CN1089583C - 霉酚酸2－(4－吗啉代)乙酯高剂量口服悬浮剂 - Google Patents

霉酚酸2－(4－吗啉代)乙酯高剂量口服悬浮剂 Download PDF

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CN1089583C
CN1089583C CN94193613A CN94193613A CN1089583C CN 1089583 C CN1089583 C CN 1089583C CN 94193613 A CN94193613 A CN 94193613A CN 94193613 A CN94193613 A CN 94193613A CN 1089583 C CN1089583 C CN 1089583C
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黛布拉·M·李德盖特
丽华·王-凯丝勒
宾杜·乔希
塞依·G·海吉
里奥·顾
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Abstract

霉酚酸2-(4-吗啉代)乙酯或霉酚酸的高剂量干颗粒剂和口服水悬浮剂，包括：活性化合物(7.5-30%)，悬浮剂/增稠剂，甜味剂，调味剂，缓冲剂(调节pH至5-7)，并任意含有增味剂，润湿剂，抗微生物剂和色素。

Description

霉酚酸2-(4-吗啉代)乙酯高剂量口服悬浮剂
本发明所属技术领域
本发明涉及霉酚酸2-(4-吗啉代)乙酯和霉酚酸，特别是它们的改进制剂以及高剂量口服悬浮剂。本发明还涉及该制剂的制备方法。
与本发明相关的背景技术
霉酚酸(“MPA”)具有如下结构，它最初被描述为弱活性抗生素，是在青霉菌(Penicillium brevi-compactum)的发酵培养基中发现的。
Figure C9419361300151
霉酚酸
最近已有许多论述，说MPA和具有如下结构的某些相关化合物如霉酚酸2-(4-吗啉代)乙酯(MPA的吗啉代乙酯)具有优越的治疗性质，例如，如作为免疫抑制药物。
Figure C9419361300161
参见美国专利3,880,995；4,727,069；4,735,935和4,786,637(在此通过引述全部合并于本文)。
尽管霉酚酸2-(4-吗啉代)乙酯的口服生物药效率性质已有改进，但它和MPA每天需要的剂量在2.0到多至3.5或4.0克量级(例如，在美国专利3,880,995中所述的，MPA每日剂量甚至达到5.0克)，这取决于患者和需要治疗的疾病情况。使用在标准尺寸1胶囊(0.48cc容积)中含有250mg的常规剂量制剂，每天需要3.0克的病人每天要服用12粒胶囊，这引起对其是否方便于患者的思考。
粗分散剂，如口服悬浮剂，即某些细小的、分开的不可溶物质悬浮于液体介质中。例如，在Ramington的Pharmaceutical Science(第15版，第22和83章，1975年)中所述那些，和Physicians’DeskReference(第46版，Medical Economics Date，1992年)中的具体产品。众所周知，口服悬浮剂便于给药，例如给小孩和老人给药，但不适于达到高剂量制剂的目的给药。某些“现配”的悬浮载体如Ora-PlusTM与Ora-SweetTM(二者均得自Minneapolis的PaddockLaboratories，Inc.，MN)的结合可满足临场化合的需要，但它们对于任何特殊活性剂的适应性必须根据实际情况决定。此外，这些载体被认为不具备长期的稳定性，因此，它们只能短期使用。
霉酚酸2-(4-吗啉代)乙酯口服悬浮剂已经公开在如美国专利4,753,935中(见实施例7)中，但是以相对低的剂量即100mL中1克活性化合物的剂量使用。虽然，这些悬浮剂是有作用的，但它们与前述低剂量胶囊制剂一样，招致了人们对其是否方便于患者的思考。
一直存在着提供MPA和霉酚酸2-(4-吗啉代)乙酯的高剂量口服制剂的需要，特别是从需要以相对高的每日剂量给药的观点来看更是如此。
发明概述
本发明涉及高剂量霉酚酸2-(4-吗啉代)乙酯或霉酚酸口服悬浮剂及其制备方法。
一方面，本发明涉及具有下列组分的高剂量口服悬浮剂。
           组分                                  ％wt/vol
霉酚酸2-(4-吗啉代)乙酯或霉酚酸                   7.5-30.0
悬浮剂/增稠剂                                    0.1-3.0
润湿剂                                           0.0-0.5
甜味剂                                           30.0-70.0
调味剂                                           0.1-2.0
提味剂/校味剂                                    0.0-1.0
缓冲剂使pH至5.0-7.0                              0.5-1.5
抗微生物剂                                       0.0-10.0
色素                                             0.0-0.01
纯水                                            q.s.至100
在目前优选的方案中，本发明涉及具有下列组分的高剂量霉酚酸2-(4-吗啉代)乙酯口服悬浮剂。
         组分                                   ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                             20
羟基丙基甲基纤维素                                 0.25
微晶纤维素                                         0.25
黄原胶                                             0.1
山梨醇，70％溶液                                   30-50
Lycasin(麦芽糖醇糖浆)                            10-30
蔗糖                                               0-10
果糖                                               0-10
阿斯巴特                                           0-0.5
卵磷脂                                             0-0.1
柠檬酸                                             0.02-0.25
磷酸二钠                                           0.19-0.67
羟基苯甲酸甲酯                                     0-0.18
羟基苯甲酸丙酯                                     0-0.02
调味剂(选自葡萄(任意与茴香混                           0.3-1.0
合)，樱桃，草莓或薄荷)
Magnasweet                                           0-1
色素(选自红28，40，蓝1，蓝2                            0.005
或绿3)
纯水                                                   q.s.至100
在目前另一个优选的方案中，本发明涉及具有下列组分的高剂量霉酚酸2-(4-吗啉代)乙酯口服悬浮剂。
           组分                                       ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                                   20
微晶纤维素                                               0.25
黄原胶                                                   0.1
山梨醇，70％溶液                                         30-50
Lycasin(麦芽糖醇糖浆)                                  10-30
蔗糖                                                     0-10
果糖                                                     0-10
阿斯巴特                                                 0-0.5
卵磷脂                                                   0-0.5
柠檬酸                                                   0.02-0.25
磷酸二钠                                                 0.19-0.8
羟基苯甲酸甲酯                                           0-0.18
羟基苯甲酸丙酯                                           0-0.02
调味剂(选自葡萄(任意与茴香混合)，樱                      0.1-3.0
桃，草莓，薄荷，橙，浆果或混合水果)
Magnasweet                                           0-1
色素(选自红28，红40，红#3，黄#6，                      0.005
蓝1，蓝2或绿3)
纯水                                                   q.s.至100
另一方面，本发明涉及将霉酚酸2-(4-吗啉代)乙酯干颗粒制剂加水冲释，得到具有下列组分的高剂量口服悬浮剂。
                 组分                                   mg/mL*
霉酚酸2-(4-吗啉代)乙酯或霉酚酸                          75-300
悬浮剂/增稠剂                                           1-30
润湿剂                                                  0-10
甜味剂                                                  1-1200
调味剂                                                  0.1-100
提味剂/校味剂                                           0-50
抗微生物剂                                              0-10
色素                                                    0-2
(*加水冲释后的浓度)
目前优选的方案，本发明涉及将霉酚酸2-(4-吗啉代)乙酯干颗粒制剂加水冲释，得到具有下列组分的高剂量口服悬浮剂。
            组分                      mg/mL*
霉酚酸2-(4-吗啉代)乙酯                  200
黄原胶                                  1-1.5
胶状二氧化硅                            5-10
山梨醇                                  0-550
阿斯巴特                                0-3
大豆卵磷脂                              1-2
羟基苯甲酸甲酯钠                        0-10
调味剂(选自葡萄(任意与茴香混合)，樱     0.1-3.0
桃，草莓，薄荷，橙，浆果或混合水果)
色素(选自红色，蓝色和/或黄色以弥补调味  0.01-0.1
剂)
(*水冲释后的浓度)本发明的详细描述定义和一般参数
下列定义是为了说明和定义这里用来描述本发明各术语的意思和范围。
对于用于本发明制剂中的活性剂“霉酚酸2-(4-吗啉代)乙酯”是要包括其药物上可接受的盐。
术语“有效量”意思是足够对需要治疗的病状进行治疗的剂量。它取决于患者，疾病和要达到的治疗效果。
术语“％wt/vol”或“百分比重量/体积”指赋形剂和/或药物在最终悬浮剂体积(毫升)中的重量(克)。悬浮剂和/或药物的量用液体产物的全部最终体积的百分比表示。制作参数
术语“q.s.”意思是添加足够的量以达到所述功能，例如，使溶液达到所需的体积(即100％)。
除非特殊说明，这里所述过程均在大气压和5-100℃(优选10-50℃；最优选在“室内”或“环境”温度如20℃)下进行。
除非另有解释，此处所说组合物百分比，时间和条件都是近似值，例如，用约1至约10小时(优选约5小时)，在约大气压和约5℃至约100℃(优选约10℃至约50℃；最优选约20℃)下，添加约10％wt/vol。实施例中所用参数都将是具体的，而非近似的。原料
霉酚酸2-(4-吗啉代)乙酯可根据前边已通过引述合并于本文的美国专利4,753,935所述来制备。根据通过引述合并于此的美国专利5,247,083所述制备霉酚酸2-(4-吗啉代)乙酯是目前优选的。霉酚酸是商品化的，例如，可以从Sigma Chemical Company，St.Louis，Mo购买。各种赋形剂的来源在下面告知，例如，当原料不是常用的或优选特殊来源的产品时。
用于本发明制剂的悬浮剂和/或增稠剂包括，例如，羟基丙基甲基纤维素(优选USP：羟基丙基甲基纤维素2910)；黄原胶(优选NF：黄原胶，最优选得自Kelco，San Diego，CA的KeltrolCR)；微晶纤维素(它是一种胶状悬浮剂，优选NF：微晶纤维素，最优选得自FMCCorporation，Philadelphia，PA的AvicelRC-591)；羧甲基纤维素钠(优选USP：羧甲基纤维素钠，或BP：羧甲醚纤维素钠或羧甲基纤维素钠)；以及胶状二氧化硅(优选NF：胶状二氧化硅，更优选得自Cabot Corporation，Tuscola，IL的Cab-o-silM-5)。
用于本发明制剂的润湿剂包括，例如，卵磷脂(凝聚或非凝聚大豆卵磷脂)和聚羟烃构体(poloxamer)(采用BASF WyandotteCorporation，Parsippany，NJ的Pluronic F68)。
用于本发明制剂的甜味剂包括，例如，70％山梨醇溶液(优选USP：山梨醇溶液)；麦芽糖醇糖浆(优选USP或NF，最优选得自Roquette Corporation，Gurnee，IL的Lycasin)；蔗糖(优选NF或BP/EP)；果糖(优选USP)；阿斯巴特(优选NF)；木糖醇(优选凝聚级)；甘露糖醇(优选USP或BP)；山梨醇粉末(优选NF或BP)；麦芽糖醇结晶(非凝聚，或优选得自Roquette Corporation，Gurnee，IL的MaltisorbSF)。当需要选择物理形态时，液体甜味剂优选用于悬浮制剂，干甜味剂优选用于干颗粒制剂。上述甜味剂(阿斯巴特除外)还具有增稠剂和/或抗微生物防腐剂功能。
用于本发明制剂的调味剂包括，例如，薄荷，草莓，樱桃，橙，浆果，混合水果和葡萄(与茴香任意混合)。它们来自Tastemaker，Cincinnatti，0H：Crompton & Knowles Corporation，Mahwah，NJ：和Internatoinal Flavors & Fragrances Inc.，Camden，NJ。
用于本发明制剂的提味剂(或校味剂)包括，例如，Magnasweet(得自MacAndrews & Forbes Company，Camden，NJ)。
用于本发明制剂的作为组分的缓冲剂包括，例如，柠檬酸(优选USP)和磷酸二钠(优选USP)。
用于本发明制剂的抗微生物剂包括，例如，苯甲酸钠；羟基苯甲酸甲酯钠(优选NF：羟基苯甲酸甲酯钠)；羟基苯甲酸甲酯(优选NF：羟基苯甲酸甲酯，或BP：羟基苯甲酸甲酯，或EP：羟基苯甲酸甲酯)；羟基苯甲酸丙酯(优选NF：羟基苯甲酸丙酯，或BP/EP：羟基苯甲酸丙酯)；和山梨酸钾(优选NF或BP)。
用于本发明制剂的染色剂(或色素)包括，例如，FD&C红28，FD&C红40，FD&C红3，FD&C蓝1，FD&C蓝2，FD&C黄6和FD&C绿3。高剂量口服悬浮剂组成
本发明高剂量口服悬浮剂一般具有下列组分：
            组分                               mg/mL*
霉酚酸2-(4-吗啉代)乙酯或霉酚酸                 7.5-30.0
悬浮剂/增稠剂                                  0.1-3.0
润湿剂                                         0-0.5
甜味剂                                         30.0-70.0
调味剂                                         0.1-2.0
提味剂/校味剂                                  0-10
缓冲剂                                         0.5-1.5
抗微生物剂                                     0-10.0
色素                                           0-0.01
纯水                                           q.s.至100
特别地，当活性剂是MPA时，pH必须保持在7.0以下以避免溶解。
本发明目前优选的口服悬浮剂具有下列组分：
           组分                              ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                           20
羟基丙基甲基纤维素                               0.25
微晶纤维素                                   0.25
黄原胶                                       0.1
山梨醇，70％溶液                             30-50
Lycasin(麦芽糖醇糖浆)                     10-30
蔗糖                                         0-10
果糖                                         0-10
阿斯巴特                                     0-0.5
卵磷脂                                       0-0.1
柠檬酸                                       0.02-0.25
磷酸二钠                                     0.19-0.67
羟基苯甲酸甲酯                               0-0.18
羟基苯甲酸丙酯                               0-0.02
调味剂                                       0.3-1.0
Magnasweet                                0-1
色素                                         0.005
纯水                                         q.s.至100
本发明目前更优选的口服悬浮剂具有下列组分：
        组分                                  ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                        20
微晶纤维素                                    0.2
黄原胶                                        0.1
山梨醇，70％溶液                              30-50
Lycasin(麦芽糖醇糖浆)                      10-30
蔗糖                               0-10
果糖                               0-10
阿斯巴特                           0-0.5
卵磷脂                             0-0.1
柠檬酸                             0.02-0.25
磷酸二钠                           0.19-0.8
羟基苯甲酸甲酯                     0-0.18
羟基苯甲酸丙酯                     0-0.02
调味剂                             0.1-1.0
Magnasweet                      0-1
色素(                              0.005
纯水                               q.s.至100制备方法
1.将抗微生物剂加入和分散到热水(约70℃)中，接着加入悬浮剂和/或增稠剂(优选微晶纤维素)，再加黄原胶。
2.搅拌下将缓冲剂(优选柠檬酸，接着加入磷酸二钠)溶解，接着加入甜味剂，润湿剂，染色剂，提味剂和调味剂。
3.将活性化合物(霉酚酸2-(4-吗啉代)乙酯或霉酚酸)加入步骤2所得混合物；将液体充分混合形成悬浮液。干颗粒制剂组成
本发明干颗粒制剂一般具有下列组分：
             组分                        mg/mL*
霉酚酸2-(4-吗啉代)乙酯或霉酚酸           75-300
悬浮剂/增稠剂                            10-30
润湿剂                                   3-10
甜味剂                                   200-1200
调味剂                                   3-100
提味剂/校味剂                            0-50
抗微生物剂                               0-10
色素                                     0-2
(*加水冲释后的浓度)
目前优选的干颗粒制剂具有下列组分：
             组分                      ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                   200
羧甲基纤维素钠                           20
蔗糖                                     0-700
果糖                                     0-700
木糖醇                                   0-700
甘露糖醇                                 0-1200
山梨醇                                   0-1080
麦芽糖醇                                 0-740
pluronic F68                             4-8
调味剂                                   10
山梨酸钾                                 0-1
色素                                     0-1
(*加水冲释后的浓度)
目前更优选的干颗粒制剂具有下列组分：
              组分                      ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                    200
黄原胶                                    1-1.5
胶状二氧化硅                              5-10
蔗糖                                      0-700
果糖                                      0-700
木糖醇                                    0-700
甘露糖醇                                  0-1200
山梨醇                                    0-1080
麦芽糖醇                                  0-740
大豆卵磷脂                                1-2
调味剂                                    1-10
羟基苯甲酸甲酯钠                          1-10
色素                             0-1
(*水冲释后的浓度)制备方法
1.将霉酚酸2-(4-吗啉代)乙酯，甜味剂，润湿剂及悬浮剂和/或增稠剂称重并在混合器中混合。
2.将着色剂和缓冲剂溶解于水中。
3.将步骤2的溶液加到步骤1的混合滚筒中混合，直到得到所需尺寸的颗粒。
4.将上述颗粒干燥，然后磨碎以减小颗粒尺寸。
5.将悬浮剂和/或增稠剂，调味剂和抗微生物剂加入掺合机。
如果用干颗粒制剂作为药物制剂进行霉酚酸2-(4-吗啉代)乙酯或霉酚酸给药时，可将干颗粒制剂加到装有水的适当容器中，然后将容器密封，摇晃，形成悬浮剂，然后口服给药。
还可以将颗粒制剂放入容器，这样，当与适当体积的水组合时，就可在一段时间内提供使用的悬浮制剂(例如，将90克霉酚酸2-(4-吗啉代)乙酯加到带刻度的瓶中，然后用纯水冲至最终的450mL体积，可提供30天时间内的供给)。优选制剂
目前优选的是下列制剂：
             组分                     ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                   20
羟基丙基甲基纤维素                       0.25
微晶纤维素                               0.25
黄原胶                                   0.1
山梨醇，70％溶液                         50
Lycasin(麦芽糖醇糖浆)                 10
蔗糖                                     10
卵磷脂                                   0.1
羟基苯甲酸甲酯                           0.036
羟基苯甲酸丙酯                           0.004
葡萄                                     1.0
茴香                                     0.01
色素(红28∶蓝1，90∶10)                  0.005
柠檬酸                                   0.0542
磷酸二钠                                 0.673
纯水                                     q.s.至100
调节pH至7，作为液体悬浮剂适于口服给药。
            组分                   ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                20
微晶纤维素                            0.2
黄原胶                                0.1
山梨醇溶液                            50
蔗糖                                  10
Lycasin(麦芽糖纯糖浆)               10
大豆卵磷脂                            0.1
羟基苯甲酸甲酯                        0.04-0.1
混合水果                             ＜0.3
色素(弥补调味剂)                      0.005
柠檬酸                                0.06
磷酸二钠                              0.7
纯水                                  q.s.至100
调节pH至7，作为液体悬浮剂适于口服给药。
             组分                       mg
霉酚酸2-(4-吗啉代)乙酯                90,000
羧基甲基纤维素钠                      9,000
甘露糖醇                              180,000
阿斯巴特                              1,575
pluronic F68                          1,800
山梨酸钾                              225
樱桃                                  4,500
色素(红40∶蓝1，90∶10)               4.5
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
              组分                       mg
霉酚酸2-(4-吗啉代)乙酯                 90,000
黄原胶                                 450
胶状二氧化硅                           2,250
大豆卵磷脂                             450
山梨醇                                 247,500
阿斯巴特                               225
羟基苯甲酸甲酯钠                       900
浆果调味剂                             1,350
色素(FD&C 红#3                         13.5
     FD&C 蓝#1)                        2.7
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
            组分                        mg
霉酚酸2-(4-吗啉代)乙酯                90,000
黄原胶                                450
胶状二氧化硅                          2,250
大豆卵磷脂                           450
山梨醇                               135,000
阿斯巴特                             450
柠檬酸                               225
柠檬酸钠                             4,500
羟基苯甲酸甲酯钠                     900
浆果调味剂                           1,350
色素(FD&C 红#3                       13.5
     FD&C 蓝#1)                      2.7
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
          组分                          mg
霉酚酸2-(4-吗啉代)乙酯                90,000
黄原胶                                675
胶状二氧化硅                          4,500
大豆卵磷脂                            900
阿斯巴特                              900
羟基苯甲酸甲酯钠                      1,035
混合水果调味剂                        900
色素(FD&C 红#3                        3.6
     FD&C 黄#6)                       0.9
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
         组分                              mg
霉酚酸2-(4-吗啉代)乙酯                   90,000
黄原胶                                   450
胶状二氧化硅                             2,250
大豆卵磷脂                               450
山梨醇                                   247,500
阿斯巴特                                 225
柠檬酸                                   225
柠檬酸钠                                 4,500
羟基苯甲酸甲酯钠                         1,035
混合水果调味剂                           900
色素(FD&C 红#3                           2.79
     FD&C 黄#6)                          0.675
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
         组分                               mg
霉酚酸2-(4-吗啉代)乙酯                    90,000
黄原胶                                    675
胶状二氧化硅                              4,500
大豆卵磷脂                                900
阿斯巴特                            900
柠檬酸                              225
柠檬酸钠                            4,500
羟基苯甲酸甲酯钠                    450
橙子调味剂                          450
色素(FD&C 黄#6)                     45
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。试验，给药和应用试验
进行下列试验是为了评价根据本发明制备的制剂的适应性。所用试验方法为本领域普通技术人员熟知的方法。
1.组成(干颗粒)的时间。
2.固体重新成为悬浮液的难易程度。
3.外观。
4.在连续水相中药物溶解的量。
5.化学稳定性(药物标记浓度的百分比)
6.形成降解物的百分比(例如，从霉酚酸2-(4-吗啉代)乙酯悬浮液中降解的霉酚酸数量)。
7.粘度。
8.密度。
9.冷冻/解冻(聚集构成)。
10.沉降率。
11.沉降体积。
12.药物的均匀性。
13.颗粒大小。
14.抗微生物效果(USP/BP试验)。
15.重力和振动应力(模拟运输)。
进行下列试验是为了评价根据本发明制备的制剂的可接受性。所用试验方法为本领域普通技术人员熟知的方法。
1.固体重新成为悬浮液的难易程度。
2.外观。
3.化学稳定性(药物标记强度的百分比)
4.随时间形成的降解物的百分比。
5.粘度。
6.密度。
7.药物的均匀性。
8.颗粒大小。
9.抗微生物效果(USP/BP试验)。
可接受性的指标包括以下内容：
重悬浮的难易程度--悬浮的沉降物应是松散裹团以致于极小地晃动之后沉降物便可再分散并恢复成原悬浮液。从实际操作的立场讲，任何沉积物应该在用手轻微晃动之后10秒钟之内分散开来。
外观--在刚刚制成的悬浮剂中，所有固体应该均衡和均匀地分散在液相中。经过一段时间沉积发生；理想地，沉积物的体积应该包围悬浮剂的体积。如果沉积物的体积小于悬浮剂的体积，则它所形成的上清液应该是清澈的(表示是絮凝体系)。
化学稳定性--药物量必须保持在所要标记浓度的90-110％之内。
随时间形成的降解物的百分比--2年时间形成的降解不超过5％便是完全可以接受的了。
粘度--粘度应该足够大以阻止快速沉积。然而，从使用者的观点讲粘度太大是不能接受的。可接受粘度应是约200-1000厘泊，优选250-500厘泊。
密度--理想地，载体的密度应该等于分散固体(药物)的密度；匹配载体和药物的密度可以阻碍沉积。本发明制剂可接受的密度是1.10-1.25g/mL。
均匀性--所有悬浮剂在用手轻微晃动之后，在整个悬浮剂的顶部、中部和底部存在的药物量相互之间的差应该在10％以内。
颗粒大小--悬浮剂的平均颗粒大小应该随时间保持在悬浮剂刚制备时平均颗粒大小的20％之内。
抗微生物效果--采用USP和BP提供的方法试验悬浮药物的抗微生物效果。为达到可接受条件，悬浮剂必须通过各项试验的要求。
当进行上述试验时本发明制剂是令人满意的。对于本领域普通技术人员来说，正如很快就会从本说明书看到的那样，具体组分及其相应的浓度的选择将改变所得制剂的平衡特性。例如，200mg/ml霉酚酸2-(4-吗啉代)乙酯可以悬浮在与Ora-SweetTM合并的Ora-PlusTM中，但是，所得制剂的平衡特性是不可接受的粘稠，并预期具有太多的药物溶解于连续水相中，导致降解形成的增加和化学稳定性的损失(即给出载体的pH在5.0以下，本制剂中霉酚酸2-(4-吗啉代)乙酯的最低可接受pH是5.0)。给药
本发明制剂适用于在霉酚酸2-(4-吗啉代)乙酯或霉酚酸的任何口服治疗方案中的口服给药。虽然，人的剂量水平还需要最后确定，一般而言，霉酚酸2-(4-吗啉代)乙酯或霉酚酸的日剂量是约2.5-5.0克，优选2.5-3.5克。当然，所用活性化合物的量将取决于患者，所需治疗疾病，病的严重程度，给药方式和时间表以及处方医师的判断。例如，对每天给药3.0克霉酚酸2-(4-吗啉代)乙酯的治疗方案，以前必须使用12粒胶囊(250mg)(比如，每天两次，每次六粒)，而使用本发明制剂给药，则只需每天两次，每次7.5mL(即一勺)。本发明制剂还特别适于通过洗胃给药。应用
本发明制剂有利于霉酚酸2-(4-吗啉代)乙酯或霉酚酸(“化合物”)作为免疫抑制剂，消炎药物，抗癌药物，抗增生药物，抗病毒药物和抗牛皮癣药物(如下面详述的)对哺乳动物，无论是家畜(如牛，猪，绵羊，山羊，马)还是宠物(如猫，狗)，特别是人给药。该化合物是次黄苷单磷酸酯脱氢酶(IMPDH)的抑制剂，并且从头抑制嘌呤的合成；它们还具有抗增生效果(例如，抗平滑肌细胞、B和T淋巴细胞)，并抑制抗体的形成以及淋巴细胞和内皮细胞中细胞粘连分子糖基化。
作为免疫抑制剂，本发明化合物被用于治疗与自身免疫有关的下列疾病，例如：I型糖尿病；肠炎(如节段性回肠炎和溃疡性结肠炎)；全身性红斑狼疮；慢性活动性肝炎；多发性硬化；突眼性甲状腺肿；淋巴瘤性甲状腺肿；贝切特综合征；重症肌无力；斯耶格伦综合征；恶性贫血；自发肾上腺机能不全；I型和II型自身免疫综合征。
该化合物还可以在哮喘，免疫性溶血性贫血，肾小球性肾炎和肝炎的治疗中作为治疗性免疫抑制剂。该化合物作为免疫抑制剂的预防用途包括治疗同种移植排斥，例如在心脏，肺，胰腺，肾脏，肝脏，皮肤和角膜移植中，以及预防移植物与受体相排斥的(Graft vs.Host)疾病。
该化合物有益于抑制血管创伤引起的增生，例如，在再狭窄血管成形术之后和再狭窄心脏旁路手术对血管壁损伤之后的狭窄。
该化合物还可以用作消炎药，例如，在治疗类风湿性关节炎，青少年类风湿性关节炎和眼色素层炎中。
作为抗肿瘤药物，该化合物可用于治疗固体肿瘤和淋巴网状内皮细胞引起的恶性肿瘤。例如，用该化合物治疗的固体肿瘤包括：头颈癌，包括鳞状细胞癌；肺癌，包括小细胞和非小细胞肺癌；纵隔肿瘤；食管癌，包括鳞状细胞癌和腺癌；胰腺癌；肝胆管系统癌，包括肝细胞癌，胆管癌，胆囊癌和胆道癌；小肠癌，包括腺癌，肉瘤，淋巴瘤和类癌瘤；结肠直肠癌，包括结肠癌和直肠癌；转移癌；生殖泌尿系统癌，包括卵巢癌，子宫瘤和肾细胞、输尿管、膀胱、前列腺、尿道、阴茎、睾丸、外阴、阴道、宫颈、子宫内膜和输卵管癌；乳腺癌；内分泌系统癌；软组织瘤；恶性间皮瘤；皮癌，包括鳞状细胞癌，基底细胞癌和黑瘤；中枢神经系统癌；恶性骨瘤；和血浆细胞瘤。
作为治疗淋巴网状内皮细胞引起的恶性肿瘤的抗癌药物，该化合物可用于治疗如淋巴瘤和白血病，包括B、T和前单核细胞恶性肿瘤，蕈样真菌病，非何杰金淋巴瘤，Burkitt淋巴细胞恶性肿瘤及其它EBV感染的B-淋巴瘤，由同种移植受体的EB病毒感染引起的淋巴瘤，慢性淋巴细胞白血病，急性淋巴细胞白血病和毛细胞白血病。
作为抗病毒药物，该化合物可用于治疗如逆转录病毒，包括I型和II型人类T白血病病毒(HTLV-1和HTLV-2)，I型和II型人类鼻烟癌病毒(NPCV)，以及治疗疱疹病毒，包括EBV感染的B-淋巴瘤，CMV感染，6型疱疹病毒，1型和2型单一疱疹(HSV-1和HSV-2)和带状疱疹。
作为抗牛皮癣药物，该化合物可用于治疗如牛皮癣和关节病性牛皮癣。
实施例
下面给出的制备例和实施例使本领域普通技术人员更清楚地理解和实践本发明。它们不应该被认为是对本发明范围的限制，而应被认为是
本发明的说明和代表。实施例1-24
这些实施例用以说明高剂量口服悬浮剂的制备。在每个实施例中，制剂是用下列各种方法之一制备的。A.    1.将羟基丙基甲基纤维素加到热水中并分散。
  2.微晶纤维素加到步骤1的分散液中并分散。
  3.黄原胶加到步骤2的混合液中并分散。
  4.搅拌着将甜味剂，调味剂，着色剂和卵磷脂分别加到步骤3的混合物中。
  5.将柠檬酸和磷酸二钠溶解于少量等分水中，然后加到步骤4的混合物中，将pH调到指定值。
  6.将羟基苯甲酸甲酯和羟基苯甲酸丙酯溶解于少量等分水(加热至80℃)中，然后加到步骤5的混合物中。
  7.将霉酚酸2-(4-吗啉代)乙酯加到步骤6的混合物中并充分混合，形成适于口服给药的悬浮液。B.    1.搅拌着将羟基苯甲酸甲酯钠加到热水(70-75℃)中。
  2.微晶纤维素加到步骤1的分散液中并分散。
  3.将山梨醇溶液加到步骤2的分散液中并搅拌。将黄原胶加到混合液中并分散。接着搅拌着加入麦芽糖醇溶液。
4.在另一个含有纯水的容器内加入柠檬酸并使之溶解，接着加入并溶解无水磷酸二钠。然后将蔗糖溶解于其中，并加入和分散大豆卵磷脂。加入霉酚酸2-(4-吗啉代)乙酯并分散。
5.将步骤3和4的分散液合并及混合。
6.制备着色溶液，并将该着色剂和调味剂加到步骤5的分散液中，同时搅拌。
7.必要时，用纯水将步骤6的分散液调至规定体积。
实施例1
         组分                         ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                   20
羟基丙基甲基纤维素                       0.25
微晶纤维素                               0.25
黄原胶                                   0.1
山梨醇，70％溶液                         50
蔗糖                                     10
Lycasin(麦芽糖醇糖浆)                  10
卵磷脂                                   0.1
羟基苯甲酸甲酯                           0.036
羟基苯甲酸丙酯                           0.004
葡萄调味剂                               1.0
茴香调味剂                               0.01
色素(红28∶蓝1，90∶10)            0.005
缓冲剂
      柠檬酸                       0.241
      磷酸二钠                     0.547
                                   pH6
纯水                               q.s.至100
实施例2
          组分                   ％wt/vol
霉酚酸2-(4-吗啉代)乙酯              20
羟基丙基甲基纤维素                  0.25
微晶纤维素                          0.25
黄原胶                              0.1
山梨醇，70％溶液                    50
蔗糖                                10
Lycasin(麦芽糖醇糖浆)             10
卵磷脂                              0.1
羟基苯甲酸甲酯                      0.036
羟基苯甲酸丙酯                      0.004
葡萄调味剂                          1.0
茴香调味剂                          0.01
色素(红28∶蓝1，90∶10)             0.005
缓冲剂
柠檬酸                            0.0542
磷酸二钠                          0.673
                                  pH7
纯水                              q.s.至100实施例3
        组分                     ％wt/vol
霉酚酸2-(4-吗啉代)乙酯              20
羟基丙基甲基纤维素                  0.25
微晶纤维素                          0.25
黄原胶                              0.1
山梨醇，70％溶液                    50
蔗糖                                10
Lycasin(麦芽糖醇糖浆)             10
葡萄调味剂                          1.0
茴香调味剂                          0.01
色素(红28∶蓝1，90∶10)             0.005
缓冲剂
     柠檬酸                         0.0542
     磷酸二钠                       0.673
                                    pH7
纯水                                q.s.至100实施例4
         组分                    ％wt/vol
霉酚酸2-(4-吗啉代)乙酯              20
羟基丙基甲基纤维素                  0.2
微晶纤维素                          0.2
黄原胶                              0.075
山梨醇，70％溶液                    50
蔗糖                                10
Lycasin(麦芽糖醇糖浆)             10
卵磷脂                              0.1
葡萄调味剂                          1.0
茴香调味剂                          0.01
色素(红28∶蓝1，90∶10)             0.005
缓冲剂
     柠檬酸                         0.0962
     磷酸二钠                       0.219
                                    pH6
纯水                                q.s.至100
实施例5
          组分                   ％wt/vol
霉酚酸2-(4-吗啉代)乙酯              20
羟基丙基甲基纤维素                  0.25
微晶纤维素                         0.25
黄原胶                             0.1
山梨醇，70％溶液                   50
蔗糖                               10
Lycasin(麦芽糖醇糖浆)            10
卵磷脂                             0.1
葡萄调味剂                         1.0
茴香调味剂                         0.01
色素(红28∶蓝1，90∶10)            0.005
缓冲剂
     柠檬酸                        0.0217
     磷酸二钠                      0.269
                                   pH7
纯水                               q.s.至100
实施例6
         组分                   ％wt/vol
霉酚酸2-(4-吗啉代)乙酯              20
羟基丙基甲基纤维素                  0.35
微晶纤维素                          0.3
黄原胶                              0.125
山梨醇，70％溶液                    30
蔗糖                                10
Lycasin(麦芽糖醇糖浆)             30
葡萄调味剂                         0.75
茴香调味剂                         0.01
色素(红28∶蓝1，90∶10)            0.005
缓冲剂
     柠檬酸                        0.0217
     磷酸二钠                      0.269
                                   pH7
纯水                               q.s.至100
实施例7
          组分                   ％wt/vol
霉酚酸2-(4-吗啉代)乙酯              20
羟基丙基甲基纤维素                  0.25
微晶纤维素                          0.25
黄原胶                              0.1
山梨醇，70％溶液                    30
蔗糖                                10
Lycasin(麦芽糖醇糖浆)             30
卵磷脂                              0.1
葡萄调味剂                          1.0
茴香调味剂                          0.01
Magnasweet                        0.2
色素(红28∶蓝1，90∶10)             0.005
缓冲剂
     柠檬酸                        0.142
     磷酸二钠                      0.438
                                   pH6
纯水                               q.s.至100
实施例8
        组分                     ％wt/vol
霉酚酸2-(4-吗啉代)乙酯              20
羟基丙基甲基纤维素                  0.25
微晶纤维素                          0.25
黄原胶                              0.1
山梨醇，70％溶液                    30
Lycasin(麦芽糖醇糖浆)             10
阿斯巴特                            0.5
卵磷脂                              0.1
葡萄调味剂                          1.0
茴香调味剂                          0.01
色素(红28∶蓝1，90∶10)             0.005
缓冲剂
     柠檬酸                         0.0217
     磷酸二钠                       0.269
                                    pH7
纯水                                q.s.至100实施例9
         组分                    ％wt/vol
霉酚酸2-(4-吗啉代)乙酯             20
羟基丙基甲基纤维素                 0.25
微晶纤维素                         0.25
黄原胶                             0.1
山梨醇，70％溶液                   30
蔗糖                               10
Lycasin(麦芽糖醇糖浆)            30
卵磷脂                             0.1
葡萄调味剂                         1.0
茴香调味剂                         0.01
色素(红28∶蓝1，90∶10)            0.005
缓冲剂
     柠檬酸                        0.136
     磷酸二钠                      0.192
                                   pH5
纯水                               q.s.至100
实施例10
           组分                  ％wt/vol
霉酚酸2-(4-吗啉代)乙酯              20
羟基丙基甲基纤维素                  1
微晶纤维素                         0.25
山梨醇，70％溶液                   50
蔗糖                               10
Lycasin(麦芽糖醇糖浆)            10
卵磷脂                             0.1
葡萄调味剂                         1.0
茴香调味剂                         0.01
Magnasweet                       1
色素(红28∶蓝1，90∶10)            0.005
缓冲剂
     柠檬酸                        0.0217
     磷酸二钠                      0.192
                                   pH7
纯水                               q.s.至100
实施例11
         组分                   ％wt/vol
霉酚酸2-(4-吗啉代)乙酯             20
微晶纤维素                         0.2
黄原胶                             0.1
山梨醇，70％溶液                   50
蔗糖                               10
Lycasin(麦芽糖醇糖浆)            10
大豆卵磷脂                         0.1
柠檬酸                                 0.06
磷酸二钠(pH7)                          0.7
羟基苯甲酸甲酯                         0.04-0.1
调味剂                                 ＜0.3
色素(弥补调味剂)                       0.005
纯水                                   q.s.至100
实施例12
本实施例说明本发明干颗粒的制备。
          组分                          mg
霉酚酸2-(4-吗啉代)乙酯                 3,000
羧基甲基纤维素钠                       300
山梨糖醇，粉末                         3,000
木糖醇                                 2,000
麦芽糖醇                               2,000
pluronic F68                           60
薄荷                                   150
FD&C 绿3                               0.1
将上述组分合并及搅拌成均匀混合物，加入适量纯水以到所需的颗粒大小。通过加入15mL纯水，再用手摇晃，就可以制成15mL制剂中含有3.0克霉酚酸2-(4-吗啉代)乙酯的悬浮液。然后，将该混合物成粒、干燥，得到适合用作药物制剂的干颗粒。实施例13
本实施例说明本发明干颗粒剂。
         组分                      mg
霉酚酸2-(4-吗啉代)乙酯            2,000
羧基甲基纤维素钠                  200
甘露糖醇                          4,000
阿斯巴特                          35
pluronic F68                      40
樱桃                              100
FD&C 红40                         0.1
FD&C 蓝1                          0.01
实施例14
本实施例说明本发明干颗粒剂。
         组分                      mg
霉酚酸2-(4-吗啉代)乙酯            2,000
羧基甲基纤维素钠                  200
山梨糖醇，粉末                    10,000
pluronic F68                      40
樱桃                              100
FD&C 红40                         0.1
FD&C 蓝1                          0.01实施例15
本实施例说明本发明干颗粒剂。
         组分                      mg
霉酚酸2-(4-吗啉代)乙酯            2,000
羧基甲基纤维素钠                  200
甘露糖醇                          4,000
阿斯巴特                          35
山梨酸钾                          5
pluronic F68                      40
樱桃                              100
FD&C 红40                         0.1
FD&C 蓝1                          0.01
实施例16
本实施例说明本发明干颗粒剂。
         组分                      mg
霉酚酸2-(4-吗啉代)乙酯            3,000
黄原胶                            15
胶状二氧化硅                      75
大豆卵磷脂                        15
山梨糖醇                          8,250
阿斯巴特                          7.5
羟基苯甲酸甲酯钠                    30
浆果调味剂                          45
色素(FD&C 红#3                      0.45
     FD&C蓝#1)                      0.09
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积15mL。
实施例17
         组分                      mg
霉酚酸2-(4-吗啉代)乙酯            3,000
黄原胶                            15
胶状二氧化硅                      75
大豆卵磷脂                        15
山梨糖醇                          8,250
阿斯巴特                          15
柠檬酸                            67.5
柠檬酸钠                          150
羟基苯甲酸甲酯钠                  30
浆果调味剂                        45
色素(FD&C 红#3                    0.45
     FD&C 蓝#1)                   0.09
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积15mL。
实施例18
         组分                      mg
霉酚酸2-(4-吗啉代)乙酯            3,000
黄原胶                            15
胶状二氧化硅                      75
大豆卵磷脂                        15
山梨糖醇                          8,250
阿斯巴特                          7.5
柠檬酸                            7.5
柠檬酸钠                          150
羟基苯甲酸甲酯钠                  34.5
混合水果调味剂                    45
色素(FD&C 红#3                    0.093
     FD&C 黄#6)                   0.0225
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积15mL。
实施例19
         组分                      mg
霉酚酸2-(4-吗啉代)乙酯            2,000
羧甲基纤维素钠                              200
甘露糖醇                                    4,000
阿斯巴特                                    35
山梨酸钾                                    5
pluronic F68                                40
樱桃                                        100
FD&C 红40                                   0.1
FD&C 蓝1                                    0.01实施例20
本实施例说明本发明干颗粒剂。将其装入一个有刻度的容器中，加入纯水冲至预定的最终体积450mL。
         组分                                mg
霉酚酸2-(4-吗啉代)乙酯                     90,000
羧甲基纤维素钠                             9,000
甘露糖醇                                   180,000
阿斯巴特                                   1,575
pluronic F68                               1,800
山梨酸钾                                   225
樱桃                                       4,500
色素(红40∶蓝1，90∶10)                    4.5实施例21
本实施例说明本发明干颗粒剂的制备。
         组分                     mg/mL*
霉酚酸2-(4-吗啉代)乙酯            200.0
黄原胶                            1.0
胶状二氧化硅                      5.0
大豆卵磷脂                        1.0
山梨糖醇                          300.0
阿斯巴特                          1.0
柠檬酸                            0.5
柠檬酸钠                          10.0
羟基苯甲酸甲酯钠                  2.0
浆果调味剂                        3.0
色素(FD&C 红#3                    0.034
     FD&C 蓝#1)                   0.006
(*加水冲释后的浓度)
为制备霉酚酸2-(4-吗啉代)乙酯干颗粒剂，要将山梨糖醇，阿斯巴特，大豆卵磷脂和黄原胶在一个混合器中搅合5分钟。在约45-55℃将着色剂与柠檬酸钠和柠檬酸一起溶解于纯水，然后将该溶液冷却至室温。搅拌的同时将上述着色剂/缓冲剂溶液以约60ml/min的速率加到装有霉酚酸2-(4-吗啉代)乙酯混合物的冷搅拌桶中。粒化温度超过30℃后停止搅拌，粒化温度允许降到20-24℃。一旦粒化温度达到20-24℃，再搅合3-8分钟后干燥。如果需要，粉碎颗粒以减小其尺寸。然后加入胶状二氧化硅，调味剂和羟基苯甲酸甲酯钠于混合器。
实施例22
本实施例说明本发明干颗粒剂的制备。
         组分                     mg/mL*
霉酚酸2-(4-吗啉代)乙酯            200.0
黄原胶                            1.5
胶状二氧化硅                      10.0
大豆卵磷脂                        2.0
阿斯巴特                          2.0
柠檬酸                            0.5
柠檬酸钠                          10.0
羟基苯甲酸甲酯钠                  1.0
橙子调味剂                        1.0
色素(FD&C 黄#6 )                  0.1
(*加水冲释后的浓度)实施例23
本实施例说明本发明干颗粒剂的制备。
         组分                     mg/mL*
霉酚酸2-(4-吗啉代)乙酯            200.0
黄原胶                            1.0
胶状二氧化硅                      5.0
大豆卵磷脂                        1.0
山梨糖醇                          550.0
阿斯巴特                          0.5
羟基苯甲酸甲酯钠                  2.0
浆果调味剂                        3.0
色素(FD&C 红#3                    0.034
     FD&C 蓝#1)                   0.006
(*加水冲释后的浓度)
实施例24
本实施例说明本发明干颗粒剂的制备。
         组分                     mg/mL*
霉酚酸2-(4-吗啉代)乙酯            200.0
黄原胶                            1.5
胶状二氧化硅                      10.0
大豆卵磷脂                        2.0
阿斯巴特                           2.0
羟基苯甲酸甲酯钠                   2.3
混合水果调味剂                     2.0
色素(FD&C 红#3                     0.008
     FD&C 黄#6)                    0.002
(*加水冲释后的浓度)
实施例25
本实施例说明本发明干颗粒剂的制备。
         组分                     mg/mL*
霉酚酸2-(4-吗啉代)乙酯            200.0
黄原胶                            1.0
胶状二氧化硅                      5.0
大豆卵磷脂                        1.0
山梨糖醇                          550.0
阿斯巴特                          0.5
柠檬酸                            0.5
柠檬酸钠                          10.0
羟基苯甲酸甲酯钠                  2.3
混合水果调味剂                    2.0
色素(FD&C 红#3                    0.0062
     FD&C 黄#6)                   0.0015
(*加水冲释后的浓度)
实施例26-50
依照实施例1-25的方法并用霉酚酸代替霉酚酸2-(4-吗啉代)乙酯进行制备，得到相应的各悬浮剂和干颗粒剂。
本发明已用其具体实例加以说明，然而，它应该为本领域普通技术人员所理解，即在不脱离本发明真正精神和范围的条件下，可有各种变化和同等替代。另外，可以进行多种变化以适应特殊情况，材料，物质组合，方法，方法步骤或步骤，以达到本发明精神和范围的目的。所有这些变化都将在所附权利要求的范围之内。上面所引用的全部专利和公开均在此合并于本申请。

Claims (21)

1.一种药物制剂，其特征在于包括：
            组分                        ％wt/vol
霉酚酸2-(4-吗啉代)乙酯或霉酚酸           7.5-30.0
悬浮剂/增稠剂                           0.1-3.0
润湿剂                                  0-0.5
甜味剂                                  30.0-70.0
调味剂                                  0.1-2.0
提味剂/校味剂                           0-1.0
缓冲剂使pH至5.0-7.0                     0.5-1.5
抗微生物剂                              0-1.0
色素                                    0-0.01
纯水                                    q.s.至100
作为适于口服给药的液体悬浮剂。
2.根据权利要求1所述的药物制剂，其特征在于具有下列组分：
       组分                           ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                  20
羟基丙基甲基纤维素                      0.25
微晶纤维素                              0.25
黄原胶                                  0.1
山梨醇，70％溶液                      30-50
Lycasin(麦芽糖醇糖浆                10-30
蔗糖                                  0-10
果糖                                  0-10
阿斯巴特                              0-0.5
卵磷脂                                0-0.1
柠檬酸                                0.02-0.25
磷酸二钠                              0.19-0.67
羟基苯甲酸甲酯                        0-0.18
羟基苯甲酸丙酯                        0-0.02
调味剂                                0.3-1.0
Magnasweet                          0-1
色素                                  0.005
纯水                                  q.s.至100
作为适于口服给药的液体悬浮剂。
3.根据权利要求1所述的药物制剂，其特征在于具有20％wt/vol霉酚酸2-(4-吗啉代)乙酯。
4.根据权利要求1所述的药物制剂，其特征在于具有下列组分：
          组分                        ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                  20
微晶纤维素                              0.2
黄原胶                                 0.1
山梨醇，70％溶液                       30-50
Lycasin(麦芽糖醇糖浆)                10-30
蔗糖                                   0-10
果糖                                   0-10
阿斯巴特                               0-0.5
卵磷脂                                 0-0.5
柠檬酸                                 0.02-0.25
磷酸二钠                               0.19-0.8
羟基苯甲酸甲酯钠                        0-0.18
羟基苯甲酸丙酯                          0-0.02
调味剂                                 0.1-1.0
Magnasweet                           0-1
色素                                   0.005
纯水                                   q.s.至100
作为适于口服给药的液体悬浮剂。
5.根据权利要求4所述的药物制剂，其特征在于具有下列组分：
           组分                       ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                  20
微晶纤维素                              0.2
黄原胶                                  0.1
山梨醇，70％溶液                         50
Lycasin(麦芽糖醇糖浆                       10
蔗糖                                         10
大豆卵磷脂                                   0.1
柠檬酸                                       0.06
磷酸二钠                                     0.7
羟基苯甲酸甲酯钠                              0.04
调味剂                                       ＜0.3
色素                                         0.005
纯水                                         q.s.至100
作为适于口服给药的液体悬浮剂。
6.一种药物制剂，包括：
         组分                                 mg/mL*
霉酚酸2-(4-吗啉代)乙酯或霉酚酸                75-300
悬浮剂/增稠剂                                 1-30
润湿剂                                        0-10
甜味剂                                        1-1200
调味剂                                        0.1-100
提味剂/校味剂                                  0-50
抗微生物剂                                     0-10
色素                                          0-2
其中mg/mL代表加水冲释后的浓度；作为干颗粒剂，当用水调合时，
形成适于口服给药的悬浮剂。
7.根据权利要求6所述的药物制剂，其特征在于具有200mg/mL霉酚酸2-(4-吗啉代)乙酯。
8.根据权利要求6所述的药物制剂，其特征在于具有下列组分：
         组分                                mg/mL
霉酚酸2-(4-吗啉代)乙酯                        200
羧基甲基纤维素钠                              20
甘露糖醇                                      400
阿斯巴特                                      3.5
pluronic F68                                  4
山梨酸钾                                      0.5
樱桃                                          10
色素(红40∶蓝1，90∶10)                       0.01
其中mg/mL代表加水冲释后的浓度；作为干颗粒剂，当用水调合时，
形成适于口服给药的悬浮剂。
9.根据权利要求6所述的药物制剂，其特征在于具有下列组分：
          组分                               mg/mL
霉酚酸2-(4-吗啉代)乙酯                         200
黄原胶                                        1-1.5
胶状二氧化硅                                 5-10
山梨糖醇                                     0-550
阿斯巴特                                     0-3.0
大豆卵磷脂                                   1-2
羟基苯甲酸甲酯钠                             0.5-2.5
调味剂                                       1-3
色素(弥补调味剂)                             1-3
其中mg/mL代表加水冲释后的浓度；作为干颗粒剂，当用水调合时，
形成适于口服给药的悬浮剂。
10.根据权利要求6所述的药物制剂，其特征在于包括：
         组分                                 mg
霉酚酸2-(4-吗啉代)乙酯                      90,000
羧基甲基纤维素钠                            9,000
甘露糖醇                                    180,000
阿斯巴特                                    1,575
pluronic F68                                1,800
山梨酸钾                                    225
樱桃                                        4,500
色素(红28∶蓝1，90∶10)                     0.01
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
11.根据权利要求6所述的药物制剂，其特征在于包括：
         组分                                mg
霉酚酸2-(4-吗啉代)乙酯                      90,000
黄原胶                                      450
胶状二氧化硅                                2,250
大豆卵磷脂                                  450
山梨醇                                      247,500
阿斯巴特                                    225
羟基苯甲酸甲酯钠                            900
浆果调味剂                                  1,350
色素(FD&C红#3    FD&C                       13.5
蓝#1)                                       2.7
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
12.根据权利要求6所述的药物制剂，其特征在于包括：
         组分                                mg
霉酚酸2-(4-吗啉代)乙酯                      90,000
黄原胶                                      450
胶状二氧化硅                                2,250
大豆卵磷脂                                  450
山梨糖醇                                    135,000
阿斯巴特                                    450
柠檬酸                                      225
柠檬酸钠                                    4,500
羟基苯甲酸甲酯钠                            900
浆果调味剂                                  1,350
色素(FD&C 红#3                              13.5
FD&C 蓝#1)                                  2.7
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
13.根据权利要求6所述的药物制剂，其特征在于包括：
         组分                                 mg
霉酚酸2-(4-吗啉代)乙酯                      90,000
黄原胶                                      675
胶状二氧化硅                                4,500
大豆卵磷脂                                  900
阿斯巴特                                    900
羟基苯甲酸甲酯钠                            1,035
混合水果调味剂                              900
色素(FD&C 红#3                              3.6
FD&C 黄#6)                                  0.9
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
14.根据权利要求6所述的药物制剂，其特征在于包括：
         组分                                 mg
霉酚酸2-(4-吗啉代)乙酯                      90,000
黄原胶                                      450
胶状二氧化硅                                2,250
大豆卵磷脂                                  450
山梨醇                                      247,500
阿斯巴特                                    225
柠檬酸                                      225
柠檬酸钠                                    4,500
羟基苯甲酸甲酯钠                            1,035
混合水果调味剂                              900
色素(FD&C 红#3                              2.79
FD&C 黄#6)                                  0.675
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
15.根据权利要求6所述的药物制剂，其特征在于包括：
         组分                                 mg
霉酚酸2-(4-吗啉代)乙酯                      90,000
黄原胶                                      675
胶状二氧化硅                                4,500
大豆卵磷脂                                    900
阿斯巴特                                      900
柠檬酸                                        225
柠檬酸钠                                      4,500
羟基苯甲酸甲酯钠                               450
橙子调味剂                                    450
色素(FD&C 黄#6)                               45
在一个有刻度的装有上述组分的容器中加入纯水使之达到预定的最终体积450mL。
16.根据权利要求6所述的药物制剂，其特征在于在一个有刻度的容器中加入纯水使之达到预定的最终体积。
17.一种含有以下基本组分的药物制剂，其特征在于
        组分                             ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                      20
羟基丙基甲基纤维素                          0.25
微晶纤维素                                  0.25
黄原胶                                      0.1
山梨醇溶液                                  50
蔗糖                                        10
Lycasin                                   10
卵磷脂                                      0.1
羟基苯甲酸甲酯                                0.036
羟基苯甲酸丙酯                                0.004
葡萄                                         1.0
茴香                                         0.01
色素(红28∶蓝1，90∶10)                       0.005
柠檬酸                                       0.0542
磷酸二钠                                     0.673
纯水                                         q.s.至100
pH调至7后作为适于口服给药的液体悬浮剂。
18.一种含有以下组分的药物制剂，其特征在于
         组分                              ％wt/vol
霉酚酸2-(4-吗啉代)乙酯                        20
微晶纤维素                                    0.2
黄原胶                                        0.1
山梨醇溶液                                     50
Lycasin                                     10
蔗糖                                          10
卵磷脂                                        0.1
柠檬酸                                        0.06
磷酸二钠                                      0.7
羟基苯甲酸甲酯钠                               0.04
调味剂                                        ＜0.3
色素                                   0.005
纯水                                   q.s.至100
pH调至7后作为适于口服给药的液体悬浮剂。
19.一种制备权利要求1药物制剂的方法，其特征在于包括：
a.将抗微生物剂加入并分散到热水(约70℃)中，然后加入悬浮剂和/或增稠剂(优选微晶纤维素，随后是黄原胶)；
b.搅拌的同时溶进缓冲剂(优选柠檬酸，随后是磷酸二钠)，接着加入甜味剂，润湿剂，着色剂，增味剂和调味剂；
c.加入活性化合物(霉酚酸2-(4-吗啉代)乙酯或霉酚酸)至步骤b所得混合物中，再使该液体充分混合形成悬浮剂。
20.一种制备权利要求6干颗粒制剂的方法，其特征在于包括：
a.将霉酚酸2-(4-吗啉代)乙酯，甜味剂，润湿剂和悬浮剂和/或增稠剂加入一个搅拌器混合；
b.将着色剂和缓冲剂溶解于水中；
c.将步骤b溶液加入步骤a的搅拌器中并与其中物质混合，直到得到所需尺寸的颗粒；
d.干燥上述颗粒，然后粉碎以减小颗粒尺寸；
e.通过混合器加入悬浮剂和/或增稠剂，调味剂和抗微生物剂至步骤d所得颗粒。
21.根据权利要求1，6，17或18所述的制剂对于制备药物制剂的用途，其特征在于该制剂用于治疗免疫抑制疾病，炎症，肿瘤，增生疾病，病毒疾病和牛皮癣病。
CN94193613A 1993-10-01 1994-09-27 霉酚酸2－(4－吗啉代)乙酯高剂量口服悬浮剂 Expired - Lifetime CN1089583C (zh)

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