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CN1313758A - 普鲁泊福的可注射水分散体 - Google Patents

普鲁泊福的可注射水分散体 Download PDF

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CN1313758A
CN1313758A CN99809799A CN99809799A CN1313758A CN 1313758 A CN1313758 A CN 1313758A CN 99809799 A CN99809799 A CN 99809799A CN 99809799 A CN99809799 A CN 99809799A CN 1313758 A CN1313758 A CN 1313758A
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A·K·米施拉
G·W·帕斯
M·G·瓦雄
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Abstract

本发明公开了一种非水溶性微滴基质的稳定、灭菌和可注射水分散体,该微滴基质的平均直径为约50nm至约1000nm,主要组成是约1%至约15%的普鲁泊福,约1%到约8%的普鲁泊福可溶稀释剂,约0.5%至约5%的表面稳定化两亲性试剂,可药用可溶于水多羟基添加剂作为张力改性剂,条件是普鲁泊福与稀释剂的比例是约1∶4至约1∶0.1和普鲁泊福与两亲性试剂的比例是约1∶0.8至约1∶2.5,并且该组合物的粘度约0.8至约15厘泊。

Description

普鲁泊福的可注射水分散体
本发明涉及具有低脂含量并且最终可蒸汽灭菌的普鲁泊福(2,6-二异丙基苯酚)(propofol)的组合物。这些制剂可以用作麻醉剂，微生物在其中生长的可能性极低或被消除。低脂质含量的这些制剂能够降低或不存在发生高脂血的危险性。此外，这些制剂在注射位点极小或不引起刺激。
                    背景技术
                    现有技术
普鲁泊福制剂业已作为麻醉剂应用。普鲁泊福的组合物及其临床应用已经公开在科学文献中。在一系列专利如美国专利4056635(1977)、美国专利4452817(1984)和美国专利4798846(1989)中，Glen和James描述了适合施用给温血动物以产生麻醉作用的含有普鲁泊福的组合物。
Glen和James在美国专利4056635和4452817中公开的组合物是普鲁泊福与表面活性剂Cremophor-RH40或Cremophor-EL或吐温-80在水介质中的混合物，它们可以含有乙醇或其他可药用组分。
在后续的美国专利4452817中，Glen和James描述了含有单独或溶于油(如花生油或油酸乙酯)(美国专利4798846)中的1％至2％普鲁泊福的普鲁泊福组合物。这些制剂可以用足够量的表面活性剂稳定，所述表面活性剂选自聚氧化乙烯月桂酸酯、硬脂酸酯或油酸酯，氧化乙烯与蓖麻油的缩合产物，聚氧化乙烯鲸蜡基、月桂基、硬脂基或油基醚，聚氧化乙烯脱水山梨糖醇单月桂酸酯、单棕榈酸酯、单硬脂酸酯或单油酸酯，聚氧化乙烯-聚氧化丙烯嵌段共聚物，卵磷脂和脱水山梨糖醇单油酸酯、单棕榈酸酯、单硬脂酸酯或单油酸酯。
基于上述专利，适合临床使用的普鲁泊福制剂(POR,1996)业已上市(Diprivan1％注射剂)，其中含有溶解在大豆油中的普鲁泊福并且用蛋黄卵磷脂稳定。每1毫升的这种制剂由10mg/mL普鲁泊福、100mg/mL大豆油、22.5mg/mL甘油、12mg/mL蛋黄卵磷脂、调节pH至7-8.5的氢氧化钠和足够量的水组成。虽然临床上可应用，但这种制剂在操作过程中需要严格的无菌技术，因为其不含有杀菌防腐剂并且伴随有微生物生长的可能性。事实上，许多在人体中发生的严重感染与使用市售普鲁泊福制剂Diprivan有关(Nichols等人(1995),Tessler等人(1992),Ardulno等人(1991),Sosis＆Braverman(1993),Sosis等人(1995),Crowther等人(1996))。
为了在静脉内给药过程中减少因操作普鲁泊福制剂所致感染的机会，Jones和Platt目前介绍了一种新的普鲁泊福制剂，其主要基于原有组合物并且加入抗微生物防腐剂的成分。这种产品公开在美国专利5714520、5731355和5731356中。加入在新制剂中的抗微生物防腐剂是乙二胺四乙酸二钠。美国专利号5714520中认为加入一定量的乙二胺四乙酸盐可限制细菌生长，使其增长不超过10倍，这是利用试验在至少24小时内通过测定金黄色葡萄球菌6538、大肠埃希氏杆菌ATCC 8739、绿铜假单胞菌ATCC 9027和白色假丝酵母ATCC 10231各自的生长来测量，其中在20-25℃内，将各种所述生物的洗涤混悬液以约50集落生成单位(CFU)/ML加入所述组合物的单独等份试样中，此后令该等份试样在20-25℃下温育并且在24小时后测试该生物的存活数量，所述乙二胺四乙酸盐的用量不超过该组合物重量的0.1％(重量)。
然而，尽管有作为抗微生物生长防腐剂存在的乙二胺四乙酸盐，一些作者如Sklar(1997)认为按照美国药典(USP)标准，美国专利5714520(Diprivan)所述的产品不是抗微生物防腐产品。虽然在数量上存在，乙二胺四乙酸盐可以有效抵抗该专利中提及的一些种类的生物的生长，但普鲁泊福给药无法如此有效抵抗多种流行于临床情况中的其他生物，例如专利5717520中所述的白色假丝酵母ATCC10231。事实上，在专利5714520中认为，配制的普鲁泊福对于白色假丝酵母10231无抗菌性，其中观测到经48小时后接种物浓度增高约10倍。这个结果显示，如果受到除上文提及微生物以外的其他生物挑战或荷载的生物高于100CFU/mL时，Diprivan中作为防腐剂抑制微生物生长的乙二胺四乙酸可能无效。事实上，在制剂中加入乙二胺四乙酸盐无法提供确凿的改进。就抗菌有效性而言，这种“改进”制剂劣于Haynes专利(美国专利5637625，参见下文)所述的发明。
基于专利US5714520、US5731355和US5731356的制剂仍然由高含量的大豆油(10％)组成，在一些患者中大豆油被认为可引起高脂血症。除了加入乙二胺四乙酸盐之外，这种制剂基本上与原有市售Diprivan制剂相同。实际中，通过目前的PDR,1999中给出的这些症状的发生率显示，副作用的发生率与早期产品相同。
市售普鲁泊福制剂在临床使用中的问题
许多作者评述了普鲁泊福制剂的临床应用。例如，Smith等人(1994)描述了普鲁泊福注射剂已被应用于产生和维持非卧床麻醉，神经外科和儿科麻醉，用于监测麻醉护理，用于增强护理镇静和其他临床情况。有报导称28-90％患者在注射市售普鲁泊福制剂后在出现疼痛，例如Mirakhur(1988)、Stark等人(1985)、Mangar和Holak(1992)。实际上普鲁泊福在低剂量镇静给药时，疼痛的发生率仍可达到33-50％(White＆Negus,1991；Ghouri等人1994)。普鲁泊福给药导致静脉疼痛的机理尚不清楚。早期普鲁泊福制剂中的原有赋形剂Cremophor EL在开始时被认为是致痛剂。然而，在将基于Cremophor EL的普鲁泊福制剂改换为市售基于大豆油和卵磷脂的制剂后并没有使疼痛有可观的减轻(例如参见：Mirakhur(1988),Stark等人(1985),Mangar＆Holak(1992),White＆Negus,1991；Ghouri等人(1994))。人们确信疼痛是由该药物本身的作用而不是制剂所致(Smith等人(1994))。
为了减小注射普鲁泊福镇静制剂时的疼痛倾向，Babl等人(1995)报导了应用1％和2％普鲁泊福制剂，该制剂含有存在于分散油相中的中链甘油三酯(MCT)和长链甘油三酯(LCT)的混合物。同样地，Doenicke等人(1996,1997)已经在人体志愿者中证明，在普鲁泊福制剂中应用MCT使注射所致的重度或中度疼痛的发生率(9％)比注射市售制剂后(59％)降低。这些作者将疼痛发生率的降低归因于通过提高制剂中油的浓度所获得的水相中游离普鲁泊福浓度降低。
虽然增加油的量可以有助于降低水中普鲁泊福的浓度并由此减小注射疼痛，但如这些作者使用了水平高达20％的油(Babl等人，1995,Doenicke等人，1996和1997)似乎进一步迫使特护病房中的患者需要长时间施用普鲁泊福，有可能导致高脂血症。
尽管注射疼痛或许和注射处的组织刺激或所给制剂的血栓形成有关，这些不良反应仍很流行，并且有关普鲁泊福在临床应用中的症状始终见诸报导。例如，在Diprivan的情况中，这些症状包括血栓形成和静脉炎，并且包括高达17.6％的灼烧/刺痛或疼痛发生率(PDR1999，第3416页)。
显然仍然需要临床可接受的普鲁泊福制剂，它们应克服三个在普通市售或现有试验制剂中最常见的缺点；也就是说：
·微生物的生长
·脂质含量过高，和
·注射位点的刺激和/或注射所致疼痛
Haynes等人(1995)在美国专利5637625中教导了其它能够克服某些上述与市售(Diprivan)或试验(例如Babl等人1995所述的那些，和Doenicke等人1996和1997)普鲁泊福注射产品有关的临床问题的普鲁泊福制剂。例如，Haynes确定两个与使用大量植物油有关的问题，这些植物油存在于由1％普鲁泊福和10％大豆油组成的市售制剂中：
(1)特护病房中接受长时间镇静的患者的高脂血，和
(2)高脂质含量和缺乏抗微生物防腐剂造成细菌污染的危险。
Haynes提出不含有脂肪和甘油三酯的磷脂涂层的普鲁泊福微滴制剂可在更长时间内提供麻醉和慢性镇静作用而不会脂肪过量。在Haynes的提议之前，没有公开过油性赋形剂少于10％(w/w)的含油普鲁泊福制剂。Haynes认为这些微滴制剂有杀菌作用(例如自体灭菌)，因为不含有支持细菌生长的物质，由此具有长效保藏期。
鉴于有关普鲁泊福的临床文献中所引证的观察，特别是上述那些观察，Haynes能够克服三个缺点中的两个，因此仍然需要一种例如在ICU中可快速浓注或输注给药的灭菌普鲁泊福制剂，并且特别具有下列所有特征：
·不含有大量的油或甘油三酯，从而减小患者患高脂血症的倾向，
·具有足够的杀菌或制菌性质，以便为患者提供更高的安全性并且在临床情况中使用保存期更长，和
·在注射位点很少引起或不引起组织刺激。
                    发明详述
                    发明概述
令人惊奇地发现，某些普鲁泊福组合物当被制成为由普鲁泊福和普鲁泊福可溶试剂组成的非水溶性基质的可注射水分散体时，能够基本上限制或抑制某些微生物的生长，并且在注射位点不产生刺激作用，如体内试验所示。
另一个意外的发现是，这种制剂抑制微生物生长的特性不需要加入任何抗微生物防腐剂。
另一个意外是，该普鲁泊福的水分散体可被制成在其水相中含有不同多羟基类化合物的最终可蒸气灭菌且稳定的产品。这些多羟基化合物普遍应用于静脉输注中。利用多羟基化合物制备的普鲁泊福可提供粘度较高的组合物。
另外认为由于降低了脂质含量，这些新的制剂在施用本发明IV制剂的人群中不易引起高脂血症。另外，已知LCT和MCT的混合物具有较快的代谢清除率，因此应用本发明的普鲁泊福制剂在临床上是适宜的(Cairns等人，1996；Sandstrom等人，1995)。所以，LCT和MCT的混合物是本发明的一个优选实施方案。
此外，本发明证实了配制含有如10％(w/w)普鲁泊福的高效普鲁泊福组合物的可行性。
                    组合物
本发明的新的组合物由分散在水相中的毫微米至微米的含有至多15％，或优选至多10％普鲁泊福的非水溶性基质组成，其中包括：
非水溶性基质，由麻醉剂普鲁泊福和调节抗菌活性水平和注射时局部反应程度的溶解亲脂性试剂组成。所述亲脂性试剂的实例包括但不限于一种或多种选自饱和或不饱和脂肪酸酯类化合物，如肉豆蔻酸异丙酯、胆甾醇油酸酯、油酸乙酯、角鲨烯、角鲨烷、α-生育酚和/或α-生育酚的衍生物、中链和/或长链合成或天然脂肪酸的酯或甘油三酯类化合物。天然甘油三酯可以特别选自植物或动物来源，例如可药用植物油或鱼油。后者还称作ω-3多不饱和油。亲脂性试剂也可以考虑可溶解普鲁泊福的试剂或稀释剂。
非水溶性基质的表面是稳定分散体并且可能严重影响注射时局部反应程度的两亲性试剂。所述两亲性试剂的实例包括：带电或不带电的天然磷脂，例如蛋黄或大豆卵磷脂；或氢化卵磷脂(例如Nattermann提供的Phospholipon-90H或Phospholipon-100H)；或合成磷脂，如磷脂酰胆碱类化合物或磷脂酰基甘油类化合物；可药用非离子表面活性剂，例如多羟基类化合物(poloxamer)(pluronic系列的表面活性剂)、聚羟胺类化合物(poloxamine)(tetronic系列的表面活性剂)、聚氧化乙烯脱水山梨糖醇酯类化合物(例如吐温系列的表面活性剂)；胆甾醇；或其它常用于药品中的表面改性剂；或这些表面改性剂的混合物。
水相，主要由可药用多羟基张力调节剂的混合物组成，例如那些常用于静脉输注的张力调节剂，如蔗糖、葡萄糖、海藻糖、甘露糖醇、乳糖、甘油等。优选多羟基化合物的用量足以使最终的组合物与血液等渗或适于静脉内注射。当选择这些多羟基化合物在制剂中的含量不与血液等渗的情况时，在注射之前可以用适当稀释剂稀释以调节张力。水相另外可含有一定量的pH调节剂，例如氢氧化钠和/或可药用酸和/或其有关盐。优选将pH调节为约9至约4，更优选约8至5。可采用可药用缓冲体系。
本发明的组合物任选地含有其它可药用试剂，例如其它抗微生物剂，局部或长效麻醉剂，螯合剂或抗氧剂。其实例包括但不限于对羟基苯甲酸酯类化合物亚硫酸盐或乙二胺四乙酸盐，利多卡因或偏硫酸氢盐。
更可取地，对本发明组合物进行选择以便在药物可接受条件下对末期灭菌稳定。
发现用多羟基化合物制备的普鲁泊福制剂提供具有较高粘度的组合物。这些制剂的粘度是约1.5至8厘泊并且更优选约4至6厘泊。虽然不受任何特定理论的制约，可以认为这种高粘度可以部分减小制剂的组织刺激作用。
                      方法
普鲁泊福是一种很难溶于水的液体。为了制备具有理想抗微生物性质、低脂质含量和低注射位点反应性并且在混合或保存过程中很少或不发生相分离的稳定可注射普鲁泊福制剂，发现不但必须选择适当的制剂组成，而且必须采用适当的加工条件。适用加工条件的实例是那些提供强机械搅拌或高剪切的加工条件，例如参见Haynes所述的方法(美国专利5637625)。制剂一般利用起始制备的亲脂相和水相来制备，随后将它们混合，所属技术领域普通技术人员应懂得其它方法也适用，并且能够很容易决定这些方法。例如，已证实下面段落中简述的单元过程是适用的。
                    预混制剂
将普鲁泊福、其它亲脂性试剂和两亲性试剂混合制得亲脂相。通过加热该混合物同时用高速匀浆器混合可以加快溶解过程。水相常常是存在于水中的多羟基化合物的混合物，并且在某些情况中还含有用高速匀浆器制备的分散充分的磷脂。在高速匀浆器搅拌和调节pH的条件下将亲脂相加入水相中制备预混物。所有这些操作是在通用惰性环境中进行，例如氮气保护，并且控制温度减少氧化。
                      均化
非水溶性基质在水介质中的分散体可以通过若干种均化方法制备。例如，通过高压均化预混物制备分散体，例如利用RannieMINI-LAB,8.30H型匀浆器(APV匀浆器部，St.Paul,MN)。另外，通过用微流化机M110EH(Microfluidics,Newton,MA)微流化预混物也可以制备分散体。流体加工的温度迅速升高，因为均化是在高压下进行。在某些情况中，在高温下高压均化(匀浆器入口温度高于约30℃)导致分散体趋于相分离。所以，将匀浆器的排放物冷却以维持一个可接受的匀浆器入口温度。
                    包装和灭菌
将利用一种上述方法制备的水分散体填充在玻璃瓶中至容积的约70-90％，用通用惰性气氛如氮气净化，并且选择适当的塞子和熔封。发现包装的新普鲁泊福制剂普遍对药物可接受的蒸气灭菌循环稳定。
                大鼠尾静脉刺激试验
通过给大鼠注射试验利用上述方法制备的普鲁泊福制剂引起静脉组织刺激的能力。约11至12周龄的雌性Sprague-Dawley大鼠购自Charles River,St Constant,PQ。经过环境适应期后，选用健康且体重为200至250g的大鼠。
试验制剂以快速浓注每天注射1次共2天，即第1和2天。在约30秒的时间内注射到距尾远端约5cm处的尾静脉中。第1天基于体重给予12.5mg/kg的普鲁泊福剂量。在研究的第1至3天每天观察大鼠：
Ⅰ.总体观察：
每天检查一次动物的全身健康/死亡率和发病率，连续3天。每天详细记录临床观察结果。观察动物自静脉内给药后的明显中毒效应。
Ⅱ.尾静脉刺激：
在试验制剂给药之前，测量大鼠距邻近动物身体中心约2.5英寸处的尾部周长。该测量值作为基线值用于评估制剂静脉内给药后尾部可能的肿胀。在研究的每天中，仔细检测处理位点以监测任何反应并且测量大鼠尾部周长。通过将第2和第3天的测量值与给药前基线值比较评估大鼠尾部周长的改变。
                      药代动力学指标
在注射前后观察各试验大鼠。记录丧失意识所需的时间(感应时间)。还测量复苏，即自发地试图用四肢站立的时间(正向反应时间)。正向反应时间减去意识丧失时的时间之差是麻醉时间。
                        溶血的可能性
体外评估本发明制剂对人全血的溶血作用是选择不易在注射位点产生刺激作用的制剂的另一个指示。制剂对血液的溶血潜在性是通过测定红细胞胞质标识酶乳酸脱氢酶(LDH)来评估。测量的由渗漏或破裂红细胞逃逸到血液的血浆隔室内的红细胞胞质标识酶LDH是一个文献中常用于评估注射制剂的溶血潜在性的定量试验(Senz和Bauer,1996)。由18-65岁的男性或女性白种人志愿者获得血液并且用肝素钠稳定。将试验制剂与等体积的人全血混合并且在37℃下保温约1小时。随后在室温下静置该混合物30分钟，随后在1500rpm离心10分钟。利用该领域普通专业人员已知的标准方法测定上清液中LDH的浓度。作为本研究的指导，利用盐酸胺碘酮通过溶血潜在性方法测量出LDH的浓度，由LDH的浓度测定出适宜的可接受上限，已知盐酸胺碘酮在临床情况中是一种静脉注射时导致静脉刺激的化合物(PDR 1999,3289页)。按照产品说明所述，测试50mg/mL和用5％葡萄糖水稀释至1.8mg/mL时的盐酸胺碘酮Ⅳ溶液，分别得到8190IU/L和673 IU/L的LDH值。
                    微生物抑制作用
测试本发明所述的制剂抑制微生物生长的能力，这些微生物在临床情况中是多数感染的潜在来源。通过试验测定金黄色葡萄球菌(ATCC 6538)、大肠埃希氏杆菌(ATCC 8739和ATCC 8454)、绿铜假单胞菌(ATCC 9027)、白色假丝酵母(ATCC 10231)和黑曲霉(ATCC16403)的生长，其中在20-25℃内，将各种所述生物的冲洗混悬液以约1000集落生成单位(CFU)/mL加入所述制剂的单独等份试样中。在20-25℃下温育该接种混合物。在24小时和48小时、第7天和其它适当长的时间后通过获取该生物的集落数量来测定接种制剂中微生物的存活率。
                    实施例
下文简单概括包括本发明那些制剂在内的多种制剂的实施例。在这些实施例中也公开了一些特定组合物的体内或体外行为。
除非另外指出，本发明中所述的全部份数或百分比是每单位重量的重量(w/w)，其中分母中的重量代表制剂的总重量。直径的大小为毫米(mm=10-3米)，微米(μm=10-6米)，或毫微米(nm=10-9米)。体积为升(L)，毫升(mL=10-3L)和微升(μm=10-6L)。稀释是以体积计。所有温度为摄氏度。本发明的组合物包括，主要由上述物质组成或由所述物质组成，并且加工或方法可以包括、基本上由或由所述步骤和物质构成。
本发明参考下列优选实施方案作进一步的解释并且也提及不适宜的组合物。上文提及了实施例的通用方法；注意例外。制剂是通过上述方法制备。用于制备本发明制剂的原料概括如下：
    原料 符号            来    源
1,2-二肉豆蔻酰基-sn-甘油-3-磷酸胆硷 DMPC Avanti Polar Lipids Inc.,Alabaster,AL,US
1,2-二肉豆蔻酰基-sn-甘油-3-[磷酸-(1-甘油)] DMPG Avanti Polar Lipids Inc.,Alabaster,AL,US
油酸乙酯，NF EO Croda leek Ltd,Staffordshire,UK
甘油，USP-FCC GLY J.T.Baker,Philipsburg,NJ,US
Lipoid E80(蛋黄卵磷脂) E80 Lipoid GmBH,Ludwigshafen
Lipoid EPC(蛋黄磷脂酰胆硷) EPC Lipoid GmBH,Ludwigshafen
Lipoid SPC(大豆磷脂酰胆硷) SPC Lipoid GmBH,Ludwigshafen
Lipoa SPC-3(饱和大豆磷脂酰胆硷) SSPC Lipoid GmBH,Ludwigshafen
甘露糖醇，USP MAN J.T.Baker,Philipsburg,NJ,US
Miglyol 810 M810 Hüls America,Piscatway,NJ,US
普鲁泊福 PRO Albemarle Corporation,BatonRouge.LA,US
大豆油，USP SO Spectrum,New Brunswick,NJ,US
(D+)α,α-海藻糖 TRE Pfanstiehl Laboratories Inc,Waukegan,IL,US
实施例1：提高制剂油含量的作用
本实施例的试验用于鉴定制剂的可变性，它们是隐藏在理想属性后的因素。
表Ⅰ概括了普鲁泊福制剂的某些实施例及其随油含量提高的属性。油酸乙酯含量由0.4％提高至10％，从而使这些制剂的油浓度提高。普鲁泊福的浓度保持在1％。随着油含量的提高调节磷脂混合物的含量(Lipoid E80和DMPG)使制剂具有良好的稳定性。
发现大鼠尾部肿胀随油含量的增高而减小，肿胀是制剂引起组织刺激倾向的一个指标(参见上文)。含有4-10％油酸乙酯的制剂#1.4-1.6似乎导致不显著的大鼠尾部肿胀。这个结果与已报导的发现(Babl等人1995和Doenicke等人1996和1997)相似，在普鲁泊福制剂中使用较大量的油可降低注射疼痛的发生率，这可能是因为降低了普鲁泊福在水中的浓度。然而，这些作者在他们的普鲁泊福制剂中采用了非常高含量(20％)的MCT和LCT混合物，这样的制剂肯定有利于微生物的生长。
              表Ⅰ：提高制剂油含量的作用
制剂ID   普鲁泊福(％,w/w)   LipoidE80(％,w/w)    DMPG(％,w/w)   油酸乙酯(％,w/w) 粘度cP 大鼠尾部肿胀48小时，mm   LDH(IU/L)
 1.1     1     0.8     0.15     0.4  0.97     1.39  10918
 1.2     1     0.8     0.10     1.0  1.08     0.6  10970
 1.3     1     0.8     0.10     2.0  1.06     0.2  10300
 1.4     1     1.0     0.25     4.0  1.04     0  3150
 1.5     1     1.0     0.25     8.0  1.25     0  1290
 1.6     1     1.0     0.25     10.0  1.34     0  770
通过测定与等量制剂混合的人全血样本中的LDH活性，按照上述方法评估表Ⅰ的制剂的溶血潜在性。表Ⅰ概括的结果证明制剂的溶血潜在性随着油酸乙酯含量的增高而降低。
虽然含有10％油酸乙酯的制剂#1.6可以具有可耐受的溶血和注射位点组织刺激作用，这种制剂远远不能够符合本发明的目的，因为它含有高含量的油，即油酸乙酯。这个问题与现有技术提及的普通市售或试验普鲁泊福制剂有关。适合快速浓注或输注的理想普鲁泊福制剂应同时具有下列全部特征：
·不合有大量的油或甘油三酯，从而减小患者患高脂血症的倾向，
·在注射位点很少引起或不引起组织刺激，和
·具有足够的杀菌或制菌性质，以便为患者提供更高的安全性并且在临床情况使用中保存期更长。
所以，一种更适用的制剂应具有可接受水平的注射位点组织刺激作用，但油含量应明显低于本实施例中的最佳制剂(#1.6)。许多满足这些标准的制剂概括在以下实施例中。
实施例2：大鼠尾静脉刺激作用和溶血潜在性
本实施例中提供了按照上述方法制备的多种制剂，并且通过大鼠尾静脉肿胀试验(参见上文)的评估证实了这些制剂具有可接受的注射位点组织刺激作用。这些制剂概括在表Ⅱ中。当尾静脉静脉内施用例如制剂2.1至2.25时，尾周长的增加为零，这表明不存在刺激作用。
然而，按照Haynes的专利(美国专利5637625)所述方法复制的多个组合物，例如制剂2.26至2.29和制剂2.30，它们引起尾静脉明显刺激作用。
在实施例1中观察到，通过使制剂中的油含量由0.4％增高至10％或更高，可以减小组织刺激作用。然而，实施例2表明，这种过分简单的想法没有超越局限，因为在某些情况中仅仅提高普鲁泊福制剂中的油含量是无法获得一种低刺激性的配方。例如，在制剂2.26中油的水平提高到油酸乙酯为6％，而且在制剂2.27和2.28中Miglyol-810达到4％，但这些制剂仍然在注射位点引起组织刺激，由这些制剂在尾部肿胀值可以明显看出。
虽然制剂2.26至2.30是刺激性的，令人惊奇的是许多含油浓度至多4％的组合物是无刺激的。例如，制剂2.15含有低至2％的油，但它也是一种非刺激制剂。这个意外的结果表明，这些制剂的优选组成本身迥异于利用线性析因试验设计的传统制剂途径，线性析因试验设计无法揭示出潜在的协同作用。一旦鉴定出具有确定可接受特性的制剂的组合要素的可接受范围，利用上述方法选择优选实施方案就成为一种例行决定。
审视表Ⅱ中的数据可以惊奇地发现，许多具有低LDH水平并且保持无注射位点组织刺激迹象的组合物在其水相中也含有甘露糖醇或海藻糖。更为惊奇的是许多这种组合物的黏度高于1.2厘泊，在某些情况下甚至高于3厘泊，这些制剂的高黏度使它们在溶血潜在性方面安全。
由实施例1和实施例2看出，仅仅提高制剂中的油含量不能降低溶血潜在性或在注射位点对组织的刺激，似乎当油低于一定量(例如＜10％)时，改善溶血作用或组织刺激性的诱发因素是源于特定组成的多种因素的综合。因此，具有低溶血作用的无刺激配方的特征在于多种制剂组分可产生协同作用使优选制剂减小刺激性。
实施例3：对微生物的抑制作用
不论证明制剂在大鼠中不存在血栓形成刺激或是引起此类刺激作用，如上文所述方法试验所有制剂杀微生物或抑制微生物的有效性，其中一些相关结果概括在表Ⅲ中。另外，在表Ⅲ中用Diprivan的杀微生物有效性试验结果作为参比。
发现多种组合物能够抑制微生物的生长。通过减少或保持一定数量集落的接种微生物测定对微生物生长的抑制作用。例如，表Ⅱ中的制剂2.1、2.3和2.4一致表现出全部所需特性；降低的刺激作用(大鼠尾静脉无肿胀)，可接受的溶血作用(低LDH值)以及抑制试验微生物的生长(参见表Ⅲ)。
表Ⅱ：一些普鲁泊福的组成，这些制剂对大鼠尾静脉的刺激和溶血作用，通过在与人血一起培养时乳酸脱氢酶(LDH)的水平测定。
  制剂号 普鲁泊福                             磷脂           油     张力调节剂             属性
E80 EPL EPC SPC SSPC DMPC DMPG EO SO M810 类型 数值 尾部肿胀48小时，mm     LDH(IU/L) 粘度
    2.1   2  2.0   .05   0.05     4     MAN     5.5     0     179  5.31
    2.2   2  2.2   0.15  4     MAN     5.5     0     287  4.44
    2.3   2  2.0   0.5   0.05     4     MAN     5.5     0     107  5.24
    2.4   2  1.6   0.10     6     TRE    12.5     0     172  4.20
    2.5   2  1.6   0.05     4     MAN     5.5     0     183  1.32
    2.6   2  1.6     4     MAN     5.5     0     168  1.21
    2.7   2   3.0   0.15  4     TRE    20.0     0     185  1.91
    2.8   2  2.0   .05   0.05  4     MAN     5.5     0     204  3.64
    2.9   2   2.4   0.15  4     MAN     7.5     0     380  1.39
   2.10   2   2.0   0.10     4     GLY     2.5     0     571  1.32
   2.11   2  1.6  4     MAN     7.5     0     604  1.21
   2.12   2   1.6   0.15     4     GLY     2.5     0     668  1.20
   2.13   2   1.6  4     MAN     7.5     0     942  1.20
   2.14   1   1.0   0.25  8     GLY     2.5     0     1290  1.25
   2.15   1   0.80   0.10     2     GLY     2.5     0     2049  1.18
   2.16   2  1.6     4     GLY     2.5     0     2197  1.08
   2.17   2  1.6   0.10  6     GLY     2.5     0     2700  1.23
   2.18   2   1.6  1.6   0.05  4     GLY     2.5     0     2826  1.17
   2.19   2  1.6   0.05     4     GLY     2.5     0     3650  1.17
                              表Ⅱ：续
制剂号   普鲁泊福                            磷脂           油   张力调节剂                属性
E80 EPL EPC SPC SSPC DMPC DMPG EO SO M810 类型 数值 尾部肿胀48小时，mm   LDH(IU/L) 粘度
 2.20     2  1.6  0.10  4  GLY  2.5     0  5035  1.13
 2.21     2  1.6  0.10   6  GLY  2.5     0  7565  1.33
 2.22     1   1.0  0.10     6  GLY  2.5     0  7720  1.45
 2.23     1   1.5  0.10     10  GLY  2.5     0  7940  2.78
 2.24     2  1.6  0.10   4  GLY  2.5     0  8250  1.15
 2.25     1   2.0  0.10     8  GLY  2.5     0  8710  2.25
 2.26     1  1.0  0.25   6  GLY  2.5     0.2  7020  1.12
 2.27     1   1.00  0.10     4  GLY  2.5     0.2  7460  1.49
 2.28     2  1.6  1.6  0.05  4  GLY  2.5     0.4  4330  1.53
 2.29     2  1.6  0.10  2  GLY  2.5     1.05  8765  1.01
 2.30     1  0.8  0.15  0.4  GLY  2.5     0.8  10720  0.95
符号和注解
DMPC：二肉豆蔻酰基磷酰胆硷；DMPG：二肉豆蔻酰基磷酰甘油；E80：Lipoid E80；E0：油酸乙酯；EPC：蛋黄磷脂胆硷；EPL：蛋黄磷脂；GLY：甘油；M810：Miglyol-80；MAN=甘露糖醇；SO：大豆油；SPC：大豆磷脂酰胆硷；SSPC：饱和大豆磷脂酰胆硷；TRE=海藻糖。这些原料的来源如上所述。表Ⅲ在某些普鲁泊福制剂存在下开始接种103CFU/ml后某些微生物的对数生长。
令人惊奇地发现，这些组合物在其水相中也含有甘露糖醇或海藻糖。进一步意外发现这些组合物的粘度高达约4.2至约5.3厘泊。
正如Haynes所教导的(美国专利5637625)，可以认为制剂中脂质营养素含量的增加导致制剂支持微生物的生长。然而，意外发现通过提高油的含量(达到4-6％)，制剂2.1、2.3或2.4没有为细菌生长提供介质。更有价值地发现是，制剂2.1、2.3或2.4既无刺激性也无溶血性，同时还可抑制微生物的生长。三种无刺激、无溶血性和杀菌或制菌制剂是本发明优选组合物的非限定实施例。
实施例4：高效价普鲁泊福制菌
按照上述方法制备表Ⅳ中的高效价普鲁泊福制剂4.1-4.3。发现这些制剂最终可蒸气灭菌而不失去稳定。
            表Ⅳ：高药物效价的普鲁泊福制剂
             制剂4.1   制剂4.2   制剂4.3普鲁泊福           5.0％    10.0％    10.0％胆甾醇            0.25％     0.4％     0.5％胆甾醇基油酸酯      ---       4.0％     3.0％Phospholipon 90H   1.5％     1.8％     1.5％DMPG               0.3％     0.3％    0.15％甘油               2.5％     2.5％     2.5％氢氧化钠         qs pH6.9  qs pH8.2  qs pH7.0水               qs100％   qs100％   qs100％
这些高效价制剂极其稳定并且采用了不改变药物功效的可药用组分。例如，在以10mg/kg对大鼠静脉内给药时，证明制剂4.1具有可接受的普通麻醉剂的功效。
制剂4.2验证了一种均化普鲁泊福分散体，其存在于含2.5％甘油的水载体中。它具有高达10％的普鲁泊福，同时保持很低的脂肪(胆甾醇和胆甾醇基油酸酯)含量。它具有82nm的容积称重平均粒度，它在受到不同应力如冷冻/溶化时没有明显改变(3个循环后为128nm)。
制剂4.3也是一种很均匀的分散体，其存在于含2.5％甘油的水载体中并且含有10％的普鲁泊福，同时维持很低的脂肪含量。它具有80nm的容积称重平均粒度，它在25℃下保存时没有明显改变(70天后71nm)。
高效制剂(例如10％普鲁泊福)将有效地减少静脉内给药所需的药物体积，同时提供同样有效的给药效果。因此，本实施例中所述的制剂将使血管壁与制剂的接触面积相对更小，并且可对减少注射疼痛的发生率或其它局部不良反应起重要作用。
本发明首次公开和制备了此类高效、稳定的普鲁泊福制剂。
实施例5：药代动力学
比较本发明的普鲁泊福制剂和参比市售制剂Diprivan(1％)和Diprivan(2％)在大鼠中麻醉感应和持续的时间。将这些制剂在大鼠中12.5mg/kg单剂量静脉内快速浓注，按照试验方法部分所述的方法测量意识丧失的时间和正向反应时间。概括在表Ⅴ中的结果举例说明了这些制剂的起效特征。
                  表Ⅴ：药代动力学参数
  制剂ID 大鼠数量 平均麻醉感应时间(秒) 平均正向反应时间(分钟)
    2.1     9     24.4     14.9
    2.2     4     31.0     16.2
    2.3     4     48.0     16.4
    2.4     9     32.7     15.8
    2.5     9     27.2     19.2
    2.6     9     38.4     19.4
    2.7     4     24.0     17.3
    2.8     4     23.8     16.7
    2.9     3     67.3     11.9
    2.10     4     34.8     16.3
    2.11     8     40.5     18.6
    2.12     4     36.3     13.7
Diprivan(1％和EDTA)     4     20.0     14.6
根据上述实施例，本发明提供普鲁泊福制剂的性质是：
(a)在蒸气灭菌期间和之后保持稳定；
(b)静脉内注射给温血动物时产生所需的麻醉效果；
(c)抑制微生物生长
(d)已经证实减少或不存在局部静脉反应的发生；
(e)具有很少或不存在发生高脂血的潜在性。
虽然对本发明和实施例结合最实际和优选的实施方案进行了描述，但应理解本发明不局限在已公开的实施方案，相反地，不同的改进和等同方法属于下文权利要求书的实质和范围内。
参考文献
Ardulno,M.J.,Bland,L.A.,McAllister,S.K.,Aguero,S.M.,Villarino,M.E.,McNeil,M.M.Jarvis,W.R.＆Favero,M.S.(1991)“静脉麻醉剂普鲁泊福中的微生物生长和内毒素产生”Inf.Control Hosp.Epidem.,12(9),535-539。
J.Babl,A.Doenicke,V.Monch(1995)“新的普鲁泊福LCT/MCT脂肪乳作为溶剂，减小普鲁泊福注射中疼痛的方法”，《欧洲医药药学》(Eur Hosp Pharmacy),1:15-21。
Cairns等人(1996)“混合脂质乳剂在新生儿中的耐受性：浓度的影响”Arch Dis Child Fetal Neonatal Ed 75(2):F 113-6。
Crowther,J.Hrazdil,J.,Jolly,D.T.,Galbraith,J.C.,Greacen,M.＆Grace,M.(1996)“微生物在普鲁泊福、硫喷妥钠和普鲁泊福与硫喷妥钠的1∶1混合物中的生长”《麻醉和镇痛》(Anesth and Anal.)82,475-478。
A.W.Doenicke,J.Babl,W.Kellermann,J.Rau,M.F.Roizen(1996)“减小普鲁泊福注射中的疼痛：溶剂的作用”《麻醉镇痛》(Anesth Analg)82:472-4。
A.W.Doenicke,J.babl,U.Klotz,J.Kugler,M.O’Connor,J.Rau,M.F.Roizen(1997)“普鲁泊福在新溶剂中的药代动力学和药效学”《麻醉镇痛》85:1399-403。
A.F.Chouri,M.A.Ramirez Ruiz,＆P.F.White(1994)“氟马西尼对咪达唑仑和普鲁泊福镇静后复苏的影响”《麻醉学》81:333-339。
J.B.Glen＆R.James“2,6-二异丙基苯酚作为麻醉剂”美国专利4056635,1977.11.1。
J.B.Glen＆R.James“含有2,6-二异丙基苯酚的麻醉剂组合物”，美国专利4452817,1984.6.5。
J.B.Glen＆R.James“药物组合物”美国专利4798846,1989.1.17。
D.H.Haynes“普鲁泊福微丸制剂”美国专利5637625,1997.6.10。
C.B.Jones＆J.H.Platt“含有乙二胺四乙酸盐的普鲁泊福组合物”美国专利5714520,1998.2.3。
C.B.Jones＆J.H.Platt“含有乙二胺四乙酸盐的药物组合物”美国专利5731355,1998.3.24。
C.B.Jones＆J.H.Platt“含有乙底酸盐和普鲁泊福的药物组合物”美国专利5731356,1998.3.24。
D.Mangar＆E.J.Holak(1992)“在50mm Hg止血带后静脉内注射利多卡因以减小与普鲁泊福注射有关的疼痛”《麻醉镇痛》74:250-252。
R.K.Mirakhur(1988)“普鲁泊福在儿童中诱发的特征：与硫喷妥钠的对比”《麻醉》43:593-598。
Nichols,R.L.＆Smith,J.W.(1995)“麻醉剂的细菌污染”《新英格兰医学杂志》(New Eng.J.Med),333(3),184-185。
PDR(1996)“Diprivan的1％注射剂”《医生工作手册》(Physicains’Desk Reference)1996,2833页。
PDR(1999)“Diprivan的1％注射剂”《医生工作手册》(Physicains’Desk Reference)1996,2833页。
PDR(1999)“Diprivan的1％注射剂”《医生工作手册》(Physicains’Desk Reference),1999。
Sandstrom等人(1995)“与长链甘油三酯比较结构化甘油三酯易于耐受并且在术后患者中使全身脂肪氧化作用增强”JPEN(JParenter Enteral Nutr)19(5):381-6。
G.E.Sklar(1997)“普鲁泊福和术后感染”《药物治疗学纪事》(Ann Pharmacother)31:1521-3。
I.Smith,P.F.White,M.Nathanson＆R.Gouldson(1994)“普鲁泊福其临床应用的革新”《麻醉学》81:1005-1043。
Sosis,M.B.＆Braverman,B.(1993)“葡萄球菌属在四种静脉麻醉剂中的生长”《麻醉和镇痛》,77,766-768。
Sosis,M.B.Braverman B.＆Villaflor,E.(1995)“普鲁泊福而不是硫喷妥钠支持白色念珠菌的生长”《麻醉和镇痛》81:132-134。
Stenz R.＆Bauer,K.H.(1996)“体外试验中用于快速评估表面活性剂溶血作用的新生理方法”《药物学》,51(5),283-287。
R.D.Stark S.M.Binks,V.N.Duka,K.M.O’Connor,M.J.A.Arnstein,J.B.Glen(1985)“普鲁泊福(Diprivan)安全性和耐受性的评价”《进修医学杂志》(Postgrad Med J)61S:152-156。
Tessler,M.Dascal,A.,Gioseffini,S,Miller,M.＆Mendelson,J.(1992)“金色葡萄球菌属、白色念珠菌属和osloensis摩拉克氏菌属在普鲁泊福和其它介质中的生长”《加拿大麻醉杂志》(Can.J.Anaesth.)39(5),509-511。
H.G.Weder“普鲁泊福的毫微分散体”PCT专利申请WO 9710814,1997.3.27。
P.F.White＆J.B.Negus(1991)“在局部和区域麻醉过程中的镇静浸剂：咪达唑仑与普鲁泊福的对比”《临床麻醉学杂志》(J.Clin.Anesth)3:32-39。

Claims (14)

1．一种非水溶性微滴基质的稳定、灭菌和可注射水分散体，该微滴基质的平均直径为约50nm至约1000nm，主要组成是：
(a)约1％至约15％的普鲁泊福；
(b)约1％至约8％的普鲁泊福可溶稀释剂；
(c)约0.5％至约5％的表面稳定化两亲性试剂；
(d)用作张力调节剂的可药用水溶性多羟基添加剂；和
(e)条件是普鲁泊福与稀释剂的比例约1∶4至约1∶0.1和普鲁泊福与两亲性试剂的比例是约1∶0.8至约1∶2.5，并且该组合物的粘度为约0.8至约15厘泊，
其中该制剂：
·阻止微生物生长，定义为通过试验测定各种金黄色葡萄球菌(ATCC 6538)、大肠埃希氏杆菌(ATCC 8739和ATCC 8454)、绿铜假单胞菌(ATCC 9027)、白色假丝酵母(ATCC 10231)和黑曲霉(ATCC16403)在至少7天内不超过起始接种物的0.5个对数增长，其中在20-25℃内，将各种所述生物的冲洗混悬液以约1000集落生成单位(cfu)/mL加入所述制剂的单独等份试样中，在20-25℃下温育该试样，在24小时和48小时、第7天和其它适当长的时间后通过获取该生物的集落数量来测定接种制剂中微生物的存活率；
·通过试验显示在注射位点引起很小或不引起刺激，其中所述组合物基于体重以12.5mg/kg每天在约30秒内单剂量静脉内快速浓注到大鼠尾静脉中，连续2或3天，并且在注射48小时后大鼠尾部周长没有明显增大。
2．权利要求1的组合物，其中表面稳定化两亲性试剂是一种或多种天然或合成表面改性剂，选自离子或非离子磷脂或胆甾醇或这些两亲性试剂的混合物，两亲性试剂的总量应使普鲁泊福和两亲性试剂的比例为约1∶0.8至约1∶2.5，并且各个两亲性试剂的种类和含量的选择条件是：
(ⅰ)该组合物不存在或很少具有使人或动物血液溶血的潜在性，和
(ⅱ)在注射位点不存在或很小对组织产生刺激性，和
(ⅲ)该组合物在静脉内给药时为温血动物和人提供麻醉作用。
3．权利要求1的组合物，其中普鲁泊福可溶稀释剂是合成或天然脂肪酸、其甘油三酯或其他适用的酯类化合物或它们的混合物。
4．权利要求1的组合物，其中普鲁泊福和普鲁泊福可溶稀释剂含量的比例是约1∶3至约1∶0.5。
5．权利要求1的组合物，其中普鲁泊福和普鲁泊福可溶稀释剂含量的比例是约1∶2至约1∶1。
6．权利要求1的组合物，其中普鲁泊福可溶稀释剂是中链甘油三酯和植物油的混合物。
7．权利要求6的组合物，其中中链甘油三酯与植物油的比例是1∶3至3∶1。
8．权利要求1的组合物，其中非水溶性基质由权利要求3的两亲性试剂和权利要求4-7的普鲁泊福可溶稀释剂和普鲁泊福的混合物组成。
9．权利要求1的组合物，其中该组合物含有约2％至约10％的普鲁泊福。
10．权利要求1的组合物，其中该组合物含有可药用可溶于水多羟基添加剂，使含普鲁泊福分散体具有约250至约700渗透压毫摩尔的重量渗透压摩尔浓度。
11．权利要求1的组合物，其中所述重量渗透压摩尔浓度是约300至约500渗透压毫摩尔。
12．权利要求1的组合物，其中所述粘度是约2至约5厘泊。
13．一种注射含普鲁泊福制剂的降低或基本上完全消除刺激性的方法，该方法用一种非水溶性微滴基质的稳定、灭菌和抗微生物的可注射水分散体给药，该微滴基质的平均直径为约50nm至约1000nm，主要组成是约1％至约15％的普鲁泊福作为活性成分，至多约7％的普鲁泊福可溶稀释剂，约0.8％至约4％的表面稳定化两亲性试剂，并且该组合物的水相由可药用可溶于水多羟基张力改性剂组成，该组合物避免加入杀菌或制菌防腐剂，条件是普鲁泊福与稀释剂的比例是
约1∶4至约1∶0.1和普鲁泊福与两亲性试剂的比例是约1∶0.8至约1∶2.5，并且该组合物的粘度约0.8至约15厘泊。
14．一种引起麻醉的方法，该方法包括给需要麻醉的对象施用麻醉诱发量的一种非水溶性微滴基质的稳定、灭菌和抗微生物的可注射水分散体，该微滴基质的平均直径为约50nm至约1000nm，主要组成是约1％至约15％的普鲁泊福作为活性成分，至多约7％的普鲁泊福可溶稀释剂，约0.8％至约4％的表面稳定化两亲性试剂，并且该组合物的水相由可药用可溶于水多羟基张力改性剂组成，该组合物避免加入杀菌或制菌防腐剂，条件是普鲁泊福与稀释剂的比例是约1∶4至约1∶0.1和普鲁泊福与两亲性试剂的比例是约1∶0.8至约1∶2.5，并且该组合物的粘度约0.8至约15厘泊。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105765306A (zh) * 2013-06-27 2016-07-13 西门子股份公司 燃气涡轮发动机中的燃烧器装置

Families Citing this family (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7255877B2 (en) 1996-08-22 2007-08-14 Jagotec Ag Fenofibrate microparticles
US6979456B1 (en) 1998-04-01 2005-12-27 Jagotec Ag Anticancer compositions
IL141095A0 (en) 1998-08-19 2002-02-10 Rtp Pharma Inc Injectable aqueous dispersions of propofol
US6100302A (en) * 1999-04-05 2000-08-08 Baxter International Inc. Propofol formulation with enhanced microbial characteristics
AU2006201100B2 (en) * 1999-09-21 2009-09-24 Jagotec Ag Surface modified particulate compositions of biologically active substances
EP1214059B1 (en) * 1999-09-21 2005-05-25 Skyepharma Canada Inc. Surface modified particulate compositions of biologically active substances
GB2359747B (en) 2000-02-29 2002-04-24 Maelor Pharmaceuticals Ltd Anaesthetic formulations
GB0012597D0 (en) * 2000-05-25 2000-07-12 Astrazeneca Ab Formulation
WO2001097779A2 (en) * 2000-06-16 2001-12-27 Rtp Pharma Inc. Improved injectable dispersions of propofol
US6399087B1 (en) * 2000-12-20 2002-06-04 Amphastar Pharmaceuticals, Inc. Propofol formulation with enhanced microbial inhibition
RU2297216C2 (ru) * 2002-04-08 2007-04-20 Эм-Джи-Ай Джи-Пи,Инк. Фармацевтические композиции, содержащие растворимые в воде пролекарства пропофола, и способы их применения
US7550155B2 (en) * 2002-07-29 2009-06-23 Transform Pharmaceuticals Inc. Aqueous pharmaceutical compositions of 2,6-diisopropylphenol (propofol) and their uses
WO2004039360A1 (en) * 2002-10-29 2004-05-13 Transform Pharmaceuticals, Inc. Aqueous 2,6-diisopropylphenol pharmaceutical compositions
PL375874A1 (pl) * 2002-07-29 2005-12-12 Transform Pharmaceuticals, Inc. Wodne kompozycje farmaceutyczne 2,6-diizopropylofenolu
AU2003286725B2 (en) * 2002-10-29 2007-07-12 Transform Pharmaceuticals, Inc. Propofol with cysteine
CN100367943C (zh) * 2002-12-06 2008-02-13 株式会社大塚制药工场 含丙泊酚的脂肪乳剂
US20040225022A1 (en) * 2003-05-09 2004-11-11 Desai Neil P. Propofol formulation containing reduced oil and surfactants
US8476010B2 (en) 2003-07-10 2013-07-02 App Pharmaceuticals Llc Propofol formulations with non-reactive container closures
BRPI0615292A8 (pt) * 2005-08-31 2018-03-06 Abraxis Bioscience Llc composições e métodos para preparação de fármacos de má solubilidade em água com estabilidade aumentada
SI3311805T1 (sl) * 2005-08-31 2020-07-31 Abraxis Bioscience, Llc Sestave, ki zajemajo slabo vodotopne farmacevtske učinkovine in antimikrobna sredstva
EP2010150A2 (en) * 2006-04-20 2009-01-07 Amgen Inc. Stable emulsion formulations
EP2818178A1 (en) 2008-01-11 2014-12-31 The Government of The United States of America as represented by The Secretary, Department of Health and Human Services Polypeptide vaccine and vaccination strategy against mycobacterium
WO2010082092A1 (en) * 2009-01-13 2010-07-22 Claris Lifesciences Limited Propofol based anesthetic with preservative
CA2770304C (en) 2009-08-04 2019-11-26 The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services, Centers For Disease Control And Prevention Anti-rsv immunogens and methods of immunization
CA2789432A1 (en) 2010-02-10 2011-08-18 Vera A. Semenova Serologic correlates of protection against bacillis anthracis infection
US9102742B2 (en) 2010-02-10 2015-08-11 The United States Of America As Represented By The Secretary, Department Of Health And Human Services, Centers For Disease Control And Prevention Serologic correlates of protection against Bacillus anthracis infection
MX2012010684A (es) 2010-03-17 2012-11-06 Novaliq Gmbh Composicion farmaceutica para el tratamiento de la presion intraocular incrementada.
JP5591603B2 (ja) * 2010-05-21 2014-09-17 富士フイルム株式会社 プロポフォール含有水中油型エマルション組成物
JP2012012331A (ja) * 2010-06-30 2012-01-19 Fujifilm Corp プロポフォール含有水中油型エマルション組成物
EP2444063A1 (en) 2010-10-20 2012-04-25 Novaliq GmbH Liquid pharmaceutical compositions for the delivery of active ingredients
EP2462921A1 (en) 2010-11-11 2012-06-13 Novaliq GmbH Liquid pharmaceutical compositions for the treatment of a posterior eye disease
CA2819988C (en) * 2011-01-04 2019-11-12 Novaliq Gmbh O/w-emulsions comprising semifluorinated alkanes
PH12013501433A1 (en) * 2011-02-02 2013-09-09 Nestec Sa High protein nutritional compositions and methods of making and using same
EP3192501B1 (en) 2011-05-25 2020-05-13 Novaliq GmbH Topical pharmaceutical composition based on semifluorinated alkanes
JP6039152B2 (ja) 2012-09-12 2016-12-07 ノバリック ゲーエムベーハー 半フッ素化アルカン組成物
BR112015004997B1 (pt) 2012-09-12 2022-09-13 Novaliq Gmbh Composições oftálmicas contendo misturas de alcanos semifluorados
CN114028560A (zh) 2013-07-23 2022-02-11 诺瓦利克有限责任公司 稳定的抗体组合物
EP3331567B1 (en) 2015-07-24 2020-09-23 Neon Laboratories Ltd. Stabilized injectable emulsion of propofol and ketamine
US9585867B2 (en) 2015-08-06 2017-03-07 Charles Everett Ankner Cannabinod formulation for the sedation of a human or animal
WO2017055453A1 (en) 2015-09-30 2017-04-06 Novaliq Gmbh Semifluorinated compounds for ophthalmic administration
CN110403923B (zh) 2015-09-30 2021-09-21 诺瓦利克有限责任公司 半氟化化合物和其组合物
PT3442480T (pt) 2016-06-23 2019-12-23 Novaliq Gmbh Método de administração tópica
EP3515420B1 (en) 2016-09-22 2023-11-08 Novaliq GmbH Pharmaceutical compositions for use in the therapy of blepharitis
AU2017329983B2 (en) 2016-09-23 2022-05-05 Novaliq Gmbh Ophthalmic compositions comprising ciclosporin
BR112019012791A2 (pt) 2016-12-23 2019-12-03 Novaliq Gmbh composição oftálmica para o tratamento da doença do olho seco
CN110678207B (zh) 2017-04-21 2024-08-02 德马利克治疗公司 碘组合物
WO2018202835A1 (en) 2017-05-05 2018-11-08 Novaliq Gmbh Process for the production of semifluorinated alkanes
WO2018206656A1 (en) 2017-05-12 2018-11-15 Novaliq Gmbh Pharmaceutical compositions comprosing semifluorinated alkanes for the treatment of contact lense-related conditions
EP3687496A1 (en) 2017-09-27 2020-08-05 Novaliq GmbH Ophthalmic compositions comprising latanoprost for use in the treatment of ocular diseases
CN120022260A (zh) 2017-10-04 2025-05-23 诺瓦利克有限责任公司 包含f6h8的眼用组合物
KR20200128407A (ko) 2018-03-02 2020-11-12 노바리크 게엠베하 네비볼롤을 포함하는 약제학적 조성물
CN112153970A (zh) 2018-04-27 2020-12-29 诺瓦利克有限责任公司 用于治疗青光眼的包含他氟前列素的眼用组合物
WO2020074697A1 (en) 2018-10-12 2020-04-16 Novaliq Gmbh Ophthalmic composition for treatment of dry eye disease
US11198831B2 (en) 2019-01-31 2021-12-14 Kvi Llc Lubricant for a device
EP3923907B1 (en) 2019-02-13 2024-09-25 Novaliq GmbH Compositions and methods for the treatment of ocular neovascularization
CN110243731B (zh) * 2019-07-03 2021-09-24 苏州新实医疗科技有限公司 抑菌圈直径动态测量方法、测量装置及可读存储介质
MX2022002667A (es) 2019-09-06 2022-04-07 Novaliq Gmbh Composicion oftalmica para el tratamiento de uveitis.
JP2025505314A (ja) * 2022-02-22 2025-02-21 デシエム ビューティー グループ インコーポレイテッド 皮膚コンディショニングのための安定な低粘度水中油型エマルジョン

Family Cites Families (413)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB235977A (en) 1924-04-04 1925-07-02 George Blackburn & Sons Ltd Improvements in or relating to machines for winding yarn
US2803582A (en) 1956-07-16 1957-08-20 Leonid S Cherney Local anesthetic composition
NL120093C (zh) 1958-07-24
US3137631A (en) 1959-12-01 1964-06-16 Faberge Inc Encapsulation in natural products
US3216897A (en) 1961-11-02 1965-11-09 Air Reduction Injectable anesthetic
US3440318A (en) 1964-02-12 1969-04-22 Herbert S Polin Methods for enhancing the effectiveness of drugs,which employ an alkylated phenoxy (polyethanol)
DE1792410B2 (de) 1967-09-01 1980-03-13 Apoteksvarucentralen Vitrum Apotekareaktiebolaget, Stockholm Arzneimittelzubereitung zur intravenösen Injektion
US3594476A (en) 1969-05-12 1971-07-20 Massachusetts Inst Technology Submicron aqueous aerosols containing lecithin
US3937668A (en) 1970-07-15 1976-02-10 Ilse Zolle Method for incorporating substances into protein microspheres
NL7012832A (zh) 1970-08-29 1972-03-02
US3715432A (en) 1971-01-22 1973-02-06 Massachusetts Inst Technology Submicron aqueous aerosols containing lecithin
US3885027A (en) * 1971-04-12 1975-05-20 West Laboratories Inc Orally administered drug composition for therapy in the treatment of narcotic drug addiction
US3776857A (en) 1971-09-24 1973-12-04 Witco Chemical Corp Water-in-oil emulsions
CA1005367A (fr) * 1972-12-08 1977-02-15 Michel Huvey Element allonge flexible comportant une armature de renforcement
US3794476A (en) 1972-12-26 1974-02-26 Ppg Industries Inc Method for thermally tempering glass sheet by liquid quenching
GB1413186A (en) 1973-06-27 1975-11-12 Toyo Jozo Kk Process for encapsulation of medicaments
GB1472793A (en) 1974-03-28 1977-05-04 Ici Ltd Pharmaceutical compositions
US4798846A (en) 1974-03-28 1989-01-17 Imperial Chemical Industries Plc Pharmaceutical compositions
US3965255A (en) 1974-05-01 1976-06-22 E. E. Eljim Ecology Ltd. Controlled drug releasing preparations
GB1502774A (en) 1974-06-25 1978-03-01 Nat Res Dev Immunological preparations
CH588887A5 (zh) 1974-07-19 1977-06-15 Battelle Memorial Institute
US4073943A (en) 1974-09-11 1978-02-14 Apoteksvarucentralen Vitrum Ab Method of enhancing the administration of pharmalogically active agents
US4107288A (en) 1974-09-18 1978-08-15 Pharmaceutical Society Of Victoria Injectable compositions, nanoparticles useful therein, and process of manufacturing same
JPS5186117A (en) 1975-01-27 1976-07-28 Tanabe Seiyaku Co Johoseibiryushiseizainoseiho
JPS5231981A (en) 1975-08-18 1977-03-10 Takeda Chem Ind Ltd Microcapsule preparation method
CA1077842A (en) 1975-10-09 1980-05-20 Minnesota Mining And Manufacturing Company Albumin medicament carrier system
US4168308A (en) 1976-03-12 1979-09-18 Apoteksvarucentralen Vitrum Ab Composition for enhancing the administration of pharmacologically active agents
GB1523965A (en) 1976-03-19 1978-09-06 Ici Ltd Pharmaceutical compositions containing steroids
GB1578776A (en) 1976-06-10 1980-11-12 Univ Illinois Hemoglobin liposome and method of making the same
US4078052A (en) 1976-06-30 1978-03-07 The United States Of America As Represented By The Secretary Of Health, Education And Welfare Large unilamellar vesicles (LUV) and method of preparing same
US4320121A (en) 1976-10-12 1982-03-16 Sears Barry D Method of emulsifying cholesterol, cholesterol esters and triglyceride compounds
US4086257A (en) 1976-10-12 1978-04-25 Sears Barry D Phosphatidyl quaternary ammonium compounds
US4351831A (en) 1977-11-02 1982-09-28 Massachusetts Institute Of Technology Process and composition for treating disorders by administering isoxsurpine and choline
US4356167A (en) 1978-01-27 1982-10-26 Sandoz, Inc. Liposome drug delivery systems
US4235871A (en) 1978-02-24 1980-11-25 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4529561A (en) 1978-03-24 1985-07-16 The Regents Of The University Of California Method for producing liposomes in selected size range
US4186183A (en) 1978-03-29 1980-01-29 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in chemotherapy of leishmaniasis
US4298594A (en) 1978-04-14 1981-11-03 Arthur D. Little, Inc. Xenobiotic delivery vehicles, method of forming them and method of using them
GB2026340B (en) 1978-07-03 1982-12-22 Ash P Stabilising microvesicles
EP0007895B1 (fr) 1978-07-19 1983-06-22 Patrick Couvreur Nanoparticules biodégradables, compositions pharmaceutiques les contenant et procédé pour leur préparation
US4219548A (en) 1978-09-01 1980-08-26 The Procter & Gamble Company Topical anti-inflammatory composition
US4369182A (en) 1978-09-27 1983-01-18 A. Nattermann & Cie Gmbh Inflammation-preventing pharmaceutical composition of oral administration
DE2856333C2 (de) 1978-12-27 1983-09-22 A. Nattermann & Cie GmbH, 5000 Köln Oral einnehmbare Arzneimittel mit entzündungshemmender Wirkung
IT1111367B (it) 1978-11-17 1986-01-13 Serono Ist Farm Processo per la preparazione estemporanea di liposomi e liposomi cosi' ottenuti
US4328222A (en) 1978-11-21 1982-05-04 Hoffmann-La Roche Inc. Pharmaceutical compositions for parenteral or local administration
GR73668B (zh) 1978-11-21 1984-03-28 Hoffmann La Roche
US4241046A (en) 1978-11-30 1980-12-23 Papahadjopoulos Demetrios P Method of encapsulating biologically active materials in lipid vesicles
US4421747A (en) 1978-12-27 1983-12-20 A. Nattermann & Cie. Gmbh Inflammation-preventing pharmaceutical composition of oral administration
US4378354A (en) 1978-12-27 1983-03-29 A. Nattermann & Cie. Gmbh Inflammation-preventing pharmaceutical composition of oral administration
US4316884A (en) 1979-01-25 1982-02-23 Adria Laboratories, Inc. Sustained release pharmaceutical formulation
JPS55141407U (zh) 1979-03-30 1980-10-09
DE2914788A1 (de) 1979-04-11 1980-10-16 Nattermann A & Cie Parenteral applizierbare, stabile arzneimittelloesungen mit entzuendungshemmender wirkung
US4345588A (en) 1979-04-23 1982-08-24 Northwestern University Method of delivering a therapeutic agent to a target capillary bed
JPS6030652B2 (ja) 1979-05-07 1985-07-17 株式会社ミドリ十字 静脈注射用脂肪乳剤
JPS562353A (en) 1979-06-20 1981-01-12 Ricoh Co Ltd Novel disazo compound and its preparation
CA1173360A (en) 1979-06-22 1984-08-28 Jurg Schrank Pharmaceutical preparations
AR220263A1 (es) 1980-02-19 1980-10-15 Bago Lab Sa Procedimiento para obtener una preparacion inyectable de sulfonamida potenciada de baja irritabilidad
US4302459A (en) 1980-03-19 1981-11-24 The United States Of America As Represented By The Secretary Of The Army Liposome carriers in leishmaniasis chemotherapy with 8-aminoquinoline derivatives
JPS56152739A (en) 1980-04-25 1981-11-26 Tanabe Seiyaku Co Ltd Production of microcapsule
JPS609726B2 (ja) 1980-05-15 1985-03-12 株式会社 ミドリ十字 ステロイド製剤
JPS56167616U (zh) 1980-05-15 1981-12-11
US4331654A (en) 1980-06-13 1982-05-25 Eli Lilly And Company Magnetically-localizable, biodegradable lipid microspheres
DE3024416C2 (de) 1980-06-28 1982-04-15 Gödecke AG, 1000 Berlin Verfahren zur Herstellung von Arzneimitteln mit retardierter Wirkstoff-Freisetzung
ATE12348T1 (de) 1980-11-10 1985-04-15 Gersonde Klaus Prof Dr Verfahren zur herstellung von lipid-vesikeln durch ultraschallbehandlung, anwendung des verfahrens und vorrichtung zur durchfuehrung des verfahrens.
US4394372A (en) 1980-12-22 1983-07-19 The Procter & Gamble Company Process for making lipid membrane structures
EP0057829A1 (en) 1981-02-07 1982-08-18 Donald Malcolm Fullard Locking devices
US4397372A (en) 1981-03-09 1983-08-09 Bell & Howell Company Pendulum suspended bumper assembly
US4397846A (en) 1981-05-15 1983-08-09 Murray Weiner Storage-stable lipid vesicles and method of preparation
US4394182A (en) 1981-10-14 1983-07-19 Rockwell International Corporation Microelectronic shadow masking process for reducing punchthrough
US4522803A (en) 1983-02-04 1985-06-11 The Liposome Company, Inc. Stable plurilamellar vesicles, their preparation and use
US4485054A (en) 1982-10-04 1984-11-27 Lipoderm Pharmaceuticals Limited Method of encapsulating biologically active materials in multilamellar lipid vesicles (MLV)
JPS59111636A (ja) 1982-12-17 1984-06-27 Fuji Photo Film Co Ltd 熱現像カラー感光材料およびそれを用いたカラー画像形成方法
US5030453A (en) 1983-03-24 1991-07-09 The Liposome Company, Inc. Stable plurilamellar vesicles
US4588578A (en) 1983-08-08 1986-05-13 The Liposome Company, Inc. Lipid vesicles prepared in a monophase
US4515736A (en) 1983-05-12 1985-05-07 The Regents Of The University Of California Method for encapsulating materials into liposomes
US4474753A (en) 1983-05-16 1984-10-02 Merck & Co., Inc. Topical drug delivery system utilizing thermosetting gels
US4725442A (en) 1983-06-17 1988-02-16 Haynes Duncan H Microdroplets of water-insoluble drugs and injectable formulations containing same
US4622219A (en) 1983-06-17 1986-11-11 Haynes Duncan H Method of inducing local anesthesia using microdroplets of a general anesthetic
JPS601122A (ja) 1983-06-20 1985-01-07 Green Cross Corp:The ビフエニリルプロピオン酸誘導体脂肪乳剤
DE3339236A1 (de) 1983-10-28 1985-05-09 Bayer Ag Arzneimittelzubereitung
US4492720A (en) 1983-11-15 1985-01-08 Benjamin Mosier Method of preparing microspheres for intravascular delivery
US4532089A (en) 1984-01-14 1985-07-30 Northwestern University Method of preparing giant size liposomes
DE3406497A1 (de) 1984-02-23 1985-09-05 Mueller Bernhard Willi Werner Hochdisperse pharmazeutische mehrkomponentensysteme und verfahren zu ihrer herstellung
US4610868A (en) 1984-03-20 1986-09-09 The Liposome Company, Inc. Lipid matrix carriers for use in drug delivery systems
JPS60208910A (ja) 1984-03-31 1985-10-21 Green Cross Corp:The 水難溶性薬物・リン脂質複合体の製造方法
FR2562421B1 (fr) 1984-04-09 1989-02-17 Sandoz Sa Perfectionnements a la therapie par l'interleukine
US4963367A (en) 1984-04-27 1990-10-16 Medaphore, Inc. Drug delivery compositions and methods
US4863737A (en) 1985-05-01 1989-09-05 University Of Utah Compositions and methods of manufacture of compressed powder medicaments
US5288498A (en) 1985-05-01 1994-02-22 University Of Utah Research Foundation Compositions of oral nondissolvable matrixes for transmucosal administration of medicaments
US5855908A (en) 1984-05-01 1999-01-05 University Of Utah Research Foundation Non-dissolvable drug-containing dosage-forms for use in the transmucosal delivery of a drug to a patient
DE3421468A1 (de) 1984-06-08 1985-12-19 Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim Lipidnanopellets als traegersystem fuer arzneimittel zur peroralen anwendung
US4761228A (en) 1984-06-08 1988-08-02 Weisenbarger Gale M Magnetic fluid conditioner
JPS6176414A (ja) 1984-09-21 1986-04-18 Shionogi & Co Ltd リポソーム製剤の製法
JPS61174940A (ja) 1985-01-29 1986-08-06 Oogawara Kakoki Kk ワックス類コーテイング単核状マイクロカプセルおよびその製造方法
US5288497A (en) 1985-05-01 1994-02-22 The University Of Utah Compositions of oral dissolvable medicaments
US5132114A (en) 1985-05-01 1992-07-21 University Of Utah Research Foundation Compositions and methods of manufacture of compressed powder medicaments
US5785989A (en) 1985-05-01 1998-07-28 University Utah Research Foundation Compositions and methods of manufacturing of oral dissolvable medicaments
JPH0688911B2 (ja) 1985-06-06 1994-11-09 国立予防衛生研究所長 インフルエンザワクチン及びその製造方法
US4766046A (en) 1985-09-27 1988-08-23 Liposome Technology, Inc. Stabilized liposome/amphotericin composition and method
US5041278A (en) 1985-10-15 1991-08-20 The Liposome Company, Inc. Alpha tocopherol-based vesicles
JPH0617309B2 (ja) 1985-11-29 1994-03-09 株式会社ビタミン研究所 アドリアマイシン包埋リポソ−ム製剤
WO1987004592A1 (en) 1986-02-10 1987-08-13 Liposome Technology, Inc. Controlled-release liposome delivery system
US5023087A (en) 1986-02-10 1991-06-11 Liposome Technology, Inc. Efficient method for preparation of prolonged release liposome-based drug delivery system
SE8600632D0 (sv) 1986-02-13 1986-02-13 Kabivitrum Ab Novel pharmaceutical composition
US4803070A (en) 1986-04-15 1989-02-07 Ribi Immunochem Research Inc. Immunological emulsion adjuvants for polysaccharide vaccines
US4806352A (en) 1986-04-15 1989-02-21 Ribi Immunochem Research Inc. Immunological lipid emulsion adjuvant
US4806350A (en) 1986-04-18 1989-02-21 Norden Laboratories, Inc. Vaccine formulation
US5118493A (en) 1986-05-02 1992-06-02 Brigham And Women's Hospital Composition having reduced nephrotoxocity comprising a fatty acid containing component and cyclosporine
DE3623376A1 (de) 1986-07-11 1988-01-21 Behringwerke Ag Pharmazeutische formulierung und verfahren zu deren herstellung
FR2602423B1 (fr) 1986-08-08 1989-05-05 Ethypharm Sa Procede de preparation d'un medicament a base de fenofibrate, medicament obtenu par ce procede
US4776991A (en) 1986-08-29 1988-10-11 The United States Of America As Represented By The Secretary Of The Navy Scaled-up production of liposome-encapsulated hemoglobin
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
CA1338736C (fr) 1986-12-05 1996-11-26 Roger Baurain Microcristaux comportant une substance active presentant une affinite pour les phospholipides, et au moins un phospholipide, procede de preparation
US5320906A (en) 1986-12-15 1994-06-14 Vestar, Inc. Delivery vehicles with amphiphile-associated active ingredient
DK175531B1 (da) 1986-12-15 2004-11-22 Nexstar Pharmaceuticals Inc Leveringsvehikel med amphiphil-associeret aktiv bestanddel
US5179079A (en) 1986-12-16 1993-01-12 Novo Nordisk A/S Nasal formulation and intranasal administration therewith
US4837028A (en) 1986-12-24 1989-06-06 Liposome Technology, Inc. Liposomes with enhanced circulation time
US4839111A (en) 1987-02-02 1989-06-13 The University Of Tennessee Research Corporation Preparation of solid core liposomes
US5234767A (en) 1987-03-13 1993-08-10 Micro-Pak, Inc. Hybrid paucilamellar lipid vesicles
KR880012221A (ko) 1987-04-13 1988-11-26 사노 가즈오 에스테르 또는 아미드를 활성성분으로 함유하는 약제 조성물
WO1988007850A1 (en) 1987-04-16 1988-10-20 The Liposome Company, Inc. Liposome continuous size reduction method and apparatus
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
US4963362A (en) 1987-08-07 1990-10-16 Regents Of The University Of Minnesota Freeze-dried liposome mixture containing cyclosporin
US4798860A (en) 1987-08-21 1989-01-17 Akzo America Inc. Flame resistant organic substances containing polymeric flame retardants
US5651991A (en) 1987-10-28 1997-07-29 Nippon Shinyaku Co. Ltd. Drug carriers
US5244925A (en) 1987-12-18 1993-09-14 Kabi Pharmacia Aktiebolag Emulsion for parenteral administration
US5807572A (en) 1988-02-18 1998-09-15 Depotech Corporation Multivesicular liposomes having a biologically active substance encapsulated therein in the presence of a hydrochloride
FR2627696B1 (fr) 1988-02-26 1991-09-13 Fournier Innovation Synergie Nouvelle forme galenique du fenofibrate
US5446070A (en) 1991-02-27 1995-08-29 Nover Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5656286A (en) 1988-03-04 1997-08-12 Noven Pharmaceuticals, Inc. Solubility parameter based drug delivery system and method for altering drug saturation concentration
US5719197A (en) 1988-03-04 1998-02-17 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5269979A (en) 1988-06-08 1993-12-14 Fountain Pharmaceuticals, Inc. Method for making solvent dilution microcarriers
US5133965A (en) 1988-06-08 1992-07-28 Fountain Pharmaceuticals, Inc. Dressing material having adsorbed thereon a solvent dilution microcarrier precursor solution
US5217707A (en) 1988-06-16 1993-06-08 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt. Pharmaceutical composition and process for the preparation thereof
US4937078A (en) 1988-08-26 1990-06-26 Mezei Associates Limited Liposomal local anesthetic and analgesic products
GB8822857D0 (en) 1988-09-29 1988-11-02 Patralan Ltd Pharmaceutical formulations
CA1337397C (en) 1988-09-29 1995-10-24 Hideo Nakajima Emulsified composition
JP2955314B2 (ja) 1988-10-27 1999-10-04 リージェンツ・オブ・ザ・ユニバーシティー・オブ・ミネソタ Ｉｌ―２含有リポソーム免疫アジュバント
US5128147A (en) 1989-01-06 1992-07-07 Thermal Developments, Inc. Heat intensifier and localizer for radiofrequency thermotherapy
DE3903056A1 (de) 1989-02-02 1990-08-09 Braun Melsungen Ag Fettemulsion zur intraperitonealen applikation, ihre herstellung und anwendung
DE3903057A1 (de) 1989-02-02 1990-08-09 Braun Melsungen Ag Fettemulsion zur endotrachealen applikation, ihre herstellung und anwendung
DE3904099C1 (zh) 1989-02-11 1990-07-12 Schuelke & Mayr Gmbh, 2000 Norderstedt, De
CA2013755C (en) 1989-04-05 1993-11-30 Simon Benita Medicinal emulsions
JP2582186B2 (ja) 1989-05-04 1997-02-19 サウザン リサーチ インスティチュート カプセル封じ法及びその製品
CH677886A5 (zh) 1989-06-26 1991-07-15 Hans Georg Prof Dr Weder
FR2649888B1 (fr) 1989-07-18 1994-08-26 Exsymol Sa Produits pour applications cutanees, a effets cosmetiques ou/et therapeutiques
FR2651680B1 (fr) 1989-09-14 1991-12-27 Medgenix Group Sa Nouveau procede de preparation de microparticules lipidiques.
GB8921222D0 (en) 1989-09-20 1989-11-08 Riker Laboratories Inc Medicinal aerosol formulations
IL95952A0 (en) 1989-10-19 1991-07-18 Sterling Drug Inc Aerosol composition for topical medicament
IE904098A1 (en) 1989-11-13 1991-05-22 Nova Pharm Corp Lipospheres for controlled delivery of substances
US5227165A (en) 1989-11-13 1993-07-13 Nova Pharmaceutical Corporation Liposphere delivery systems for local anesthetics
US5188837A (en) 1989-11-13 1993-02-23 Nova Pharmaceutical Corporation Lipsopheres for controlled delivery of substances
JP2785981B2 (ja) 1989-11-20 1998-08-13 株式会社資生堂 乳化組成物
US5294604A (en) 1989-12-20 1994-03-15 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Method of treating ocular diseases by periocular administration of cyclosporine A or G
US5580575A (en) 1989-12-22 1996-12-03 Imarx Pharmaceutical Corp. Therapeutic drug delivery systems
US5389377A (en) 1989-12-22 1995-02-14 Molecular Bioquest, Inc. Solid care therapeutic compositions and methods for making same
US5733572A (en) 1989-12-22 1998-03-31 Imarx Pharmaceutical Corp. Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles
DE4000397A1 (de) 1990-01-09 1991-07-11 Hoechst Ag Lipidselektive antioxidantien sowie deren herstellung und verwendung
CA2033725C (en) 1990-01-24 2001-05-29 Folker Pittrof Pharmaceutical and cosmetic compositions containing a salt of cholanic acid
US5648375A (en) 1990-02-12 1997-07-15 Virginia Commonwealth University Use of hydrophobic compounds and anesthetics in combination with allosteric hemoglobin modifiers
GB9007052D0 (en) 1990-03-29 1990-05-30 Skua Investments Ltd Pharmaceutical formulations
US5091188A (en) 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5246707A (en) 1990-04-26 1993-09-21 Haynes Duncan H Sustained release delivery of water-soluble bio-molecules and drugs using phospholipid-coated microcrystals, microdroplets and high-concentration liposomes
US5091187A (en) 1990-04-26 1992-02-25 Haynes Duncan H Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs
US5679650A (en) 1993-11-24 1997-10-21 Fukunaga; Atsuo F. Pharmaceutical compositions including mixtures of an adenosine compound and a catecholamine
DE4015108A1 (de) 1990-05-11 1991-11-14 Leopold Pharma Gmbh Stabile emulsion zur applikation pharmakologisch aktiver wirkstoffe
US5753258A (en) 1990-10-19 1998-05-19 University Of Florida Artificial viral envelopes
US5256641A (en) 1990-11-01 1993-10-26 State Of Oregon Covalent polar lipid-peptide conjugates for immunological targeting
HU211580A9 (hu) 1990-11-27 1995-12-28 Egyt Gyogyszervegyeszeti Gyar Megnövelt stabilitású, szövetkárosító hatás nélküli piroxikam-oldatok Az átmeneti oltalom az 1., 2., 5. és 6. igénypontokra vonatkozik.
HU205550B (en) 1990-11-27 1992-05-28 Egyt Gyogyszervegyeszeti Gyar Process for producing pyroxycam solution of increased stability, free from effects damaging tussues
US5536413A (en) 1990-12-03 1996-07-16 Pall Corporation Method for treating a parenteral emulsion-containing medicament fluid
DE4039602A1 (de) 1990-12-12 1992-06-17 Bauer Kurt Heinz Prof Dr Pharmazeutische formulierungen
US5399363A (en) 1991-01-25 1995-03-21 Eastman Kodak Company Surface modified anticancer nanoparticles
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
JP2546551B2 (ja) 1991-01-31 1996-10-23 新日本製鐵株式会社 γ及びβ二相ＴｉＡｌ基金属間化合物合金及びその製造方法
US5332576A (en) 1991-02-27 1994-07-26 Noven Pharmaceuticals, Inc. Compositions and methods for topical administration of pharmaceutically active agents
US5256422A (en) 1991-03-28 1993-10-26 Micro Vesicular Systems, Inc. Lipid vesicle containing water-in-oil emulsions
US5167950A (en) 1991-03-28 1992-12-01 S. C. Johnson & Son High alcohol content aerosol antimicrobial mousse
US5498420A (en) 1991-04-12 1996-03-12 Merz & Co. Gmbh & Co. Stable small particle liposome preparations, their production and use in topical cosmetic, and pharmaceutical compositions
KR920019370A (ko) 1991-04-26 1992-11-19 스야마 다다카즈 주입 제제
US5192802A (en) 1991-09-25 1993-03-09 Mcneil-Ppc, Inc. Bioadhesive pharmaceutical carrier
DE4132677C2 (de) 1991-10-01 1995-08-24 Braun Melsungen Ag Flüchtige Inhalationsnarkotika enthaltende Liposomen, ihre Herstellung und Verwendung
DE4133694C2 (de) 1991-10-11 1993-10-07 Fresenius Ag Verwendung einer Emulsion mit mehrfach ungesättigten Fettsären zur i.v.-Verabreichung zur Behandlung von Hauterkrankungen
US5925014A (en) 1992-12-07 1999-07-20 Teeple Jr.; Edward Method and apparatus for preparing and administering intravenous anesthesia infusions
US5807316A (en) 1991-12-06 1998-09-15 Teeple, Jr.; Edward Method and apparatus for preparing and administering intravenous anesthesia infusions
US5876754A (en) 1992-01-17 1999-03-02 Alfatec-Pharma Gmbh Solid bodies containing active substances and a structure consisting of hydrophilic macromolecules, plus a method of producing such bodies
IL101007A (en) 1992-02-18 1997-08-14 Pharmos Ltd Dry stable compositions prepared by lyophilization
JPH06507918A (ja) 1992-03-04 1994-09-08 アクゾ・エヌ・ヴエー ｉｎ　ｖｉｖｏ　結合対プレターゲティング
IL101387A (en) 1992-03-26 1999-11-30 Pharmos Ltd Emulsion with enhanced topical and/or transdermal systemic effect utilizing submicron oil droplets
SE9200951D0 (sv) 1992-03-27 1992-03-27 Kabi Pharmacia Ab Pharmaceutical composition containing a defined lipid system
SE9200952D0 (sv) 1992-03-27 1992-03-27 Kabi Pharmacia Ab Pharmaceutical carrier system containing defined lipids
US5641508A (en) 1994-01-13 1997-06-24 Anticancer, Inc. Method for delivering melanin to hair follicles
US5527537A (en) 1992-05-18 1996-06-18 Dietl; Hans Pharmaceutical preparation containing cyclosporine(s) for intravenous administration and a process for its production
ES2105262T3 (es) 1992-05-18 1997-10-16 Minnesota Mining & Mfg Dispositivo de suministro de farmaco a traves de las mucosas.
US5518730A (en) 1992-06-03 1996-05-21 Fuisz Technologies Ltd. Biodegradable controlled release flash flow melt-spun delivery system
DE4221256C2 (de) 1992-06-26 1997-07-10 Lancaster Group Ag Galenische Zusammensetzung für die topische Anwendung
US5308874A (en) 1992-06-26 1994-05-03 Vyrex Corporation Airborne protectants against oxidative tissue damage
WO1994005298A1 (en) 1992-08-28 1994-03-17 Pharmos Corporation Submicron emulsions as ocular drug delivery vehicles
US5922340A (en) 1992-09-10 1999-07-13 Children's Medical Center Corporation High load formulations and methods for providing prolonged local anesthesia
DE69331387T2 (de) 1992-09-10 2002-08-22 Childrens Medical Center Biodegradierbare polymeren matrizen mit verzoegerter freisetzung von lokalanaesthetika
AU660852B2 (en) 1992-11-25 1995-07-06 Elan Pharma International Limited Method of grinding pharmaceutical substances
US5958449A (en) 1992-12-02 1999-09-28 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for bacterial infections
AU3244393A (en) 1992-12-02 1994-06-22 Vestar, Inc. Antibiotic formulation and process
US6117066A (en) 1992-12-04 2000-09-12 Somatics, Inc. Prevention of seizure arising from medical magnetoictal non-convulsive stimulation therapy
US5346702A (en) 1992-12-04 1994-09-13 Sterling Winthrop Inc. Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization
US5298262A (en) 1992-12-04 1994-03-29 Sterling Winthrop Inc. Use of ionic cloud point modifiers to prevent particle aggregation during sterilization
US5302401A (en) 1992-12-09 1994-04-12 Sterling Winthrop Inc. Method to reduce particle size growth during lyophilization
US5336507A (en) 1992-12-11 1994-08-09 Sterling Winthrop Inc. Use of charged phospholipids to reduce nanoparticle aggregation
US5429824A (en) 1992-12-15 1995-07-04 Eastman Kodak Company Use of tyloxapole as a nanoparticle stabilizer and dispersant
US5352459A (en) 1992-12-16 1994-10-04 Sterling Winthrop Inc. Use of purified surface modifiers to prevent particle aggregation during sterilization
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
US5916596A (en) 1993-02-22 1999-06-29 Vivorx Pharmaceuticals, Inc. Protein stabilized pharmacologically active agents, methods for the preparation thereof and methods for the use thereof
US5498421A (en) 1993-02-22 1996-03-12 Vivorx Pharmaceuticals, Inc. Composition useful for in vivo delivery of biologics and methods employing same
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
US5785976A (en) 1993-03-05 1998-07-28 Pharmacia & Upjohn Ab Solid lipid particles, particles of bioactive agents and methods for the manufacture and use thereof
US6190894B1 (en) 1993-03-19 2001-02-20 The Regents Of The University Of California Method and compositions for disrupting the epithelial barrier function
ATE218855T1 (de) 1993-03-22 2002-06-15 Cognis Australia Pty Ltd Wasserdispersible therapeutische carotenoid verbindungen
US6113921A (en) 1993-03-23 2000-09-05 Pharmos Corp. Topical and transdermal delivery system utilizing submicron oil spheres
DE59406065D1 (de) 1993-03-24 1998-07-02 Ciba Geigy Ag Verfahren zur Herstellung einer Liposomendispersion im Hochdruckbereich
CA2120197A1 (en) 1993-04-02 1994-10-03 Kenji Endo Stable aqueous dispersions containing liposomes
US5759571A (en) 1993-05-11 1998-06-02 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for drug resistant infections
US5576016A (en) 1993-05-18 1996-11-19 Pharmos Corporation Solid fat nanoemulsions as drug delivery vehicles
CH686761A5 (de) 1993-05-27 1996-06-28 Sandoz Ag Galenische Formulierungen.
US5478860A (en) 1993-06-04 1995-12-26 Inex Pharmaceuticals Corp. Stable microemulsions for hydrophobic compound delivery
US5639474A (en) 1993-07-01 1997-06-17 Hanmi Pharm. Ind., Ltd. Cyclosporin soft capsule composition
US5853755A (en) 1993-07-28 1998-12-29 Pharmaderm Laboratories Ltd. Biphasic multilamellar lipid vesicles
AU679793B2 (en) 1993-09-29 1997-07-10 Alza Corporation Monoglyceride/lactate ester permeation enhancer
US5994318A (en) 1993-10-04 1999-11-30 Albany Medical College Cochleate delivery vehicles
SE9303281D0 (sv) 1993-10-07 1993-10-07 Astra Ab New formulation
GB9323588D0 (en) 1993-11-16 1994-01-05 Cortecs Ltd Hydrophobic preparation
RO116341B1 (ro) 1993-11-16 2001-01-30 Depotech Corp La Jolia Lipozom multivezicular si procedeu de obtinere a acestuia
US5766627A (en) 1993-11-16 1998-06-16 Depotech Multivescular liposomes with controlled release of encapsulated biologically active substances
WO1995016437A1 (en) 1993-12-17 1995-06-22 Micro-Pak, Inc. Method of transmitting a biologically active material to a cell
AU691248B2 (en) 1994-02-04 1998-05-14 Scotia Lipidteknik Ab Oil-in-water emulsions
ATE241340T1 (de) 1994-02-17 2003-06-15 New York Blood Ct Inc Biologische bioadhäsive präparate, die fibrinkleber und liposomen enthalten, verfahren für ihre herstellung und verwendung
US5746223A (en) 1996-10-11 1998-05-05 Williams; Kevin Jon Method of forcing the reverse transport of cholesterol from a body part to the liver while avoiding harmful disruptions of hepatic cholesterol homeostasis
CA2184834A1 (en) 1994-03-11 1995-09-14 Yoshiyuki Mori Liposome preparation
US5364633A (en) 1994-03-14 1994-11-15 Dow Corning Corporation Silicone vesicles and entrapment
GB9405304D0 (en) 1994-03-16 1994-04-27 Scherer Ltd R P Delivery systems for hydrophobic drugs
US20020173547A1 (en) 1994-03-22 2002-11-21 Jones Christopher Buchan Pharmaceuticals compositions
US5731356A (en) 1994-03-22 1998-03-24 Zeneca Limited Pharmaceutical compositions of propofol and edetate
GB9405593D0 (en) 1994-03-22 1994-05-11 Zeneca Ltd Pharmaceutical compositions
US5451408A (en) 1994-03-23 1995-09-19 Liposome Pain Management, Ltd. Pain management with liposome-encapsulated analgesic drugs
SE518578C2 (sv) 1994-06-15 2002-10-29 Gs Dev Ab Lipidbaserad komposition
SE9402453D0 (sv) 1994-07-12 1994-07-12 Astra Ab New pharmaceutical preparation
US5693337A (en) 1994-07-13 1997-12-02 Wakamoto Pharmaceutical Co., Ltd. Stable lipid emulsion
FR2722984B1 (fr) 1994-07-26 1996-10-18 Effik Lab Procede de preparation de formes pharmaceutiques seches et les compositions pharmaceutiques ainsi realisees
US5993850A (en) 1994-09-13 1999-11-30 Skyepharma Inc. Preparation of multivesicular liposomes for controlled release of encapsulated biologically active substances
IT1270093B (it) 1994-09-28 1997-04-28 Zambon Spa Processo per la purificazione di 2,6-diisopropilfenolo
US5635203A (en) 1994-09-29 1997-06-03 Alza Corporation Transdermal device having decreased delamination
EP0704206B1 (de) 1994-09-30 2002-09-04 MIKA Pharma Gesellschaft für die Entwicklung und Vermarktung pharmazeutischer Produkte mbH Pharmazeutische Zusammensetzung
US5773106A (en) 1994-10-21 1998-06-30 The Dow Chemical Company Polyolefin compositions exhibiting heat resistivity, low hexane-extractives and controlled modulus
US5858398A (en) 1994-11-03 1999-01-12 Isomed Inc. Microparticular pharmaceutical compositions
US5603951A (en) 1994-11-09 1997-02-18 Hanmi Pharm. Ind. Co., Ltd. Cyclosporin-containing soft capsule compositions
DE4440337A1 (de) 1994-11-11 1996-05-15 Dds Drug Delivery Services Ges Pharmazeutische Nanosuspensionen zur Arzneistoffapplikation als Systeme mit erhöhter Sättigungslöslichkeit und Lösungsgeschwindigkeit
US5660854A (en) 1994-11-28 1997-08-26 Haynes; Duncan H Drug releasing surgical implant or dressing material
US5589177A (en) 1994-12-06 1996-12-31 Helene Curtis, Inc. Rinse-off water-in-oil-in-water compositions
US5656280A (en) 1994-12-06 1997-08-12 Helene Curtis, Inc. Water-in-oil-in-water compositions
US5635536A (en) 1994-12-07 1997-06-03 Pharmacia & Upjohn Aktiebolag Emulsion suitable for administering a sphingolipid
US5635540A (en) 1994-12-09 1997-06-03 The University Of Virginia Patent Foundation Stabilized topical pharmaceutical preparations
US5664207A (en) 1994-12-16 1997-09-02 Xcellenet, Inc. Systems and methods for automatically sharing information among remote/mobile nodes
GB9426104D0 (en) * 1994-12-23 1995-02-22 Merck Sharp & Dohme Use of surfactants and emulsions
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
US5618522A (en) 1995-01-20 1997-04-08 The Procter & Gamble Company Emulsion compositions
US5885172A (en) 1997-05-27 1999-03-23 Acushnet Company Multilayer golf ball with a thin thermoset outer layer
FR2730231B1 (fr) 1995-02-02 1997-04-04 Fournier Sca Lab Association de fenofibrate et de vitamine e, utilisation en therapeutique
US5571536A (en) 1995-02-06 1996-11-05 Nano Systems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5560931A (en) 1995-02-14 1996-10-01 Nawosystems L.L.C. Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5534270A (en) 1995-02-09 1996-07-09 Nanosystems Llc Method of preparing stable drug nanoparticles
US5510118A (en) 1995-02-14 1996-04-23 Nanosystems Llc Process for preparing therapeutic compositions containing nanoparticles
US6282712B1 (en) 1995-03-10 2001-08-28 Microsoft Corporation Automatic software installation on heterogeneous networked computer systems
US5496537A (en) 1995-03-23 1996-03-05 Henry; Richard A. Propofol hydrofluorocarbon propellant formulations
ZA962214B (en) 1995-04-10 1996-10-07 Farmarc Nederland Bv Pharmaceutical composition
US5827534A (en) 1995-05-24 1998-10-27 University Of Maryland At Baltimore Oral dosage composition comprising zonnula occludens toxin and a therapeutic agent for intestinal delivery
US5882676A (en) 1995-05-26 1999-03-16 Alza Corporation Skin permeation enhancer compositions using acyl lactylates
US5785991A (en) 1995-06-07 1998-07-28 Alza Corporation Skin permeation enhancer compositions comprising glycerol monolaurate and lauryl acetate
US5667809A (en) 1995-06-07 1997-09-16 Alliance Pharmaceutical Corp. Continuous fluorochemical microdispersions for the delivery of lipophilic pharmaceutical agents
GB9514878D0 (en) 1995-07-20 1995-09-20 Danbiosyst Uk Vitamin E as a solubilizer for drugs contained in lipid vehicles
FR2737121B1 (fr) 1995-07-27 1997-10-03 Cl Pharma Nouvelles formulations galeniques du fenofibrate et leurs applications
US5658583A (en) 1995-07-28 1997-08-19 Zhang; Jie Apparatus and methods for improved noninvasive dermal administration of pharmaceuticals
US5827822A (en) 1996-03-25 1998-10-27 Sangstat Medical Corporation Cyclosporin a formulations as nanoparticles
US6004962A (en) 1995-09-11 1999-12-21 Gooberman; Lance L. Rapid opioid detoxification
US5789411A (en) 1995-09-11 1998-08-04 Lance L. Gooberman P. C. Improvements to rapid opioid detoxification
SE9503143D0 (sv) 1995-09-12 1995-09-12 Astra Ab New preparation
WO1997010814A1 (en) 1995-09-18 1997-03-27 Vesifact Ag Propofol nanodispersions
EP0863748A4 (en) 1995-10-11 1999-11-03 Kevin Jon William LIPOSOMAL COMPOSITIONS AND METHODS OF USE
US5705039A (en) 1995-10-13 1998-01-06 Albemarle Corporation Process for purifying a 2,6-dialkylphenol
ATE386506T1 (de) 1995-10-17 2008-03-15 Jagotec Ag Verabreichung unlöslicher arzneistoffe
FR2740042B1 (fr) 1995-10-23 1997-11-14 Oreal Support, et composition contenant ce support et un actif cosmetique ou dermatologique stabilise
US5591311A (en) 1995-10-26 1997-01-07 Albemarle Corporation Process for purifying a 2,6-dialkylphenol
EP0770387B1 (en) 1995-10-28 1999-08-11 B. Braun Melsungen Ag Pharmaceutical composition containing a local anesthetic and/or centrally acting analgesic
US5702720A (en) 1995-12-22 1997-12-30 Minnesota Mining And Manufacturing Company Transdermal device for the delivery of flurbiprofen
CZ288631B6 (cs) 1996-01-18 2001-08-15 Galena, A. S. Léčivé přípravky s obsahem cyklosporinu
US5858401A (en) 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
US5912007A (en) 1996-02-29 1999-06-15 Warner-Lambert Company Delivery system for the localized administration of medicaments to the upper respiratory tract and methods for preparing and using same
US5637625A (en) * 1996-03-19 1997-06-10 Research Triangle Pharmaceuticals Ltd. Propofol microdroplet formulations
US5747060A (en) 1996-03-26 1998-05-05 Euro-Celtique, S.A. Prolonged local anesthesia with colchicine
US5660858A (en) 1996-04-03 1997-08-26 Research Triangle Pharmaceuticals Cyclosporin emulsions
SE9601421D0 (sv) 1996-04-12 1996-04-12 Astra Ab New composition
US5922705A (en) 1996-04-12 1999-07-13 Intensive Narcotic Detoxification Centers Of America, Llc Rapid narcotic detoxification
US5804585A (en) * 1996-04-15 1998-09-08 Texas Biotechnology Corporation Thieno-pyridine sulfonamides derivatives thereof and related compounds that modulate the activity of endothelin
EA001574B1 (ru) 1996-06-21 2001-06-25 Мерк Шарп Энд Домэ Лимитед Производные спиропиперидина и их использование в качестве терапевтических агентов
GB9613969D0 (en) 1996-07-03 1996-09-04 Merck Sharp & Dohme Therapeutic agents
US6284267B1 (en) 1996-08-14 2001-09-04 Nutrimed Biotech Amphiphilic materials and liposome formulations thereof
ES2252780T3 (es) 1996-08-22 2006-05-16 Jagotec Ag Composiciones que comprenden microparticulas de sustancias insolubles en agua y metodo para su preparacion.
ES2241055T3 (es) 1996-08-23 2005-10-16 Endo Pharmaceuticals Inc Composicion que contiene un anticonvulsionante para tratar el dolor neuropatico.
US6046187A (en) 1996-09-16 2000-04-04 Children's Medical Center Corporation Formulations and methods for providing prolonged local anesthesia
FR2753626B1 (fr) 1996-09-20 1998-11-06 Centre International De Rech Dermatologiques Galderma Cird Galderma Nouvelles compositions topiques sous forme d'emulsion fluide h/e a forte teneur en glycol pro-penetrant
CA2276269C (en) 1996-10-15 2008-09-02 The Liposome Company, Inc. N-acyl phosphatidylethanolamine-mediated liposomal drug delivery
US6261537B1 (en) 1996-10-28 2001-07-17 Nycomed Imaging As Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors
KR20000052829A (ko) 1996-10-28 2000-08-25 조오지 디빈센조, 토브 아스 헬지, 에바 요한손 진단/치료제 또는 그와 관련된 개선
US6331289B1 (en) 1996-10-28 2001-12-18 Nycomed Imaging As Targeted diagnostic/therapeutic agents having more than one different vectors
US6096291A (en) 1996-12-27 2000-08-01 Biovector Therapeutics, S.A. Mucosal administration of substances to mammals
US5985248A (en) 1996-12-31 1999-11-16 Inhale Therapeutic Systems Processes for spray drying solutions of hydrophobic drugs and compositions thereof
US5908619A (en) 1997-01-09 1999-06-01 Minnesota Mining And Manufacturing Company Hydroalcoholic compositions thickened using surfactant/polymer complexes
US6019997A (en) 1997-01-09 2000-02-01 Minnesota Mining And Manufacturing Hydroalcoholic compositions for transdermal penetration of pharmaceutical agents
US5908825A (en) 1997-01-09 1999-06-01 University Of Maryland At Baltimore Dosage composition for nasal delivery and method of use of the same
US5990176A (en) 1997-01-27 1999-11-23 Abbott Laboratories Fluoroether compositions and methods for inhibiting their degradation in the presence of a Lewis acid
US5827533A (en) 1997-02-06 1998-10-27 Duke University Liposomes containing active agents aggregated with lipid surfactants
DE19709704C2 (de) 1997-03-10 1999-11-04 Michael Georgieff Verwendung einer flüssigen Präparation von Xenon zur intravenösen Verabreichung bei Einleitung und/oder Aufrechterhaltung der Anaesthesie
US6090800A (en) 1997-05-06 2000-07-18 Imarx Pharmaceutical Corp. Lipid soluble steroid prodrugs
US5945510A (en) 1997-05-21 1999-08-31 University Of Maryland, Baltimore Substantially pure zonulin, a physiological modulator of mammalian tight junctions
CH692322A5 (it) 1997-05-26 2002-05-15 Westy Ag Formulazione iniettabile limpida di Propofol.
US20020107291A1 (en) 1997-05-26 2002-08-08 Vincenzo De Tommaso Clear, injectable formulation of an anesthetic compound
US6372234B1 (en) 1997-05-27 2002-04-16 Sembiosys Genetics Inc. Products for topical applications comprising oil bodies
US6217886B1 (en) 1997-07-14 2001-04-17 The Board Of Trustees Of The University Of Illinois Materials and methods for making improved micelle compositions
WO1999003448A1 (en) 1997-07-14 1999-01-28 The Board Of Trustees Of The University Of Illinois Materials and methods for making improved micelle compositions
US20020115609A1 (en) 1997-07-14 2002-08-22 Hayat Onyuksel Materials and methods for making improved micelle compositions
DE69823851D1 (de) 1997-07-15 2004-06-17 Daiichi Seiyaku Co Nefiracetam zur prophylaxe und behandlung von propofol verursachtem gedächtnisschwund
US5980936A (en) 1997-08-07 1999-11-09 Alliance Pharmaceutical Corp. Multiple emulsions comprising a hydrophobic continuous phase
US6106858A (en) 1997-09-08 2000-08-22 Skyepharma, Inc. Modulation of drug loading in multivescular liposomes
US6391336B1 (en) 1997-09-22 2002-05-21 Royer Biomedical, Inc. Inorganic-polymer complexes for the controlled release of compounds including medicinals
US6281175B1 (en) 1997-09-23 2001-08-28 Scimed Life Systems, Inc. Medical emulsion for lubrication and delivery of drugs
US6054421A (en) 1997-09-23 2000-04-25 Scimed Life Systems, Inc. Medical emulsion lubricant
US6309623B1 (en) 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
US6433040B1 (en) 1997-09-29 2002-08-13 Inhale Therapeutic Systems, Inc. Stabilized bioactive preparations and methods of use
US5885597A (en) 1997-10-01 1999-03-23 Medical Research Industries,Inc. Topical composition for the relief of pain
DE19745950A1 (de) 1997-10-17 1999-04-22 Dds Drug Delivery Service Ges Arzneistoffträgerpartikel für die gewebespezifische Arzneistoffapplikation
US6121261A (en) 1997-11-19 2000-09-19 Merck & Co., Inc. Method for treating attention deficit disorder
US5972938A (en) 1997-12-01 1999-10-26 Merck & Co., Inc. Method for treating or preventing psychoimmunological disorders
IT1296914B1 (it) 1997-12-01 1999-08-03 Maria Rosa Gasco Composizione farmaceutica comprendente microparticelle atte al passaggio transmucosale ed al superamento della barriera
US6063762A (en) 1997-12-05 2000-05-16 Chong Kun Dang Corp. Cyclosporin-containing microemulsion preconcentrate composition
US6013665A (en) 1997-12-16 2000-01-11 Abbott Laboratories Method for enhancing the absorption and transport of lipid soluble compounds using structured glycerides
US6123923A (en) 1997-12-18 2000-09-26 Imarx Pharmaceutical Corp. Optoacoustic contrast agents and methods for their use
US6585752B2 (en) 1998-06-23 2003-07-01 Innercool Therapies, Inc. Fever regulation method and apparatus
US6843800B1 (en) 1998-01-23 2005-01-18 Innercool Therapies, Inc. Patient temperature regulation method and apparatus
US6086376A (en) 1998-01-30 2000-07-11 Rtp Pharma Inc. Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant
PT1052975E (pt) 1998-02-10 2007-10-29 Sicor Inc Composição de propofol que contém sulfito
BE1011899A6 (fr) 1998-04-30 2000-02-01 Ucb Sa Compositions pharmaceutiques gelifiables utilisables.
US6312715B1 (en) 1998-05-01 2001-11-06 3M Innovative Properties Company Adhesive microsphere drug delivery composition
US6254853B1 (en) 1998-05-08 2001-07-03 Vyrex Corporation Water soluble pro-drugs of propofol
MXPA00011835A (es) 1998-06-03 2002-10-17 Scott Lab Inc Aparato y metodo para proveer alivio del dolor de un paciente consciente y ansiedad asociada con procedimientos medicos o quirurgicos.
US5962536A (en) 1998-07-31 1999-10-05 Komer; Gene Injectable propofol formulations
US6204257B1 (en) 1998-08-07 2001-03-20 Universtiy Of Kansas Water soluble prodrugs of hindered alcohols
IL141095A0 (en) 1998-08-19 2002-02-10 Rtp Pharma Inc Injectable aqueous dispersions of propofol
US6025362A (en) 1998-08-31 2000-02-15 Fukunaga; Atsuo F. Uses of xanthine compounds
FR2784601B1 (fr) 1998-09-21 2000-11-17 Gerard Auberger Concentre hydrosoluble obtenu a partir d'une phase emulgatrice ou hydrosolubilisante et d'un complexe de matieres lipophiles liquides d'origine vegetale
JP2000119177A (ja) 1998-10-06 2000-04-25 Torii Yakuhin Kk 鎮痛剤
US6150423A (en) 1998-10-15 2000-11-21 Phoenix Scientific, Inc. Propofol-based anesthetic and method of making same
US6028108A (en) 1998-10-22 2000-02-22 America Home Products Corporation Propofol composition comprising pentetate
US6140374A (en) 1998-10-23 2000-10-31 Abbott Laboratories Propofol composition
US6140373A (en) 1998-10-23 2000-10-31 Abbott Laboratories Propofol composition
US6180136B1 (en) 1998-11-10 2001-01-30 Idexx Laboratories, Inc. Phospholipid-coated microcrystals for the sustained release of pharmacologically active compounds and methods of their manufacture and use
PL348193A1 (en) 1998-12-11 2002-05-06 Pharmasolutions Self-emulsifying compositions for drugs poorly soluble in water
FR2787322B1 (fr) 1998-12-18 2002-10-18 Galderma Res & Dev Emulsion huile-dans-eau comprenant un agent actif micronise et un systeme emulsionnant approprie
US6436367B1 (en) 1998-12-21 2002-08-20 Generex Pharmaceuticals Inc. Aerosol formulations for buccal and pulmonary application
US7214711B2 (en) 1998-12-23 2007-05-08 Neurotherapeutics Pharma Llc Method of treating migraine headache without aura
FR2788449B1 (fr) 1999-01-14 2001-02-16 Oreal Nanoemulsion a base de citrates d'alkylether, et ses utilisations dans les domaines cosmetique, dermatologique, pharmaceutique et/ou ophtalmologique
US6153217A (en) 1999-01-22 2000-11-28 Biodelivery Sciences, Inc. Nanocochleate formulations, process of preparation and method of delivery of pharmaceutical agents
EP1143962B1 (en) 1999-01-28 2004-11-24 Dinesh Shantilal Patel Parenteral solution of propofol (2,6-diisoprophylphenol) and 2.5-di-0-methyl-1.4;3.6-dianhydro-d-glucitol as a solvent
US6075059A (en) 1999-02-24 2000-06-13 The Ohio State University Compositions for dental anesthesia
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US6761903B2 (en) 1999-06-30 2004-07-13 Lipocine, Inc. Clear oil-containing pharmaceutical compositions containing a therapeutic agent
US6267985B1 (en) 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
EP1124416A1 (en) 1999-03-15 2001-08-22 John Claude Krusz Treatment of acute headaches and chronic pain using rapidly-cleared anesthetic drug at sub-anesthetic dosages
US6177477B1 (en) 1999-03-24 2001-01-23 American Home Products Corporation Propofol formulation containing TRIS
JP2002541087A (ja) 1999-04-05 2002-12-03 バクスター・インターナショナル・インコーポレイテッド 防腐添加剤を含有するプロポフォール組成物
US6100302A (en) 1999-04-05 2000-08-08 Baxter International Inc. Propofol formulation with enhanced microbial characteristics
US6383471B1 (en) 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
US6057289A (en) 1999-04-30 2000-05-02 Pharmasolutions, Inc. Pharmaceutical composition comprising cyclosporin in association with a carrier in a self-emulsifying drug delivery system
US6291013B1 (en) 1999-05-03 2001-09-18 Southern Biosystems, Inc. Emulsion-based processes for making microparticles
US6440456B1 (en) 1999-06-09 2002-08-27 L'oreal S.A. Aqueous carrier systems for lipophilic ingredients
US6011067A (en) 1999-06-11 2000-01-04 Thione International, Inc. Antioxidant composition for the treatment of psoriasis and related diseases
ATE327741T1 (de) 1999-06-21 2006-06-15 Kuhnil Pharmaceutical Co Ltd Propofol enthaltende anästhetische zusammensetzung zur intravenösen injektion
WO2001008032A2 (en) 1999-07-23 2001-02-01 Merck & Co., Inc. Method and storage/retrieval system of chemical substances in a database
US6653354B2 (en) 1999-07-29 2003-11-25 Protexeon Limited NMDA antagonist comprising xenon
GB9917822D0 (en) 1999-07-29 1999-09-29 Imperial College Nmda antagonist
KR100339428B1 (ko) 1999-09-07 2002-05-31 박종섭 불휘발성 강유전체 메모리의 셀 블록 구조
US6720001B2 (en) 1999-10-18 2004-04-13 Lipocine, Inc. Emulsion compositions for polyfunctional active ingredients
DE19951617A1 (de) 1999-10-26 2001-05-03 Basf Ag Zubereitungen pharmazeutische Wirkstoffe
US6264981B1 (en) 1999-10-27 2001-07-24 Anesta Corporation Oral transmucosal drug dosage using solid solution
US6071933A (en) 1999-12-03 2000-06-06 Diversified Medical Innovations, Inc. Homogeneous remifentanil-propofol blend for patient controlled anesthesia and process for its use
US6350480B1 (en) 1999-12-30 2002-02-26 Wm. Wrigley Jr. Company Chewing gum product including a hydrophilic gum base and method of producing
GB2359747B (en) 2000-02-29 2002-04-24 Maelor Pharmaceuticals Ltd Anaesthetic formulations
NZ522896A (en) 2000-05-10 2004-05-28 Skyepharma Canada Inc Media milling
SE0001865D0 (sv) 2000-05-19 2000-05-19 Astrazeneca Ab Management of septic shock
US6938619B1 (en) 2000-06-13 2005-09-06 Scott Laboratories, Inc. Mask free delivery of oxygen and ventilatory monitoring
WO2001097779A2 (en) 2000-06-16 2001-12-27 Rtp Pharma Inc. Improved injectable dispersions of propofol
US6410583B1 (en) 2000-07-25 2002-06-25 Merck Frosst Canada & Co. Cyclopentanoindoles, compositions containing such compounds and methods of treatment
US6623765B1 (en) 2000-08-01 2003-09-23 University Of Florida, Research Foundation, Incorporated Microemulsion and micelle systems for solubilizing drugs
US6362234B1 (en) 2000-08-15 2002-03-26 Vyrex Corporation Water-soluble prodrugs of propofol for treatment of migrane
CN100457090C (zh) 2000-08-31 2009-02-04 斯凯伊药品加拿大公司 磨制颗粒
JPWO2002021517A1 (ja) 2000-09-04 2004-01-15 日本ゼオン株式会社 磁気ディスク基板及び磁気ディスク
US6638966B2 (en) 2000-09-19 2003-10-28 University Of Iowa Research Foundation Use of melatonin analogues for induction of general anesthesia
US6613308B2 (en) 2000-09-19 2003-09-02 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US6552064B2 (en) 2000-09-19 2003-04-22 University Of Iowa Research Foundation Use of melatonin for induction of general anesthesia
WO2002032398A2 (en) 2000-10-16 2002-04-25 Massachusetts Institute Of Technology Lipid-protein-sugar particles for drug delivery
JP2002179562A (ja) 2000-12-14 2002-06-26 Towa Yakuhin Kk 安定な静注用無痛プロポフォール脂肪乳剤
US6399087B1 (en) 2000-12-20 2002-06-04 Amphastar Pharmaceuticals, Inc. Propofol formulation with enhanced microbial inhibition
US7179449B2 (en) 2001-01-30 2007-02-20 Barnes-Jewish Hospital Enhanced ultrasound detection with temperature-dependent contrast agents
US20020160043A1 (en) 2001-02-27 2002-10-31 Dennis Coleman Compositions and method of manufacture for oral dissolvable dosage forms
JP4334229B2 (ja) 2001-03-20 2009-09-30 サイデックス・ファーマシューティカルズ・インコーポレイテッド プロポフォール及びスルホアルキルエーテルシクロデキストリン含有製剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105765306A (zh) * 2013-06-27 2016-07-13 西门子股份公司 燃气涡轮发动机中的燃烧器装置

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