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CN1025283C - 生产控制释放产品时用的小珠的制备方法 - Google Patents

生产控制释放产品时用的小珠的制备方法 Download PDF

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CN1025283C
CN1025283C CN86106651A CN86106651A CN1025283C CN 1025283 C CN1025283 C CN 1025283C CN 86106651 A CN86106651 A CN 86106651A CN 86106651 A CN86106651 A CN 86106651A CN 1025283 C CN1025283 C CN 1025283C
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拉斯-埃里克.戴维.达尔林德
马茨·奥夫·约翰森
约翰·安德斯·桑德伯格
约翰·艾伯特·削格伦
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Abstract

含有若干覆盖有一种或多种药物活性化合物的不溶性的小珠的控制释放制剂，它的制备方法以及在需要控制释放药物活性化合物的治疗中的使用。

Description

本发明涉及具有药物活性化合物的控制释放的新药物制剂，此类制剂的制造方法以及获得药物活性化合物的控制释放的方法。
在医疗各种疾病中，例如在心血管、胃肠道和化疗方面，使所给药物在血中具有恒定的浓度是有好处的。因此需要从药物制剂中有控制地释放药物。
重要的是控制释放的制剂所释放出来的药物量，应能在整个治疗剂量期间维持相当的和稳定的效果。这通常意味着，药物的释放应该有恒定速率以使血液中的所给药物浓度保持稳定，这对于具有小治疗指数，即有效浓度与毒性浓度之间差别很小的药物特别重要。对于当在大的局部浓度存在时具有能引起胃肠道紊乱的潜在危险的局部刺激性药物或对于具有短排除半衰期的药物，药物的延缓和恒定释放也将是重要的。在排除半衰期短的药物中，控制释放的制剂比常规剂量形式给药次数较少，因此患者有较好的顺应性（参看Hayes    R.B.等Clin.Pharm.Therap.（1977年），22卷，125-130页）。
一个药物能通过任何给药途经用控制的方法进行释放，但该类制剂最好要具有某些共同的特征，例如提供有控制的和能重复产生的药物释放并有助于重复的吸收，没有毒性或没有刺激性的成分，并且也适宜于高剂量药物。
对于口服用药物，可以控制释放药物的体系的例子为不溶性基质类型的持续释放片剂，如DurulesR，和渗透活性片剂，即OROSR。OROSR体系在美国专利案号4，036，227中以及由英国Theeuwes F.等在Journal of Clinical Pharmacology（1985年），19卷，695-765页（补充部分）中曾有描述。它的主要部分是药物的片剂核心，核的周围包有钻一小孔的半渗透聚合物膜。联邦德国专利（DE-A-2030501）描述包含无定形二氧化硅的基质类型的制剂。活性化合物通过基质扩散释放出来。上述那些例子是单一单位体系，所有药物集中在一单位内，而本发明是多一单位原理。
从英国专利（GB-A-1542414）一种已知制剂含有一种与活性化合物物理地或化学地相结合的有机载体材料，以及一种与所述的支载体料相接触的玻璃材料。该玻璃含有可溶性的金属离子。药物的释放受控于离子交换作用引起的玻璃中金属离子的溶解作用。显然玻璃在该制剂中不是一个不溶性的惰性化合物。
包含大量小单位的制剂库的一些好处已在文献中描述。例如当粒子小于1-2毫米时有可能获得从胃进入小肠时可重复出现的单位排空（参看Bogentoft    C.等：食物对于肠衣形式的乙酰水杨酸的吸收的影响，Europ.J.Clin.Pharmacol（1978年），14卷351-355页）。药物在胃肠道中大面积分散能够使总通过时间更具重现性，这对吸收过程是有利的（参看Edgar    B。等：用检测血中和尿中稳定状态的水杨酸及其代谢物的水平比较两种肠衣乙酰水杨酸制剂。Biopharmaceu tics    &    Drug    Disposition。（1984年5卷251-260页）。此外当药物剂量在肠子中发散时，多单位制剂优于单一单位制剂。局部刺激的危险和由于消化道收缩引起的一些药量积聚也认为是较低的（参看McMahan    F.G.等：补充氯化钾后刺激性药物的胃肠道损伤：一个控制的临床试验The    Lancet，11月13日1059-1061页）。
多单位制剂的又一好处是它可以分成具有相同吸收性能的较小部分。这样，在选择剂量大小时，就可能有较大的灵活性。
本发明涉及一种可以控制释放一种或多种药物活性化合物的新型制剂。
该制剂由大量不溶性小粒子，即核心组成，这些核心表面被药物活性化合物复盖。核心的大小是0.1-2毫米，最好0.1-0.5毫米，由不溶性惰性材料组成。不溶性的意义是：该材料不溶于水，生理液体或一般用于静脉输注的液体内。不溶性惰性材料的例子有二氧化硅、玻璃或塑料树脂颗粒。塑料材料的适宜类型是可用于医药的塑料，如聚丙烯或聚乙烯，最好是聚丙烯。核心材料应该具有标准的大小和形状，最好是有平滑表面的球状。最好，核心材料应该具有足够高的密度，这可使它适合于流化床处理。更进一步，该核心材料要有高纯度也很重要，也就是说，不含可溶性的杂质。
药物活性化合物最好先配成溶液，再用喷雾法用于核心材料上。因此该活性化合物在不溶性核心上形成一个致密层。所用的药物活性化合物是具有心血管、胃肠道或化疗效应的药物，特别是肾上腺素β-阻断剂和抗生素。能用于核心材料上的适宜的药物活性化合物的例子有心得舒、美多心安、奎尼丁、镁和氨苄西林的盐。产生的颗粒或 小珠的大小为0.2-3.0毫米，最好0.3-1.0毫米。然而对于大部分需要做成控制释放制剂的药物，只要它们能溶于某一溶剂并且此溶剂又能在干燥过程中除掉，都有可能按照上述方法制成控制释放制剂。
本发明的这些小珠是紧密的，这意味着孔隙度少于15%。
小珠用聚合物的膜包衣以限制和控制药物释放。聚合物的膜能根据不同的释放曲线图，例如PH相关的、肠包衣、PH无关的、要或不要延缓时间来释放药物。最重要的用途是在PH1-8范围内与PH无关的控制释放。适宜的聚合物的材料例子有乙基纤维素，羟丙基甲基纤维素羟丙基纤维素，邻苯二甲酸羟丙基甲基酯（例如HP55），乙酸邻苯二甲酸纤维素，EudragitRRL，EudragitRRS。乙基纤维素能单独使用或与例如水溶性的聚合物如羟丙基甲基纤维素合并使用，以调整包衣层的渗透性。
不同粘度等级的乙基纤维素都可以使用，在下面给出的例子中，使用了粘度为10、50或100厘泊的乙基纤维素，但其它类型的乙基纤维素也是适用的。
EudragitR是一些以丙烯酸树脂为基础的由Roehm Pharma。生产的薄膜包衣物料的商品名称，例如Eudragit RL和RS是由丙烯酸酯和甲基丙烯酸酯合成的含少量季铵基团的共聚物。这些铵基团与其余中性的（甲基）丙烯酸酯的摩尔比，对EudragitRRL为1∶20，对EudragitRRS为1∶40，从而产生不同的渗透特性。其它能够使用的Eudragit变体有Eudragit L、Eudragit S和Eudragit E。
为了改良膜的工艺性质或修改释放特征，在聚合物的溶液中可以加色素和/或增塑剂。可以使用的增塑剂的例子是柠檬酸酯、乙酰化单甘油酯和甘油三乙酸酯。
新制剂有若干优点，例如颗粒含有高百分数的活性成分，且不受可溶性的惰性化合物污染，例如乳糖或糖的核心用治疗用的活性化合物包衣正是这个情况。当制剂用于非肠道给药时这一点特别重要。
用小的致密颗粒例如二氧化硅作为核心材料，有可能获得具有高浓度活性化合物的小珠（粒剂），这对于高剂量制剂是个优点，例如氯化镁。
新制剂的一个优点是：包裹用活性化合物复盖的不溶性核心与包裹具有可溶性核心材料的制剂，二者相比较时，为了延缓药物释放，一般来说，前者需要较少的聚合物材料（参看图1）。按照本发明的制剂能以各种途径给药，例如口服或非肠道给药。一个静脉给药的例子是通过在欧洲专利（EP-B1-59694）中描述的药物给予装置给药的。
当把本发明的活性化合物包衣小珠用于口服时，有可能将制剂加工成颗粒填入硬明胶胶囊、填入小药囊中或加工成片剂而给药后仍然可以得到所希望的血浆浓度曲线和持续有效时间。
当小珠做成片剂时，它们与含有微晶纤维素（如AvicelR）的添加剂混合，这样改进压片的性能，并促进片剂的崩解，释放出单个的小珠。
利用本发明，可能在减少给药次数时，而在下次给药前的整个期间血浆中仍具有几乎恒定的药物浓度。用新制剂常常是一天一个单剂量用药就足够了。
控制释放制剂的制造方法是本发明的另一方面。药物活性化合物溶于合适的溶剂例如二氯甲烷、乙醇、异丙醇或水中，并在包衣盘中喷到不溶性的核心材料上面或最好在流化床中喷施，干燥除去溶剂。然后将得到的小珠用上述聚合物层包衣。聚合物的混合物溶于溶剂如乙醇、异丙醇和/或二氯甲烷中。喷雾可以在包衣盘中进行，但最好在流化床中进行。乙基纤维素也可通过水分散体系（乳液）喷施。
当需要有控制地和恒定地释放治疗用活性化合物时，本发明的制剂是特别有利的。关于治疗用活性化合物的控制释放的方法是本发明的又一方面。
通过下列实施例对本发明进行详细说明：
例1
核心
美多心安反丁烯二酸盐    1440克
二氯甲烷    9618克
乙醇95%    3888克
SiO2（0.15-0.25毫米） 375克
聚合物层
乙基纤维素10厘泊    265.6克
羟丙基甲基纤维素    58.4克
柠檬酸乙酰基三丁基酯    36.0克
二氯甲烷    6141克
异丙醇    1544克
在流化床成粒机中将美多心安反丁烯二酸盐的95%乙醇溶液喷施到二氧化硅核心上。这样形成的小珠400克（0.4-0.63 毫米部分）用含有10厘泊乙基纤维素、羟丙基甲基纤维素和柠檬酸乙酰基三丁基酯的聚合物溶液覆盖，复盖方法是将上述物质的二氯甲烷和异丙醇溶液喷施在上述400克小珠上。然后将包衣的小珠填入硬明胶胶囊中。
例2-3和参考例1
核心
2    3    参考例1
美多心安琥珀酸盐    1440克    1440克    1440克
二氯甲烷    9618克    9618克    9618克
乙醇95%    3888克    3888克    3888克
SiO2（0.15-0.25毫米） 375克
玻璃（0.2毫米）    375克
NaCl（0.15-0.25毫米）    375克
聚合物层
400克上面的颗粒（0.4-0.5毫米部分）用下列物质的组合物包衣
乙基纤维素10厘泊    52.3克
柠檬酸乙酰基三丁基酯    8.6克
二氯甲烷    1111克
异丙醇    218克
美多心安琥珀酸盐的95%乙醇和二氯甲烷溶液，分别喷雾到二氧化硅、玻璃和氯化钠核心上。这样形成的小珠用喷雾法，含有粘度为10厘泊的乙基纤维素和柠檬酸乙酰基三丁基酯的二氯甲烷和异丙醇溶液包衣。图1说明在20小时期间内美多心安琥珀酸盐的累积释 放情况。从图中可以看到，当活性化合物用于二氧化硅或玻璃上时，活性化合物可以控制地和几乎恒定地释放，而可溶性氯化钠的核心，产生相当高的起始释放速率，图2（下面参考例2）也说明了这一点，该例是用可溶性氯化钾作为核心材料。
参考例2
核心
美多心安琥珀酸盐    2000克
KCl（0.1-0.2毫米）    400克
二氯甲烷    13360克
乙醇95%    7900克
参考例2的400克颗粒用包括下列聚合物的组合物包衣：
聚合物层
乙基纤维素10厘泊    135.3克
EudragitRRS 27.4克
柠檬酸乙酰基三丁基酯    27.4克
二氯甲烷    4469克
异丙醇    661克
该颗粒按前面例子中所述方法加工。
例4-6
核心    例
4    5    6
美多心安琥珀酸盐    1440克    1440克    1440克
二氯甲烷    9618克    9618克    9618克
乙醇95%    3888克    3888克    3888克
SiO2（0.15-0.2毫米） 375克
SiO2（0.25-0.3毫米） 375克
SiO2（0.4-0.5毫米） 375克
按照例4-6的400克颗粒以包括下列聚合物的组合物包衣：
聚合物层
按照下面各例制成颗粒
4    5    6
乙基纤维素10厘泊    187.2克    144.0克    92.2克
羟丙基甲基纤维素    46.8克    36.0克    23.0克
柠檬酸乙酰基三丁基酯    26.0克    20.0克    12.8克
二氯甲烷    4428克    3408克    2168克
异丙醇    1114克    858克    546克
该制剂按照上述方法加工。在表Ⅰ中给出美多心安琥珀酸盐在20小时期间内的释放。所有制剂都在长时间内使药物得以控制释放。
例7
核心
氯化镁，六水合物    1100克
乙醇99.5%    6200克
二氧化硅（0.15-0.30毫米）    400克
聚合物层
乙基纤维素50厘泊    533克
二氯甲烷    14107克
异丙醇    5481克
将氯化镁（MgCl2）的99.5%乙醇溶液喷雾到二氧化硅 的核心上。400克这样形成的小珠通过粘度为50厘泊的乙基纤维素的二氯甲烷-异丙醇溶液包衣，得到含有347毫克/克氯化镁（MgCl2）的颗粒。在体外，1小时后药物释放为38%，2小时后为58%和6小时后为82%。
例8
核心
氨苄西林-Na    600克
乙醇95%    894克
纯净水    1020克
玻璃（0.5毫米）    500克
聚合物层
乙基纤维素100厘泊    15克
二氯甲烷    600克
异丙醇    150克
氨苄西林-Na的乙醇/水溶液喷雾到玻璃核心上，然后将500克的氨苄西林-Na小珠用100厘泊乙基纤维素的二氯甲烷/异丙醇的聚合物溶液包衣。在体外溶解40分钟后，药物含量的50%从小珠中释放出来。
例9
核心
美多心安琥珀酸盐    1440克
二氯甲烷    9618克
乙醇95%    3888克
SiO2（0.15-0.25毫米） 375克
聚合物层
乙基纤维素N-10    166.2克
羟丙基甲基纤维素    39.0克
柠檬酸乙酰基三丁基酯    22.8克
二氯甲烷    3889克
异丙醇    978克
片剂添加剂
微晶纤维素    429.3克
玉米淀粉    67.1克
乳糖粉    40.3克
聚乙烯吡咯酮（polyvidone）    55.5克
纯净水    314.7克
硬脂酸镁    1.2克
片剂包衣（12，500片）
羟丙基甲基纤维素6厘泊    159.6克
聚乙二醇6000    39.9克
染料二氧化钛    39.9克
纯净水    1356克
石蜡    1.6克
按照前面例子中描述的过程将美多心安琥珀酸盐喷雾到二氧化硅的核心上。这样得到的400克小珠（0.4-0.63毫米部分）用上述聚合物溶液包衣。美多心安琥珀酸盐的包衣小珠与添加剂等份混合，在加入0.1%硬脂酸镁后，干燥的混合物压制成片，最后该片子在包衣盘中用上述聚合物溶液包衣。
用很小的致密的SiO2颗粒（0.15-0.25毫米）作核心材料，有助于在形成的小珠（0.4-0.63毫米）中有很高的药物含量，因此减小了最后制剂的体积。
表1总结了例1-6和9及参考例1和2的制剂的药物释放数据。
生物药剂学研究
本发明的口服应用（例9）说明于图3。为了寻找每日一次剂量并在24小时内有稳定的血浆浓度，将多单位体系用于美多心安琥珀酸盐。
将含有单剂量的190毫克美多心安琥珀酸盐（相当于200毫克美多心安酒石酸盐）的本发明的控制释放制剂给予10个健康的男性受试者。所述美多心安的血浆浓度与用单剂量的持续释放片剂（Durules
Figure 861066510_IMG1
）之后的血浆浓度比较（该持续释放片剂是根据不溶性基质原理含有200毫克美多心安酒石酸盐制成的）。可以看到，按照本发明的制剂给出几乎不变的美多心安的血浆浓度，而基质片剂在给药后的最初几小时内血浆浓度有一个所不希望有的高峰。
实行本发明的最好模式在目前认为是例9。
表1.在磷酸盐缓冲液PH6.8中美多心安的体外累积释放方法：USP仪器    NOⅡ，旋转桨100转/分
Figure 861066510_IMG2

Claims (9)

1、生产控制释放产品时用的小珠的制备方法，其特征在于将溶于溶剂的药物活性化合物喷雾到大小为0.1-2毫米的不溶性核心材料上，干燥除去溶剂，得到用活性化合物紧密层复盖的，具有0.2-3.0毫米大小的小珠，而后，得到的小珠再用控制释放的聚合物的膜复盖。
2、根据权利要求1的方法，其特征在于核心材料大小为0.1-0.5毫米，而用药物活性化合物复盖了的所述核心材料大小为0.3-1.0毫米。
3、根据权利要求1的方法，其特征在于核心材料是二氧化硅。
4、根据权利要求1的方法，其特征在于核心材料是小颗粒的玻璃。
5、根据权利要求1的方法，其特征在于小珠中含有一种希望不立即释放的药物活性化合物。
6、根据权利要求1的方法，其特征在于药物活性化合物是以口服或非肠道给药。
7、根据权利要求1的方法，其特征在于药物活性化合物是用于心血管、胃肠道或化疗方面。
8、根据权利要求1的方法，其特征在于药物活性化合物是肾上腺素β-阻断剂的盐。
9、根据权利要求1的方法，其特征在于药物活性化合物是抗生素。
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US4927640A (en) 1990-05-22
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AU593038B2 (en) 1990-02-01
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SE8504720L (sv) 1987-04-12
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