CN100515413C - 他克莫司口服制剂 - Google Patents

他克莫司口服制剂 Download PDF

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Publication number
CN100515413C
CN100515413C CNB2006100218596A CN200610021859A CN100515413C CN 100515413 C CN100515413 C CN 100515413C CN B2006100218596 A CNB2006100218596 A CN B2006100218596A CN 200610021859 A CN200610021859 A CN 200610021859A CN 100515413 C CN100515413 C CN 100515413C
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tacrolimus
polyvinylpolypyrrolidone
polyvidone
ethanol
lactose
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CN1919186A (zh
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张为群
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Qu Jingping Ankang medical and health care Co., Ltd.
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HANGZHOU PINGHEANKANG PHARMACEUTICAL TECHNOLOGY Co Ltd
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Abstract

本发明为他克莫司口服制剂，解决已有他克莫司口服制剂使用有毒有机溶剂制备中间体，制备工艺复杂，成品质量差的问题。包括如下重量份的原料制成：他克莫司0.5、表面活性剂0.5-4.5、乙醇3.2-6、聚维酮0.5-4.5、交联聚维酮17.6-35，所说的表面活性剂为聚乙醇-6甘油单油酸酯，泊洛沙姆、十二烷基硫酸钠、聚氧乙烯篦麻油中的一种或二种，如用两种为任意重量比，其制备方法为将他克莫司与表面活性剂一个或二个混合使他克莫司完全浸润，加入乙醇使他克莫司溶解得澄明溶液，立即加入聚维酮迅速搅拌均匀，得澄明溶液，迅速加入交联聚维酮混合均匀得成品。

Description

他克莫司口服制剂
技术领域：
本发明与他克莫司作为主药的制剂有关。
背景技术：
他克莫司为白色晶体或结晶性粉末，不溶于水，易溶于乙醇。已有的他克莫司胶囊是先将他克莫司制成固体分散体，再将固体分散体制成胶囊，其制法如下：
固体分散体(SDF)处方：
他克莫司                            1.0g
羟丙基甲基纤微素2910(TC-5R)         1.0g
乙醇                                适量
二氯甲烷                            适量
乳糖                                2.0g
交联羧甲基纤微素钠(AC-Di-Sol)       1.0g
固体分散体(SDF)的制备工艺：
精密称取处方量他克莫司溶解在一定量的乙醇中得澄明溶液；再加入处方量的羟丙基甲基纤微素混合均匀，得类白色混悬液；立即加入一定量的二氯甲烷迅速搅拌均匀，得澄明溶液；迅速加入处方量的交联羧甲基纤微素钠和乳糖混合均匀，得白色乳液。约50℃水浴加热干燥，挥干溶媒，室温真空干燥20小时。将干燥物粉碎，过100目筛，得他克莫司固体分散体。
他克莫司胶囊处方：
(1)规格：每粒含他克莫司(C44H69NO2.H2O)1mg
SDF                               5.0g
乳糖                              59.15g
硬脂酸镁                          0.65g
                                              
                               共制成1000粒
(2)规格：每粒含他克莫司(C44H69NO2.H2O)5mg
SDF                                  5.0g
乳糖                                 113.6g
硬脂酸镁                             1.4g
                                                 
                              共制成1000粒
制备工艺：
称取上述他克莫司固体分散体与硬脂酸镁充分混合均匀，以等量多次加入乳糖充分混合均匀。装入5号(规格：1mg)和4号(规格：5mg)空胶囊，经检验合格，包装即得成品。
已有的他克莫司胶囊的缺点：
1.使用有害原料有机溶剂二氯甲烷。
2.固体分散体制备工艺复杂。
3.固体分散体与乳糖混合均匀难度大，含量均匀度不易合格。
4.固体分散体久贮产生老化现象，造成溶出度降低，成品稳定性差。
发明的内容：
本发明的目的是提供一种制备工艺简单，不使用有机溶剂二氯甲烷，工艺稳定性好，溶出度好，成品稳定性好的他克莫司口服制剂。
本发明是这样实现的：
本发明他克莫司口服制剂，由包括如下重量份的原料制成：
他克莫司            0.5
表面活性剂          0.5-4.5
乙醇                3.2-6
聚维酮              0.5-4.5
交联聚维酮          17.6-35，
所说的表面活性剂为聚乙二醇-6甘油单油酸酯，泊洛沙姆、十二烷基硫酸钠、聚氧乙烯箆麻油中的一种或二种，如用两种为任意重量比，其制备方法为将他克莫司与表面活性剂一个或二个混合使他克莫司完全浸润，加入乙醇使他克莫司溶解得澄明溶液，立即加入聚维酮迅速搅拌均匀，得澄明溶液，迅速加入交联聚维酮混合均匀得成品。
将成品制成胶囊剂。
将成品制成片剂，原料中有乳糖15-27重量份、交联羧甲基纤维素钠1.75-3重量份、硬脂酸镁0.125-0.3重量份，将成品干燥，整粒后与乳糖、交联羧甲基纤维素钠和硬脂酸镁混合、用冲膜压片制得。
将成品制成干混悬剂，辅料中还含有乳糖15-27重量份、矫味剂2-20重量份和增稠剂1.2-10重量份，将成品制粒后干燥、整粒、与乳糖、矫味剂和增稠剂混合均匀即得。
聚维酮为
Figure C20061002185900051
系列，交联聚维酮为Polplasdone
Figure C20061002185900052
系列。
本发明有如下优点：
1.不使用有机溶剂二氯甲烷.
2.制备工艺简单。
3.原料混合易均匀，制剂各组分含量均匀度容易合格。
4.各组分在工艺制备过程中稳定不易老化，溶出度合格，制剂稳定性好。
具体实施方式：
实施例1：
1.胶囊剂处方：
(1)规格：胶囊每粒含他克莫司(C44H69NO2.H2O)0.5mg
处方1：
他克莫司                                 0.5g
乙醇                                     4.0g
泊洛沙姆(Lutorl F 68(R)                  1.5g
聚维酮(
Figure C20061002185900053
K25)                  4.5g
交联聚维酮(
Figure C20061002185900054
XL)           22.0g
                                                      
                                      共制成1000粒
处方2：
他克莫司                                 0.5g
乙醇                                     5.0g
十二烷基硫酸钠                           2.0g
聚维酮(
Figure C20061002185900055
K90)                  1.0g
交联聚维酮(
Figure C20061002185900056
XL-10)         25.0g
                                                        
                                      共制成1000粒
处方3：
他克莫司                                       0.5g
乙醇                                           6.0g
聚乙二醇-6甘油单油酸酯(M 1944)      0.5g
聚维酮(
Figure C20061002185900062
K31/29)                     1.5g
交联聚维酮(
Figure C20061002185900063
XL)                 26.0g
                                                
                                 共制成1000粒
处方4：
他克莫司                              0.5g
乙醇                                  6.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  0.5g
聚维酮(
Figure C20061002185900064
K90D)              0.5g
交联聚维酮(
Figure C20061002185900065
XL)        27.0g
                                                 
                                  共制成1000粒
处方5：
他克莫司                                  0.5g
乙醇                                      6.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900066
M 1944) 0.5g
聚维酮(
Figure C20061002185900067
K31/29)                1.5g
交联聚维酮(XL)            22.0g
十二烷基硫酸钠                            2.0g
                                                
                                  共制成1000粒
处方6：
他克莫司                              0.5g
乙醇                                  6.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  0.5g
聚维酮(
Figure C20061002185900069
K31/29)            2.5g
交联聚维酮(
Figure C200610021859000610
XL)        22.0g
十二烷基硫酸钠                        2.0g
                                                 
                                  共制成1000粒
(2)规格：胶囊每粒含他克莫司(C44H69NO2.H2O)1mg
处方1：
他克莫司                                    1.0g
乙醇                                        8.0g
泊洛沙姆(Lutorl F 68(R)                     3.0g
聚维酮(
Figure C20061002185900071
K25)                     9.0g
交联聚维酮(
Figure C20061002185900072
XL)              44.0g
                                                   
                                        共制成1000粒
处方2：
他克莫司                                    1.0g
乙醇                                        10.0g
十二烷基硫酸钠                              4.0g
聚维酮(
Figure C20061002185900073
K90)                      2.0g
交联聚维酮(
Figure C20061002185900074
XL-10)            50.0g
                                                          
                                        共制成1000粒
处方3：
他克莫司                                    1.0g
乙醇                                        12.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900075
M 1944)   1.0g
聚维酮(
Figure C20061002185900076
K31/29)                   3.0g
交联聚维酮(
Figure C20061002185900077
XL)               52.0g
                                                   
                                        共制成1000粒
处方4：
他克莫司                                    1.0g
乙醇                                        12.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)        1.0g
聚维酮(K90D)                     1.0g
交联聚维酮(
Figure C20061002185900079
XL)               54.0g
                                                        
                                        共制成1000粒
处方5：
他克莫司                                   1.0g
乙醇                                       8.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900081
M 1944)  1.0g
聚维酮(
Figure C20061002185900082
K31/29)                  3.0g
交联聚维酮(
Figure C20061002185900083
XL)              44.0g
十二烷基硫酸钠                             4.0g
                                                        
                                       共制成1000粒
处方6：
他克莫司                                   1.0g
乙醇                                       8.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)       1.0g
聚维酮(
Figure C20061002185900084
K31/29)                  5.0g
交联聚维酮(
Figure C20061002185900085
XL-10)           44.0g
十二烷基硫酸钠                             4.0g
                                                         
                                       共制成1000粒
(3)规格：胶囊每粒含他克莫司(C44H69NO.H2O)5mg
处方1：
他克莫司                                   5.0g
乙醇                                       32.0g
泊洛沙姆(Lutorl F 68(R)                    15.0g
聚维酮(K25)                     45.0g
交联聚维酮(XL)              176.0g
                                                       
                                        共制成1000粒
其中他克莫司与聚维酮(
Figure C20061002185900088
K25)的用量比为：1∶1～9。
处方2：
他克莫司                                   5.0g
乙醇                                       40.0g
十二烷基硫酸钠                             10.0g
聚维酮(K90)                     10.0g
交联聚维酮(
Figure C200610021859000810
XL-10)           200.0g
                                                
                                        共制成1000粒
处方3：
他克莫司                                       5.0g
乙醇                                           48.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900091
M 1944)      5.0g
聚维酮(
Figure C20061002185900092
K31/29)                     15.0g
交联聚维酮(
Figure C20061002185900093
XL)                 208.0g
                                              
                                  共制成1000粒
处方4：
他克莫司                              5.0g
乙醇                                  48.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  5.0g
聚维酮(
Figure C20061002185900094
K90D)              5.0g
交联聚维酮(
Figure C20061002185900095
XL)        216.0g
                                                   
                                   共制成1000粒
处方5：
他克莫司                                       5.0g
乙醇                                           32.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900096
M 1944)      5.0g
聚维酮(
Figure C20061002185900097
K31/29)                     15.0g
交联聚维酮(
Figure C20061002185900098
XL)                 176.0g
十二烷基硫酸钠                                 10.0g
                                                  
                                   共制成1000粒
处方6：
他克莫司                              5.0g
乙醇                                  35.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  5.0g
聚维酮(K31/29)            25.0g
交联聚维酮(XL-10)     176.0g
十二烷基硫酸钠                        10g
                                                       
                                  共制成1000粒
制备工艺：
精密称取处方量他克莫司加入处方量的表面活性剂使其主药完全浸润，再加入一定量的乙醇使其溶解得澄明溶液，；立即加入处方量的聚维酮迅速搅拌均匀，得澄明溶液；迅速加入处方量的交联聚维酮混合均匀，制粒。将其放入50℃鼓风干燥箱干燥，整粒，装入5号(规格：0.5mg)、4号(规格：1mg)和0号(规格：5mg)空胶囊即得。
2.片剂处方
(1)规格：每片含他克莫司(C44H66NO2.H2O)0.5mg
处方1：
他克莫司                                0.5g
乙醇                                    4.0g
泊洛沙姆(Lutorl F 68(R)                 1.5g
聚维酮(
Figure C20061002185900101
K25)                  4.5g
交联聚维酮(
Figure C20061002185900102
XL)           22.0g
乳糖                                    27.0g
交联羧甲基纤微素钠                      3.0g
硬脂酸镁                                0.3g
                                               
                                   共制成1000片
处方2：
他克莫司                                0.5g
乙醇                                    5.0g
十二烷基硫酸钠                          2.0g
聚维酮(
Figure C20061002185900103
K90)                  1.0g
交联聚维酮(
Figure C20061002185900104
XL-10)        25.0g
乳糖                                    25.0g
交联羧甲基纤微素钠                      3.0g
硬脂酸镁                                0.3g
                                                       
                                   共制成1000片
处方3：
他克莫司                                    0.5g
乙醇                                        6.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900105
M 1944)   0.5g
聚维酮(
Figure C20061002185900106
K31/29)                   1.5g
交联聚维酮(
Figure C20061002185900107
XL)              30.0g
乳糖                                  25.0g
交联羧甲基纤微素钠                    3.0g
硬脂酸镁                              0.3g
                                        
                                  共制成1000片
处方4：
他克莫司                              0.5g
乙醇                                  6.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  0.5g
聚维酮(
Figure C20061002185900111
K90D)              0.5g
交联聚维酮(
Figure C20061002185900112
XL)         35.5g
乳糖                                  27.0g
交联羧甲基纤微素钠                    3.0g
硬脂酸镁                              0.3g
                                                 
                                  共制成1000片
处方5：
他克莫司                                  0.5g
乙醇                                      6.0g
聚乙二醇-6甘油单油酸酯(M 1944) 0.5g
聚维酮(
Figure C20061002185900114
K31/29)                1.5g
交联聚维酮(
Figure C20061002185900115
XL)            35.0g
十二烷基硫酸钠                            4g
乳糖                                      22.0g
交联羧甲基纤微素钠                        3.0g
硬脂酸镁                                  0.3g
                                                   
                                  共制成1000片
处方6：
他克莫司                              0.5g
乙醇                                  6.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  0.5g
聚维酮(K31/29)            2.5g
交联聚维酮(
Figure C20061002185900117
XL)        22.0g
十二烷基硫酸钠                        4g
乳糖                                    25.0g
交联羧甲基纤微素钠                      3.0g
硬脂酸镁                                0.3g
                                                
                                    共制成1000片
(2)规格：每片含他克莫司(C44H69NO2.H2O)1mg
处方1：
他克莫司                                1.0g
乙醇                                    8.0g
泊洛沙姆(Lutorl F 68(R)                 3.0g
聚维酮(K25)                  9.0g
交联聚维酮(
Figure C20061002185900122
XL)           44.0g
乳糖                                    45.0g
交联羧甲基纤微素钠                      5.0g
硬脂酸镁                                0.5g
                                             
                                    共制成1000片
处方2：
他克莫司                                1.0g
乙醇                                    10.0g
十二烷基硫酸钠                          4.0g
聚维酮(
Figure C20061002185900123
K90)                  2.0g
交联聚维酮(
Figure C20061002185900124
XL-10)        50.0g
乳糖                                    45.0g
交联羧甲基纤微素钠                      5.0g
硬脂酸镁                                0.5g
                                                   
                                    共制成1000片
处方3：
他克莫司                                  1.0g
乙醇                                      12.0g
聚乙二醇-6甘油单油酸酯(M 1944) 1.0g
聚维酮(
Figure C20061002185900126
K31/29)                 3.0g
交联聚维酮(
Figure C20061002185900127
XL)             52.0g
乳糖                                      45.0g
交联羧甲基纤微素钠                    5.0g
硬脂酸镁                              0.5g
                                                
                                  共制成1000片
处方4：
他克莫司                              1.0g
乙醇                                  12.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  1.0g
聚维酮(
Figure C20061002185900131
K90D)              1.0g
交联聚维酮(
Figure C20061002185900132
XL)         54.0g
乳糖                                  45.0g
交联羧甲基纤微素钠                    5.0g
硬脂酸镁                              0.5g
                                                 
                                  共制成1000片
处方5：
他克莫司                                       1.0g
乙醇                                           8.0g
聚乙二醇-6甘油单油酸酯(M 1944)      1.0g
聚维酮(
Figure C20061002185900134
K31/29)                     3.0g
交联聚维酮(
Figure C20061002185900135
XL)                  44.0g
十二烷基硫酸钠                                 4g
乳糖                                           45.0g
交联羧甲基纤微素钠                             5.0g
硬脂酸镁                                       0.5g
                                               
                                  共制成1000片
处方6：
他克莫司                              1.0g
乙醇                                  8.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  1.0g
聚维酮(K31/29)            5.0g
交联聚维酮(
Figure C20061002185900137
XL-10)      44.0g
十二烷基硫酸钠                        4g
乳糖                                  45.0g
交联羧甲基纤微素钠                      5.0g
硬脂酸镁                                0.5g
                                                      
                                    共制成1000片
(3)规格：每片含他克莫司(C44H69NO2.H2O)5mg
处方1：
他克莫司                                5.0g
乙醇                                    32.0g
泊洛沙姆(Lutorl F 68(R)                 15.0g
聚维酮(
Figure C20061002185900141
K25)                  45.0g
交联聚维酮(
Figure C20061002185900142
XL)           176.0g
乳糖                                    150.0
交联羧甲基纤微素钠                      17.5g
硬脂酸镁                                1.25g
                                                  
                                     共制成1000片
处方2：
他克莫司                                5.0g
乙醇                                    40.0g
十二烷基硫酸钠                          10.0g
聚维酮(
Figure C20061002185900143
K90)                  10.0g
交联聚维酮(
Figure C20061002185900144
XL-10)        200.0g
乳糖                                    150.0
交联羧甲基纤微素钠                      17.5g
硬脂酸镁                                1.25g
                                                    
                                    共制成1000片
处方3：
他克莫司                                  5.0g
乙醇                                      48.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900145
M 1944) 5.0g
聚维酮(
Figure C20061002185900146
K31/29)                 15.0g
交联聚维酮(
Figure C20061002185900147
XL)             208.0g
乳糖                                      150.0
交联羧甲基纤微素钠                      17.5g
硬脂酸镁                                1.25g
                                                   
                                    共制成1000片
处方4：
他克莫司                                5.0g
乙醇                                    48.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)    5.0g
聚维酮(
Figure C20061002185900151
K90D)                5.0g
交联聚维酮(
Figure C20061002185900152
XL)          216.0g
乳糖                                    150.0
交联羧甲基纤微素钠                      17.5g
硬脂酸镁                                1.25g
                                                  
                                    共制成1000片
处方5：
他克莫司                                        5.0g
乙醇                                            32.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900153
M 1944)       5.0g
聚维酮(
Figure C20061002185900154
K31/29)                      15.0g
交联聚维酮(
Figure C20061002185900155
XL)                   176.0g
十二烷基硫酸钠                                  10.0g
乳糖                                            150.0
交联羧甲基纤微素钠                              17.5g
硬脂酸镁                                        1.25g
                                                   
                                    共制成1000片
处方6：
他克莫司                                5.0g
乙醇                                    32.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)    5.0g
聚维酮(
Figure C20061002185900156
K31/29)              25.0g
交联聚维酮(
Figure C20061002185900157
XL-10)       176.0g
十二烷基硫酸钠                          10g
乳糖                                    150.0
交联羧甲基纤微素钠      17.5g
硬脂酸镁                1.25g
                                    
                     共制成1000片
制备工艺：
精密称取处方量他克莫司加入处方量的表面活性剂使其主药完全浸润，再加入一定量的乙醇使其溶解得澄明溶液，；立即加入处方量的聚维酮迅速搅拌均匀，得澄明溶液；迅速加入处方量的交联聚维酮混合均匀，制粒。将其放入50℃鼓风干燥箱干燥，整粒，与乳糖和交联羧甲基纤微素钠和硬脂酸镁混合均匀，不同规格选择相应冲模压片即得。
3.干混悬剂处方：
(1)规格：每袋含他克莫司(C44H69NO2.H2O)0.5mg
处方1：
他克莫司                                0.5g
乙醇                                    4.0g
泊洛沙姆(Lutorl F 68(R)                 1.5g
聚维酮(
Figure C20061002185900161
K25)                  4.5g
交联聚维酮(XL)           22.5g
乳糖                                    27.0g
矫味剂                                  5g
增稠剂                                  3g
                                                      
                                    共制成1000袋
处方2：
他克莫司                                0.5g
乙醇                                    5.0g
十二烷基硫酸钠                          2.0g
聚维酮(
Figure C20061002185900163
K90)                  1.0g
交联聚维酮(
Figure C20061002185900164
XL-10)        25.0g
乳糖                                    27.0g
矫味剂                                  20g
增稠剂                                  10g
                                                   
                                    共制成1000袋
处方3：
他克莫司                                          0.5g
乙醇                                              6.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900171
M 1944)        0.5g
聚维酮(
Figure C20061002185900172
K31/29)                        1.5g
交联聚维酮(
Figure C20061002185900173
XL)                    26.0g
乳糖                                              27.0g
矫味剂                                            15g
增稠剂                                            8g
                                                   
                                    共制成1000袋
处方4：
他克莫司                                0.5g
乙醇                                    6.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)    0.5g
聚维酮(
Figure C20061002185900174
K90D)                 0.5g
交联聚维酮(
Figure C20061002185900175
XL)           27.0g
乳糖                                    27.0g
矫味剂                                  12g
增稠剂                                  20g
                                                  
                                    共制成1000袋
处方5：
他克莫司                                          0.5g
乙醇                                              4.0g
聚乙二醇-6甘油单油酸酯(M 1944)        0.5g
聚维酮(
Figure C20061002185900177
K31/29)                        1.5g
交联聚维酮(
Figure C20061002185900178
XL)                    22.0g
十二烷基硫酸钠                                    4g
乳糖                                              27.0g
矫味剂                                            10g
增稠剂                                            8g
                                                  
                                    共制成1000袋
处方6：
他克莫司                                0.5g
乙醇                                    4.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)    0.5g
聚维酮(
Figure C20061002185900181
K31/29)               2.5g
交联聚维酮(
Figure C20061002185900182
XL)           22.0g
十二烷基硫酸钠                          4g
乳糖                                    27.0g
矫味剂                                  15g
增稠剂                                  10g
                                                      
                                   共制成1000袋
(2)规格：每袋含他克莫司(C44H69NO2.H2O)1mg
处方1：他克莫司                         1.0g
乙醇                                    4.0g
泊洛沙姆(Lutorl F 68(R)                 3.0g
聚维酮(
Figure C20061002185900183
K25)                  9.0g
交联聚维酮(
Figure C20061002185900184
XL)           44.0g
乳糖                                    45.0g
矫味剂                                  10g
增稠剂                                  5g
                                                 
                                   共制成1000袋
处方2：
他克莫司                                1.0g
乙醇                                    10.0g
十二烷基硫酸钠                          4.0g
聚维酮(
Figure C20061002185900185
K90)                  2.0g
交联聚维酮(
Figure C20061002185900186
XL-10)        50.0g
乳糖                                    45.0g
矫味剂                                  15g
增稠剂                                  10g
                                                  
                                   共制成1000袋
处方3：
他克莫司                                         1.0g
乙醇                                             12.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900191
M 1944)        1.0g
聚维酮(
Figure C20061002185900192
K31/29)                       3.0g
交联聚维酮(
Figure C20061002185900193
XL)                    52.0g
乳糖                                             45.0g
矫味剂                                           15g
增稠剂                                           10g
                                                  
                                   共制成1000袋
处方4：
他克莫司                                1.0g
乙醇                                    12.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)    1.0g
聚维酮(
Figure C20061002185900194
K90D)                1.0g
交联聚维酮(XL)           54.0g
乳糖                                    45.0g
矫味剂                                  20g
增稠剂                                  12g
                                                    
                                    共制成1000袋
处方5：
他克莫司                                          1.0g
乙醇                                              12.0g
聚乙二醇-6甘油单油酸酯(
Figure C20061002185900196
M 1944)         1.0g
聚维酮(
Figure C20061002185900197
K31/29)                         3.0g
交联聚维酮(
Figure C20061002185900198
XL)                     44.0g
十二烷基硫酸钠                                    4g
乳糖                                              45.0g
矫味剂                                            18g
增稠剂                                            15g
                                                     
                                   共制成1000袋
处方6：
他克莫司                                1.0g
乙醇                                    12.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)    1.0g
聚维酮(
Figure C20061002185900201
K31/29)               5.0g
交联聚维酮(
Figure C20061002185900202
XL-10)        44.0g
十二烷基硫酸钠                          4g
乳糖                                    45.0g
矫味剂                                  20g
增稠剂                                  12g
                                                   
                                    共制成1000袋
(3)规格：每袋含他克莫司(C44H69NO2.H2O)5mg
处方1：
他克莫司                                5.0g
乙醇                                    32.0g
泊洛沙姆(Lutorl F 68(R)                 15.0g
聚维酮(
Figure C20061002185900203
K25)                  45.0g
交联聚维酮(XL)           176.0g
乳糖                                    150.0
矫味剂                                  20g
增稠剂                                  15g
                                                   
                                    共制成1000袋
处方2：
他克莫司                                5.0g
乙醇                                    40.0g
十二烷基硫酸钠                          10.0g
聚维酮(
Figure C20061002185900205
K90)                  10.0g
交联聚维酮(
Figure C20061002185900206
XL-10)        200.0g
乳糖                                    150.0
矫味剂                                  25g
增稠剂                                  20g
                                                      
                                    共制成1000袋
处方3：
他克莫司                                         5.0g
乙醇                                             48.0g
聚乙二醇-6甘油单油酸酯(M 1944)        5.0g
聚维酮(
Figure C20061002185900212
K31/29)                        15.0g
交联聚维酮(
Figure C20061002185900213
XL)                    208.0g
乳糖                                             150.0
矫味剂                                           20g
增稠剂                                           18g
                                                  
                                    共制成1000袋
处方4：
他克莫司                                5.0g
乙醇                                    48.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)    5.0g
聚维酮(
Figure C20061002185900214
K90D)                 5.0g
交联聚维酮(
Figure C20061002185900215
XL)           216.0g
乳糖                                    150.0
矫味剂                                  30g
增稠剂                                  15g
                                                     
                                    共制成1000袋
处方5：
他克莫司                                         5.0g
乙醇                                             32.0g
聚乙二醇-6甘油单油酸酯(M 1944)        5.0g
聚维酮(K31/29)                        15.0g
交联聚维酮(
Figure C20061002185900218
XL)                    176.0g
十二烷基硫酸钠                                   10.0g
乳糖                                             150.0
矫味剂                                           28g
增稠剂                                           18g
                                                  
                                   共制成1000袋
处方6：
他克莫司                              5.0g
乙醇                                  32.0g
聚氧乙烯篦麻油商品名：(Cremophor EL)  5.0g
聚维酮(
Figure C20061002185900221
K31/29)             25.0g
交联聚维酮(
Figure C20061002185900222
XL-10)      176.0g
十二烷基硫酸钠                        10g
乳糖                                  150.0
矫味剂                                30g
增稠剂                                20g
                                                  
                                 共制成1000袋
制备工艺：
精密称取处方量他克莫司加入处方量的表面活性剂使其主药完全浸润，再加入一定量的乙醇使其溶解得澄明溶液，；立即加入处方量的聚维酮迅速搅拌均匀，得澄明溶液；迅速加入处方量的交联聚维酮混合均匀，制粒。将其放入50℃鼓风干燥箱干燥，整粒，与矫味剂和增稠剂混合均匀，装袋、密封，即得。

Claims (5)

1、他克莫司口服制剂，其特征在于由包括如下重量份的原料制成：
他克莫司        0.5
表面活性剂      0.5-4.5
乙醇            3.2-6
聚维酮          0.5-4.5
交联聚维酮      17.6-35，
所说的表面活性剂为聚乙二醇-6甘油单油酸酯，泊洛沙姆、十二烷基硫酸钠、聚氧乙烯箆麻油中的一种或二种，如用两种为任意重量比，其制备方法为将他克莫司与表面活性剂一个或二个混合使他克莫司完全浸润，加入乙醇使他克莫司溶解得澄明溶液，立即加入聚维酮迅速搅拌均匀，得澄明溶液，迅速加入交联聚维酮混合均匀，然后将其制成口服制剂。
2、根据权利要求1所述的制剂，其特征在于制成胶囊剂。
3、根据权利要求1所述的制剂，其特征在于制成片剂，原料中有乳糖15-27重量份、交联羧甲基纤维素钠1.75-3重量份、硬脂酸镁0.125-0.3重量份，将加入交联聚维酮混合均匀的物质干燥，整粒后与乳糖、交联羧甲基纤维素钠和硬脂酸镁混合，用冲膜压片制得。
4、根据权利要求1所述的制剂，其特征在于制成干混悬剂，原料中还含有乳糖15-27重量份、矫味剂2-20重量份和增稠剂1.2-10重量份，将加入交联聚维酮混合均匀的物质制粒后干燥、整粒，与乳糖、矫味剂和增稠剂混合均匀即得。
5、根据权利要求1所述的制剂，其特征在于聚维酮为
Figure C2006100218590002C1
系列，交联聚维酮为Polplasdone
Figure C2006100218590002C2
系列。
CNB2006100218596A 2006-09-15 2006-09-15 他克莫司口服制剂 Expired - Fee Related CN100515413C (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104840446A (zh) * 2015-05-27 2015-08-19 福建科瑞药业有限公司 一种他克莫司药物组合物及其制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CL2008000374A1 (es) 2008-02-05 2008-04-04 Igloo Zone Chile S A Composicion farmaceutica que comprende un polvo para suspension oral de tacrolimus o una de sus sales, hidratos o solvatos y excipientes farmaceuticamente aceptables; procedimiento de preparacion de dicha composicion farmaceutica; y uso para la preve

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104840446A (zh) * 2015-05-27 2015-08-19 福建科瑞药业有限公司 一种他克莫司药物组合物及其制备方法
CN104840446B (zh) * 2015-05-27 2017-08-11 福建科瑞药业有限公司 一种他克莫司药物组合物及其制备方法

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