CN1038474C - 稳定的延长释放口服组合物 - Google Patents

稳定的延长释放口服组合物 Download PDF

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CN1038474C
CN1038474C CN93118769A CN93118769A CN1038474C CN 1038474 C CN1038474 C CN 1038474C CN 93118769 A CN93118769 A CN 93118769A CN 93118769 A CN93118769 A CN 93118769A CN 1038474 C CN1038474 C CN 1038474C
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coating
loratadine
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centipoise
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H·K·关
S·M·李波维茨
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Merck Sharp and Dohme Corp
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    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

公开了一种薄膜包衣延长释放的口服组合物,其中在独特的聚合物基质核心中含有减轻鼻充血剂假麻黄碱或其盐,例如假麻黄碱硫酸盐,在该核心上的薄膜包衣中含有非镇静性的抗组胺剂氯雷它定,该组合物可用来治疗显示出上呼吸道疾病和算充血迹象和症状的患者。

Description

稳定的延长释放口服组合物
本发明涉及一种薄膜包衣延长释放的口服组合物,在其独特的聚合物基质核心中含有减轻鼻充血剂假麻黄碱,该核心处的薄膜包衣中则含有非镇静性的抗组胺剂氯雷它定(Loratadine)。本发明的口服组合物可用来治疗显现了感冒、上呼吸道疾病、过敏性鼻炎和鼻充血等迹象和症状的患者。
在美国专利4,282,233中公开了氯雷它定是一种非镇静性的抗组胺剂,它可以作为抗过敏剂用于例如季节性过敏性鼻炎症状,如打喷嚏和瘙痒。
假麻黄碱及其药学上可接受的酸加成盐,例如其盐酸或硫酸盐,是本领域技术人员都了解的一种拟交感神经药,它对治疗鼻充血安全有效,通常与一种抗组胺药一起口服施用,用以治疗与过敏性鼻炎有关的鼻充血。例如,一种基质核心复效药片产品,含有5mg氯雷它定和120mg假麻黄碱硫酸盐("PES"),其中PES均等地分布在复效药片包衣和被阻挡层包住的核心中,而所有的氯雷它定都在包衣里。当把这种复效药片放在搅动的0.1N HCl溶液中时(与胃中情形相似),在复效药片的包衣中存在的所有PES和氯雷它定,在1小时之内都溶于搅动的酸性介质中。核心中的PES则一点也没有溶于酸性介质中,因为核心上的阻挡层包衣是耐酸的。需要一种碱性介质(模拟的肠内流体)在5小时内将核心包衣溶解并释放出剩余的50%PES。为发挥药效,推荐该复效药片一天服用两次。美国专利4,990,535和5,100,675公开了一种一天服用两次的缓释的包衣药片,其中药片的包衣中含有氯雷它定、一种亲水性聚合物和聚乙二醇,药片核心中则含有扑热息痛、假麻黄碱或其盐、一种可溶胀的亲水性聚合物和药学上可接受的赋形剂。无论是一天服用两次的缓释药片,或是一天两次的复效药片,都没有明显地提到或披露本发明的这种一天一次的口服组合物。
成功地研制出一种氯雷它定-假麻黄碱配方的一天一次服用的产品是很理想的,但是这要求假麻黄碱组分的释放速度达到12小时以上的一段更长的时间,最好是至少16小时,同时又保持氯雷它定的安全性和有效性。含有与假麻黄碱相组合的非镇静性抗组胺药的产品是已知的,例如Seldane-D(丁苯哌丁醇和假麻黄碱的一种压片包衣制品)和Hismanal-D(假麻黄碱小粒和分离的阿司咪唑片的组合物),但是并没有使本发明的延长释放的组合物变得明显易见。另外,人类服用丁苯哌丁醇和阿司咪唑产品已发现会有不良作用,包括心律失常,而且当丁苯哌丁醇或阿司咪唑与其它药物(例如酮哌咪唑和红霉素)一起服用或是过量服用非镇静性抗组胺药时,这些心律失常的发生会增多。
为提高患者的顺应性,最好是有一种延长释放的口服氯雷它定-假麻黄碱组合物,它在一天一次服用时,对于和感冒、上呼吸道疾病、过敏性鼻炎和鼻充血等有关的迹象及症状的治疗、处理和/或缓解安全而有效。
我们发现,在一个于特殊的聚合物基质内含有假麻黄碱盐(优选假麻黄碱硫酸盐)的核心药片上的氯雷它定薄膜包衣,能立即释放出氯雷它定,而基质核心则在超过12小时的一段时间里长期释放出假麻黄碱硫酸盐。
因此,本发明提供一种薄膜包衣延长释放的口服组合物,其中含有:a.基质核心,它含有:
                                 mg/核心假麻黄碱硫酸盐                      120-360羟丙基甲基纤维素2208(100000厘泊)    160-480乙基纤维素                          40-120磷酸氢钙二水合物                    56-164聚乙烯吡咯酮                        20-60二氧化硅                            6-12硬脂酸镁                            2-6基质核心重量范围                400-1200mgb.所述核心外的包衣,它含有:
                               mg/片氯雷它定                           5-15羟丙基甲基纤维素2910(6厘泊)       17-50聚乙二醇400                     0.25-5.0聚乙二醇3350                    3.4-10.2包衣的大致重量范围:                 26-80mg组合物(基质核心和包衣)的大致重量范围:                   426-1280mg
在一项优选的方案中,本发明提供了薄膜包衣延长释放的口服组合物,其中含有a.基质核心,它含有
                                mg/核心假麻黄碱硫酸盐                      240羟丙基甲基纤维素2208(100000厘泊)   160-480乙基纤维素                         40-120磷酸氢钙二水合物                   56-164聚乙烯吡咯酮                       20-60二氧化硅                           6-12硬脂酸镁                           2-6基质核心大致重量范围:        524-1082mgb.所述核心外的包衣,它含有:
                               mg/片氯雷它定                            10羟丙基甲基纤维素2910(6厘泊)       17-50聚乙二醇400                       0.25-5.0聚乙二醇3350                   3.4-10.15包衣的大致重量范围              31-75mg组合物(基质核心和包衣)的大致重量范围:              555-1157mg
在一项更优选的方案中,本发明提供了一种薄膜包衣延长释放的口服组合物,其中含有:a.基质核心,它含有:
                                mg/核心假麻黄碱硫酸盐USP(美国药典)           240羟丙基甲基纤维素2208,USP100000厘泊   320乙基纤维素NF(国家处方集)7型           80磷酸氢钙(USP)二水合物                 108聚乙烯吡咯硐(USP)                     40二氧化硅(NF)                          8硬脂酸镁(NF)                          4基质核心大致重量:                   800mgb.所述核心外的包衣,它含有:
                                 mg/片氯雷它定(微粉化的)                   10羟丙基甲基纤维素2910(USP,6厘泊)           33聚乙二醇400(NF)                           0.67聚乙二醇3350(NF)                          6.75色素分散体(固体)                          6.25包衣的大致重量:                          57mg组合物(基质核心和包衣)的大致重量                                857mg
我们发现了一种独特的含有特选组分的口服组合物,其中在聚合物基质核心中包含有特定数量的假麻黄碱盐,优选假麻黄碱硫酸盐,在核心外的立即释放的聚合物薄膜包衣中含有氯雷它定。本发明的口服组合物:(1)立即释放(即,在患者口服后的1小时之内)出全部剂量的氯雷它定以保持氯雷它定一天一次的效力;(2)在口服后的至少12小时、优选12至16小时、最好是至少16小时内,从基质聚合物核心内长期释放出假麻黄碱硫酸盐;(3)大小合理的剂量以提高患者的顺应性;和(4)至少24个月的存放寿命。
在研制本发明的口服组合物期间,发现特殊聚合物的选择和用于聚合物基质核心的这些聚合物的特定比例对于实现假麻黄碱的理想的延长释放(至少12小时,优选12至16小时,最好是至少16小时)是关键因素。例如,使用4000厘泊或15000厘泊的羟丙基甲基纤维素作为基质核心中的聚合物时,对于假麻黄碱硫酸盐的剂量不能实现至少16小时的更优选的延长释放期。我们发现,只有选择在基质核心中包括特定重量比的三种特殊聚合物时,才能达到所要求的假麻黄碱释放方式。只有把(1)4重量份的羟丙基甲基纤维素2208(USP,100000厘泊)与(2)1重量份乙基纤维素和(3)0.5重量份作为辅助粘合剂的聚乙烯吡咯酮组合在一起,才能实现假麻黄碱硫酸盐从基质核心中释放至少16小时的更优选的延长释放方式。基质核心中还含有特定数量的二氧化硅作为助流剂和硬脂酸镁作为润滑剂。药片硬度22±6 Strong-Cobb单位(SCU)不受润滑剂含量较高(6mg/片)的影响。但是优选将润滑剂含量保持在1/10重量份的润滑剂用1重量份的辅助粘合剂聚乙烯吡咯酮的比例。
羟丙基甲基纤维素2910在薄膜包衣中起成膜剂的作用,聚乙二醇起塑化剂的作用。可以使用的其它合适的成膜聚合物包括羟丙基纤维素、甲基羟乙基纤维素和羧甲基纤维素钠。
本发明的口服组合物还具有24个月以上的存放寿命,例如最高达36和48个月,只要药片是在标准包装里在2℃和30℃之间的环境下存放。
在制备药片核心时,将聚乙烯吡咯酮溶于醇和水的混合物中。假麻黄碱硫酸盐、羟丙基甲基纤维素2208(USP,100000厘泊)、乙基纤维素和磷酸氢钙与含聚乙烯吡咯酮的醇水溶液相掺混并且制粒。将颗粒研磨,干燥到干燥失重在0.5%至2.0%之间。
将干燥的颗粒研磨,与所要求数量的二氧化硅和硬脂酸镁掺混。将最终的掺混物压制成片剂的优选形式的口服组合物。
包衣通常以下列方式施加到药片核心上:
将核心装到合适的包衣盘中。将羟丙基甲基纤维素2910(USP)和聚乙二醇3350 NF的水分散体施加到核心上。然后用氯雷它定、羟丙基甲基纤维素2910 USP、聚乙二醇3350NF和白色料分散液的分散体涂敷这些包了底衣的核心。接着涂敷含有羟丙基甲基纤维素和聚乙二醇400 NF的抛光涂布分散体。随后将包衣药片打印(用黑墨水),包装在塑料瓶和泡孔中,以便在2℃和30℃的环境温度下贮存。
实施例1
此实施例说明本发明的优选的口服组合物的制备。各组分及具体数量列出如下。
1.药片核心
A.制造方法
1.将聚乙烯吡咯酮溶解在醇水混合物中。
2.将假麻黄碱硫酸盐、羟丙基甲基纤维素2208、乙基纤维素和磷酸氢钙二水合物在合适的混合器内掺混。
3.用步骤1的溶液将步骤2的掺混物制粒,将湿颗粒过筛。
4.将颗粒干燥到用湿度天平或相应装置测得干燥失重在0.5%到2.0%之间。
5.将干燥过的颗粒过筛。
6.向干燥和研磨过的颗粒中加入所需数量的二氧化硅和硬脂酸镁并掺混之。
7.将掺混物在合适的压片机上压片。
在压片操作中,抽取代表性的核心样品并进行加工中的试验。
核心基质满足以下规定:
重量:800±5%(mg)
厚度:0.280±0.010英寸
硬度:22±6 Strong-Cobb单位
核心按以下方式包衣:
A.包衣分散体和溶液的制备
1.包底衣溶液
(1)将羟丙基甲基纤维素(USP 2910)和聚乙二醇3350分散在一部分热的纯化水中。
(2)将剩余的纯化水加入,将溶液冷到室温。
2.活性包衣分散体
(1)将羟丙基甲基纤维素(SP 2910)和聚乙二醇3350分散在一部分热的纯化水中。加入另外的水并将分散体冷却到室温。
(2)将氯雷它定分散在室温下的剩余的纯化水中。与羟丙基甲基纤维素/聚乙二醇分散体(步骤1)合并。
(3)加入白色料分散体,并混合均匀。
3.抛光包衣溶液
(1)将羟丙基甲基纤维素(USP 2910)和聚乙二醇400分散在一部分热的纯水中。
(2)加入剩余的纯水,将溶液冷却到室温。
B.药片核心的包衣
(1)将所需数量的药片核心装到合适的包衣盘中。
(2)施加包底衣溶液。
(3)定量地施加活性包衣分散体。
(4)施加抛光包衣溶液。
C.打印
(1)用黑的盖印墨水将包衣药片打印。
药片核心和包衣的优选成分给出如下:
                                       mg/核心假麻黄碱硫酸盐(USP)                          240羟丙基甲基纤维素2208(USP 100000厘泊)         320乙基纤维素(NF)7型                            80磷酸氢钙二水合物(USP)                        108聚乙烯吡略酮(USP)                            40二氧化硅(NF)                                 8硬脂酸镁(NF)                                 4基质核心的大致重量                        800毫克药片包衣                                   mg/片氯雷它定(微粒化)                            10羟丙基甲基纤维2910(USP,6厘泊)              33聚乙二醇400(NF)                            0.67聚乙二醇3350(NF)                          6.75色料分散体(固体)                          6.25打印墨水                                   …
包衣的大致重量                        57mg
药片(基质核心和包衣)的
大致重量                              857mg
实施例1的药片的体外溶解情况在37℃下于搅动的0.1N HCl溶液中(第1小时)和随后(另加15小时)在37℃下于pH7.5的磷酸盐缓冲液中测定。包衣中的氯雷它定在头一小时内溶解,核心中的全部剂量的假麻黄碱硫酸盐通过腐蚀和溶解机制在至少16小时的时间内缓慢释放(见后面表A)。
如果用对抗充血有效数量的另一种药学上可接受的假麻黄碱盐(例如氯化假麻黄碱)代替假麻黄碱硫酸盐,预期会得到类似的结果。
               表A
  氯雷它定和假麻黄碱硫酸("PES")
    从实施例1延长释放的药片中
        体外溶解的情况
                                   溶解%
时间(小时)               氯雷它定
                 PESb
    1                      97         25
    2                      --         37
    4                      --         53
    6                      --         64
    8                      --         74
    10                     --         82
    12                     --         88
    16                     --         96a  介质:1000ml 0.1N HCL,37℃;美国药典浆片,100rpm:
                   12片的平均值b  介质:1000ml纯水,37℃;美国药典浆片,100rpm;12片的平均值

Claims (3)

1.一种薄膜包衣延长释放的口服组合物,其中含有:
a.一种基质核心,它含有:
                                mg/核心假麻黄碱硫酸盐                      120-360羟丙基甲基纤维素2208,100000厘泊    160480乙基纤维素                          40-120磷酸氢钙二水合物                    56-164聚乙烯吡咯酮                        20-60二氧化硅                            6-12硬脂酸镁                            2-6基质核心重量范围:               400-1200mgb.在该核心上的包衣,它含有:
                                mg/片氯雷它定                            5-15羟丙基甲基纤维素2910,6厘泊         17-50聚乙二醇400                       0.25-5.0聚乙二醇3350                      3.4-10.2包衣的重量范围:                  26-80mg组合物基质核心和包衣的重量范围:                     426-1280mg
2.权利要求1的口服组合物,其中在基质核心中有240mg假麻磺碱硫酸盐,包衣中有10mg氯雷它定。
3.一种薄膜包衣延长释放的口服组合物,其中含有:a.一种基质核心,它含有:
                                  mg/核心假麻黄碱硫酸盐                          240羟丙基甲基纤维素2208,100000厘泊      160-480乙基纤维素                             40-120磷酸氢钙二水合物                       56-164聚乙烯吡咯酮                           20-60二氧化硅                                6-12硬脂酸镁                                2-6基质核心重量范围:                   524-1082mgb.该核心上的包衣,它含有:
                                   mg/片氯雷它定                                10羟丙基甲基纤维素2910,6厘泊            17-50聚乙二醇400                          0.25-5.0聚乙二醇3350                         3.4-10.2包衣的重量范围:                     31-75mg组合物基质核心和包衣的重量范围:                        555-1157mg4.一种薄膜包衣延长释放的口服组合物,其中含有:a.一种基质核心,它含有:
                                  mg/核心假麻黄碱硫酸盐,USP                    240羟丙基甲基纤维素2208,USP100000厘泊    320乙基纤维素,NF7型                      80磷酸氢钙二水合物,USP                  108聚乙烯吡咯硐,USP                    40二氧化硅,NF                         8硬脂酸镁,NF                         4基质核心重量:                      800mgb.所述核心上的包衣,它含有:
                                mg/片氯雷它定,微粒化                     10羟丙基甲基纤维素2910,USP,6厘泊     33聚乙二醇400,NF                      0.67聚乙二醇3350,NF                     6.75色素分散体,固体                     6.25包衣的重量:                         57mg组合物基质核心和包衣的重量                               857mg包衣的大致重量范围:                  26-80mg组合物(基质核心和包衣)的大致重量范围:                      426-1280mg
在一项优选的方案中,本发明提供了薄膜包衣延长释放的口服组合物,其中含有a.基质核心,它含有
                                  mg/核心假麻黄碱硫酸盐                          240羟丙基甲基纤维素2208(100000厘泊米)    160-480乙基纤维素                             40-120磷酸氢钙二水合物                       56-164聚乙烯吡咯酮                            20-60二氧化硅                                6-12硬脂酸镁                                2-6基质核心大致重量范围:                524-1082mgb.所述核心外的包衣,它含有:
                                     mg/片氯雷它定                                  10羟丙基甲基纤维素2910(6厘泊)              17-50聚乙二醇400                            0.25-5.0
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