CN1303985C - 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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CN1303985C
CN1303985C CNB971973652A CN97197365A CN1303985C CN 1303985 C CN1303985 C CN 1303985C CN B971973652 A CNB971973652 A CN B971973652A CN 97197365 A CN97197365 A CN 97197365A CN 1303985 C CN1303985 C CN 1303985C
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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，十六醇十八醇混合物，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，氯化苄烷基钠，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PluronicTMF68、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TetronicTM908(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；CarbowaxTM3550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 BH 2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4℃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 (12)

1.一种减小微颗粒的颗粒大小的方法，所述微颗粒包含水不溶性或难溶化合物，它具有能吸附或粘附磷脂和至少一种表面活性剂的表面，所述化合物在生理pH 6.5-7.4下的水溶性低于5mg/ml，所述方法包括以下步骤：
(a)将水不溶性或难溶化合物的颗粒，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的组合混合，形成混合物，所述混合物中磷脂和表面活性剂以有效减小颗粒大小的量存在；
(b)减小步骤(a)的混合物的颗粒大小，其方法包括以下方法中的一种或几种：超声、均化、研磨、微观流体化和沉淀、从超临界流体重结晶、或从超临界流体沉淀；以及
(c)所产生的化合物微颗粒的容重平均颗粒大小数值，比在(i)无步骤(a)中的表面活性剂，并且(ii)使用与步骤(b)相同的减小颗粒大小的方法的情况下，减小50％至90％。
2.权利要求1的方法，其中磷脂为卵源的或植物源的，或半合成的或合成的，或部分氢化或全部氢化形式的，或盐形式或去盐形式的，或它们的组合。
3.权利要求1的方法，其中磷脂选自磷脂酰胆碱、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。
4.权利要求1的方法，其中表面活性剂为聚氧乙烯脱水山梨糖醇脂肪酸酯、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。
5.权利要求1的方法，其中表面活性剂是酪蛋白、明胶、黄蓍胶、腊、肠溶树脂、石蜡、阿拉伯树胶、胆甾醇酯、三甘油酯、聚氧乙烯脂肪醇醚、脱水山梨糖醇脂肪酸酯、聚氧乙烯脂肪酸酯、脱水山梨糖醇酯、甘油单硬脂酸酯、聚乙二醇、鲸腊醇、十六醇十八醇混合物、硬脂醇、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、合成的磷脂、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、磷脂酰甘油、磷脂酰肌醇、磷脂酰丝氨酸、磷脂酸或其盐、带负电荷的甘油酯、羧甲基纤维素钠、羧甲基纤维素钙、季铵化合物、氯化苯甲烃铵、溴化鲸腊基二甲基铵、脱乙酰壳多糖、氯化月桂基二甲基苄基铵或胶体粘土。
6.权利要求1的方法，其中水不溶性或难溶化合物是药物。
7.权利要求1的方法，其中水不溶性或难溶化合物是环孢菌素。
8.权利要求6的方法，其中药物选自免疫抑制剂、免疫活化剂、抗病毒剂、抗真菌剂、抗肿瘤剂、镇痛剂、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、抗胆碱能剂、拟胆碱能剂、抗蕈毒碱剂、蕈毒碱剂、抗肾上腺能剂、抗心律不齐剂、抗高血压剂、激素、营养剂，以及它们的组合。
9.权利要求1的方法，其中水不溶性或难溶化合物是造影剂。
10.权利要求1的方法，其中水不溶性或难溶化合物是抗真菌剂。
11.权利要求1的方法，其中表面活性剂的浓度为0.1至50％，高于临界胶束浓度。
12.包含微颗粒的组合物，所述微颗粒包含水不溶性或难溶化合物，它具有吸附或粘附磷脂和至少一种表面活性剂的表面，所述化合物在生理pH 6.5-7.4下的水溶性低于5mg/ml，所述微颗粒由权利要求1的方法产生，与通过未用表面活性剂的相同的减小颗粒大小的方法产生的化合物颗粒的大小相比，容重平均颗粒大小减少50％至90％。
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US6228399B1 (en) 2001-05-08
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HUP9903537A2 (hu) 2000-02-28
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US5922355A (en) 1999-07-13
CZ59699A3 (cs) 1999-06-16
DE69734988T2 (de) 2006-09-21
CA2263102C (en) 2006-08-15
NO990790D0 (no) 1999-02-19
RO120603B1 (ro) 2006-05-30
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CN1228021A (zh) 1999-09-08
NO990790L (no) 1999-04-19
PL192560B1 (pl) 2006-11-30
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AU2587197A (en) 1998-03-06
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ATE314055T1 (de) 2006-01-15
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