CN1228021A - 含有水不溶性物质微粒的组合物及其制备法 - Google Patents

含有水不溶性物质微粒的组合物及其制备法 Download PDF

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CN1228021A
CN1228021A CN97197365A CN97197365A CN1228021A CN 1228021 A CN1228021 A CN 1228021A CN 97197365 A CN97197365 A CN 97197365A CN 97197365 A CN97197365 A CN 97197365A CN 1228021 A CN1228021 A CN 1228021A
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I·帕里克
U·塞尔瓦拉
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Abstract

通过使用一种或多种表面改性剂/表面活性剂，如Polaxomers，Poloxamines，聚氧乙烯脱水甘露糖醇脂肪酸酯等与天然的或合成的磷脂一起组合来制备药物或其他水不溶或难溶于水的物质的亚微米大小的颗粒。这样生成的颗粒具有的体积重量的平均颗粒大小至少要比单独应用磷脂所得到的小一半。这样得到的组合物在贮存时可以阻止颗粒大小的增长。

Description

含有水不溶性物质微粒 的组合物及其制备法
本发明涉及组合物和可产生水不溶或难溶药物或其他工业上有用的不溶性化合物亚微米和微米稳定颗粒的方法。本发明的组合物包括天然或合成的磷脂，和一种或多种包裹在或粘附在水不溶化合物颗粒表面上的非-离子的、阴离子的或阳离子的表面活性剂的组合。磷脂和表面活性剂的组合通过亲水的、亲脂的和静电相互作用使得亚-微米和微米大小的化合物颗粒形成并且稳定化，并因此防止这些颗粒聚合或絮凝。
                       发明背景
在药物和其他以生物为基础的工业方面迫切需要将水不溶的或难溶的物质配制成供口服、注射、吸入和眼用给药的制剂。水不溶性化合物是那些难溶于水的，即在生理pH(6.5-7.4)下水溶解度＜5mg/ml的。优选是它们的水溶解度＜1mg/ml，更优选＜0.1mg/ml。期望的是该药物在作为分散剂的水中是稳定的；另外，一种冻干的或喷雾-干燥的固体形式是理想的。
在本文中使用的，“微”指的是颗粒所具的直径从钠米到微米。本文使用的“微粒”，指的是不规则，非-球形或球形的固体颗粒。含有这些微粒的制剂要比非配制的非-微粒化的药物颗粒具有一些特定的优点，这包括对那些在胃肠道难于吸收的药物有改善了的口服生物利用度，能将目前只有口服的剂型开发出其注射制剂，从目前用有机溶剂制备的开发出其较低毒性的注射制剂，将目前需每日注射或持续灌注给药的药物调配成可肌肉注射的持续释放剂型，并将药物调配成吸入，眼用的制剂，否则它们不能配制成供鼻腔或眼用制剂。
美国专利5,091,188；5,091,187和4,725,442描述的供输送不溶性药物的现有技术集中在(a)用天然的或合成的磷脂对小的药物颗粒进行包衣；或(b)将药物溶解在适当的亲脂性载体中形成一种乳剂，并用天然的或半合成的磷脂使之稳定。这些制剂的缺点之一是，悬浮剂中的一些药物颗粒在一段时间后趋于增大，这是由于溶解和重新沉淀现象，称之为“Oswald熟成”所致。
                       发明详述
本发明集中在，使用表面改性剂和磷脂的组合来制备亚微米大小的颗粒，并通过于制剂中加入表面改性剂和磷脂的组合物来控制颗粒大小增长，并从而控制其贮存的稳定性。
使用表面改性剂或将表面改性剂和磷脂组合物的特征在于，它能导致形成的容重的平均颗粒大小值是(i)比单独使用磷脂而不用表面活性剂在相同的能量输入下达到的平均颗粒大小至少小50％，优选约小50-90％，和(ii)给出的组合物在贮存时能阻止颗粒大小的增长。当在贮存中阻止颗粒大小增长是本发明的目的时，我们惊异地观察到随着表面活性剂的加入，颗粒大小显著减小。为了达到本发明的优点，需要磷脂和表面活性剂在颗粒大小减小时或沉淀时同时存在。
虽然我们并不希望受任何特定理论的限制，但，似乎是这些表面改性剂，一般来说即磷脂和一种或多种表面活性剂，吸附到药物颗粒的表面，和(a)随着增加立体位阻/稳定性转变亲脂性为亲水性表面，和(b)随着更多的电荷排斥稳定作用可能改变了表面的ζ电位。这里描述的方法中所用的表面改性剂的浓度一般要高于它们的临界胶束浓度(CMC)并因此通过稳定颗粒而加速亚-微米颗粒的形成。
通过本技术领域中熟知的一种或多种方法的组合，如超声、均化、研磨、微观流体化，沉淀或重结晶或从超临界流体沉淀，使磷脂和表面改性剂以足够量吸附到药物颗粒的表面，以阻止药物颗粒的增长，并将药物的平均颗粒大小从5到100μm减小至亚微米和微米大小颗粒，并在随后以悬浮剂或固体剂型贮存时，维持亚微米和微米大小的颗粒。
在悬浮剂或固体剂型中存在的磷脂和表面改性剂的浓度范围为0.1到50％，优选0.2到20％，和更优选为0.5至10％。
本发明制备的制剂可冻干为粉末，它可被重新悬浮或填充至胶囊中，或通过加入粘合剂和片剂制备技术领域中熟知的其他赋形剂，将它转变成颗粒剂或片剂。
就工业上有用的不溶的或难溶的化合物而言，我们包括生物学上有用的化合物，造影剂，药物上有用的化合物和对人和畜医药用的一些特定药物。水不溶的化合物是那些难溶于水的，即在生理pH6.5到7.4时，溶解度低于5mg/ml，虽然水溶解度可以小于1mg/ml，甚至小于0.1mg/ml。
一些优选的水-不溶药物的例子包括免疫抑制剂和免疫活化剂，抗病毒和抗真菌剂，抗肿瘤剂，镇痛和抗炎剂，抗生素，抗癫痫剂，麻醉剂，催眠剂，镇定剂，精神抑制剂，神经安定剂，抗抑郁剂，解焦虑剂，抗惊厥剂，拮抗剂，神经元阻断剂，抗胆碱能和凝胆碱能剂，抗蕈毒碱和蕈毒碱剂，抗肾上腺能剂和抗心律不齐剂，抗高血压剂，抗新生物剂，激素和营养剂。这些或其他适当药物的详细描述可以在Remington′s药物科学，第18版，1990，Mack出版公司，Philadelphia，PA中找到。
磷脂可以是任何天然的或合成的磷脂，例如磷脂酰胆碱，磷脂酰乙醇胺，磷脂酰色氨酸，磷脂酰肌醇，磷脂酰甘油，磷脂酸，溶血磷脂，卵或大豆磷脂或它们的组合、磷脂可以盐化的或脱盐的，氢化的或部分氢化的或天然的，半合成的或合成的。
一些适宜的第二表面改性剂的例子包括：(a)天然的表面活性剂如酪蛋白，明胶，黄蓍胶，腊，肠溶树脂，石蜡，阿拉伯胶，明胶，胆甾醇酯和三甘油酯，(b)非离子表面活性剂如聚氧乙烯脂肪醇醚，脱水甘露糖醇脂肪酸酯，聚氧乙烯脂肪酸酯，脱水甘露糖醇酯，甘油单硬脂酸酯，聚乙烯二醇，鲸腊醇，乙酰硬脂醇，硬脂醇，Poloxamers，Polaxamines，甲基纤维素，羟基纤维素，羟丙基纤维素，羟丙基甲基纤维素，非晶形纤维素，聚乙烯醇，聚乙烯吡咯烷酮，和合成的磷脂，(c)阴离子表面活性剂如月桂酸钾，三乙醇胺硬脂酸酯，月桂基硫酸钠，烷基聚氧乙烯硫酸酯，藻酸钠，二辛基磺酰琥珀酸钠，带负电荷的磷脂(磷脂酰甘油，磷脂酰肌醇，磷脂酰丝氨酸，磷脂酸及它们的盐)，和带负电荷的甘油酯，羧甲基纤维素钠，和羧甲基纤维素钙，(d)阳离子表面活性剂如季铵化合物，氯化苄烷基铵，溴化鲸腊基二甲基铵，脱乙酰壳多糖和氯化月桂基二甲基苄基铵，(e)胶体粘土如皂粘土和veegum。这些表面活性剂的详细描述可以从Remington′s药物科学，和工业药房的理论和实践，Lachman等，1986中找到。
更具体地，适宜的第二表面改性剂的例子下述改性剂的一种或组合：polaxomers，诸如PluronicTM F68、F108和F127，它们是可从BASF购得的环氧乙烷和环氧丙烷的嵌段共聚物；和Poloxamines，诸如TetronicTM 908(T908)，它是将环氧乙烷和环氧丙烷顺序加至乙二胺衍生而得的四功能嵌段共聚物，可自BASF购得；和TritonTM X-200，它为一种烷基芳基聚醚磺酸酯，可从Rohm和Haas购得。吐温20、40、60和80，它们为聚氧乙烯脱水甘露糖醇脂肪酸酯，可从ICI SpecialityChemicals购得；CarbowaxTM 3550和934，它们是聚乙二醇，可从UnionCarbide购得；羟丙基甲基纤维素，二肉豆蔻酰磷脂酰甘油钠盐，十二烷基硫酸钠，脱氧胆酸钠，和溴化鲸腊基三甲基铵。
据认为与本发明有关的第二表面改性剂的某些作用是，抑制“Oswald熟成”的过程并因此维持了颗粒的大小，增加了贮存的稳定性，使沉降最少，并在冷冻干燥和再生期间减少了颗粒的增长；牢牢地粘附或包裹在水不溶性药物颗粒的表面上并因此改进颗粒和所得制剂中液体间的界面作用；增加了水不溶性药物颗粒和液体间界面的相容性；并可能随着亲水部分粘进水溶液中并将亲脂部分强烈吸附在水不溶性药物颗粒表面，而优先定位它们自己。
取决于所选择的药物或活性剂，应该预期到所用的磷脂，特别是表面活性剂或试剂的种类和类型含有较大的变化，这是因为这些(药物和活性剂)中颗粒的表面性质是不同的。对不溶性药物最具优点的表面活性剂将显然遵照经验试验以检定出能得到所要求的颗粒大小并在贮存一段时间后颗粒大小稳定的那些表面活性剂或表面活性剂体系/组合。
可用各种方法来产生这些稳定的亚-微米和微米大小的颗粒，这包括将不溶性物质与磷脂混合并从用其他表面活性剂溶解的物质，磷脂和表面活性剂混合物中，用超声、研磨、均化、微观流体化以及抗溶剂和溶剂沉淀作用沉淀出。可以加入甘露糖醇和其它试剂调节最终的制剂为等渗以及在干燥时帮助稳定化。
除非另有注明，这里报告的所有“份数”和百分比均为每单位体积的重量(w/v)，其中分母的体积代表了体系的总体积。规格的直径是以毫米(mm＝10-3米)，微米(μm＝10-6米)，纳米(nm＝10-9米)或埃单位(＝0.1nm)表示。体积以升(L)，毫升(mL＝10-3L)和微升(μL＝10-6L)表示，稀释是以体积。所用温度是指摄氏度。本发明的组合物可以包括，基本上组成自，或者组成自规定的物质，而过程和方法可以包括，基本上组成自，或者组成自规定的步骤与这些物质。
下述例子进一步说明和阐明本发明：
                       实例1
一种免疫抑制药物的微粒-环孢菌素是按如下制备的。微粒环孢菌素制剂的赋形剂组成和浓度如下：
环孢菌素                               50mg/ml
卵磷脂酰胆碱                           100mg/ml
甘露糖醇                               55mg/ml
吐温80                                 10mg/ml
蒸馏水                                 至100％
总体积                                 20ml
环孢菌素平均颗粒大小从5～100μm，甘露糖醇购自Sigma，卵磷脂酰胆碱由Pfanstiehl生产，吐温从ICI购得。
将上述组分置于30ml烧杯中并用手持生物匀浆器(Honeywell DR4200型GP)预混合1-5分钟。在均化时，将稀HaOH加入到预混合物中以调节pH从3.1到7±0.5。将预混合物放置在水夹套容器中(50ml容量)并通过循环4℃恒温的水于该容器中以控制制剂的温度。将该预混合物用0.5英寸直径探头的探头超声仪进行高剪切能超声处理。使用能量调在5上，以10秒间隔超声脉冲10秒。在超声处理时制剂的温度为18±2℃。超声时用稀NaOH，将pH调至7±0.5。用于制备微粒环孢菌素的总超声时间通常为10.5小时或更少。将微粒环孢菌素制剂置于20ml小瓶中并于4℃和25℃贮存供进一步和稳定性研究。
混悬剂的颗粒大小分布是用NICOMP型370颗粒大小分析仪进行分析。该仪器于亚微米区域对颗粒大小使用光子相关的光谱。用水稀释小体积的混悬剂并置于颗粒大小分析器的槽中。颗粒大小测定是基于混悬剂的容重和数重的颗粒大小测定，用NICOMP 370软件以Gaussian分布代表，产生的平均颗粒大小值列于如下表1中。
表1：微粒-环孢菌素的容重和数重的颗粒大小稳定性
  贮存时间     贮存在4℃     贮存在25℃
  平均颗粒大小(nm)   平均颗粒大小(nm)
  天数     容重     数重     容重     数重
  0     361     63     361     63
  7     337     69     423     67
  51     358     76     455     66
将约20μl的新制备的混悬液置于干净的玻片上，并用干净的载玻片盖上，并于Olympus BH2显微镜下用1000×倍数进行检查。用配制有分度镜的目镜测定颗粒的大小。混悬液中的大多数颗粒为0.3～0.5μm。此外，对混悬液的显微镜检查证实非凝结的或絮凝的微米和亚微米大小的药物颗粒显示布朗运动。
                        实例2
为了比较的目的(不按照本发明)仅仅使用一种磷脂，按实例1的相同操作单独用卵磷脂(不用第二表面改性剂，吐温80)也制备了微粒-环孢菌素。将混悬液贮存于20ml玻璃小瓶中供贮存稳定性研究。贮存于4℃和25℃的混悬液的容重和数重的平均颗粒大小值列表如下。表II中的结果说明单独存在卵磷脂(不存在吐温80)并不能提供如实例1所述的颗粒大小的减小和增加贮存稳定性。
表II：微粒-环孢菌素的容重的颗粒大小稳定性
  贮存时间     在4℃贮存     在25℃贮存
  平均颗粒大小(nm)   平均颗粒大小(nm)
  天数     容重     数重     容重     数重
  0     704     91     704     91
  1     1472     503     2230     755
  6     1740     416     2290     874
                        实例3
为了比较的目的(不按照本发明)仅仅使用一种表面改性剂，按如实例1的相同操作单用吐温80(但不用磷脂、卵磷脂酰胆碱)也制备了微粒-环孢菌素。将混悬液贮存于20ml玻璃小瓶中。在表III的结果说明，单独存在吐温80(但不存在磷脂)并不像实例1那样，能提供颗粒大小的减小。
表III：微粒-环孢菌素的容重-和数重的颗粒大小稳定性
    平均颗粒大小(nm)
    天     容重     数重
    0     521     67
                        实例4
下面的微粒-二十二烷醇制剂是用本发明的方法用吐温80，吐温20，卵磷脂酰胆碱，和/或Phospholipon 90H作为表面改性剂制备的。得自Sigma，制剂是按实例1的操作制备的。微粒制剂的赋形剂的组成和浓度如下：微粒-二十二烷醇(实例4.1，比较)
二十二烷醇                       20mg/ml
卵磷脂酰胆碱                     50mg/ml
甘露糖醇                         55mg/ml
蒸馏水                           至100％
总体积                           20ml微粒-二十二烷醇(实例4.2)
二十二烷醇                        20mg/ml
卵磷脂酰胆碱                      50mg/ml
甘露糖醇                          55mg/ml
吐温80                            10mg/ml
蒸馏水                            足量至100％
总体积                            20ml微粒-二十二烷醇(实例4.3)
二十二烷醇                       20mg/ml
卵磷脂酰胆碱                     50mg/ml
甘露糖醇                         55mg/ml
吐温20                           10mg/ml
蒸馏水                           足量至100％
总体积                           20ml微粒-二十二烷醇(实例4.4)
二十二烷醇                       20mg/ml
Phospholipon 90H                 30mg/ml
甘露糖醇                         55mg/ml
吐温80                           10mg/ml
蒸馏水                           足量至100％
总体积                           20ml微粒-二十二烷醇(实例4.5，比较)
二十二烷醇                       20mg/ml
甘露糖醇                         55mg/ml
吐温80                           10mg/ml
蒸馏水                           足量至100％
总体积                           20ml混悬液的容重和数重的平均颗粒大小数值各自为286nm和98nm。
贮存于4℃的上述混悬液的容重平均颗粒大小数值列于表IV中。
表IV：贮存于4℃的微米-二十二烷醇的容重的和数重的颗粒大小的稳定性：
  贮存时间      (实例4.1)      (实例4.2)
  平均颗粒大小(nm)   平均颗粒大小(nm)
  天数     容重     数重     容重     数重
  0     688     --     112     55
  30     ND     ND     156     81
  贮存时间       (实例4.3)      (实例4.4)
   平均颗粒大小(nm)   平均颗粒大小(nm)
  天数     容重     数重     容重     数重
  0     129     61     90     35
  30     184     99     127     39
ND＝未测定。
上述数据说明，除磷脂外在表面活性剂存在下，用本发明可制备出小得多的颗粒，而且这些颗粒在一段时间后可保持它们的颗粒大小而不显著地增加其大小。
                    实例5
下面的7种微粒-RTP-4055(一种抗病毒药)制剂是用吐温80，Tetronic 908，Pluronic F-68，卵磷脂酰胆碱，和/或Phospholipon90H作为表面改性剂的组合制备的。超声方法的细节是与实例1中所讨论的相似。微粒制剂的赋形剂的组成和浓度如下：微粒-RTP-4055(实例5.1，比较)
RTP-4055                       50mg/ml
卵磷脂酰胆碱                   50mg/ml
蒸馏水                         足量至100％
总体积                         25ml
悬浮液的平均容重颗粒大小为3195nm。微粒-RTP-4055(实例5.2)
RTP-4055                       50mg/ml
卵磷脂酰胆碱                   50mg/ml
甘露糖醇                       55mg/ml
Pluronic F-68                  5mg/ml
蒸馏水                         足量至100％
总体积                         25ml
混悬液的平均容重和数重颗粒大小的数值各为672nm和76nm。微粒-RTP-4055(实例5.3)
RTP-4055                              50mg/ml
卵磷脂酰胆碱                          50mg/ml
甘露糖醇                              55mg/ml
Tetronic 908                          5mg/ml
蒸馏水                                足量至100％
总体积                                25ml
混悬液的平均容重和数重颗粒大小的数值各为436nm和59nm。微粒-RTP-4055(实例5.4，比较)
RTP-4055                            50mg/ml
Phorpholipon 90H                    30mg/ml
蒸馏水                              足量至100％
总体积                              25ml
混悬液的平均容重和数重颗粒大小数值各为1117nm和108nm。微粒-RTP-4055(实例5.5)
RTP-4055                            50mg/ml
Phospholipon 90H                    30mg/ml
甘露糖醇                               55mg/ml
二豆蔻基磷脂酰胆碱(DMPG)               3mg/ml
吐温80                                 10mg/ml
蒸馏水                                 足量至100％
总体积                                 25ml
混悬液的平均容重颗粒大小为236nm。混悬液的颗粒大小于4℃贮存一周和1月各为328和397nm，它表明了混悬液的稳定性。微粒-RTP-4055(实例5.6)
RTP-4055                               50mg/ml
Phospholipon 90H                       30mg/ml
甘露糖醇                               55mg/ml
吐温80                                 10mg/ml
蒸馏水                                 足量至100％
总体积                                 25ml
混悬液的平均容重和数重颗粒大小的数值各为382nm和59nm。在误差极限内，于4℃贮存一周后平均颗粒大小并去差别。微粒-RTP-4055(实例5.7，比较)
RTP-4055                               50mg/ml
甘露糖醇                               55mg/ml
吐温80                                 10mg/ml
蒸馏水                                 足量至100％
总体积                                 25ml
混悬液的容重和数重平均颗粒大小的数值各为545nm和75nm。在误差极限内，于4C贮存一周后平均颗粒大小并去差别。
                     实例6
下面6种微粒-炎痛喜康制剂是用吐温80，Tetronic 908，Pluronic F-68，和/或卵磷脂酰胆碱作为表面改性剂的组合而制备的。炎痛喜康得自Cipla。超声方法的细节是与实例1中所讨论的相似。微粒制剂的赋形剂的组成和浓度如下：微粒-炎痛喜康(实例6.1)
炎痛喜康                                  67mg/ml
卵磷脂酰胆碱                              67mg/ml
甘露糖醇                                67mg/ml
吐温80                                  5mg/ml
Tetronic 908                            5mg/ml
蒸馏水                                  足量至100％(w/v)
总体积                                  15ml
混悬液的平均容重和数重的颗粒大小的数值各为674nm和72nm。微粒-炎痛喜康(实例6.2)
炎痛喜康                                   67mg/ml
卵磷脂酰胆碱                               67mg/ml
甘露糖醇                                   67mg/ml
Tetronic 908                               5mg/ml
蒸馏水                                     足量至100％(w/v)
总体积                                     15ml
混悬液的平均容重和数重的颗粒大小的数值各为455nm和58nm。微粒-炎痛喜康(实例6.3)
炎痛喜康                                  67mg/ml
卵磷脂酰胆碱                              67mg/ml
甘露糖醇                                  67mg/ml
Pluronic F-68                             5mg/ml
蒸馏水                                    足量至100％(w/v)
总体积                                    15ml
混悬液的平均容重和数重的颗粒大小的数值各为564nm和68nm。微粒-炎痛喜康(实例6.4)
炎痛喜康                                   67mg/ml
卵磷脂酰胆碱                               67mg/ml
甘露糖醇                                   67mg/ml
吐温80                                     5mg/ml
溴化鲸腊基三甲基铵                         10mg/ml
蒸馏水                                     足量至100％(w/v)
总体积                                     15ml
混悬液的平均容重和数重的颗粒大小的数值分别为479nm和80nm。微粒-炎痛喜康(实例6.5)
炎痛喜康                                  67mg/ml
卵磷脂酰胆碱                              67mg/ml
甘露糖醇                                  67mg/ml
溴化鲸腊基三甲基铵                        10mg/ml
蒸馏水                                    足量至100％(w/v)
总体积                                    15ml
混悬液的平均容重和数重的颗粒大小的数值分别为670nm和128nm。微粒-炎痛喜康(实例6.6，比较)
炎痛喜康                                 67mg/ml
甘露糖醇                                 67mg/ml
吐温80                                   5mg/ml
Tetronic 908                             5mg/ml
蒸馏水                                   足量至100％(w/v)
总体积                                   25ml
混悬液的平均容重和数重的颗粒大小的数值分别为1184nm和385nm。

Claims (17)

1.一种水-不溶性物质的微粒组合物，它包含有一种工业上有用的水-不溶的或难溶的化合物，一种磷脂和至少一种非离子的，阴离子的或阳离子的表面活性剂，其中一种或多种表面活性剂提供的水不溶物质的容重平均颗粒大小数值在使用相同的能量输入时，要比无表面活性剂存在时产生的颗粒至少要小50％。
2.一种水-不溶性物质的微粒药物组合物，它包含有一种磷脂和至少一种非离子的，阴离子的或阳离子的表面活性剂，其中一种或多种表面活性剂提供的水不溶物质的容重平均颗粒大小数值在使用相同的能量输入时，要比无表面活性剂存在时产生的颗粒至少要小50％。
3.供口服，吸入，眼、鼻或注射给药的权利要求2的药物组合物。
4.权利要求3的药物组合物，用于静脉内、动脉内、肌肉内、表皮内、皮下、关节内、脑脊髓的、硬膜外的、肋内、腹膜内、肿瘤内、膀胱内、损伤部内或结膜下给药的注射剂型。
5.可以在水性或非-水性介质中重新悬浮的权利要求4的组合物的干燥混悬剂。
6.权利要求2的组合物的混悬剂，喷雾干燥粉剂，冻干粉剂，颗粒剂或片剂。
7.权利要求1的组合物，其中水-不溶性化合物为一种生物学有用的化合物或一种造影剂。
8.权利要求1或权利要求2的组合物，其中表面活性剂为聚氧乙烯脱水甘露糖醇脂肪酸酯，环氧乙烷和环氧丙烷的嵌段共聚物，由顺序加入环氧乙烷和环氧丙烷至乙二胺衍生的四官能嵌段共聚物，烷基芳基聚醚磺酸酯，聚乙二醇，羟丙基甲基纤维素，十二烷基硫酸钠，去氧胆酸钠，溴化鲸腊基三甲基铵或它们的组合物。
9.权利要求1或2的方法，其中磷脂为卵的或植物源或半合成的或部分合成的或全氢化的形式或去盐或盐的形式，如磷脂酰胆碱，Phospholipon 90H或二豆蔻酰基磷脂酰甘油钠盐，磷脂酰乙醇胺，磷脂酰丝氨酸，磷脂酸，溶血磷脂或它们的组合。
10.应用天然的或合成的磷脂制备水-不溶的或难溶的工业上有用的化合物的亚微米和微粒大小的、稳定的颗粒的方法，该方法包括用下述方法来减小颗粒大小，超声，均化，研磨，微观流体化和沉淀，或用抗溶剂重结晶和沉淀化合物和包括在磷脂和至少一种非离子的、阴离子的或阳离子表面活性剂存在下从临界液体的溶剂沉淀。
11.制备水-不溶的或难溶的化合物的微粒的方法，它包括如下步骤：
(1)将水-不溶的或难溶的工业上有用的化合物与磷脂和至少一种非离子的、阴离子的或阳离子的表面活性剂混合成粒，然后
(2)对该混合物施加能量足以产生化合物的容重平均颗粒大小值与在相同的能量输入下不存在表面活性剂时产生的颗粒相比至少要小50％。
12.权利要求10或11的方法，其中磷脂为卵的或植物源或半合成的或部分合成的或部全氢化的形式或去盐或盐的形式，如磷脂酰胆碱，Phospholipon 90H或二豆蔻酰基磷脂酰甘油钠盐，磷脂酰乙醇胺，磷脂酰丝氨酸，磷脂酸，溶血磷脂或它们的组合。
13.权利要求10或11的方法，其中表面活性剂为聚氧乙烯脱水甘露糖醇脂肪酸酯，环氧乙烷和环氧丙烷的嵌段共聚物，由顺序加入环氧乙烷和环氧丙烷至乙二胺衍生的四官能嵌段共聚物，烷基芳基聚醚磺酸酯，聚乙二醇，羟丙基甲基纤维素，十二烷基硫酸钠，去氧胆酸钠，溴化鲸腊基三甲基铵或它们的组合物。
14.权利要求10或11的方法，其中表面活性剂是以高于临界胶束浓度存在。
15.权利要求10或11的方法，其中化合物为生物学有用的化合物或造影剂。
16.一种组合物，它包含有应用权利要求10的方法制备的微粒。
17.一种组合物，它包含有应用权利要求11的方法制备的微粒。
CNB971973652A 1996-08-22 1997-03-28 含有水不溶性物质微粒的组合物及其制备法 Expired - Fee Related CN1303985C (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101959896A (zh) * 2008-03-04 2011-01-26 大不列颠药品有限公司 结晶磷脂、生产其的方法及其在治疗受损组织中的应用
CN105612284A (zh) * 2013-11-07 2016-05-25 尤妮佳股份有限公司 吸收性物品用复合化材料及其制造方法
CN107875436A (zh) * 2017-11-10 2018-04-06 华威（深圳）医疗器械有限责任公司 一种负载小苏打粉末的液体栓塞剂的组合物及其用途
CN108348468A (zh) * 2015-08-11 2018-07-31 Eyesiu医疗股份有限公司 具有生物活性亲脂性化合物的聚乙二醇化脂质纳米粒
CN109091451A (zh) * 2018-09-10 2018-12-28 武汉百纳礼康生物制药有限公司 亲水性药物的油相液晶凝胶前体制剂及其制备方法

Families Citing this family (163)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996025918A1 (en) * 1995-02-24 1996-08-29 Nanosystems L.L.C. Aerosols containing nanoparticle dispersions
US6143211A (en) * 1995-07-21 2000-11-07 Brown University Foundation Process for preparing microparticles through phase inversion phenomena
CA2234957C (en) * 1995-10-17 2006-12-19 Inge B. Henriksen Insoluble drug delivery
US5858401A (en) 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
US6465016B2 (en) * 1996-08-22 2002-10-15 Research Triangle Pharmaceuticals Cyclosporiine particles
US7255877B2 (en) * 1996-08-22 2007-08-14 Jagotec Ag Fenofibrate microparticles
US20060165606A1 (en) 1997-09-29 2006-07-27 Nektar Therapeutics Pulmonary delivery particles comprising water insoluble or crystalline active agents
US6337092B1 (en) 1998-03-30 2002-01-08 Rtp Pharma Inc. Composition and method of preparing microparticles of water-insoluble substances
ES2257041T3 (es) * 1998-03-30 2006-07-16 Jagotec Ag Composicion y metodo para preparar microparticulas de substancias insolubles en agua.
DE69914742T2 (de) 1998-05-29 2004-11-25 Skyepharma Canada Inc., Verdun Gegen hitzeeinwirkung geschützte mikropartikel und verfahren zur terminalen dampfsterilisation derselben
CA2335472C (en) 1998-06-19 2008-10-28 Rtp Pharma Inc. Processes to generate submicron particles of water-insoluble compounds
US6551613B1 (en) * 1998-09-08 2003-04-22 Alza Corporation Dosage form comprising therapeutic formulation
US20040013613A1 (en) * 2001-05-18 2004-01-22 Jain Rajeev A Rapidly disintegrating solid oral dosage form
US8236352B2 (en) * 1998-10-01 2012-08-07 Alkermes Pharma Ireland Limited Glipizide compositions
WO2000018374A1 (en) * 1998-10-01 2000-04-06 Elan Pharma International, Ltd. Controlled release nanoparticulate compositions
US20090297602A1 (en) * 1998-11-02 2009-12-03 Devane John G Modified Release Loxoprofen Compositions
US7521068B2 (en) * 1998-11-12 2009-04-21 Elan Pharma International Ltd. Dry powder aerosols of nanoparticulate drugs
US6428814B1 (en) * 1999-10-08 2002-08-06 Elan Pharma International Ltd. Bioadhesive nanoparticulate compositions having cationic surface stabilizers
US6969529B2 (en) 2000-09-21 2005-11-29 Elan Pharma International Ltd. Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers
ID29270A (id) 1998-11-20 2001-08-16 Rtp Pharma Inc Partikel-partikel mikro yang distabilkan oleh fosfolipid yang dapat menyebar
AU767737B2 (en) * 1998-11-20 2003-11-20 Skyepharma Canada Inc. Method of preparing stable suspensions of insoluble microparticles
US6251886B1 (en) 1998-12-07 2001-06-26 Schering Corporation Methods of using temozolomide in the treatment of cancers
ATE272391T1 (de) 1998-12-23 2004-08-15 Idea Ag Verbesserte formulierung zur topischen, nichtinvasiven anwendung in vivo
US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US20030236236A1 (en) * 1999-06-30 2003-12-25 Feng-Jing Chen Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
DE19932157A1 (de) * 1999-07-13 2001-01-18 Pharmasol Gmbh Verfahren zur schonenden Herstellung von hochfeinen Mikropartikeln und Nanopartikeln
US6656504B1 (en) 1999-09-09 2003-12-02 Elan Pharma International Ltd. Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions
CN1174741C (zh) * 1999-09-21 2004-11-10 Rtp药品公司 生物活性物质的表面改性微粒组合物
US7732404B2 (en) * 1999-12-30 2010-06-08 Dexcel Ltd Pro-nanodispersion for the delivery of cyclosporin
US6682761B2 (en) 2000-04-20 2004-01-27 Rtp Pharma, Inc. Water-insoluble drug particle process
AU5967101A (en) 2000-05-10 2001-11-20 Rtp Pharma Inc Media milling
US7871598B1 (en) 2000-05-10 2011-01-18 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
AU8847101A (en) 2000-08-31 2002-03-13 Rtp Pharma Inc Milled particles
ES2372746T3 (es) * 2000-09-20 2012-01-26 Jagotec Ag Micropartículas de fibrato estabilizadas.
US8586094B2 (en) 2000-09-20 2013-11-19 Jagotec Ag Coated tablets
AU6294501A (en) * 2000-09-20 2002-04-02 Rtp Pharma Inc Spray drying process and compositions of fenofibrate
US7998507B2 (en) 2000-09-21 2011-08-16 Elan Pharma International Ltd. Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors
US7198795B2 (en) 2000-09-21 2007-04-03 Elan Pharma International Ltd. In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions
AU2001297844A1 (en) * 2000-11-20 2002-12-03 Elan Pharma International Ltd. Nanoparticulate compositions comprising a drug and copolymers of vinyl pyrrolidone and vimyl acetate as surface stabilizers
EP1216713A1 (en) * 2000-12-20 2002-06-26 Schering Aktiengesellschaft Compositions of estrogen-cyclodextrin complexes
US7193084B2 (en) * 2000-12-22 2007-03-20 Baxter International Inc. Polymorphic form of itraconazole
US20050048126A1 (en) * 2000-12-22 2005-03-03 Barrett Rabinow Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug
US6977085B2 (en) * 2000-12-22 2005-12-20 Baxter International Inc. Method for preparing submicron suspensions with polymorph control
US6884436B2 (en) 2000-12-22 2005-04-26 Baxter International Inc. Method for preparing submicron particle suspensions
US20040256749A1 (en) * 2000-12-22 2004-12-23 Mahesh Chaubal Process for production of essentially solvent-free small particles
US20030096013A1 (en) * 2000-12-22 2003-05-22 Jane Werling Preparation of submicron sized particles with polymorph control
US6951656B2 (en) * 2000-12-22 2005-10-04 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US7037528B2 (en) * 2000-12-22 2006-05-02 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US9700866B2 (en) 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
CN1273112C (zh) * 2001-02-22 2006-09-06 斯凯伊药品加拿大公司 具有减少进食－禁食作用的贝特－它汀组合
US6984395B2 (en) * 2001-04-11 2006-01-10 Qlt, Inc. Drug delivery system for hydrophobic drugs
CN1522140A (zh) * 2001-05-18 2004-08-18 兰贝克赛实验室有限公司 奥卡西平剂型
GB0208742D0 (en) 2002-04-17 2002-05-29 Bradford Particle Design Ltd Particulate materials
JP2004537401A (ja) * 2001-08-08 2004-12-16 ブラウン ユニバーシティ リサーチ ファウンデーション 疎水性薬物の微粉砕方法
US20030054042A1 (en) * 2001-09-14 2003-03-20 Elaine Liversidge Stabilization of chemical compounds using nanoparticulate formulations
US20060003012A9 (en) 2001-09-26 2006-01-05 Sean Brynjelsen Preparation of submicron solid particle suspensions by sonication of multiphase systems
CA2461349C (en) 2001-09-26 2011-11-29 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal
US6878693B2 (en) * 2001-09-28 2005-04-12 Solubest Ltd. Hydrophilic complexes of lipophilic materials and an apparatus and method for their production
US20050233003A1 (en) * 2001-09-28 2005-10-20 Solubest Ltd. Hydrophilic dispersions of nanoparticles of inclusion complexes of salicylic acid
US20050227911A1 (en) * 2001-09-28 2005-10-13 Solubest Ltd. Hydrophilic dispersions of nanoparticles of inclusion complexes of macromolecules
US8663687B2 (en) * 2001-10-12 2014-03-04 Monosol Rx, Llc Film compositions for delivery of actives
US7112340B2 (en) * 2001-10-19 2006-09-26 Baxter International Inc. Compositions of and method for preparing stable particles in a frozen aqueous matrix
IL161156A0 (en) 2001-10-30 2004-08-31 Novartis Ag Staurosporine derivatives as inhibitors of flt3 receptor tyrosine kinase activity
ATE390121T1 (de) * 2001-11-02 2008-04-15 Univ Alberta Micelle-zusammensetzungen enthaltend pegylierten phospholipide und einen photosensibilisator
US7700851B2 (en) * 2001-11-13 2010-04-20 U.S. Smokeless Tobacco Company Tobacco nicotine demethylase genomic clone and uses thereof
GB0127832D0 (en) * 2001-11-20 2002-01-09 Jagotec Ag Method for the preparation of pharmaceutical nanosuspensions
JP2005514393A (ja) 2001-12-19 2005-05-19 ネクター セラピューティクス アミノグリコシドの肺への供給
US20030129242A1 (en) * 2002-01-04 2003-07-10 Bosch H. William Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer
CA2475092C (en) 2002-02-04 2012-05-01 Christian F. Wertz Nanoparticulate compositions having lysozyme as a surface stabilizer
US20060280761A1 (en) * 2002-03-11 2006-12-14 Health Plus International, Inc. Nanofluidized B-12 composition and process for treating pernicious anemia
US6861066B2 (en) * 2002-03-11 2005-03-01 Health Plus International Inc. Method for the delivery of a biologically active agent
CA2479665C (en) * 2002-03-20 2011-08-30 Elan Pharma International Ltd. Nanoparticulate compositions of angiogenesis inhibitors
US20080220075A1 (en) * 2002-03-20 2008-09-11 Elan Pharma International Ltd. Nanoparticulate compositions of angiogenesis inhibitors
WO2003088951A1 (en) * 2002-04-15 2003-10-30 Eiffel Technologies Limited Formulation of fine particles using liquefied or dense gases
US7582284B2 (en) * 2002-04-17 2009-09-01 Nektar Therapeutics Particulate materials
AU2003241477A1 (en) * 2002-06-10 2003-12-22 Elan Pharma International, Ltd. Nanoparticulate polycosanol formulations and novel polycosanol combinations
US6998051B2 (en) * 2002-07-03 2006-02-14 Ferro Corporation Particles from supercritical fluid extraction of emulsion
US20040258757A1 (en) * 2002-07-16 2004-12-23 Elan Pharma International, Ltd. Liquid dosage compositions of stable nanoparticulate active agents
AU2003266884A1 (en) * 2002-09-16 2004-04-30 Vasogen Ireland Limited Accelerating recovery from trauma
WO2004032980A1 (en) * 2002-10-04 2004-04-22 Elan Pharma International Limited Gamma irradiation of solid nanoparticulate active agents
US6966990B2 (en) 2002-10-11 2005-11-22 Ferro Corporation Composite particles and method for preparing
CN1243538C (zh) * 2002-11-21 2006-03-01 武汉利元亨药物技术有限公司 熊果酸豆磷脂纳米粒冻干粉针及制备方法
EP1581004B1 (en) * 2002-11-29 2014-10-29 Sony Corporation Encoder and its method
EP1576953A4 (en) * 2002-12-06 2008-08-06 Otsuka Pharma Co Ltd FATTY EMULSIONS CONTAINING PROPOFOL
GB0302673D0 (en) 2003-02-06 2003-03-12 Astrazeneca Ab Pharmaceutical formulations
US7083748B2 (en) * 2003-02-07 2006-08-01 Ferro Corporation Method and apparatus for continuous particle production using supercritical fluid
US6931888B2 (en) 2003-02-07 2005-08-23 Ferro Corporation Lyophilization method and apparatus for producing particles
JP2004323444A (ja) * 2003-04-25 2004-11-18 Hamamatsu Kagaku Gijutsu Kenkyu Shinkokai 凍結乾燥微粒子製剤およびその製法
US20060008531A1 (en) * 2003-05-08 2006-01-12 Ferro Corporation Method for producing solid-lipid composite drug particles
JP2007501683A (ja) * 2003-05-22 2007-02-01 エラン ファーマ インターナショナル リミテッド γ線照射によるナノ粒子活性物質分散体の滅菌法
GB0319797D0 (en) * 2003-08-26 2003-09-24 Leuven K U Res & Dev Particle size reduction of poorly soluble drugs
WO2005070393A2 (en) * 2004-01-08 2005-08-04 Wyeth Directly compressible pharmaceutical composition of the rapamycin ester cci-779
NZ548195A (en) * 2004-01-14 2011-01-28 Gilead Sciences Inc Lipid-based dispersions useful for drug delivery
US20050170063A1 (en) * 2004-01-29 2005-08-04 Lalit Chordia Production of powder and viscous material
EP1711163A2 (en) * 2004-02-05 2006-10-18 Baxter International Inc. Dispersions prepared by use of self-stabilizing agents
EP1750677B1 (en) * 2004-05-28 2017-02-01 Imaginot Pty Ltd. Oral therapeutic compound delivery system
US8216610B2 (en) * 2004-05-28 2012-07-10 Imaginot Pty Ltd. Oral paracetamol formulations
WO2006026592A2 (en) * 2004-08-27 2006-03-09 Spherics, Inc. Oral administration of poorly absorbed drugs, methods and compositions related thereto
WO2006026504A2 (en) * 2004-08-27 2006-03-09 Spherics, Inc. Mucoadhesive oral formulations of high permeability, high solubility drugs
WO2006034147A2 (en) * 2004-09-16 2006-03-30 Abraxis Bioscience, Inc. Compositions and methods for the preparation and administration of poorly water soluble drugs
MX2007009812A (es) * 2005-02-15 2007-10-23 Wyeth Corp Formulaciones en tableta de 42-ester de rapamicina con acido 3-hidroxi-2-(hidroximetil)-2-metilpropionico oralmente biodisponibles.
US9248101B2 (en) * 2005-04-13 2016-02-02 Abbvie Deutschland Gmbh & Co Kg Method for the gentle production of ultrafine particle suspensions and ultrafine particles and the use thereof
BRPI0612071A2 (pt) * 2005-06-14 2010-10-19 Baxter Int formulações farmacêuticas para minimizar interações entre fármacos
US20060280787A1 (en) * 2005-06-14 2006-12-14 Baxter International Inc. Pharmaceutical formulation of the tubulin inhibitor indibulin for oral administration with improved pharmacokinetic properties, and process for the manufacture thereof
CA2628630A1 (en) * 2005-11-15 2007-05-24 Baxter International Inc. Compositions of lipoxygenase inhibitors
EP1954298A4 (en) 2005-11-28 2012-10-31 Imaginot Pty Ltd DISPENSING SYSTEM FOR ORAL THERAPEUTIC CONNECTION
US7703698B2 (en) * 2006-09-08 2010-04-27 Kimberly-Clark Worldwide, Inc. Ultrasonic liquid treatment chamber and continuous flow mixing system
US7810743B2 (en) 2006-01-23 2010-10-12 Kimberly-Clark Worldwide, Inc. Ultrasonic liquid delivery device
KR100919731B1 (ko) * 2006-05-11 2009-09-29 재단법인서울대학교산학협력재단 안정제로서 폴리에테르를 함유한 백신전달용 키토산미립자
US8034286B2 (en) * 2006-09-08 2011-10-11 Kimberly-Clark Worldwide, Inc. Ultrasonic treatment system for separating compounds from aqueous effluent
US9283188B2 (en) * 2006-09-08 2016-03-15 Kimberly-Clark Worldwide, Inc. Delivery systems for delivering functional compounds to substrates and processes of using the same
US20100068251A1 (en) * 2006-10-10 2010-03-18 Jina Pharmaceuticals, Inc. Aqueous Systems For The Preparation Of Lipid Based Pharmaceutical Compounds; Compositions, Methods, And Uses Thereof
US20090152176A1 (en) * 2006-12-23 2009-06-18 Baxter International Inc. Magnetic separation of fine particles from compositions
US7712353B2 (en) 2006-12-28 2010-05-11 Kimberly-Clark Worldwide, Inc. Ultrasonic liquid treatment system
US7673516B2 (en) * 2006-12-28 2010-03-09 Kimberly-Clark Worldwide, Inc. Ultrasonic liquid treatment system
KR20090129998A (ko) 2007-02-11 2009-12-17 맵 파마슈티컬스, 인코포레이티드 부작용 프로파일을 최소화하면서 편두통의 빠른 완화를 가능하게 하는 ｄｈｅ의 치료적 투여 방법
KR101434706B1 (ko) 2007-02-16 2014-08-26 아스카 세이야쿠 가부시키가이샤 미립자 유성 현탁액을 포함하는 의약 조성물
US8722736B2 (en) 2007-05-22 2014-05-13 Baxter International Inc. Multi-dose concentrate esmolol with benzyl alcohol
US20080293814A1 (en) * 2007-05-22 2008-11-27 Deepak Tiwari Concentrate esmolol
US8426467B2 (en) 2007-05-22 2013-04-23 Baxter International Inc. Colored esmolol concentrate
US7947184B2 (en) * 2007-07-12 2011-05-24 Kimberly-Clark Worldwide, Inc. Treatment chamber for separating compounds from aqueous effluent
US7998322B2 (en) * 2007-07-12 2011-08-16 Kimberly-Clark Worldwide, Inc. Ultrasonic treatment chamber having electrode properties
US7785674B2 (en) * 2007-07-12 2010-08-31 Kimberly-Clark Worldwide, Inc. Delivery systems for delivering functional compounds to substrates and processes of using the same
US8858892B2 (en) 2007-12-21 2014-10-14 Kimberly-Clark Worldwide, Inc. Liquid treatment system
US8454889B2 (en) 2007-12-21 2013-06-04 Kimberly-Clark Worldwide, Inc. Gas treatment system
US8632613B2 (en) 2007-12-27 2014-01-21 Kimberly-Clark Worldwide, Inc. Process for applying one or more treatment agents to a textile web
US8206024B2 (en) 2007-12-28 2012-06-26 Kimberly-Clark Worldwide, Inc. Ultrasonic treatment chamber for particle dispersion into formulations
US8057573B2 (en) 2007-12-28 2011-11-15 Kimberly-Clark Worldwide, Inc. Ultrasonic treatment chamber for increasing the shelf life of formulations
US8215822B2 (en) * 2007-12-28 2012-07-10 Kimberly-Clark Worldwide, Inc. Ultrasonic treatment chamber for preparing antimicrobial formulations
US9421504B2 (en) 2007-12-28 2016-08-23 Kimberly-Clark Worldwide, Inc. Ultrasonic treatment chamber for preparing emulsions
US20090166177A1 (en) 2007-12-28 2009-07-02 Kimberly-Clark Worldwide, Inc. Ultrasonic treatment chamber for preparing emulsions
US20090311335A1 (en) * 2008-06-12 2009-12-17 Scott Jenkins Combination of a triptan and an nsaid
GB0818403D0 (en) * 2008-10-08 2008-11-12 Univ Leuven Kath Aqueous electrophoretic deposition
WO2010040648A2 (en) * 2008-10-06 2010-04-15 Katholieke Universiteit Leuven, K.U.Leuven R&D Functional layers of biomolecules and living cells, and a novel system to produce such
US8163388B2 (en) 2008-12-15 2012-04-24 Kimberly-Clark Worldwide, Inc. Compositions comprising metal-modified silica nanoparticles
US8685178B2 (en) 2008-12-15 2014-04-01 Kimberly-Clark Worldwide, Inc. Methods of preparing metal-modified silica nanoparticles
US11304960B2 (en) 2009-01-08 2022-04-19 Chandrashekar Giliyar Steroidal compositions
EP2266546A1 (en) 2009-06-08 2010-12-29 Advancell Advanced in Vitro Cell Technologies,S.A. Process for the preparation of colloidal systems for the delivery of active compounds
IT1398857B1 (it) 2009-06-10 2013-03-21 Univ Padova Coniugati polimerici fosfolipidi
FR2949063B1 (fr) * 2009-08-11 2011-09-30 Pf Medicament Composition pharmaceutique comprenant un ester de dha destinee a etre administree par voie parenterale
CA2780292A1 (en) * 2009-11-10 2011-05-19 Celgene Corporation Nanosus pens ion of a poorly soluble drug made by microfluidization process
NZ601109A (en) * 2009-12-10 2014-06-27 Merck Patent Gmbh Pharmaceutical composition comprising oligopeptides, preferably cilengitide
EP2559347B1 (en) * 2010-04-16 2014-11-12 San-Ei Gen F.F.I., INC. Method for masking flavor of curcumin
CA2816119C (en) 2010-10-29 2019-03-05 Western University Of Health Sciences Ternary mixture formulations
US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9034858B2 (en) 2010-11-30 2015-05-19 Lipocine Inc. High-strength testosterone undecanoate compositions
US20180153904A1 (en) 2010-11-30 2018-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US20120148675A1 (en) 2010-12-10 2012-06-14 Basawaraj Chickmath Testosterone undecanoate compositions
RU2757859C2 (ru) 2011-03-18 2021-10-21 Алкермес Фарма Айэленд Лимитед Фармацевтические композиции, содержащие водонерастворимое антипсихотическое средство и сложные эфиры сорбитана
JP2014532655A (ja) 2011-10-31 2014-12-08 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． ナノ懸濁過程
US9993556B2 (en) 2012-03-19 2018-06-12 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising fatty glycerol esters
WO2013142205A1 (en) 2012-03-19 2013-09-26 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising benzyl alcohol
US10004807B2 (en) 2012-03-19 2018-06-26 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising fatty acid esters
US9193685B2 (en) 2012-09-19 2015-11-24 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
EP3119399A4 (en) 2014-03-20 2017-09-27 Alkermes Pharma Ireland Limited Aripiprazole formulations having increased injection speeds
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
WO2016033549A2 (en) 2014-08-28 2016-03-03 Lipocine Inc. (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE
TW201613888A (en) * 2014-09-26 2016-04-16 Helsinn Healthcare Sa Crystalline forms of an NK-1 antagonist
US20170320862A1 (en) * 2016-05-03 2017-11-09 Cadila Healthcare Limited Process for the preparation of brexpiprazole and intermediates thereof
JP2020503269A (ja) 2016-11-28 2020-01-30 リポカイン インコーポレーテッド 経口ウンデカン酸テストステロン療法
WO2019173230A1 (en) 2018-03-05 2019-09-12 Alkermes Pharma Ireland Limited Aripiprazole dosing strategy
EP4056038A1 (en) * 2021-03-10 2022-09-14 Basf Se Microparticles containing active substances

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56152739A (en) * 1980-04-25 1981-11-26 Tanabe Seiyaku Co Ltd Production of microcapsule
US4725442A (en) 1983-06-17 1988-02-16 Haynes Duncan H Microdroplets of water-insoluble drugs and injectable formulations containing same
US4963367A (en) * 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
DE3421468A1 (de) 1984-06-08 1985-12-19 Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim Lipidnanopellets als traegersystem fuer arzneimittel zur peroralen anwendung
FR2617047B1 (fr) 1987-06-23 1991-05-10 Sanofi Sa Composition de gelatine resistant au tannage, capsules a base de cette composition et leur application pharmaceutique, notamment au fenofibrate
ES2033086T3 (es) 1988-01-29 1993-03-01 Sankyo Company Limited Un procedimiento para la preparacion de una composicion farmaceutica.
FR2627696B1 (fr) 1988-02-26 1991-09-13 Fournier Innovation Synergie Nouvelle forme galenique du fenofibrate
CA2013755C (en) * 1989-04-05 1993-11-30 Simon Benita Medicinal emulsions
US5389377A (en) * 1989-12-22 1995-02-14 Molecular Bioquest, Inc. Solid care therapeutic compositions and methods for making same
US5091187A (en) * 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5091188A (en) 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
DE59310166D1 (de) 1992-05-18 2001-05-31 Ciclomulsion Ag Cyclosporin(e) enthaltende pharmazeutische Zubereitung zur intravenösen Applikation sowie Verfahren zu ihrer Herstellung
US5336507A (en) * 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5326552A (en) * 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
CA2091152C (en) * 1993-03-05 2005-05-03 Kirsten Westesen Solid lipid particles, particles of bioactive agents and methods for the manfuacture and use thereof
US5576016A (en) * 1993-05-18 1996-11-19 Pharmos Corporation Solid fat nanoemulsions as drug delivery vehicles
US5639474A (en) 1993-07-01 1997-06-17 Hanmi Pharm. Ind., Ltd. Cyclosporin soft capsule composition
US5364633A (en) * 1994-03-14 1994-11-15 Dow Corning Corporation Silicone vesicles and entrapment
US5603951A (en) 1994-11-09 1997-02-18 Hanmi Pharm. Ind. Co., Ltd. Cyclosporin-containing soft capsule compositions
KR0167613B1 (ko) 1994-12-28 1999-01-15 한스 루돌프 하우스, 니콜 케르커 사이클로스포린-함유 연질캅셀제 조성물
US5545628A (en) 1995-01-10 1996-08-13 Galephar P.R. Inc. Pharmaceutical composition containing fenofibrate
FR2730231B1 (fr) 1995-02-02 1997-04-04 Fournier Sca Lab Association de fenofibrate et de vitamine e, utilisation en therapeutique
FR2737121B1 (fr) 1995-07-27 1997-10-03 Cl Pharma Nouvelles formulations galeniques du fenofibrate et leurs applications
CA2234957C (en) * 1995-10-17 2006-12-19 Inge B. Henriksen Insoluble drug delivery

Cited By (6)

* Cited by examiner, † Cited by third party
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CN101959896A (zh) * 2008-03-04 2011-01-26 大不列颠药品有限公司 结晶磷脂、生产其的方法及其在治疗受损组织中的应用
CN105612284A (zh) * 2013-11-07 2016-05-25 尤妮佳股份有限公司 吸收性物品用复合化材料及其制造方法
CN108348468A (zh) * 2015-08-11 2018-07-31 Eyesiu医疗股份有限公司 具有生物活性亲脂性化合物的聚乙二醇化脂质纳米粒
CN107875436A (zh) * 2017-11-10 2018-04-06 华威（深圳）医疗器械有限责任公司 一种负载小苏打粉末的液体栓塞剂的组合物及其用途
CN109091451A (zh) * 2018-09-10 2018-12-28 武汉百纳礼康生物制药有限公司 亲水性药物的油相液晶凝胶前体制剂及其制备方法
CN109091451B (zh) * 2018-09-10 2021-08-13 武汉百纳礼康生物制药有限公司 亲水性药物的油相液晶凝胶前体制剂及其制备方法

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NO325197B1 (no) 2008-02-18
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US5922355A (en) 1999-07-13
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CN1303985C (zh) 2007-03-14
HUP9903537A2 (hu) 2000-02-28
CA2263102A1 (en) 1998-02-26
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