纤维素醚，纤维素酯-醚，纤维素酰化物，纤维素二酰化物，纤维素三酰化物，纤维素乙酸酯，纤维素二乙酸酯，纤维素三乙酸酯，纤维素乙酸丙酸酯以及纤维素乙酸丁酸酯。其他适合的聚合物见于美国专利申请案第3,845,770，3,916,899，4,008,719，4,036,228及4,11210号中，其内容并入本文以供参考。较好的是，形成半透膜的聚合物是非水溶性纤维素衍生物。最佳的半透膜为纤维素乙酸酯，其包含39.3至40.3％的乙酰基含量，其可由市面上得自Eastman Fine Chemicals公司。
在另外一个较佳实施例中，半透膜可由上述聚合物以及流动增进剂(fluxenhancing agent)，流动增进剂会增加吸收到核心中的液体体积，以使该剂型可以分配几乎所有的抗高血糖药通过通道及/或多孔薄膜。该流动增进剂可为水溶性物质或肠衣物质，作为流动增进剂有效的较佳物质的实例为氯化钠，氯化钾，蔗糖，山梨醇，甘露醇，聚乙二醇(PEG)，丙二醇，羟基丙基纤维素，羟丙基甲基纤维素，羟丙基甲基纤维素苯二甲酸酯，纤维素乙酸苯二甲酸酯，聚乙烯醇，甲基丙烯酸共聚物以及其混合物。较佳的流动增进剂为PEG400。
流动增进剂也可为水溶性药物，例如二甲双胍或其医药上可接受的盐类，或是在肠环境下可溶性的药物。若是流动增进剂为一药物，则本发明的剂型具有提供选作流动增进剂的药物立即释放的额外优点。
流动增进剂包含涂覆物总重量的约0至约40％，最佳为涂覆物总重量的约2％至约20％。流动增进剂会溶解或自半透膜中渗出，而在半透膜中形成通道(paths)以使液体进入核心且溶解活性成分。
半透膜也可以公知赋形剂例如塑化剂而形成。一些公知的塑化剂包括己二酸盐、壬二酸盐、安索盐(enzoate)、柠檬酸盐、硬脂酸盐、异布卡盐(isoebucate)、癸二酸盐、三乙基柠檬酸盐、三-正丁基柠檬酸盐、乙酰基三-正丁基柠檬酸盐、柠檬酸酯，及John Wiley & Sons出版的Encyclopedia of Polymer Science andTechnology，Vol.10(1969)中所描述的物质。较佳的塑化剂为甘油三醋酸酯(triacetin)，乙酰化单甘油酯，葡萄子油，橄榄油，芝麻油，乙酰基三丁基柠檬酸酯，乙酰基三乙基柠檬酸酯，甘油山梨醇，二乙基草酸酯，二乙基苹果酸酯，二乙基反式丁烯二酸酯，二丁基琥珀酸酯，二乙基丙二酸酯，二辛基苯二甲酸酯，二丁基癸二酸酯，三乙基柠檬酸酯，三丁基柠檬酸酯，甘油三丁酸酯，及类似物。视特定的塑化剂而定，可基于涂覆物总重量使用约0至约25％、且较佳约2％至约15％的塑化剂。
如在此所使用，通道一词包括孔(aperture)、孔口(orifice)、穿孔(bore)、洞、脆弱区域或磨损元件，例如明胶塞(plug)，其可被侵蚀而形成渗透性通道以使抗高血糖药由剂型中释放出来。本发明的剂型也可以包含两个或两个以上通道。通道的详细叙述见于如美国专利案第3,845,770，3,916,899，4,034,758，4,077,407，4,783,337以及5,071,607号中。
一般而言，核心周围的薄膜涂覆物将包含基于核心及涂覆物总重量约1％至约5％且较佳约2％至约3％。
在另一个具体实施例中，本发明的剂型也可包含-有效量的可用于立即释放的抗高血糖药。有效量的用于立即释放的抗高血糖药的可被涂覆在剂型的半透膜上或可被加入到半透膜中。
在一个较佳具体实施例中，剂型具有下列的组成：
                            较佳                   最佳
核心：
药物                        50-98％                 75-95％
粘合剂                      0-40％                  3-15％
吸收增进剂                  0-20％                  2-10％
涂覆物：
半渗透性聚合物              50-99％                 75-95％
流动增进剂                  0-40％                  2-20％
塑化剂                      0-25％                  2-15％
当于900毫升的模拟肠液(pH 7.5的磷酸缓冲液)中及在37℃以75rpm于美国药典(USP)第2剂型装置测试时，根据本发明制备的剂型应显示下列的溶解分布：
                          较佳                  最佳
   时间(小时)
      2                   0-25％                 0-15％
      4                   10-45％                20-40％
      8                   30-90％                45-90％
      12                  NTL 50％               NTL 60％
      16                  NTL 60％               NTL 70％
      20                  NTL 70％               NTL 80％
NTL＝不少于
在本发明片剂的制备上，可使用不同公知的溶剂以制备颗粒且施用外部涂覆物于本发明的片剂上。除此之外，可使用揭示于Remington’s PharmaceuticalSciences，1995版本中的不同稀释剂、赋形剂、润滑剂、染料、颜料、分散剂等以使本发明的配方最佳化。
附图的简要说明
图1为实施例1所述配方的模拟肠液(pH 7.5磷酸缓冲液)及模拟胃液(SGF)中的溶解分布图，根据美国药典XXIII(United States Pharmacopeia XIII)，第2剂型装置(Apparatus 2)以75rpm中的程序来测试。
图2为实施例2所述配方的模拟肠液(pH 7.5磷酸缓冲液)及模拟胃液(SGF)中的溶解分布图，根据美国药典XXIII，第2剂型装置(Apparatus 2)以75rpm中的程序来测试。
图3为实施例3所述配方的模拟肠液(pH 7.5磷酸缓冲液)及模拟胃液(SGF)中的溶解分布图，根据美国药典XXIII，第2剂型装置(Aparatus 2)以75rpm中的程序来测试。
图4为禁食情况下实施例1中所述配方的体内二甲双胍血浆分布以及商业上可购得的盐酸二甲双胍产品GLUCOPHAGE的体内二甲双胍血浆分布图。
图5为禁食情况下实施例2中所述配方的体内二甲双胍血浆分布以及商业上可购得的盐酸二甲双胍产品GLUCOPHAGE的体内二甲双胍血浆分布图。
图6为喂食情况下实施例2中所述配方的体内二甲双胍血浆分布以及商业上可购得的盐酸二甲双胍产品GLUCOPHAGE的体内二甲双胍血浆分布图。
图7为喂食情况(早餐后)下实施例3中所述配方的体内二甲双胍血浆分布以及商业上可购得的盐酸二甲双胍产品GLUCOPHAGE的体内二甲双胍血浆分布图。
图8为喂食情况(晚餐后)下实施例3中所述配方的体内二甲双胍血浆分布以及商业上可购得的盐酸二甲双胍产品GLUCOPHAGE的体内二甲双胍血浆分布图。
具体实施方式
实施例1
一种含有850毫克的盐酸二甲双胍且具有下列配方的控释片剂制备如下：
I. 核心
盐酸二甲双胍                          90.53％
聚乙烯吡咯酮(providone)1，USP        4.38
三元磷酸钠                            4.58％
硬脂酸镁                              0.5％
1大约分子量＝50,000；动力粘性(在20℃时10％w/v溶液)＝5.5-8.5mPas。
(a)制粒
将盐酸二甲双胍通过一个40目筛去除团块，收集在干净、聚乙烯衬里的容器中。聚乙烯吡咯酮(providone)K-30以及三元磷酸钠系溶解于纯水中。接着将去除团块的盐酸二甲双胍加入一顶端喷淋的流化床制粒器中，且在下列条件下藉由喷淋聚乙烯吡咯酮及三元磷酸纳的结合溶液而制成颗粒：入口气温50-70℃；雾化(atomization)气压1-3巴；以及喷淋速率10-100毫升/分钟。
(b)压片
将硬脂酸镁通过一个40目筛且与盐酸二甲双胍颗粒混合约五分钟。混合后，将颗粒在装设有15/32”圆形标准凹面冲头，具有约1毫米压痕针的上冲头)的旋转压模上压片。
(c)密封涂覆(选择性)
核心片系以Opadry物质或其他合适的水溶性物质密封涂覆，先将Opadry
(b)压片
将硬脂酸镁通过一个40目筛且与盐酸二甲双胍颗粒混合约五分钟。混合后，将颗粒在装设有15/32”圆形标准凹面冲头(平坦的下冲模，具有约1毫米压痕针的上冲头)的旋转压模上压片。
(c)密封涂覆(选择性)
核心片系以Opadry物质或其他合适的水溶性物质密封涂覆，先将Opadry物质、较佳为Opadry Clear溶解于纯水中，接着在下列条件下使用一盘涂料器将Opadry溶液喷淋至核心片上：排气气温38至42℃；务化压力28至40psi；喷淋速率10-15毫升/分钟。以密封用溶液涂覆核心片，直到得到理论值约为2％的涂覆含量。
II. 缓释涂覆物
纤维素乙酸酯(398-10)2                  85％
甘油三醋酸酯                            5％
PEG 400                                 10％
2乙酰基含量39.3-40.3％。
(d)缓释涂覆
在以均质器搅拌下将纤维素乙酸酯溶解于丙酮中，将聚乙二醇400及甘油三醋酸酯加入纤维素乙酸酯溶液中且搅拌直到得到一清澈的溶液。然后，使用下列条件于一流化床涂料器中将清澈的涂覆溶液喷淋至密封涂覆片剂上：产物温度16至22℃；务化压力约3巴；喷淋速率120至150毫升/分钟。密封的核心片被涂覆，直到得到理论涂覆量约为3％。
所得到的片剂在模拟的肠液(pH 7.5)以及模拟胃液(SGF)中测试，根据美国药典XXIII中的程序于第2剂型装置(Aparatus 2)以75rpm进行，发现得到下列释放分布：
   时間(小时)           ％释放(SGF)      ％释放(pH 7.5)
       2                      9                  12
       3                      27                 32
       8                      62                 82
       12                     82                 100
       16                     88                 105
       20                     92                 08
在此实施例中所制备的缓释产物于pH 7.5及SGF中的释放分布示于表1中。
图4系说明此实施例中所制备的缓释产物的体内二甲双胍血浆分布。图4也显示GLUCOPHAGE(一种市面上可得之含有药物盐酸二甲双胍的医药产品)的体内二甲双胍血浆分布。
实施例2
一种含有850毫克的盐酸二甲双胍且具有下列配方的控释片剂制备如下：
I. 核心
盐酸二甲双胍                          88.555
聚乙烯吡咯酮(providone)3，USP        6.368％
月桂基硫酸钠                          3.577％
硬脂酸镁                              0.5％
3大约分子量＝1,000,000；动力粘性(在20℃时10％w/v溶液)＝300-700mPas。
(a)制粒
将盐酸二甲双胍及月桂基硫酸钠通过一个40目筛去除团块，收集其于一干净、聚乙烯襯裎的容器中。将聚乙烯吡咯酮(providone)K-90F溶解于纯水中。接着将去除团块的盐酸二甲双胍及月桂基硫酸钠加入一顶端喷淋的流化床制粒器中，且在下列条件下藉由喷淋聚乙烯吡咯酮的結合溶液而制成颗粒：入口气温50-70℃；务化气压1-3巴；喷淋速率10-100毫升/分钟。
一旦去除結合溶液，使颗粒于制粒器中干燥，直到干燥的损失少于2％。将干燥的颗粒通过一装配有一个18目筛的相等物之Comil。
(b)压片
将使硬脂酸镁通过40目不锈钢筛，与盐酸二甲双胍颗粒混合约五分钟。混合后，将颗粒在一装设有15/32”圆形标准凹面冲头(平坦的下冲模，具有约1毫米压痕针的上冲头)的旋转压模上压片。
(c)密封涂覆(选择性)
将核心片以Opadry物质或其他合适的水溶性物质密封涂覆，首先将Opadry物质、较佳为Opadry Clear溶解于纯水中，接着在下列条件下使用一盘涂料器将Opadry溶液喷淋至核心片上：排气气温38至42℃；雾化压力28至40psi；喷淋速率10-15毫升/分钟。以密封用溶液涂覆核心片，直到得到理论值约为2％的涂覆含量。
II. 缓释涂覆物
纤维素乙酸酯(398-10)4                 85％
甘油三醋酸酯                           5％
PEG 400                                10％
4乙酰基含量39.3-40.3％。
(d)缓释涂覆
在以均质器搅拌下将纤维素乙酸酯溶解于丙酮中，将聚乙二醇400及甘油三醋酸酯加入纤维素乙酸酯溶液中，搅拌直到得到一清澈的溶液。然后，使用下列条件在一流化床涂料器中将清澈的涂覆溶液喷淋至密封涂覆片剂上：产物温度16至22℃；雾化压力约3巴；喷淋速率120至150毫升/分钟。密封的核心片被涂覆，直到得到理论涂覆量约为3％。
所得到的片剂在模拟肠液(pH 7.5)以及模拟胃液(SGF)中测试，根据美国药典XXIII中的程序于第2剂型装置(Aparatus 2)以75rpm进行，发现得到下列释放分布：
    时間(小时)           ％释放(SGF)       ％释放(pH 7.5)
       2                     13                   12
       3                     29                   27
       8                     55                   52
       12                    72                   71
       16                    81                   83
       20                    87                   91
在此实施例中所制备的缓释产物在pH 7.5及SGF中的释放分布示于表2中。
图5系说明在禁食情况下此实施例中所制备的缓释产物的体内二甲双胍血浆分布。图5也显示在禁食情况下GLUCOPHAGE产品的体内二甲双胍血浆分布。
图6系说明在喂食情况下此实施例中所制备的缓释产物的体内二甲双胍血浆分布。图6也显示在喂食情况下GLUCOPHAGE产品的体内二甲双胍血浆分布。
图5及6清楚显示根据本发明所制备的剂型在喂食及禁食情况下显现恒定的生物可利用性，而GLUCOPHAGE产品的生物利用度则在食物出现时会降低。
实施例3
一种含有850毫克的盐酸二甲双胍且具有如实施例2相同配方的控释片剂如同实施例2中所述制备，除了在涂覆的片剂的平坦面上钻的一个额外的洞以外，此额外的洞具有大约1毫米的直径。
所得到的片剂在模拟肠液(pH 7.5)以及模拟胃液(SGF)中测试，根据美国药典XXIII中的程序于第2剂型装置(Aparatus 2)以75rpm进行，发现得到下列释放分布：
    时間(小时)          ％释放(SGF)      ％释放(pH 7.5)
       2                      13                 13
       3                      27                 28
       8                      50                 63
       12                     67                 83
       16                     83                 95
       20                     97                 102
在此实施例中所制备的缓释产物在pH 7.5及SGF中的释放分布示于表3中。
图7系说明此实施例中所制备的缓释产物在早餐不久后施用时的体内二甲双胍血浆分布。图7也显示在早餐不久后施用时GLUCOPHAGE产品的体内二甲双胍血浆分布。
图8系说明此实施例中所制备的缓释产物在晚餐不久后施用时的体内二甲双胍血浆分布。图8也显示在晚餐不久后施用时GLUCOPHAGE产品的体内二甲双胍血浆分布。
表1系示于图3至8中生物可利用性比较数据(即試验/参考組比率)之总览，其中GLUCOPHAGE产品为n＝6的两方双向(two way crossover)生物試验中之参考产品。
表1
配方        图     試验           AUC      Cmax   Tmax
实施例1      3       禁食            0.202     012     2.15
实施例2      5       禁食            0.369     0213    1.73
实施例2      6       喂食(bkft)      0.628     0305    1.93
实施例3      7       喂食(bkft)      0.797     0528    1.82
实施例3      8       喂食(晚餐)      0.850     0751    2.00
bkft＝早餐
表1以及图3至8所记载的結果显示根据本发明所制备的剂型在食物存在时表现抗高血糖药的生物利用度的增加，特别是当与晚餐一起或在晚餐不久后服用时。
虽然本发明特定较佳及另外的具体实施例系已为揭示本发明的目的而阐述，但是熟习此技术者可对揭示的具体实施例作修改。因此，所附权利要求意欲包含本发明的所有具体实施例以及其修改形式，而不背离本发明的精神及范围。

Claims (49)

1.一种控释医药片剂，包含：
(a)一个核心，其包含：
(i)50-98％双胍类药；
(ii)0-40％粘合剂；及
(iii)0-20％吸收增进剂；
(b)包围该核心的半透膜涂覆物，所述半透膜对于水及生物液体的通过具有可渗透性，而对所述抗高血糖药的通过不具可渗透性，所述涂覆物包含50-99％半渗透性聚合物，0-40％流动增进剂和0-25％塑化剂；以及
(c)使所述双胍类药得以释放的至少一个半透膜内的通道。
2.如权利要求1所述控释医药片剂，在所述核芯和半透膜之间还具有一层水溶性密封涂覆物。
3.如权利要求1所述控释医药片剂，其中所述核心的基本组成为：
75-95％的双胍类药；
3-15％的粘合剂；以及
2-10％的吸收增进剂；且所述涂覆物包含：
75-95％的半渗透性聚合物；
2-20％的流动增进剂；以及
2-15％的塑化剂。
4.如权利要求1所述控释医药片剂，其在900毫升含pH 7.5磷酸缓冲液的模拟肠液中及在37℃以75rpm于美国药典第2剂型装置测试时，显示如下溶解分布：
2小时后有0-25％双胍类药释出；
4小时后有10-45％双胍类药释出；
8小时后有30-90％双胍类药释出；
12小时后有不少于50％的双胍类药释出；
16小时后有不少于60％的双胍类药释出；
及20小时后有不少于70％的双胍类药释出。
5.如权利要求1所述控释医药片剂，其在900毫升含pH 7.5磷酸缓冲液的模拟肠液中及在37℃以75rpm于美国药典第2剂型装置测试时，显示如下溶解分布：
2小时后有0-15％双胍类药释出；
4小时后有20-40％双胍类药释出；
8小时后有45-90％双胍类药释出；
12小时后有不少于60％的双胍类药释出；
16小时后有不少于70％的双胍类药释出；
及20小时后有不少于80％的双胍类药释出。
6.如权利要求1所述控释医药片剂，其与晚餐一起或在晚餐不久后服用。
7.如权利要求1所述控释医药片剂，其中所述粘合剂具有水溶性。
8.如权利要求1所述控释医药片剂，其中所述水溶性粘合剂为聚乙烯吡咯烷酮，羟基丙基纤维素，羟基乙基纤维素，蜡质或其混合物。
9.如权利要求8所述控释医药片剂，其中所述水溶性粘合剂为聚乙烯吡咯烷酮。
10.如权利要求1所述控释医药片剂，其中所述吸收增进剂选自脂肪酸、表面活性剂、螯合剂、胆盐或其混合物。
11.如权利要求1所述控释医药片剂，其中所述吸收增进剂为脂肪酸，所述脂肪酸选自癸酸、油酸或其单甘油酯所组成的组。
12.如权利要求1所述控释医药片剂，其中所述吸收增进剂为表面活性剂，所述表面活性剂选自月桂基硫酸钠、牛磺胆酸钠及聚山梨酸酯80所组成的组。
13.如权利要求1所述控释医药片剂，其中所述吸收增进剂为螯合剂，所述螫合剂选自柠檬酸、植酸、乙二胺四乙酸及乙二醇-二(β-胺基乙基醚)-N，N，N，N-四乙酸所组成的组。
14.如权利要求1所述控释医药片剂，其中所述吸收增进剂为胆盐。
15.如权利要求1所述控释医药片剂，其中所述吸收增进剂为月桂基硫酸钠。
16.如权利要求1所述控释医药片剂，其中包围所述核心的半透膜涂覆物中的半渗透性聚合物为非水溶性纤维素衍生物。
17.如权利要求第16所述控释医药片剂，其中所述非水溶性纤维素衍生物为纤维素乙酸酯。
18.如权利要求1所述控释医药片剂，其中所述半透膜包含流动增进剂。
19.如权利要求18所述控释医药片剂，其中所述流动增进剂选自氯化钠，氯化钾，蔗糖，山梨醇，甘露醇，聚乙二醇，丙二醇，羟基丙基纤维素，羟丙基甲基纤维素，羟丙基甲基纤维素苯二甲酸酯，纤维素乙酸苯二甲酸酯，聚乙烯醇，甲基丙烯酸共聚物或其混合物。
20.如权利要求19所述控释医药片剂，其中所述流动增进剂为聚乙二醇400。
21.如权利要求1所述控释医药片剂，其中所述塑化剂为甘油三醋酸酯。
22.如权利要求1所述控释医药片剂，其中至少两个通道形成于该半透膜中。
23.如权利要求1所述控释医药片剂，其血浆峰浓度在服用8至12小时后达到。
24.如权利要求1所述控释医药片剂，其中所述双胍类药为二甲双胍或其医药上可接受的盐类。
25.如权利要求1所述控释医药片剂，其中，所述核心的基本组成为：
(i)50-98％二甲双胍或其医药上可接受的盐；
(ii)0-40％水溶性粘合剂；及
(iii)0-20％吸收增进剂。
26.如权利要求25所述控释医药片剂，在所述核芯和半透膜之间还具有一层水溶性密封涂覆物。
27.如权利要求25所述控释医药片剂，其中所述核心的基本组成为：
75-95％的二甲双胍或其医药上可接受的盐；
3-15％的粘合剂；以及
2-10％的吸收增进剂；且所述涂覆物包含：
75-95％的聚合物；
2-20％的流动增进剂；以及
2-15％的塑化剂；
所述半透膜内有至少一个释放二甲双胍的通道。
28.如权利要求25所述控释医药片剂，其在900毫升以pH 7.5磷酸缓冲液配制的模拟肠液中及在37℃以75rpm于美国药典第2剂型装置测试时，显示如下溶解分布：
2小时后有0-25％二甲双胍释出；
4小时后有10-45％二甲双胍释出；
8小时后有30-90％二甲双胍释出；
12小时后有不少于50％的二甲双胍释出；
16小时后有不少于60％的二甲双胍释出；
及20小时后有不少于70％的二甲双胍释出。
29.如权利要求25所述控释医药片剂，其在900毫升以pH 7.5磷酸缓冲液配制的模拟肠液中及在37℃以75rpm于美国药典第2剂型装置测试时，显示如下溶解分布：
2小时后有0-15％二甲双胍释出；
4小时后有20-40％二甲双胍释出；
8小时后有45-90％二甲双胍释出；
12小时后有不少于60％的二甲双胍释出；
16小时后有不少于70％的二甲双胍释出；
及20小时后有不少于80％的二甲双胍释出。
30.如权利要求25所述控释医药片剂，其与晚餐一起或在晚餐不久后服用。
31.如权利要求25所述控释医药片剂，其中所述水溶性粘合剂为聚乙烯吡咯烷酮，羟基丙基纤维素，羟基乙基纤维素，蜡质或其混合物。
32.如权利要求25所述控释医药片剂，其中所述水溶性粘合剂为聚乙烯吡咯烷酮。
33.如权利要求25所述控释医药片剂，其中所述吸收增进剂选自脂肪酸、表面活性剂、螯合剂、胆盐或其混合物。
34.如权利要求25所述控释医药片剂，其中所述吸收增进剂为脂肪酸，所述脂防酸选自癸酸、油酸或其单甘油酯所组成的组。
35.如权利要求25所述控释医药片剂，其中所述吸收增进剂为表面活性剂，所述表面活性剂选自月桂基硫酸钠、牛磺胆酸钠及聚山梨酸酯80所组成的组。
36.如权利要求25所述控释医药片剂，其中所述吸收增进剂为螯合剂，所述螯合剂选自柠檬酸、植酸、乙二胺四乙酸及乙二醇-二(β-胺基乙基醚)-N，N，N，N-四乙酸所组成的组。
37.如权利要求25所述控释医药片剂，其中所述吸收增进剂为胆盐。
38.如权利要求25所述控释医药片剂，其中所述吸收增进剂为月桂基硫酸钠。
39.如权利要求25所述控释医药片剂，其中包围所述核心的半透膜涂覆物中的半渗透性聚合物为非水溶性纤维素衍生物。
40.如权利要求第25所述控释医药片剂，其中所述非水溶性纤维素衍生物为纤维素乙酸酯。
41.如权利要求25所述控释医药片剂，其中所述半透膜包含流动增进剂。
42.如权利要求41所述控释医药片剂，其中所述流动增进剂为氯化钠，氯化钾，蔗糖，山梨醇，甘露醇，聚乙二醇，丙二醇，羟基丙基纤维素，羟丙基甲基纤维素，羟丙基甲基纤维素苯二甲酸酯，纤维素乙酸苯二甲酸酯，聚乙烯醇，甲基丙烯酸共聚物或其混合物。
43.如权利要求42所述控释医药片剂，其中所述流动增进剂为聚乙二醇400。
44.如权利要求25所述控释医药片剂，其中所述塑化剂为甘油三醋酸酯。
45.如权利要求25所述控释医药片剂，其中至少两个通道形成于该半透膜中。
46.如权利要求25所述控释医药片剂，其血浆峰浓度在服用8至12小时后达到。
47.如权利要求25所述控释医药片剂，其进一步包含有效量的二甲双胍，其被涂覆在半透膜上或混合至半透膜中，以提供立即释放该有效量的二甲双胍。
48.如权利要求1所述控释医药片剂，包含：
(a)一个核心，基本组成为：
(i)75-95％二甲双胍或其医药上可接受的盐；
(ii)3-15％水溶性粘合剂；及
(iii)2-10％吸收增进剂；(b)包围该核心的半透膜涂覆物，所述半透膜对于水及生物液体的通过具有可渗透性，而对所述二甲双胍的通过不具可渗透性，所述涂覆物包含75-95％半渗透性聚合物，2-20％流动增进剂和2-15％塑化剂；以及(c)使二甲双胍得以释放的至少一个半透膜内的通道。
49.如权利要求48所述控释医药片剂，其中的半渗透性聚合物是纤维素乙酸酯。
CNB998064343A 1998-03-20 1999-03-19 具有单一核心的控释口服片剂 Expired - Fee Related CN1158999C (zh)

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CN1308520A (zh) 2001-08-15
HK1037963A1 (en) 2002-03-01
EP2087889A2 (en) 2009-08-12
US20010024659A1 (en) 2001-09-27
ES2540972T3 (es) 2015-07-15
AU739226B2 (en) 2001-10-04

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