CN1235824A - 包肠溶衣的胰酶颗粒的制备方法 - Google Patents

包肠溶衣的胰酶颗粒的制备方法 Download PDF

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CN1235824A
CN1235824A CN99103124A CN99103124A CN1235824A CN 1235824 A CN1235824 A CN 1235824A CN 99103124 A CN99103124 A CN 99103124A CN 99103124 A CN99103124 A CN 99103124A CN 1235824 A CN1235824 A CN 1235824A
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acid
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朴东雨
全泓烈
李炅姬
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Il Yang Pharmaceutical Co Ltd
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Abstract

本发明公开一种制备包肠溶衣胰酶颗粒的方法,包括:在低温下飘浮胰酶粉末,以高速度把一种包衣溶液喷到该胰酶粉末上,得到包衣的胰酶颗粒。所得到的颗粒在酸性pH条件下和压片时非常稳定。

Description

包肠溶衣的胰酶颗粒的制备方法
本发明涉及一种包肠溶衣胰酶颗粒的制备和压片方法，其中的包肠溶衣胰酶颗粒能在酸性pH条件下保持稳定。
胰酶是从哺乳动物如牛和猪的胰腺中分离得到的一种消化性酶，它具有淀粉酶、蛋白酶和脂肪酶的活性。已知淀粉酶能够治疗胆囊纤维化、胰腺炎和无胰综合症等疾病。由胰腺产生的胰酶释放到pH值接近中性或微碱性的十二指肠中。在这样的pH条件下，释放的胰酶具有活性，因此，在小肠的上段，酶消化食物正常地进行。然而，在需要治疗胰腺机能障碍时，胰酶外源性地给药于病人，胃中的胃环境，也就是在酸和胃蛋白酶存在下，能不可逆地使酶失活。在酸性条件下，这些酶显示正常活性的10％-40％。酸性pH值尤其影响脂肪酶活性。因此，由于胃酸的作用，必须保护口服酶以免失活，从而，当它们经过胃进入到十二指肠时能保持原样。
包肠溶衣是保护酶的最好方法。有两种技术可用于包肠溶衣。第一种技术是众所周知的，包括胰酶与适当的辅料混合、压片得到的混合物，然后在药片上包肠溶衣即得。胰酶经常与其它消化酶组合使用，而不是作为单独成分使用。因此，即使那些其它应该在胃中起作用的消化酶也可包衣，但它们不能充分显示它们的用处。其它的技术公开在U.S.5,260,074和US 5,302,400专利说明书中。它包括：胰酶和合适的辅料、粘合剂以及有机溶剂混合，将混合物颗粒化，压制使成球状颗粒，干燥球状颗粒和在该干燥颗粒上包肠溶衣。特别是，胰酶与US 4,079,125所公开的合适的粘合剂、稳定剂、崩解剂和有机溶剂混合，然后将混合物颗粒化。用Marumerize压制法使颗粒成为珠状，再对此珠状物进行包衣。或者，胰酶粉末与润滑剂混合，用滚压法(roller compaction)、凹压法(concave compaction)或凸压法(convex compaction)把混合物压成球状片，将得到的球片辗碎，过筛，然后在没有有机溶剂的情况下包衣。这种技术的缺点是：颗粒化时应用的溶剂和压制时产生的热量使酶的活性降低。该技术包括许多步骤也使它的效率较低。当包肠溶衣的颗粒压片时，它们必须在压片压力下保持稳定，而且必须微小。这样，由于压片压力的消散，包肠溶衣的颗粒能够成型并且不会变碎。然而，现有技术不能产生细小均匀的颗粒，因此不会产生在酸性条件下和压片时稳定的包肠溶衣颗粒。
因此，尽管用作复合制剂时，即通过无包衣压片或胃溶包衣形成胃肠隔室的片剂，胰酶有许多优点，然而仍然需要开发在单独应用时能在压片压力下保持稳定的包肠溶衣颗粒。我们完成了一种改进的包肠溶衣技术，该技术可确保：胰酶在胃环境中的活性不受影响、肠溶衣颗粒在肠中能迅速溶解和在压片压力下包衣颗粒保持稳定。
一方面，本发明提供一种制备包肠溶衣胰酶颗粒的方法，包括：在低温下使胰酶粉末浮动时，以高速度把包衣溶液喷到该胰酶粉末上，得到精细包衣的胰酶颗粒；如果有必要，在低温下使所得到的精细颗粒浮动时，再以高速度把另一种包衣溶液喷到该颗粒上，产生包衣的胰酶颗粒。其中，第二次的包衣溶液可以与第一次的包衣溶液相同或不相同。
另一方面，本发明提供一种制备胰酶片剂的方法，包括：在低温下使胰酶粉末浮动时以高速度把包衣溶液喷到该胰酶粉末上，得到精细包衣的胰酶颗粒；如果有必要，在低温下使所得到的精细颗粒浮动时，再以高速度把另一种包衣溶液喷到该颗粒上，产生包衣的胰酶颗粒。其中，第二次的包衣溶液可以与第一次的包衣溶液相同或不相同。把占药片总重量5％-80％的包衣颗粒和药学上可接受的辅料混合，然后压片得到的混合物。
本发明的包衣基质包括玉米蛋白质提取物、藻酸钠、藻酸、甲基丙烯酸一甲基丙烯酸乙酯共聚物、紫胶、丙烯酸聚合物(carbomer，羧基乙烯聚合物)、邻苯二甲酸羟丙甲基纤维素酯、乙酸琥珀酸羟丙甲基纤维素、乙酸琥珀酸羟丙基甲酯、羧甲基纤维素、乙酸邻苯二甲酸纤维素、羟丙基纤维素、乙基纤维素、甲基纤维素、聚乙酸邻苯二甲酸乙烯酯、大豆蛋白质、小麦蛋白质、壳多糖、壳多糖酸(chitinic acid)、琼脂、角叉菜胶、果胶、瓜尔胶、槐树豆胶、黄原胶、凝胶(gellan gum)、阿拉伯树胶和6-12个碳原子的中链脂肪酸。这些物质可单独使用或作为两个或更多物质的混合物使用。包衣基质的用量为所用胰酶总重量的1％-250％，优选50％-180％重量。
本发明中用于包衣的增塑剂包括聚乙二醇、甘油脂肪酸酯、脱水山梨糖脂肪酸酯、丙二醇、甘油、柠檬酸三乙酯、甘油三乙酸酯、鲸蜡醇和硬脂醇。这些物质可单独应用或作为两个或更多物质的混合物应用。增塑剂的用量为所用胰酶总重量的1％-50％，优选5％-30％重量。
如果包衣基质和增塑剂的用量不是上述比例，则包衣颗粒的崩解延迟或者在胃液中包衣变得不稳定。所以，胰酶或者作用不迅速或者活性降低。
本发明包衣溶液的溶剂包括水、乙醇、丙酮、乙腈、二氯甲烷、乙醚、己烷、氯仿、1,4-二氧六环、四氢呋喃、二甲亚砜、乙酸乙酯、乙酸甲酯或它们的混合物。
许多流化床或类似设备可用来包衣。本发明应用SFC-MINI流化床(Freund Co，日本)。注入空气的温度范围为35-70℃。整个过程期间为了防止颗粒的聚集和破碎，颗粒的温度至少为25℃。更可取的是，在此过程中调整颗粒的温度范围为25-60℃，因为当温度超过60℃时，该酶的效价降低。
下列实施例阐明符合本发明的包肠溶衣胰酶颗粒的组合物和制备方法，本发明不局限于这些范围。实施例实施例1
第一次包衣药种        胰酶粉末      300g包衣溶液    HPMC2208      15g水            300ml聚乙二醇6000  2g第二次包衣药种     第一次精制的包衣颗粒 300g包衣溶液 EudragitL 30D   1,320ml(水分散的)(400g作为固体粉末)水                 500ml丙二醇             40g
(A)第一次精细包衣颗粒的制备
当胰酶粉末浮在流化床(SFC-MINI)中时，把上述第一种包衣溶液喷于该胰酶粉末上。调整流化床产品的温度至25-60℃。
(B)第二次包衣颗粒的制备
当第一次得到的精细包衣颗粒浮在流化床中时，把上述第二种含有EuragitL30D和增塑剂的包衣溶液喷于该颗粒上。流化床中颗粒的温度范围不能偏离25-60℃范围。作为第二种包衣基质，可用Kollicoat MAE 30 DP代替。实施例2
    第一次包衣药种        胰酶粉末                   300g包衣溶液    藻酸钠                     3g水                         300ml甘油                       3g第二次包衣药种        第一次精制的包衣颗粒       300g包衣溶液    Zein-DP(玉米蛋白质提取物)  150g紫胶                       30g80％乙醇                   1,200ml丙二醇                     6g甘油                       12g
按与实施例1所述相同的方式制备第一次和第二次包衣的颗粒，但所用的成分如上。实施例3
第一次包衣药种      胰酶粉末             300g包衣溶液  HPMC2910             10g水                   200ml甘油                 2g第二次包衣药种      第一次精制的包衣颗粒 300g包衣溶液  HPMCP                400g80％乙醇             4,000ml甘油脂肪酸酯         30g
按与实施例1所述相同的方式制备第一次和第二次包衣颗粒，但所用的成分如上。可用HPC代替用作第一种包衣基质。实施例4
第一次包衣药种      胰酶粉末               300g包衣溶液  HPC                    10g水                     200ml甘油                   4g第二次包衣药种     第一次精制的包衣颗粒    300g包衣溶液 聚乙酸邻苯二甲酸乙烯酯  400g水                      4,000ml丙二醇                  10g
按与实施例1所述相同的方式制备第一次和第二次包衣颗粒，但所用的成分如上。实施例5
药种     胰酶粉末  300g包衣溶液 HPMCP     400g80％乙醇4,000ml甘油脂肪酸酯30g
按与实施例1所述相同的方式使胰酶单层包衣，但所用的成分如上。实施例6
药种     胰酶粉末          300g包衣溶液 Eudragit L 30D    1485ml(450g作为固体粉末)水                300ml柠檬酸三乙酯      30g
按与实施例1所述方式使胰酶单层包衣，但所用的成分如上。如果需要，Kollicoat 30DP可用来代替上述包衣基质。通过提高喷雾速度制备单层包衣颗粒可防止因包衣溶液引起的酶效价降低。实验实施例1
由实施例1至6所制备的包衣颗粒，对其粒子大小分布进行了测定。结果如下面的表1所示。
表1包衣胰酶颗粒的粒子大小分布(％)
                                       筛孔尺寸(mm)
    20(0.84)      30(0.59)      40(0.42)    50(0.297)
实施例1     7.4      50.5      38.6    3.5
实施例2     9.5      47.6      34.4    8.5
实施例3     9.3      45.8      37.3    7.6
实施例4     11.7      44.1      40.0    4.2
实施例5     4.8      52.2      38.6    4.4
实施例6     9.0      54.7      30.5    5.8
从表1中可以看出，30-40目的粒子至少占整个包衣颗粒的80％。这个结果表明，本发明制备的包衣颗粒是均匀的。实验实施例2
由上面实施例1至6所制备的包衣胰酶颗粒，按照欧洲药典描述的胰酶测定方法对其脂肪酶、淀粉酶和蛋白酶的活性进行了测定。应用原料胰酶作为对照。结果如下面的表2所示。表2
包衣颗粒的胰酶含量(％)     酶活性(U/mg)
   脂肪酶    淀粉酶    蛋白酶
原料实施例1实施例2实施例3实施例4实施例5实施例6 38.459.139.537.741.138.5     73.128.343.328.927.430.328.2     80.531.547.032.030.933.831.3     6.12.43.62.42.32.62.3
从表2可以看出，由上面实施例1-6制备得到的包衣胰酶，把包衣基质和增塑剂排除在外，其效价与作为对照的原料胰酶一致。这个结果表明：在包衣过程中，胰酶的酶效价没有降低。实验实施例3
由实施例1-6制备得到的包衣颗粒，按目大小选择两种颗粒并压成药片。对所得药片进行溶解试验以确定压片压力对不同目大小包衣颗粒的作用。应用微晶纤维素作辅料，包衣颗粒占药片重量的50％。每800ml pH 2.0和pH 3.0的人工制备的胃液在溶解试验仪1中以100rpm的转速搅拌60分钟，这些人工胃液转移到人工制造的肠液(磷酸缓冲液，pH6.0)，在溶解试验仪2中以100rpm的速度搅拌30分钟。取合适量的样品，测试其脂肪酶活性。结果如下面的表3所示。表3
pH2.0的人工制造的胃液 pH为3.0的人工制造的胃液
脂肪酶活性(U/mg) 耐受性(％)     脂肪酶活性(U/mg) 耐受性(％)
实施例1实施例2实施例3实施例4实施例5实施例6  20-30目30-40目20-30目30-40目20-30目30-40目20-30目30-40目20-30目30-40目20-30目30-40目  23.824.715.018.024.125.023.224.524.926.522.824.8   84.187.334.641.683.486.584.789.482.287.580.987.9     26.127.418.519.126.527.524.526.227.228.725.126.8  92.296.842.744.191.795.289.495.689.894.789.095.0
表3的结果表明：依赖于颗粒目的大小，包肠溶衣胰酶颗粒足以在酸性条件下作为保护性屏障。
在本发明的包肠溶衣胰酶颗粒中，压片压力并不破坏包衣层。酸耐受性试验显示：包衣颗粒越大，酶效价降低得越多。这意味越小的包衣颗粒越能耗散和吸收压片压力，它的包衣层不会被破坏。实验实施例4
用微晶纤维素作辅料，压紧包衣胰酶颗粒。对所获得的药片进行溶解试验以确定辅料对药片的作用。应用30-40目的包衣胰酶颗粒，占药片的重量比分别为25％、50％、75％和90％。这些药片中包衣胰酶颗粒的绝对量相同。结果如下面的表4所示。表4
    pH2.0的人工制造的胃液     pH3.0的人工制造的胃液
包衣胰酶颗粒含量(％)  脂肪酶活性(U/mg)     耐受性(％) 脂肪酶活性(U/mg)    耐受性*％)
实施例1     25     26.1     92.2     27.9     98.6
    50     24.7     87.3     27.4     96.8
    75     21.2     74.9     24.4     86.2
    90     18.3     64.7     21.0     74.2
实施例2     25     20.4     47.1     21.3     49.2
    50     18.0     41.6     19.1     44.1
    75     14.2     32.8     16.7     38.6
    90     10.5     24.2     13.5     31.2
实施例3     25     26.8     92.7     28.2     95.2
    50     25.0     86.5     27.5     86.9
    75     22.7     78.5     25.1     72.7
    90     19.4     67.1     21.0     98.5
实施例4     25     26.0     94.9     27.0     98.5
    50     24.5     89.4     26.2     95.6
    75     21.7     79.2     23.9     87.2
    90     19.2     70.1     20.7     75.5
实施例5     25     28.6     94.4     29.3     96.7
    50     26.5     87.5     28.7     94.7
    75     23.2     76.6     26.4     87.1
    90     20.0     66.0     23.1     76.2
实施例6     25     26.9     95.4     27.9     98.9
    50     24.8     87.9     26.8     95.0
    75     21.5     76.2     24.0     85.1
    90     18.7     66.3     21.2     75.2
表4的结果表明：当药片中的辅料含量太低时，它不能缓冲压片压力，包衣层容易被破坏。

Claims (11)

1．一种制备包肠溶衣胰酶颗粒的方法，包括：在低温下使胰酶粉末浮动时，把一种包衣溶液以高速度喷在该胰酶粉末上得到包衣胰酶颗粒。
2．根据权利要求1所述的方法，其中，在低温下使所获得的包衣胰酶颗粒浮动时，又把一种与第一种包衣溶液相同或不同的包衣溶液以高速度喷在该颗粒上。
3．根据权利要求1或2所述的方法，其中包衣基质选自玉米蛋白质提取物、藻酸钠、藻酸、甲基丙烯酸-甲基丙烯酸乙酯共聚物、紫胶、丙烯酸聚合物(carbomer，羧基乙烯聚合物)、邻苯二甲酸羟丙甲基纤维素酯、乙酸琥珀酸羟丙甲基纤维素、乙酸琥珀酸羟丙基甲酯、羧甲基纤维素、乙酸邻苯二甲酸纤维素、羟丙基纤维素、乙基纤维素、甲基纤维素、聚乙酸邻苯二甲酸乙烯酯、大豆蛋白质、小麦蛋白质、壳多糖、壳多糖酸(chitinic acid)、琼脂、角叉菜胶、果胶、瓜尔胶、槐树豆胶、黄原胶、凝胶(gellan gum)、阿拉伯树胶和6-12个碳原子的中链脂肪酸。
4．根据权利要求1或2所述的方法，其中增塑剂选自聚乙二醇、甘油脂肪酸酯、脱水山梨糖脂肪酸酯、丙二醇、甘油、柠檬酸三乙酯、甘油三乙酸酯、鲸蜡醇、硬脂醇和它们的混合物。
5．根据权利要求1或2所述的方法，其中增塑剂的用量占所用胰酶总重量的1％-50％。
6．根据权利要求1或2所述的方法，其中胰酶的用量占颗粒总重量的1％-95％。
7．根据权利要求1或2所述的方法，其中包衣基质的用量为所用胰酶总重量的1％-250％。
8．根据权利要求1或2所述的方法，其中的溶剂选自水、乙醇、丙酮、乙腈、二氯甲烷、乙醚、己烷、氯仿、1,4-二氧六环、四氢呋喃、二甲亚砜、乙酸乙酯、乙酸甲酯或它们的混合物。
9．根据权利要求1或2所述的方法，其中整个过程进行的温度为20-70℃。
10．根据权利要求1或2所述的方法，其中应用流化床涂料器或CF-造粒机。
11．一种制造胰酶片剂的方法，包括：把权利要求1或2所述的占药片总重量5％-80％的包肠溶衣颗粒和药学上可接受的辅料混合，然后压片所获得的混合物。
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