CN1461639A - 含氢化蓖麻油/治疗药物固体分散体微粒的缓释注射剂 - Google Patents
含氢化蓖麻油/治疗药物固体分散体微粒的缓释注射剂 Download PDFInfo
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- CN1461639A CN1461639A CN03119164A CN03119164A CN1461639A CN 1461639 A CN1461639 A CN 1461639A CN 03119164 A CN03119164 A CN 03119164A CN 03119164 A CN03119164 A CN 03119164A CN 1461639 A CN1461639 A CN 1461639A
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Abstract
本发明介绍了用氢化蓖麻油与水不溶性或微水溶性治疗药物制备的固体分散体微粒，来制备医用或兽用缓释注射剂，制剂组成为：a.含氢化蓖麻油/治疗药物的固体分散体微粒；b.分散介质；c.必要时，加入抗氧化剂、助悬剂或其它助剂。氢化蓖麻油/治疗药物的固体分散体的制备可采用熔化分散冷凝法、溶剂－非溶剂法、熔融法、溶剂法或溶剂－熔融法。本发明制剂的特点是：稳定性好，生物相容性好，缓释效果显著。
Description
技术领域
本发明是将氢化蓖麻油(hydrogenated castor oil，以下简称HCO)与治疗药物组合，制备成固体分散体，并将该固体分散体与生物相容性好的分散介质组合，制备成医用或兽用缓释注射剂。
背景技术
在以往的药物制剂制备中，用氢化蓖麻油(hydrogenated castor oil，以下简称HCO)制备的固体分散体是用于制备供口服使用的制剂，如片剂、颗粒剂或胶囊剂等(郑俊民主编，药用高分子材料学，中国医药科技出版社，2000年；高申主编，现代药物新剂型新技术，人民军医出版社，2002年，73-86页；陆彬主编，药物新剂型与新技术，人民卫生出版社，1998年，4页)。专利WO99/27906和专利EP0535734公开了将HCO用于缓释注射剂的制备，优化的制剂配方组成为：a.治疗药物；b.HCO；c.疏水性液体介质，如甘油三乙酸酯或苯甲酸苄酯；d.乙酰化单甘油酯。由于甘油三乙酸酯或苯甲酸苄酯对活性成份有一定的溶解能力和乙酰化单甘油酯(非离子亲油性表面活性剂)对HCO有很强的分散能力，因此，制剂中的活性成份与HCO被均匀地分散于甘油三乙酸酯或苯甲酸苄酯和乙酰化单甘油酯中，制剂呈胶体状态。
本发明是将HCO与治疗药物组合成固体分散体微粒(以下简称HCO载药微粒)，并将HCO载药微粒分散于分散介质中，制备成缓释注射剂。该制剂实质上是一种混悬剂，治疗药物被均匀地分散于HCO中，构成固体分散体。由于HCO的强疏水性和缓慢的可生物降解性，因此，用HCO载药微粒制备的注射剂既具有很好的缓释作用，又没有持久性残留，载药微粒本身生物相容性好，对注射部位刺激性很小。为使含载药微粒的注射剂达到一定的缓释作用和较好的稳定性及较好的生物相容性，除了要求载药微粒的载药量及载药微粒大小合适外，作为组成制剂的液体分散介质同样对制剂的缓释效果、稳定性、生物相容性有很大的影响，液体介质选择不当时，载药微粒中的药物可能会被溶出，或部分溶出，这样对缓释效果影响很大，还可能会导致药剂分层，甚至于导致载药微粒解体(如将HCO载药微粒长时间的分散于某些植物油中)。因此，用HCO载药微粒制备缓释注射剂时，选择合适的液体分散介质，对于保证制剂的稳定性、临床效果和生物相容性同样是至关重要的。本发明制剂采用的液体分散介质主要是水和适量的非离子表面活性剂及少量的生物相容性好的有机液体介质(如丙三醇、聚乙二醇、甲醛缩甘油、1，2-丙二醇)。
综上所述：本发明的突出特征就是将含HCO/治疗药物的固体分散体用于制备缓释注射制剂。用本方法制备的含抗菌药物或非甾体抗炎药物或其它治疗药物的制剂，临床都表现出了长时间的活性；本发明制剂可依据临床要求的不同，通过调整载药微粒中HCO与活性成份的比例或调整HCO与其它载体材料的比例，或调整给药剂量等，可达到不同的持效期；本发明制剂介质可以不含有机溶剂，因此，除可做为动物用缓释注射剂的制备，还适用于人用缓释注射剂的制备。
实施本发明技术的关键有以下几个方面：(1)通过调整HCO与药物或其它载体材料的比例，使之在保证期望的缓释效果的同时，尽可能地使载药微粒的比重接近于液体介质的比重，也可通过加入比重较小的乙醇、1，2-丙二醇或比重较大的丙三醇或甲醛缩甘油来调整制剂液体介质的比重，以保证制剂物理性状的稳定。(2)根据载药微粒的含量，调整制剂中亲油性非离子表面活性剂与亲水性表面活性剂的比例。(3)在制备过程中注意各种成份的加入顺序，及需要分步加入的成份(如水)必须分步加入，否则，表面活性剂与载药微粒不能“结合牢固”而长时间地均匀分散于水相中。(4)制备含HCO的载药微粒可采用以下几种方法：熔化分散冷凝法、溶剂-非溶剂法、熔融法、溶剂法或溶剂-熔融法。
发明内容本发明制剂的组成为：
a、氢化蓖麻油(hydrogenated castor oil，简称HCO)与治疗药物组成的固体分散体微粒(以下简称含HCO的载药微粒)；
b、分散介质；
c、必要时，加入其它助剂，如助悬剂、抗氧化剂、非离子表面活性剂及其它亲水性或疏水性载体材料。
必要时，载药微粒中可加入少许水溶性载体材料，以增加药物的溶出速率，或加入其它疏水性载体材料；以加强载药微粒的稳定性和药剂的缓释效果。优选的水溶性载体材料或其它疏水性载体材料为乙基纤维素、氢化植物油、巴西蜡、聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)。
所述的载药微粒载药量为5-90％(W/W)，载体含量为10-95％(W/W)；在制剂中，载药微粒含量为1-60％(W/V)。
所述的治疗药物包括抗微生物药物、抗肿瘤药物、非甾体抗炎药物、镇痛药物、激素类药物、具有调节免疫功能的药物、脂溶性维生素和抗肝片吸虫药物。
所述的抗微生物药物优选头孢菌素类、氨基糖苷类、四环素类、大环内酯类、磺胺类、喹诺酮类和抗结核病药物；抗肿瘤药物优选烷化剂、抗代谢药物、抗肿瘤抗生素(如放线菌素D dactinomycin D、丝裂霉素mitomycin、柔红霉素daunorubicin、阿霉素doxorubicin、阿克拉霉素A aclacinomycin A)、植物提取的抗肿瘤药物(包括长春碱vinblastine、长春新碱vincristine、紫杉醇等)、抗肿瘤激素类和其它抗肿瘤药物如米托蒽醌(mitoxantrone)；优选的镇痛药物包括吗啡morphine、哌替啶pethidine、芬太尼fentanyl、布桂嗪bucinnazine、四氢帕马丁tetrahydropalamatine、二氢埃托啡dihydroetorphine、曲马朵tramadol、丁丙诺啡buprenorpine、氨酚待因paracetamol and codeine等；优选的非甾体抗炎药物包括吲哚美辛indomethacin、酮洛芬ketoprofen、美洛昔康meloxican、萘普生naproxen、卡布洛芬caprofen、酮洛酸ketorolac、氟尼辛flunixin、双氯酚酸diclofenac、吡罗昔康piroxican。优选的激素类药物包括雄激素及同化激素如甲睾酮、雌激素及孕激素(如雌二醇、己烯雌酚、黄体酮等)；所述的具有调节免疫功能的药物为左旋咪唑。所述的脂溶性维生素包括维生素A、D、E、K。所述的抗肝片吸虫药物为氯氰碘柳胺钠。
所述的非离子表面活性剂包括医药上可用的非离子表面活性剂；优选烷基酚聚氧乙烯醚类、聚氧乙烯失水山梨醇脂肪酸酯(Tween系列)、失水山梨醇脂肪酸酯(Span系列)、蓖麻油聚氧乙烯醚(EL系列)；特别优选司盘(Span)类、吐温(Tween)类非离子型表面活性剂用于本发明制剂，它们可单一应用，可联合应用。所述的分散介质包括水和有机液体分散介质；优选的有机液体分散介质为：乙醇、1，2-丙二醇、丙三醇、聚乙二醇、甲醛缩甘油、甘油三乙酸酯、苯甲酸苄酯，它们可一种以上一起使用，或与水一起使用。所述的抗氧化剂为亲油性抗氧剂和水溶性抗氧剂，优选硫代硫酸钠、硫脲、BHT、BHA、抗坏血酸，所述的助悬剂优选聚乙烯吡咯烷酮、聚乙二醇、水可溶解或溶胀的纤维素类衍生物，黄原胶、阿拉伯胶。
本发明制剂制备方法如下。
方法(1)：
a.将治疗药物和亲油性抗氧剂用沸点低于100℃的有机溶剂溶解，再与已融化的HCO混匀；或将治疗药物微粉(细度小于10μm)与已融化的HCO混合均匀；在搅拌条件下，使含HCO和治疗药物的液体降温至45℃以下，使之固化，之后减压干燥或在室温条件下自然干燥，除去溶媒，将制备的治疗药物/HCO固体分散体粉碎至小于100μm，即得治疗药物/固体分散体微粉(含HCO载药微粒)。
b.定量取上法制得的载药微粒，加或不加非离子表面活性剂，加或不加助悬剂，加少量的水稀释至一定粘度之后，研磨，之后加入水溶性抗氧剂、防腐剂(苯甲醇或三氯叔丁醇)和注射用水至终体积，即得本发明制剂。
方法(2)：将溶解的或微粒化的治疗药物均匀分散于已经融化的HCO中，然后与水或其它对治疗药物溶解能力差的液体分散介质混合，待治疗药物/HCO固化形成固体分散体后，研磨至细度小于150μm，之后加入或不加非离子表面活性剂，并加入剩余液体介质至终体积(或终重量)，即得含治疗药物/HCO固体分散体微粒的缓释注射剂。或将溶解的或微粒化的治疗药物均匀分散于已经融化的HCO中，加入非离子表面活性剂，均质化，然后与水或其它对治疗药物溶解能力差的液体分散介质混合，均质化，加入剩余液体介质至终体积(或终重量)，即得含治疗药物/HCO固体分散体微粒的缓释注射剂。
方法(3)：a、将溶解的或微粉化的(微粒粒径小于5μm)治疗药物分散于已融化的或溶解的HCO中，然后与水或其它对治疗药物溶解能力差的液体分散介质混合，待治疗药物/HCO固化后，过滤或离心，分离固化物并研磨或粉碎使之粒径达到100μm以下，即得治疗药物/HCO固体分散体微粒。b、取以上制备的固体分散体微粒，分散于介质中，即得内服或非肠道给药的缓释制剂(口服固体或液体制剂或缓释注射剂)。
按上述方法制备的含HCO的载药微粒，其特征在于该载药微粒还可用于制备粉针注射剂，使用时，在用液体介质，如三乙酸甘油酯或植物油等进行分散，制备成混悬液，该混悬液可皮下注射给药，也可肌注，药剂缓释效果显著。
本发明的由HCO载药微粒与分散介质组合的缓释注射剂，可以是液体制剂，也可以是半固体(膏状)制剂，也可是固体制剂；载药微粒中的药物可以分子状态分散于HCO中，也可以超微颗粒(粒径小于5μm)状态分散于HCO中。
具体实施方式
下面用实例予以说明本发明制剂，但实例不限制本发明的范围，本发明的范围与核心内容依据权利要求书加以确定。
实例1：(1)取10g酮洛芬和0.6g BHT，加入20ml乙醇使之溶解，之后加入到10g已融化的HCO中，混匀之后，迅速降温至30℃，使之固化，得HCO/酮洛芬固体分散体。(2)将上述制备的HCO/酮洛芬固体分散体减压干燥，并粉碎至100μm以下，得HCO/酮洛芬固体分散体微粒。(3)取HCO/酮洛芬固体分散体微粒，加入20g Tween-80和20g Span-80，再加入60ml水，过胶体磨使之均质化，而后加入含抗氧剂的注射用水至200ml，即得本制剂。
该制剂用于猪、牛、羊解热、消炎、镇痛，皮下注射3-10mg/kg b.w.，药物持效期可达24-96小时。用普通酮洛芬注射液治疗，一般每隔4-6小时注射一次，因此，本制剂显著地延长了药剂持效时间。
实例2：(1)取10g吲哚美辛和0.3g BHT，加入30ml乙醇，于70℃以上加热使之溶解，之后加入到10g已融化的HCO中，混匀之后，迅速降温使之固化，减压干燥，除去乙醇，得HCO/吲哚美辛固体分散体。(2)将上述制备的HCO/吲哚美辛固体分散体，粉碎至100μm以下，得HCO/吲哚美辛固体分散体微粒。(3)将以上制得的HCO/吲哚美辛固体分散体微粒，加入15g Tween-80和20gSpan-80，再加入40ml水调成膏状，过胶体磨磨至粒径小于20μm，加注射用水至200ml，即得。
实例3：将已超微粉碎的庆大霉素微粉10g分散于20g已融化的HCO/PEG-10000中，均质化后，迅速降温使之固化，之后将之磨碎至100μm以下的微粒，加入Tween-80和Span-80，再加入50ml水调成膏状，过胶体磨磨成粒径小于25μm，加入含抗氧剂的注射用水至终体积。
实例4：将阿克拉霉素A微粉10g或溶(熔)解的阿克拉霉素A分散于40g已融化的HCO/PEG-10000中，均质化后，迅速降温使之固化，之后将之磨碎至100μm以下的微粒，加入Tween-80和Span-80，再加入50ml水调成膏状，过胶体磨磨成粒径小于10μm，加入含抗氧剂的注射用水至终体积。
实例5：将米托蒽醌微粉10g或溶(熔)解的米托蒽醌分散于40g已融化的HCO/PEG-10000中，均质化后，迅速降温使之固化，之后将之磨碎至100μm以下的微粒，加入Tween-80和Span-80，再加入50ml水调成膏状，过胶体磨磨成粒径小于10μm，加入含抗氧剂的注射用水至终体积。
实例6：(1)取10g氯氰碘柳胺钠和0.6g BHT，加入20ml丙酮使之溶解，之后加入到10g已融化的HCO中，混匀之后，迅速降温至30℃，使之固化，得HCO/氯氰碘柳胺钠固体分散体。(2)将上述制备的HCO/氯氰碘柳胺钠固体分散体真空干燥，并粉碎至100μm以下，得HCO/氯氰碘柳胺钠(1∶1)固体分散体微粒。(3)取HCO/氯氰碘柳胺钠(1∶1)固体分散体微粒，加入20gTween-80和20g Span-80，再加入60ml水，过胶体磨使之均质化，而后加入含抗氧剂的注射用水至200ml，即得本制剂。
实例7、制备含酮洛芬的缓释注射液
取1-3kg HCO，加入1升1，2-丙二醇加热至85℃，待完全熔化后，加入1kg酮洛芬，混匀，待熔化后，在搅拌条件下冷却至30℃左右，加入4升水，研磨(过胶体磨)，然后加Tween-80/Span-80(6∶4)，均质化后加水至终体积即得。
动物皮下注射本剂，药物持效期可达3-7天或更长，加入HCO越高，给药剂量越大，持效期越长。
实例8、制备含双氯芬酸的缓释注射剂
取1kg双氯芬酸、1-3kg HCO、0.3-0.6kg PVP，加入1升二甲基乙酰胺，90-95℃溶解，之后冷却至刚刚半固化时，加入2升水，研磨，使体系中固形物粒径小于100μm时，加入水/甘油至10升即得。
实例9、制备含吲哚美辛的缓释注射剂
取1kg吲哚美辛，加入1升二甲基乙酰胺，加热溶解，加入2kg HCO，融化后，混匀，冷却至刚刚凝固时，加入4升水和Tween-80/Span-80(6∶4)，研磨，加水至终体积即得。
实例10、制备含普鲁卡因青霉素的缓释注射剂
取20g普鲁卡因青霉素微粉，加入到已融化的20g HCO中，混匀，冷至半固化时，加入水，过胶体磨，加入甘油/水液至终体积即得。本制剂持效期是常规普鲁卡因青霉素的1.5-2倍。
实例11、制备含氨苄青霉素的缓释注射剂
取氨苄青霉素分散于已融化的HCO中，加水，使之固化后，研磨，之后再加水/甘油液至终体积。
Claims (10)
1、一种医用或兽用缓释注射剂，其特征在于制剂是用氢化蓖麻油(hydrogenated castor oil，简称HCO)与治疗药物组成的固体分散体微粒(以下简称含HCO的载药微粒)制备而成，制剂具体组成为：
a、HCO的载药微粒；
b、分散介质；
c、必要时，加入其它助剂，如助悬剂、抗氧化剂、非离子表面活性剂、局部疼痛减轻剂及其它亲水性或疏水性载体材料。
2、按权利要求1所述的制剂，其特征在于所述的载药微粒是由治疗药物与HCO为主体制备的固体分散体，必要时加入少许水溶性载体材料，或加入其它疏水性载体材料；优选的水溶性载体材料或其它疏水性载体材料为乙基纤维素、氢化植物油、巴西蜡、聚乙烯吡咯烷酮(PVP)、聚乙二醇(PEG)；载药微粒载药量为5-90％(W/W)，载体含量为10-95％(W/W)；在制剂中，载药微粒含量为1-60％(W/V)。
3、按权利要求1所述的制剂，其特征在于所述的治疗药物包括抗微生物药物、抗肿瘤药物、非甾体抗炎药物、镇痛药物、激素类药物、具有调节免疫功能的药物、脂溶性维生素和抗肝片吸虫药物。
4、按权利要求3所述的制剂，其特征在于所述的抗微生物药物优选头孢菌素类、氨基糖苷类、四环素类、大环内酯类、磺胺类、喹诺酮类和抗结核病药物；抗肿瘤药物优选烷化剂、抗代谢药、抗肿瘤抗生素(如放线菌素D dactinomycinD、丝裂霉素mitomycin、柔红霉素daunorubicin、阿霉素doxorubicin、阿克拉霉素A aclacinomycin A)、植物提取的抗肿瘤药物(包括长春碱vinblastine、长春新碱vincristine、紫杉醇等)、抗肿瘤激素类和其它抗肿瘤药物如米托蒽醌(mitoxantrone)；优选的镇痛药物包括吗啡morphine、哌替啶pethidine、芬太尼fentanyl、布桂嗪bucinnazine、四氢帕马丁tetrahydropalamatine、二氢埃托啡dihydroetorphine、曲马朵tramadol、丁丙诺啡buprenorpine、氨酚待因paracetamol and codeine等；优选的非甾体抗炎药物包括吲哚美辛indomethacin、酮洛芬ketoprofen、美洛昔康meloxican、萘普生naproxen、卡布洛芬caprofen、酮洛酸ketorolac、氟尼辛flunixin、双氯酚酸diclofenac、吡罗昔康piroxican。优选的激素类药物包括雄激素及同化激素如甲睾酮、雌激素及孕激素(如雌二醇、己烯雌酚、黄体酮等)；所述的具有调节免疫功能的药物为左旋咪唑。所述的脂溶性维生素包括维生素A、D、E、K。所述的抗肝片吸虫药物为氯氰碘柳胺钠。
5、按权利要求1所述的制剂，其特征在于所述的非离子表面活性剂包括医药上可用的非离子表面活性剂；优选烷基酚聚氧乙烯醚类、聚氧乙烯失水山梨醇脂肪酸酯(Tween系列)、失水山梨醇脂肪酸酯(Span系列)、蓖麻油聚氧乙烯醚(EL系列)；特别优选司盘(Span)类、吐温(Tween)类非离子型表面活性剂用于本发明制剂，它们可单一应用，可联合应用。所述的分散介质包括水和有机液体分散介质；优选的有机液体分散介质为：乙醇、1，2-丙二醇、丙三醇、聚乙二醇、甲醛缩甘油、甘油三乙酸酯、苯甲酸苄酯，它们可一种以上一起使用，或与水一起使用。所述的抗氧化剂为亲油性抗氧剂和水溶性抗氧剂，优选硫代硫酸钠、硫脲、BHT、BHA、抗坏血酸，所述的助悬剂优选聚乙烯吡咯烷酮、聚乙二醇、水可溶解或溶胀的纤维素类衍生物，黄原胶、阿拉伯胶。
6、按权利要求1所述的制剂，其特征在于其制备工艺如下：
a.将治疗药物和亲油性抗氧剂用沸点低于100℃的有机溶剂溶解，再与已融(熔)化的HCO混匀；或将治疗药物微粉(细度小于10μm)与已融(熔)化的HCO混合均匀；在搅拌条件下，使含HCO和治疗药物的液体降温至45℃以下，使之固化，之后减压干燥或在室温条件下自然干燥，除去溶媒，将制备的治疗药物/HCO固体分散体粉碎至小于100μm，即得治疗药物/固体分散体微粉(含HCO载药微粒)。
b.定量取上法制得的载药微粒，加或不加非离子表面活性剂，加或不加助悬剂，加少量的水稀释至一定粘度之后，研磨，之后加入注射用水及助剂至终体积，即得本发明制剂。
7、按权利要求1的制剂，其特征在于制备方法如下。
方法(1)：将溶解的或微粒化的治疗药物均匀分散于已经熔化的HCO中，加或不加PVP，然后与水或其它对治疗药物溶解能力差的液体分散介质混合，待治疗药物与HCO固化形成固体分散体后，研磨至细度小于150μm，加入剩余液体介质及助剂至终体积(或终重量)，即得含治疗药物/HCO固体分散体微粒的缓释注射剂。或将溶解的或微粒化的治疗药物均匀分散于已经融化的HCO中，加入非离子表面活性剂，均质化，然后与水或其它对治疗药物溶解能力差的液体分散介质混合，均质化，加入剩余液体介质及助悬剂至终体积(或终重量)，即得含治疗药物/HCO固体分散体微粒的缓释注射剂。
方法(2)：a、将溶解的或微粉化的(微粒粒径小于5μm)治疗药物分散于已融化的或溶解的HCO中，然后与水或其它对治疗药物溶解能力差的液体分散介质混合，待治疗药物与HCO固化后，过滤或离心，分离固化物并研磨或粉碎使之粒径达到100μm以下，即得治疗药物/HCO固体分散体微粒。b、取以上制备的固体分散体微粒，分散于介质及助剂中，即得内服或非肠道给药的缓释制剂(口服固体或液体制剂或缓释注射剂)。
8、按权利要求1和2所述的制剂，其特征在于制剂中的载药微粒粒径小于100μm，载药微粒中含的治疗药物可以是一种，也可以由一种以上组成；载药微粒中的疏水性载体可以是一种，也可以是一种以上组成；也可由含不同治疗药物的载药微粒组合成复方缓释注射剂。
9、按权利要求6和7所述的方法制备的含HCO的载药微粒，其特征在于该载药微粒还可用于制备粉针注射剂，使用时，在用液体介质(如三乙酸甘油酯或植物油或液体石蜡油)分散，制备成混悬液，该混悬液可皮下注射给药，也可肌注。
10、按权利要求1和9所述的制剂，其特征在于由HCO载药微粒与分散介质组合的缓释注射剂，可以是液体制剂，也可以是半固体制剂，也可是固体制剂；载药微粒中的药物可以分子状态分散于HCO中，也可以超微颗粒(粒径小于5μm)状态分散于HCO中。
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| CN103721263A (zh) * | 2014-01-08 | 2014-04-16 | 王玉万 | 含抗菌药物/聚乙二醇载药微粒的油质注射剂 |
| CN103720651A (zh) * | 2014-01-06 | 2014-04-16 | 王玉万 | 含氟苯尼考/氢化蓖麻油的原位胶凝注射剂 |
| CN103735502A (zh) * | 2014-01-06 | 2014-04-23 | 王玉万 | 含非甾体抗炎药物/氢化蓖麻油的原位胶凝注射剂 |
| CN104906591A (zh) * | 2015-05-11 | 2015-09-16 | 王玉万 | 一种泰妙菌素胶体注射剂及其制备方法 |
| CN104906590A (zh) * | 2015-05-11 | 2015-09-16 | 王玉万 | 含巴西蜡的沃尼妙林注射液 |
-
2003
- 2003-03-17 CN CNB031191649A patent/CN1236758C/zh not_active Expired - Lifetime
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923281B (zh) * | 2005-08-30 | 2010-05-05 | 孔庆忠 | 一种含植物生物碱的抗癌缓释注射剂 |
| CN102204940A (zh) * | 2011-05-17 | 2011-10-05 | 黑龙江大学 | 月见草油微胶囊及粉末化方法 |
| CN102204940B (zh) * | 2011-05-17 | 2014-06-11 | 黑龙江大学 | 月见草油微胶囊及粉末化方法 |
| CN103705451A (zh) * | 2014-01-06 | 2014-04-09 | 王玉万 | 含吡喹酮/氢化蓖麻油的原位胶凝注射剂 |
| CN103705445A (zh) * | 2014-01-06 | 2014-04-09 | 王玉万 | 含乙酰甲喹/氢化蓖麻油的原位胶凝注射剂 |
| CN103720651A (zh) * | 2014-01-06 | 2014-04-16 | 王玉万 | 含氟苯尼考/氢化蓖麻油的原位胶凝注射剂 |
| CN103735502A (zh) * | 2014-01-06 | 2014-04-23 | 王玉万 | 含非甾体抗炎药物/氢化蓖麻油的原位胶凝注射剂 |
| CN103721263A (zh) * | 2014-01-08 | 2014-04-16 | 王玉万 | 含抗菌药物/聚乙二醇载药微粒的油质注射剂 |
| CN104906591A (zh) * | 2015-05-11 | 2015-09-16 | 王玉万 | 一种泰妙菌素胶体注射剂及其制备方法 |
| CN104906590A (zh) * | 2015-05-11 | 2015-09-16 | 王玉万 | 含巴西蜡的沃尼妙林注射液 |
| CN104906590B (zh) * | 2015-05-11 | 2017-09-15 | 王玉万 | 含巴西蜡的沃尼妙林注射液 |
| CN104906591B (zh) * | 2015-05-11 | 2017-09-15 | 王玉万 | 一种泰妙菌素胶体注射剂及其制备方法 |
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| CN1236758C (zh) | 2006-01-18 |
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