CN1939298A - 硫酸舒欣啶固体和靶向制剂及其制备方法 - Google Patents
硫酸舒欣啶固体和靶向制剂及其制备方法 Download PDFInfo
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- CN1939298A CN1939298A CN 200510030150 CN200510030150A CN1939298A CN 1939298 A CN1939298 A CN 1939298A CN 200510030150 CN200510030150 CN 200510030150 CN 200510030150 A CN200510030150 A CN 200510030150A CN 1939298 A CN1939298 A CN 1939298A
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- Medicinal Preparation (AREA)
Abstract
本发明提供了一种可用于口服的硫酸舒欣啶固体制剂A及靶向制剂B。固体制剂A的特点是利用普通固体制剂辅料或缓控释辅料将其制成片剂、胶囊、小丸、颗粒剂等剂型，该制剂具有稳定性好、生物利用度高、速释或缓控释等优点；靶向制剂B的特点是利用载体材料将硫酸舒欣啶制成微球、毫微球、脂质体、微乳等制剂，此类制剂具有靶向性，能延长硫酸舒欣啶的作用时间，降低毒副作用，提高硫酸舒欣啶抗心率失常的治疗效果。本发明还涉及硫酸舒欣啶固体及靶向制剂的多种制备方法，制备工艺简单，成本低廉，适合工业化大生产。
Description
技术领域
本发明属于药品制剂领域，具体讲涉及含有抗心率失常活性成分硫酸舒欣啶的固体制剂A和靶向制剂B，以及它们的制备方法。
技术背景
硫酸舒欣啶(Sulcardine sulfate)，化学名为4-甲氧基-N-(3，5-双-(1-吡咯烷甲基)-4-羟基苄基)苯磺酰胺硫酸盐，是以具有抗心律失常作用的天然产物衍生物作为先导化合物，经结构修饰合成大量类似物后，从中筛选出的具有很强抗心律失常活性的新结构类型化合物(中国专利号ZL99124236.X)。它直接作用于心肌细胞膜的钠通道、钙通道和钾通道，通过减慢动作电位的最大除极速度，提高兴奋阈，减慢传导速度，改变动作电位时间和有效不应期，使有效不应期相对延长，可用于治疗折返性心律失常；通过舒张期除极的抑制，可用于治疗自律性心律失常。从药学研究和实验动物药效学研究的结果显示：硫酸舒欣啶是一个安全、高效、质量可控的，具有开发前景的抗心律失常药物。
由于硫酸舒欣啶是一类创新药物，目前对其制剂的研究未见文献报道。本发明所做的各种制剂研究，填补了硫酸舒欣啶制剂领域的空白。
发明内容
本发明的目的在于研制一种性质稳定且可采用现有技术工业化生产的硫酸舒欣啶固体制剂A及其靶向制剂B。
本发明的另一目的是提供了硫酸舒欣啶固体制剂A及其靶向制剂B的制备方法。本发明所述的硫酸舒欣啶固体制剂A可以为普通制剂，其组成成分(以重量分计)为：
硫酸舒欣啶 1份，
辅料 0.1-100份
其中硫酸舒欣啶化学名：4-甲氧基-N-[3，5-双-(1-吡咯烷甲基)-4-羟基苄基]苯磺酰胺硫酸盐(Sulcardine Sulfate)，化学结构式为：
分子量：611.75，分子式：C24H41N3O11S2
该化合物已知合成路线和工艺反应条件为：
硫酸舒欣啶制备工艺反应条件温和，收率稳定，成本低廉，适合工业化生产。
本发明所述的固体制剂A的普通制剂辅料选自淀粉、乳糖、微晶纤维素、糊精、糖粉、葡萄糖、甘露醇、硫酸钙、磷酸氢钙、水、乙醇、淀粉浆、糊精、阿拉伯胶浆、糖浆、明胶浆、聚乙烯吡咯烷酮、聚乙二醇、甲基纤维素、羧甲基纤维素钠、乙基纤维素、羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、海藻酸、淀粉乙醇酸钠、硬脂酸、硬脂酸钙、硬脂酸镁、氢化植物油、苯甲酸钠、月桂醇硫酸钠、聚乙二醇(PEG6000，PEG8000)、月桂醇硫酸镁、滑石粉、微粉硅胶等。
本发明所述的硫酸舒欣啶普通制剂可由以下不同方法制备：
方法一：按处方量称取硫酸舒欣啶、各种辅料，分别研细，混合均匀后，用粘合剂适量制备软材，制粒或制丸，干燥，即得颗粒剂或小丸，也可将此颗粒压制成片剂或灌装胶囊。
方法二：按处方量称取硫酸舒欣啶和各种流动性、可压性好的辅料如二水磷酸氢二钙、磷酸钙、硫酸钙、无水乳糖、喷雾干燥乳糖、预胶化淀粉、可压性糖粉、甘露醇、微晶纤维素等，按等量递加法混合均匀后，直接粉末压片或灌装胶囊。
另外，还可将制成的颗粒、素片、小丸包糖衣或薄膜衣制成硫酸舒欣啶普通包衣制剂。
本发明所述的硫酸舒欣啶固体制剂A可以进一步制成服用方便的缓控释制剂，该制剂可以为骨架型或薄膜包衣型。其中骨架型缓控释制剂的辅料选自乙基纤维素Ec、聚丙烯酸树脂类Eudragit、聚乙二醇PEG、聚乙烯、聚丙烯、聚氯乙烯、聚硅氧烷、聚乙烯吡咯烷酮PVC、胆固醇，β-谷甾醇、棕榈酸甘油脂、胆固醇硬脂酸脂、硬脂酸、硬脂酸丁酯、巴西棕榈蜡、蓖麻油蜡、石蜡、蜂蜡、氢化植物油、合成蜡、十八烷醇、甲基纤维素MC、羟丙基甲基纤维素HPMC、羟丙基纤维素HPC、Carbopol、聚乙烯醇PVA、甲壳素、海藻酸钠、脱乙酰壳多糖、聚乳酸类、卡波姆、羧甲基纤维素、羟丙基纤维素HPC；薄膜包衣材料选自于包衣材料可选自聚丙烯酸树脂类Eudragit、乙基纤维素、苯二甲酸醋酸纤维素、单双醋酸纤维素、蜂蜡等。
本发明所述的硫酸舒欣啶骨架型缓控释制剂，可由以下不同方法制备：
方法一：将处方量的主药和各种缓控释辅料及普通固体制剂辅料过80-100目筛混和均匀，加黏合剂适量制软材，用20-24目筛制粒，置50-60℃条件下干燥2-4小时，用18-24目筛整粒混匀，即得颗粒剂，也可将此颗粒压制成片剂或灌装胶囊。
方法二：按处方量称取硫酸舒欣啶及各种缓控释辅料及普通固体制剂辅料混合均匀，直接粉末压片或灌装胶囊。
方法三：按处方量称取硫酸舒欣啶及各种缓控释辅料及普通固体制剂辅料混和均匀后，用黏合剂适量制成软材后制成小丸。
本发明所述的硫酸舒欣啶薄膜包衣型缓控释制剂，其制备方法为按常规方法制成普通制剂后，用缓控释薄膜包衣材料加入增塑剂进行包衣，即可。其中缓控释薄膜包衣材料可选自聚丙烯酸树脂类Eudragit、乙基纤维素、苯二甲酸醋酸纤维素、单双醋酸纤维素、蜂蜡等。增塑剂可以选自丙二醇、甘油、聚乙二醇、甘油三醋酸酯、乙酰单甘油酯、邻苯二甲酸酯类，抗粘剂滑石粉、二氧化钛、铝色淀、二氧化硅、硬脂酸铝等。
本发明所述的硫酸舒欣啶靶向制剂B的组分含量(以重量份计)为，
硫酸舒欣啶 1份，
载体材料 0.5-500份。
这里的载体材料可选自白蛋白、人血清蛋白、牛血清蛋白、纤维蛋白原、玉米朊、明胶、树胶、松香、石蜡、聚乳酸、聚丙烯酸、聚羟基丁脂、聚ε-己内酯、聚羟基戊酸脂、聚丙交脂、聚乙交脂/丙交脂共聚物、聚原酸酯、聚酐、多肽、聚膦腈及其改性、淀粉、聚氰基丙烯酸脂、乙基纤维素、聚酰胺、聚苯乙烯、聚乙烯醇、葡聚糖、右旋糖苷、糊精、聚丙稀酰胺、聚丙烯酰右旋糖苷、聚丙烯酰淀粉、聚碳酸脂、聚戊二醛、壳聚糖、聚乙醇酸，聚醋酸乙烯脂，聚维酮，淀粉，蛋白质，琼脂糖，乙基纤维素，聚丙烯葡聚糖，磷脂，卵磷脂，大豆磷脂，磷脂的衍生物等。
本发明所述的硫酸舒欣啶靶向制剂B采用以下方法制备：
方法一：溶剂蒸发法，将载体材料溶解于有机溶剂后，溶液在不同的转速搅拌下注入到一定浓度的表面活性剂的水溶液中，待有机溶剂挥发后，制成微球、纳米粒、微囊、乳剂等。
方法二：乳化加热固化法：将处方量的硫酸舒欣啶和载体材料蛋白水溶液用食油(棉子油)乳化成W/O型乳浊液，将此乳浊液滴注到高温(130-180℃)的油中，搅拌，固化，洗涤即得微球、毫微球。
方法三：凝聚法，明胶溶液中加适量表面活性剂(如吐温)，然后加入脱水剂，再加入交连剂使微球固化，即得微球、毫微球。其中脱水剂可以是硫酸钠浓溶液或95％乙醇；连剂可以是甲醛或戊二醛。
方法四：薄膜超声乳化法，将载体材料溶于有机溶剂，蒸发除去有机溶剂形成薄膜，加入含乳化剂的水溶液，超声或乳匀分散，就可得到纳米粒、微乳等。
方法五：高压乳匀法，将载体材料加热熔融，再将熔融液加到溶有表面活性剂的水相，高速搅拌形成初乳，高压匀化，骤冷，即可得到纳米粒。
方法六：将磷脂、卵磷脂、大豆磷脂、磷脂的衍生物之一或它们的混合物与胆固醇等溶解于有机溶剂后，按脂质体的常规制备技术制备成脂质体。
上述硫酸舒欣啶靶向制剂B制备方法中所述的有机溶剂可以选自二氯甲烷、三氯甲烷、乙醇、甲醇、丙酮、异丙醇、乙酸乙酯、乙醚或它们的混合物；表面活性剂可以为磷脂、胆酸盐、去氧胆酸盐、短链醇、泊洛沙姆、聚山梨醇酯、聚氧乙烯脂肪醇醚聚氧乙烯脂肪酸酯、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚乙二醇及其混合物。其中，磷脂选自磷脂酰胆碱，磷脂酰肌醇磷脂酰丝氨酸，磷脂酰甘油，磷脂酸，二月桂酰磷脂酰胆碱，二肉豆蔻酰磷脂酰胆碱，二棕榈酰磷脂酰胆碱，二硬脂酰磷脂酰胆碱，二硬脂酰磷脂酰甘油，二棕榈酰磷脂酰，二棕榈酰磷脂酸，二油酰磷脂酰胆碱、二油酰磷脂酰乙醇胺、大豆磷脂、卵磷脂、卵黄磷脂及其混合物；胆酸盐选自胆酸钠、甘胆酸钠、牛磺胆酸钠及其混合物；脱氧胆酸盐选自脱氧胆酸钠、去氧牛磺胆酸钠及其混合物；短链醇选自丁醇、甘油、异丙醇、乙醇；泊洛沙姆优选poloxamer 108，188，182，407，908；聚山梨醇酯优选吐温-80，85，65，60，40，20；聚氧乙烯脂肪醇醚优选Brij 78，35，30；聚氧乙烯脂肪酸酯优选Myrj 53，59；聚氧乙烯蓖麻油选自cromophor EL系列；聚氧乙烯氢化蓖麻油cromophor RH系列。
采用本发明方法制备的硫酸舒欣啶制剂B，经实验证明具有速释或缓控释、靶向等优点，能延长药物的作用时间，降低药物的毒副作用，提高药物的生物利用度及治疗效果。而且，该制剂的制备工艺成熟，产品质量稳定，便于工业化生产。
附图说明
图1是硫酸舒欣啶长期毒性的体重变化。
有益效果
该项发明能提高硫酸舒欣啶抗心率失常效果，延长作用时间，降低毒副作用，提高硫酸舒欣啶的生物利用度。且制备方法灵活多样，均采用常规的工艺设备，可工业化规模、高效率生产，产品质量保持稳定。
具体实施方式
实施例1：
硫酸舒欣啶片的制备
按处方量称取硫酸舒欣啶200g，微晶纤维素20g，分别研细，过80目筛，按等量递加法混合均匀后，用淀粉浆(5％)适量制备软材，用24目筛制粒，置60℃条件下干燥3小时，用24目筛整粒后，加入硬脂酸镁0.66g，混匀后，压片。
2.溶出度测定
取硫酸舒欣啶片6片，采用桨法进行溶出度测定法实验。溶出杯中加入蒸馏水900mL，水浴温度(37±0.5)℃，转速50r/min。依法操作，定时(1、5、10、15、20、30、45min)取样6ml(即刻补蒸馏水6mL)，立即经0.8μm滤膜过滤，弃去粗滤液。精取续滤液3mL至10mL容量瓶中，加蒸馏水定容，摇匀。照分光光度法，以蒸馏水为空白，在240nm处测定吸收度，计算药片在各个时间点的累积溶出率(Q)和平均累积溶出率(Q)。
溶出试验数据表明：硫酸舒欣啶片45分钟时的累积溶出量达到90％。
实施例2：
实施例1中硫酸舒欣啶片影响因素3实验
根据中国药典2000版二部附录(XIX C)药物制剂稳定性重点考察项目表确定硫酸舒欣啶片稳定性实验的考察项目为：性状、含量、有关物质和溶出度。
1光照实验
取硫酸舒欣啶片片剂各3个批号，露置日光灯下(光线强度为4500Lx)，照射10d，于放置0，5，10d取样，分别对性状、有关物质、含量、溶出度等项目进行考察测定。
2高温试验
取硫酸舒欣啶片片剂各3个批号，在密闭器皿中干热60℃放置10d，于放置0，5，10d取样，分别对性状、有关物质、含量、溶出度等项目进行考察测定。
3高湿实验
取硫酸舒欣啶片片剂各3个批号，在恒湿密闭容器中，在25℃于相对湿度90％±5％条件下放置10天，于第5，10天取样，分别对性状、有关物质、含量、溶出度等项目进行考察测定。
表1
| 批号 | 贮存条件 | 时间(天) | 性状 | 有关物质 | 含量(％) | 溶出度 |
| 030901030902030903 | 光照高温高湿光照高温高湿光照高温高湿 | 051005100510051005100510051005100510 | 白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片白色片 | 0.60.660.70.60.640.680.60.680.740.580.640.70.610.630.670.620.680.740.60.660.70.620.660.690.610.670.74 | 99.8199.4599.199.8199.5499.299.8199.7499.4199.8999.4999.0199.8599.5699.2499.8699.7699.4499.8399.3599.1199.6199.6499.299.7199.6499.46 | 91.291.490.591.290.589.291.290.489.791.3191.4290.5691.2990.5889.2191.2490.4289.7591.2391.3490.1591.2690.589.291.4590.5489.71 |
影响因素试验结果表明：硫酸舒欣啶片经强光、高温和高湿试验，其性状未发生变化，有关物质略有增加，含量测定及溶出度略有降低，但变化均不明显。
实施例3
实施例1中硫酸舒欣啶片加速实验及长期实验
1加速实验
取硫酸舒欣啶片剂各3个批号，在40℃，RH75％放置6个月，于1，2，3。6个月时取样，分别对性状、有关物质、含量、溶出度进行考察。
2长期实验
取硫酸舒欣啶片剂各3个批号，在25℃，RH60％放置12个月，于0，3、6、9、12个月时取样，分别对性状、有关物质、含量、溶出度进行考察。
表2
| 贮存条件 | 时间(天) | 性状 | 有关物质 | 含量(％) | 溶出度 |
| 40℃RH75％25℃RH60％ | 0123036912 | 白色片白色片白色片白色片白色片白色片白色片白色片白色片 | 0.60.670.70.750.570.640.680.740.77 | 99.8199.6899.198.8199.8299.61100.199.3899.51 | 90.590.289.8688.4592.391.5790.6389.5488.78 |
加速实验及长期实验表明，硫酸舒欣啶片稳定性良好。
实施例4：硫酸舒欣啶缓释片的制备
每片用量
处方：硫酸舒欣啶 100mg
羟丙基甲基纤维素K4M 50mg
淀粉 40mg
3％HPMC(50％乙醇) 适量
硬脂酸镁 10mg
制备工艺：按处方量称取硫酸舒欣啶过100目筛，然后与羟丙基甲基纤维素、淀粉等辅料按等量递加法混合均匀，加3％HPMC(50％乙醇)适量制软材，过20目筛制粒，于60℃烘干，压片，片重约200mg，片剂硬度在5-7kg。
实施例5：
实施例4中硫酸舒欣啶缓释片释放度的测定
采用溶出度测定桨法的装置，转速50r/min，释放介质为水，依法操作。在各时间点(0.5，1，2，3，4，6，8，12小时)分别取样5mL，并补充等温释放介质5mL，样液立即用0.8μm微孔膜过滤。精密吸取续滤液3mL置于10mL量瓶，用蒸馏水定容。于240nm波长处测定吸收度A，计算累积释放百分率(X)。结果见表3。
表3
| 片号 | 1 | 2 | 3 | 4 | 5 | 6 | 8 | 10 | 12 |
| 123456平均释放度RSD | 9.456.25.736.488.616.317.130.21 | 21.8516.1114.119.2318.919.6118.30.15 | 33.9331.4525.7227.6526.5728.0828.90.11 | 46.9546.0240.1341.2739.8139.6242.30.08 | 60.2358.2654.3950.7251.1454.6654.90.07 | 70.6969.3265.8559.6160.2961.8464.60.07 | 83.5384.3182.978.5879.7578.1381.20.03 | 93.2895.3991.7387.6290.4988.4791.160.03 | 98.1199.6192.6393.4398.9496.2696.50.03 |
结果表明，本品可持续释药12小时，具有缓释效果。
实施例6
硫酸舒欣啶微球
称取PLGA 200mg溶解于1ml二氯甲烷中，作有机相；另取硫酸舒欣啶100mg分散于1％海藻酸钠及0.2％吐温-20(m/m)的100ml溶液中，作水相；在500r/min搅拌的条件下，将有机相注入到水相中搅拌30min，不断搅拌下将该混合溶液移至水浴中，45℃搅拌4h挥发去二氯甲烷，布氏漏斗抽滤分离微球，蒸馏水洗涤，30℃真空干燥，得白色流动性粉末状微球。微球呈圆球型.大小均匀，微球垃径呈正态分布，在55～135μm粒径范围的微球占83.3％，其包封率和载药量分别为86.78％和26.92％。
实施例7
实施例6中硫酸舒欣啶微球的药效学研究
采用犬冠状动脉左前降支二期结扎法诱发心律失常模型，观察硫酸舒欣啶微球灌胃给药对犬心律失常的治疗作用。手术后24小时，各组犬分别给予硫酸舒欣啶微球20，30，60mg/kg和奎尼丁60mg/kg，连续记录清醒犬的心电图，观察给药后4小时内心率和心律失常的变化。结果见表4。
表4
| 制剂 | 心率失常比值 | |||
| 剂量(mg/kg) | 给药前 | 给药后1小时 | 给药后4小时 | |
| 硫酸舒欣啶微球硫酸奎尼丁片 | 20306060 | 0.780.780.80.79 | 0.470.410.10.15 | 0.4990.450.110.38 |
结果表明，硫酸舒欣啶微球具有明显的抗心率失常作用。
实施例8
硫酸舒欣啶毫微球的制备
有机相：0.25g单体α-氰基丙烯酸正丁酯BCA、1.89g辛酸二癸酸甘油酯溶解在25mL乙醇(无水)中构成有机相。水相：将0.1g硫酸舒欣啶、1g F68和0.5g葡聚糖T-70分散在pH＝6的磷酸缓冲溶液中构成连续相。室温，用硅胶管和注射器将有机相缓慢加到不断搅拌的水相中，注射速度0.2mL/min，搅拌速度1000r/min。注射器针头要尽可能接近搅拌头，使有机相尽可能分散，维持3h。得乳白色悬浮有丁铎尔现象的胶体溶液，室温真空旋转蒸发浓缩至约20mL，用G4(9～15Lm)垂熔漏斗过滤，得硫酸舒欣啶-聚氰基丙烯酸正丁酯毫微囊(52Fu2PBCA)胶体浓缩液。
实施例9
实施例8中硫酸舒欣啶毫微球的理化性质研究
1.表面形态和粒径测定
分别取硫酸舒欣啶毫微球悬浮胶体浓缩液适量，超速低温离心，分离沉淀，加少许蒸馏水分散，扫描电镜观察、摄片，测定300个毫微囊的平均直径。
结果表明：毫微囊形态规则呈椭球形，表面光滑，实际测得平均粒径为232±17nm(n＝300)。
2包封率和载药量测定
取硫酸舒欣啶毫微球胶体浓缩液超速低温离心，分离沉淀。用紫外光分光光度计于240nm处测定上清液A值，用标准曲线法定量。
按下式计算毫微囊的载药量和包封率：
包封率＝[(Wa-Ws)/Wa]×100％
载药量＝[(Wa-Ws)/W总]×100％
其中，Wa为初始投药量；Ws：为上清液中含药量；W总为毫微囊总质量。结果见表5。
表5
| 样品 | 包封率(％) | 载药量(％) |
| 123 | 87.43±0.3287.56±0.2487.53±0.28 | 25.02±0.2126.86±0.3225.74±0.25 |
实施例10
实施例8中硫酸舒欣啶毫微球的药效学实验
豚鼠(每组10只)分别灌胃给予硫酸舒欣啶毫微球胶体溶液，给药剂量为每公斤豚鼠给予硫酸舒欣啶25，50和100mg，给药2.5小时后，静脉恒速注射哇巴因，分别测定诱导室性早搏的哇巴因剂量。
表6
| 制剂 | 剂量(mg/kg) | 诱发室性早搏剂量(μg/kg) |
| 硫酸舒欣啶毫微球空白对照组硫酸奎尼丁片 | 2550100-50 | 156±9176±16187±14134±8182 15 |
从表6说明，硫酸舒欣啶毫微球具有较好的抗室性早搏的作用。
实施例11
硫酸舒欣啶脂质体的制备
准确称取120mg卵磷脂和30mg胆固醇，溶于10ml无水乙醚，在1000r/min搅拌条件下将所得的类脂溶液缓慢匀速的注入到含100mg硫酸舒欣啶的40ml水相(40℃)中，注入完毕后，继续40℃恒温搅拌至乙醚完全除尽，得到乳白色硫酸舒欣啶脂质体混悬液。
实施例12
取实施例11中的脂质体进行形态观察、粒径及其分布测定。
取脂质体适量，加入注射用水适量稀释，用1％的磷钨酸染色，透射电镜下观察粒子形态。
取脂质体悬液适量，加入适量水稀释，以Zetamaster光子相关光谱仪测定脂质体的粒径大小和分布以及Zeta电位。
电镜下观察多烯紫杉醇脂质体呈均匀规则的球形粒子，无聚集粘联。
实验测得的多烯紫杉醇脂质体粒径分布均匀，平均粒径为120nm，多分散指数为0.158，zeta电位为-26.4mv。
实施例13
取实施11中的硫酸舒欣啶脂质体进行包封率的测定。
包封率依据紫外分光光度法测定，脂质体溶液经透析法分离未包裹的硫酸舒欣啶，用紫外分光光度计测定游离硫酸舒欣啶含量。按下列公式计算包封率。
包封率(％)＝(脂质体中加药量一游离药物量)/加药量
依此公式测得包封率为87.45％。
实施例14
实施例11中硫酸舒欣啶长期毒性实验
将SD大鼠随机分为4组，每组22只(雌雄各半)，按大鼠200，400，1000mg/kg剂量灌胃给药。在给药3个月各组解剖12只大鼠和恢复期30天后解剖各组10只大鼠，戊巴比妥30mg/kg按体重麻醉股动脉放血处死。并作血液生化测定。大鼠解剖作病理学检查。
观察指标：
1.死亡率：如有濒死或死亡，记录死亡数。
结果表明：各组均未见大鼠死亡。
2.一般症状：给药期和停药期间，观察大鼠体征、外观行为、活动和粪便形状和颜色，并观察给药后皮毛贴身或稀疏竖散。眼、鼻的异常分泌物等。每天逐个进行观察并记录。
结果为：给药期初期200、400mg/kg组各1只大鼠出现鼻腔旁血迹和前肢踝部细红圈，1000mg/kg组大鼠有7只大鼠(31.3％)出现眼、嘴角、鼻腔血色分泌物及前肢踝部红圈，2～3天后症状消失。显示与药物剂量相关。
3.体重：每周称2次，2个月后每周称1次。
由图1看出，给药组与对照组体重增长相似，组间无显著差异。
4.组织学检查：各组大鼠取心、肺、肝、脾、肾、脑、脑垂体、甲状腺、肾上腺、胸腺、附睾、前列腺/子宫和睾丸/卵巢、乳腺、气管、唾液腺、食管、胃、十二指肠、回肠、结肠、胰腺、眼球和视神经、胸骨(含骨髓)等组织立即固定于10％中性福尔马林溶液，常规包埋、切片、染色。
结果为：400、1000mg/kg组各有2、7只大鼠肝细胞内有红棕色颗粒。恢复期各组未见明显变化。
Claims (14)
1.一种含如下结构的硫酸舒欣啶口服固体制剂A和靶向制剂B，
其特征在于制剂A包含硫酸舒欣啶及辅料，以重量份计相对于1份硫酸舒欣啶，含辅料0.1-100份；制剂B包含硫酸舒欣啶及载体材料，以重量份计相对于1份硫酸舒欣啶，含载体材料0.5-500份。
2.根据权利要求1所述的硫酸舒欣啶固体制剂A，其特征在于可以为普通制剂和缓控释制剂。
3.根据权利要求2所述的硫酸舒欣啶固体制剂A，其特征在于普通制剂的辅料选自淀粉、乳糖、微晶纤维素、糊精、糖粉、葡萄糖、甘露醇、硫酸钙、磷酸氢钙、水、乙醇、淀粉浆、糊精、阿拉伯胶浆、糖浆、明胶浆、聚乙烯吡咯烷酮、聚乙二醇、甲基纤维素、羧甲基纤维素钠、乙基纤维素、羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素、海藻酸、淀粉乙醇酸钠、硬脂酸、硬脂酸钙、硬脂酸镁、氢化植物油、聚乙二醇(PEG6000，PEG8000)、苯甲酸钠、月桂醇硫酸钠、月桂醇硫酸镁、滑石粉、微粉硅胶。
4.根据权利要求2所述的硫酸舒欣啶固体制剂A，其特征在于普通制剂采用传统方法制备成片剂、胶囊、颗粒剂、小丸，普通包衣制剂。
5.根据权利要求2所述的硫酸舒欣啶缓控释制剂，其特征在于可以为骨架型缓控释制剂或薄膜包衣型缓控释制剂。
6.如权利要求5所述的硫酸舒欣啶骨架型缓控释制剂的制备方法，由以下不同法制备：
1)将处方量的主药和各种缓控释辅料及普通固体制剂辅料过80-100目筛混合均匀，黏合剂适量制软材，用20-24目筛制粒，置50-60℃条件下干燥2-4小时，用18-24目筛整粒混匀，即得颗粒剂，也可将此颗粒压制成片剂或灌装胶囊；
2)按处方量称取硫酸舒欣啶及各种缓控释辅料及普通固体制剂辅料混合均匀，直接粉末压片或灌装胶囊；
3)按处方量称取硫酸舒欣啶及各种缓控释敷料及普通固体制剂敷料混合均匀后，用粘合剂适量制备软材后制成小丸。
7.根据权利要求6所述的硫酸舒欣啶骨架型缓控释制剂的制备方法，其特征在于缓控释辅料可以选自：乙基纤维素Ec、聚丙烯酸树脂类Eudragit、聚乙二醇PEG、聚乙烯、聚丙烯、聚氯乙烯、聚硅氧烷、聚乙烯吡咯烷酮PVC、胆固醇，β-谷甾醇、棕榈酸甘油脂、胆固醇硬脂酸脂、硬脂酸、硬脂酸丁酯、巴西棕榈蜡、蓖麻油蜡、石蜡、蜂蜡、氢化植物油、合成蜡、十八烷醇、甲基纤维素MC、羟丙基甲基纤维素HPMC、羟丙基纤维素HPC、Carbopol、聚乙烯醇PVA、甲壳素、海藻酸钠、脱乙酰壳多糖、聚乳酸类、卡波姆、羧甲基纤维素、羟丙基纤维素HPC。
8.根据权利要求5所述的硫酸舒欣啶薄膜包衣型缓控释制剂的制备方法，其特征在于将硫酸舒欣啶按照常规方法制成普通制剂后，取缓控释薄膜包衣材料加入增塑剂进行包衣即可制得。
9.根据权利要求8所述的硫酸舒欣啶薄膜包衣型缓控释制剂的制备方法，其特征在于缓控释薄膜包衣材料可选自聚丙烯酸树脂类Eudragit、乙基纤维素、苯二甲酸醋酸纤维素、单双醋酸纤维素、蜂蜡。
10.根据权利要求8所述的硫酸舒欣啶薄膜包衣型缓控释制剂的制备方法，其特征在于增塑剂可以选自丙二醇、甘油、聚乙二醇、甘油三醋酸酯、乙酰单甘油酯、邻苯二甲酸酯类，抗粘剂滑石粉、二氧化钛、铝色淀、二氧化硅、硬脂酸铝。
11.根据权利要求1所述的硫酸舒欣啶靶向制剂B，其特征在于载体材料可选自白蛋白、人血清蛋白、牛血清蛋白、纤维蛋白原、玉米朊、明胶、树胶、松香、石蜡、聚乳酸、聚丙烯酸、聚羟基丁脂、聚ε-己内酯、聚羟基戊酸脂、聚丙交脂、聚乙交脂/丙交脂共聚物、聚原酸酯、聚酐、多肽、聚膦腈及其改性、淀粉、聚氰基丙烯酸脂、乙基纤维素、聚酰胺、聚苯乙烯、聚乙烯醇、葡聚糖、右旋糖苷、糊精、聚丙稀酰胺、聚丙烯酰右旋糖苷、聚丙烯酰淀粉、聚碳酸脂、聚戊二醛、壳聚糖、聚乙醇酸，聚醋酸乙烯脂，聚维酮，淀粉，蛋白质，琼脂糖，乙基纤维素，聚丙烯葡聚糖，磷脂，卵磷脂，大豆磷脂，磷脂的衍生物。
12.根据权利要求1所述的硫酸舒欣啶靶向制剂B的制备方法，其特征在于可以采用以下不同方法制备：
1)溶剂蒸发法，将载体材料溶解于有机溶剂后，溶液在不同的转速搅拌下注入到一定浓度的表面活性剂的水溶液中，待有机溶剂挥发后，制成微球、纳米粒、微囊、乳剂。
2)乳化加热固化法，将处方量的硫酸舒欣啶和载体材料蛋白水溶液用食油乳化成W/O型乳浊液，将此乳浊液滴注到130-180℃的油中，搅拌，固化，洗涤即得微球、毫微球，其中食油可以选用棉子油。
3)凝聚法，明胶溶液中加适量表面活性剂(如吐温)，然后加入脱水剂，再加入交连剂使微球固化，即得微球、毫微球，其中脱水剂可以是硫酸钠浓溶液或95％乙醇，交连剂可以是甲醛或戊二醛。
4)薄膜超声乳化法，将载体材料溶于有机溶剂，蒸发除去有机溶剂形成薄膜，加入含乳化剂的水溶液，超声或乳匀分散，就可得到纳米粒、微乳。
5)高压乳匀法，将载体材料加热熔融，再将熔融液加到溶有表面活性剂的水相，高速搅拌形成初乳，高压匀化，骤冷，即可得到纳米粒。
6)将磷脂、卵磷脂、大豆磷脂、磷脂的衍生物之一或它们的混合物与胆固醇等溶解于有机溶剂后，按脂质体的常规制备技术制备成脂质体。
13.根据权利要求12所述的硫酸舒欣啶靶向制剂B的制备方法，其特征在于有机溶剂选自二氯甲烷、三氯甲烷、乙醇、甲醇、丙酮、异丙醇、乙酸乙酯、乙醚或它们的混合物。
14.根据权利要求12所述的硫酸舒欣啶靶向制剂B的制备方法，其特征在于表面活性剂可以为磷脂、胆酸盐、去氧胆酸盐、短链醇、泊洛沙姆、聚山梨醇酯、聚氧乙烯脂肪醇醚聚氧乙烯脂肪酸酯、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚乙二醇及其混合物；其中磷脂选自磷脂酰胆碱，磷脂酰肌醇磷脂酰丝氨酸，磷脂酰甘油，磷脂酸，二月桂酰磷脂酰胆碱，二肉豆蔻酰磷脂酰胆碱，二棕榈酰磷脂酰胆碱，二硬脂酰磷脂酰胆碱，二硬脂酰磷脂酰甘油，二棕榈酰磷脂酰，二棕榈酰磷脂酸，二油酰磷脂酰胆碱、二油酰磷脂酰乙醇胺、大豆磷脂、卵磷脂、卵黄磷脂及其混合物；胆酸盐选自胆酸钠、甘胆酸钠、牛磺胆酸钠及其混合物；脱氧胆酸盐选自脱氧胆酸钠、去氧牛磺胆酸钠及其混合物；短链醇选自丁醇、甘油、异丙醇、乙醇；泊洛沙姆优选poloxamer 108，188，182，407，908；聚山梨醇酯优选吐温-80，85，65，60，40，20；聚氧乙烯脂肪醇醚优选Brij 78，35，30；聚氧乙烯脂肪酸酯优选Myrj 53，59；聚氧乙烯蓖麻油选自cromophor EL系列；聚氧乙烯氢化蓖麻油cromophorRH系列。
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