CN1882508A - 水溶性二萜的制备方法及其应用 - Google Patents
水溶性二萜的制备方法及其应用 Download PDFInfo
- Publication number
- CN1882508A CN1882508A CNA2004800288047A CN200480028804A CN1882508A CN 1882508 A CN1882508 A CN 1882508A CN A2004800288047 A CNA2004800288047 A CN A2004800288047A CN 200480028804 A CN200480028804 A CN 200480028804A CN 1882508 A CN1882508 A CN 1882508A
- Authority
- CN
- China
- Prior art keywords
- forskolin
- cyclodextrin
- diterpene
- water
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
使用合适的取代环糊精作为增溶剂来制备浓度高达约6%的二萜水溶液,所述二萜诸如为福司可林、其同类物、类似物和衍生物。不含环糊精的情况下,某些二萜诸如福司可林溶于水后的浓度仅仅达约0.001%。这样的水溶液可作为包含诸如福司可林和其同类物的二萜的药物、化妆品和营养品等制剂而用于局部使用和全身使用中。
Description
技术领域
本发明描述了使微溶或不溶于水的诸如福司可林的二萜的水溶液浓度高达约6%的制备。使用合适的取代环糊精作为增溶剂来制备这些溶液。在不含环糊精的情况下,福司可林几乎不溶于水,其得到的水溶液浓度仅仅约为0.001%。活性成分含量较高的福司可林和/或其同类物的水溶液可局部使用和全身性使用,从而提供多方面的健康益处。
背景技术
一些活性药物成分本身不溶于或极难溶解于水或含水溶剂。它们的用途可能经常要求应用于水或水溶剂中。因此,人们一直在寻求这些不溶于水的活性药物成分能以稳定形式达到治疗活性的浓度。虽然不溶于水的活性药物成分可以采用分子结构修饰的技术,加入结构特征以促进水溶性,但可能会导致所需要药理学特性的减弱或改变。因此,也许最为理想的是发明通过其它手段使原结构活性物质得到增溶的方法。
从多方面考虑,药物的水溶性都是一个理想的特性。通过例如过滤等公知方法对水制剂灭菌来制备这些适合全身性给药的制剂。水制剂优选用于皮肤、妇科、耳科、鼻科和粘膜等用途中。特别有用的是眼用水药物制剂。
福司可林(Forskolin,CAS No 66575-29-9)是一种天然存在于毛喉鞘蕊花(Coleus forskohlii)的劳丹烷型二萜(Bhat,S.V.;Bajwa,B.S.;Dornauer,H.;de Souza,N.J.;Fehlabar,H.-W.;TetrahedronLett.,(1977),18,1669)。其具有几种理想的药理学特性。
福司可林具有增强肌力收缩、抗高血压和抗支气管痉挛活性;(Bhat,S.V.;Dohadwalla,A.N.;Bajwa,B.S.;Dadkar,N.;Dornauer,H.;de Souza,N.J.;J Med Chem.,(1983),26,486)。
福司可林能降低眼压(Caprioli J,Sears M.;Lancet(1983);Apr 30;1(8331):958-60;.Badian M et al.;Klin Monatsbl Augenheilkd(1984);185:5226,Zeng S,et al.Yan Ke Xue Bao(1995);11:173-176,Lee PY,et al.;ArchOphthalmol(1987);105:249-252,.Meyer BH,et al.S Afr Med J.(1987);71:570-571;Seto C,et al.;Jpn J Ophthalmol(1986);30:238-244.;BursteinNI et al.Exp Eye Res(1984);39:745-749;Brubaker RF etal.Arch Ophthalmol(1987);105:637-641)。
使用腺苷酸环化酶的强非肾上腺素激动剂福司可林进行腺苷酸环化酶刺激对人眼的非侵害性研究;例如,根据房水动力学来增加cAMP(环腺苷酸)的产生。根据眼压降低、流入减少和流出通畅性不变的结果,该研究的作者假定这些观察结果支持这种想法,即,激活的睫状上皮腺苷酸环化酶受体络合物可以减少网状房水流入(Sears,ML;Am J Ophthalmol.1985 Jul 15;100(1):194-198)。
其它报告揭示通过降低房水流入量而没有增加流出通畅性,在玻璃体内注射或局部给予福司可林能显著降低兔子眼压。在正常人类志愿者中局部施用福司可林悬浮剂能有效降低眼压和房水流量而没有改变流出通畅性(Caprioli,J.et al.Lancet.1983Apr 30;1(8331):958-60)。
对18个健康男性受试者(每组6人)进行了福司可林滴眼剂(0.3%-0.6%-1.0%)的双盲个体内对照试验。该研究证明了0.3%-0.6%-1.0%的福司可林滴眼剂降低了健康男性受试者的眼压。眼压的减少值在23-28%之间,作用持续时间随浓度的升高从3个小时增长至5个小时(Witte PU In:Proceedings of theInternational symposium on forskolin,Bombay,India,1985,175-182)。
另一组研究人员报告了对患有开角型青光眼成年病人进行了福司可林滴眼剂的两项研究。一个研究中,包括26个病人(没有安慰剂组)。第二个研究中,11个病人接受福司可林来治疗青光眼。在第一个研究中出现从1小时到4小时的眼压降低。在第二个研究中,福司可林降低眼压能达到6小时。安慰剂组没有眼压的改变。这些研究中,使用的是羧甲基纤维素中的1%福司可林悬浮剂。(Pinto-Pereira L.In:Proceedings of the International symposium on forskolin,Bombay,lndia,1985,183-190)。
通过提高cAMP的浓度可以观察到不同的生物学活性,并因此激活了蛋白激酶。这些特性导致福司可林的多种用途。由于这些活性,在2001年化学文摘发表的有关福司可林生理学特性的引用文献超过1500篇。然而,福司可林极难溶于水。
对福司可林的分子修饰已进行了深入工作,并使这些福司可林衍生物成为水溶物。这些尝试始终不是很成功(Lal,B.;Gangopadhyay,A.K.;Rajagopalan,R.;Ghate,A.V.;Bioorganic & Medicinal Chemistry,(1998),6(11),2061-2073;Lal,B.;Gangopadhyay,A.K.;Gidwani,R.M.;Fernandez,M.;Rajagopalan,R.;Ghate,A.V.;Bioorganic & Medicinal Chemistry,(1998),6(11),2075-2083)。
除药物分子结构化学修饰,还有一种选择方法,即使用物理化学技术来提高未经衍生的药物在水中的溶解度。重要的技术包括使用表面活性剂的胶束增溶,其形成含有药物的水溶性胶束。另一个相关技术是药物分子和主分子的复合。主分子通常是具有良好水溶性的分子。主分子不与药物分子形成任何共价键,但通过非共价作用形成弱的络合物(complex),该主分子使药物分子处于水溶液中。
环糊精,这种环状低聚糖已用作有用的药用赋形剂。根据环状低聚糖结构所含葡萄糖分子数目,通常的环糊精包括α-、β-、γ-和δ-环糊精。这些环糊精是α-D-吡喃型葡萄糖的(α-1,4)-链接的低聚糖,其包含相对疏水的内腔和亲水的外围。由于糖分子单元连接键的完全自由转动受到限制,因此这些分子并非纯粹的筒状结构,被设想为环面形或截断的锥形。仲醇羟基位于环的宽边缘,而伯醇羟基位于环的窄边。这些分子的溶解度和内腔的直径是公知的(Loftsson,T.;Brewster,M.E.;J Pharmaceutical Sciences,(1996),85,1017 & Rajewski,R.A.;Stella,V.J.;J Pharmaceutical Sciences,(1996),85,1142)。作为一个例子,含有7个葡萄糖单元的β-环糊精结构如下所示:
α-环糊精环内含有6个葡糖酐分子;γ-和δ-环糊精分别含有8和9个葡糖酐分子。α-、β-、γ-和δ-环糊精在25℃时的水中溶解度分别为14.5、1.85、23.2和8.19(g/100ml)。α-、β-、γ-和δ-环糊精有时被称作天然环糊精,它们在水中的溶解度处于理想范围内的低端。尽管如此,已证明这些环糊精是一些水不溶性分子的良好增溶剂。为了增加天然环糊精的水中溶解度,对α-、β-、γ-和δ-环糊精的分子修饰早已在文献中公开。
修饰的环糊精比天然对应物具有更高的溶解度,可以分类为β-环糊精的甲基化衍生物、2-羟丙基化的β-和γ-环糊精、磺丁基化的β-环糊精、支链环糊精、酰化的β-和γ-环糊精。
使用甲基氯化物在加压下采用Wacker’s方法通过Kuhn-Trischmann甲基化使环糊精进行甲基化,以及采用甲基卤化物和氢化钠,通过Hakamori甲基化进行甲基化(Szente,L.;Szejtli,J.;Advanced Drug Delivery Reviews,(1996),36,17)。前面两个技术已经用于制备任意甲基化的环糊精混合物。另一方面,有报道Hakamori甲基化反应可制备完全甲基化的7元2,3,6-三-氧-甲基化环糊精。引入甲基取代基替换母体环糊精羟基上的氢,可以显著改进任意甲基化环糊精的溶解度,此时本发明所指是RAMEBCD而不是母体β-环糊精。
β-环糊精共有21个羟基(14个仲醇羟基和7个伯醇羟基)。对于单个β-环糊精分子,当甲基数目达到约13-14时,RAMEBCD的水溶性增加,甲基化导致接近21个甲氧基时,RAMEBCD的水溶性下降。可商购得到的一种RAMEBCD产品是由WackerChemie生产的,商品名为CAVASOLW7M Pharma(CAS no 128446-36-6)。RAMEBCD的水中溶解度通常为~220g/100ml水。这样的RAMEBCD的平均甲基化度为~1.7-1.9/每葡糖酐单元。这些RAMEBCD可商购得到,且具有良好水溶性。这些RAMEBCD的一般结构如下所示:
环糊精与环氧丙烷在碱性溶液中反应导致环糊精羟基的取代,得到2-羟丙基衍生物。羟基被环氧丙烷的更高度取代也会生成低聚羟基环氧丙烷(hydroxypropylene oxide)侧链的生成。本发明中作为HPBCD的2-羟基-丙基-β-环糊精由以下通式表示。该物质可商购获得。
类似于HPBCD,γ-环糊精羟丙基化可以得到羟丙基γ-环糊精,即本发明的HPGCD。该物质可商购获得。
环糊精在眼科领域应用的综述已有报道(Loftssona,T.;Jarvinen,T.;Advanced Drug Delivery Reviews,(1999),36,59)。美国专利6,346,273描述了通过使用聚乙烯吡咯烷酮和表面活性剂聚乙二醇-蓖麻酸三甘油酯来增溶水中的福司可林。该专利中福司可林的最大溶解度达到0.2%。
美国专利4476140描述了一种组合物和通过给予有效剂量的选自福司可林、colforsin和聚氧化劳丹烷衍生物中的一种物质治疗青光眼的方法。当作为局部眼用的悬浮剂时,其报道的生理学上有效的活性物质浓度为0.1%至4%。
US5070209、US4978678、US5023344、US4871764描述了新的12-卤代的福司可林衍生物、中间体和其制备方法,以及利用这些化合物或组合物来降低眼压的方法。
EP0268256描述了新的12-卤代的福司可林衍生物、中间体和其制备方法,以及利用化合物或组合物来降低眼压的方法。
然而这些现有技术文献并没有描述未修饰的福司可林的增溶而得到浓度为1%或大于1%的澄清溶液。本发明描述了微溶或不溶于水的诸如福司可林的二萜水溶液的制备,所得溶液的浓度高达约6%。使用合适的取代环糊精作为增溶剂来制备这些溶液。在没有环糊精的情况下,福司可林几乎不溶于水,所得到的水溶液浓度仅约0.001%。福司可林和/或其同类物的水溶液含有较高含量的活性成分,可以局部或全身性使用而得到各种健康益处。
发明详述
福司可林具有以下结构:
非常相关的异构体称作异福司可林,其具有以下结构:
已报道,异福司可林具有许多与福司可林类似的药理学特性。我们使用六种可商购得到的环糊精,即α-、β-和γ-环糊精和它们的衍生物如RAMEBCD、HPBCD、HPGCD来增溶极难溶于水的福司可林。
使用环糊精增溶福司可林,将选择的环糊精和福司可林以特定比例混合于水中。过滤除去所有不溶颗粒,得到福司可林的澄清水溶液。
或者,将一定比例环糊精和福司可林溶于合适溶剂例如乙醇或丙酮或乙酸乙酯中。除去溶剂得到白色粉末。作为实施例将举例说明该粉末可自由地溶于水。进一步,也可以向福司可林水溶液加入添加剂。这些添加剂通常用于维持无菌、维持pH、维持渗透浓度等。
这些添加剂的选择范围很宽。虽然在示例性实施例中使用了苯扎氯铵作为防腐剂,但可以同等地从其它添加剂如苄索氯铵、氯代丁醇、对羟基苯甲酸甲酯(methyl paraben)、对羟基苯甲酸丙酯(propyl paraben)、硫汞撒等中选择一种。
用抗氧化剂如EDTA的二钠盐来稳定制剂;也可以使用其它抗氧化剂如亚硫酸氢钠、偏亚硫酸氢钠、硫脲等。
特别对于眼用溶液,眼用溶液的理想粘度在25至50cps之间。可以使用粘度增强剂如聚乙烯醇、聚乙烯吡咯烷酮、甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素。
以下所述的实施例仅用于举例说明,而并没有对本发明的范围进行任何限制。
本发明的实施方式
实施例1:测定福司可林水溶性。
在105℃下干燥福司可林(300mg)6个小时。室温下搅拌200mg福司可林和100ml水达48小时,用于测定其在环境温度下本身的溶解度。用0.45μm尼龙滤器过滤所得到的溶液,通过HPLC分析福司可林含量。通过HPLC分析的福司可林含量为0.01mg/ml或0.001%w/v;换言之,福司可林在水中具有~0.001%w/v的溶解度。
实施例2:将福司可林(98.5%定量分析,25mg)加入到溶解了500mg羟丙基β-环糊精HPBCD(~50%)的1ml水中。在~30℃的等温振荡器中以75RPM的速度搅拌悬浮液达60小时。用0.45μm尼龙滤器过滤所得到的溶液,通过HPLC分析的福司可林含量为1.33mg/ml或0.133%w/v。
实施例3:将福司可林(98.5%定量分析,50mg)加入到溶解了500mg羟丙基γ-环糊精HPGCD(~50%)的1ml水中。在~30℃的等温振荡器中以75RPM的速度搅拌悬浮液达60小时。用0.45μm尼龙滤器过滤所得到的溶液,通过HPLC分析的福司可林含量为1.52mg/ml或0.152%w/v。
实施例4:通过在二氯甲烷和在乙酸乙酯中重结晶,进行“改变”福司可林晶状的实验。将所得到的“无定形的”福司可林与羟丙基γ-环糊精HPGCD复合。将用二氯甲烷重结晶的福司可林(29.3mg)(福司可林定量分析99.0%)加入到含有1.5g羟丙基γ-环糊精HPGCD(~50%)的3ml水中。悬浮液在30℃的等温振荡器中以75RPM的速度搅拌160小时。用0.45μm尼龙滤器过滤所得到的溶液,通过HPLC分析的福司可林含量为1.74mg/ml或0.174%w/v。
将在乙酸乙酯中重结晶的福司可林(30.3mg)(福司可林定量分析98.8%)加入到含有1.5g羟基丙基γ-环糊精HPGCD(~50%)的3ml水中。悬浮液在30℃的等温振荡器中以75RPM的速度搅拌160小时。用0.45μm尼龙滤器过滤所得到的溶液,通过HPLC分析的福司可林含量为3.38mg/ml或0.338%w/v。
实施例6:将福司可林(98.5%定量分析,330mg)加入到含有4g RAMEBCD(~40%)的10ml水中。悬浮液在30℃的等温振荡器中以75RPM的速度搅拌40小时。用0.45μm尼龙滤器过滤所得到的溶液,通过HPLC分析的福司可林含量为20.46mg/ml或2.046%w/v。
实施例7:测定福司可林在含5%-66%的不同浓度的RAMEBCD的水中溶解度。该关系几乎为线性,并表明通过增加RAMEBCD的浓度可以增加福司可林的溶解度。
S.N.RA MEBCD浓度% 福司可林%w/v
1 5%RAMEBCD 0.09
2 10%RAMEBCD 0.272
3 15%RAMEBCD 0.767
4 20%RAMEBCD 1.15
5 40%RAMEBCD 2.746
6 53.28%RAMEBCD 4.165
7 66.6%RAMEBCD 5.029
实施例8:通常,福司可林与环糊精的水制剂的制备如下,用RAMEBCD作为环糊精的例子。将RAMEBCD(100g)加入至机械或磁力搅拌装置的1升烧瓶中。向烧瓶加入福司可林(5.5g)。向烧瓶加入水(400ml),室温下搅拌混合液。得到透明溶液。如果有能看见的未溶解福司可林颗粒,将其再悬浮并搅拌。向烧瓶加入苯扎氯铵(50mg)和EDTA二钠(500mg),使其溶解。混合液的pH可以通过0.1N氢氧化钠来调节至理想范围(通常pH范围3.5-7.5)。加入计算量的氯化钠溶液以保持溶液的渗透浓度相当于0.9%氯化钠。无菌过滤后,将溶液的总容量配至500ml。这样制备的溶液具有约1%的溶解状态的福司可林。也可以使用其它环糊精,随环糊精的不同,福司可林的水中溶解度也不同。
实施例9:福司可林(50mg)溶解于5ml丙酮,另外将1g RAMEBCD溶解于5ml丙酮。混合这两种溶液,并在减压下蒸发溶剂丙酮。干燥残余物并溶于5ml水中。搅拌1小时,残余物很容易溶解,并得到无色透明溶液。
实施例10:也可使用异福司可林来代替福司可林。在一个制备例中,异福司可林(50mg)悬浮于含有适量环糊精的水中,例如,含RAMEBCD(20g)的约100ml水中。在室温下搅拌后,过滤溶液并用HPLC分析所得溶液,显示异福司可林的含量约为0.5%;通过改变RAMEBCD的含量可改变异福司可林的溶解度。
实施例11:呈现制备物的生物活性的示例性例子。用白化病兔研究福司可林组合物的抗青光眼活性。如实施例8所述的1%福司可林溶液用于本实施例。
研究设计:
动物模型:白化病兔
组数:4
每组动物数:6只在试验组,2只在对照组。
材料和方法:选择6只雌雄、重1.0-1.5磅(1b)的新西兰种白化病兔。这些兔子处在干净、通风良好的空间。每个兔子每日进行标准饮食喂养,整个研究中可以随意喂水。
用Bonomi等报告的方法(Invest Ophthalmol.1976Sep;15(9);781-4)诱导眼内高血压。在三个星期内每天给兔子每只眼结膜下注射含有4mg/ml倍他米松钠的0.3ml倍他米松磷酸酯(Betnesol)(根据文献记载,第三周眼压(IOP)为最高值)。在结膜下注射之前使用局部麻醉propracaine滴眼剂。
每个兔子的左眼保持为青光眼作为对照,用福司可林、噻吗洛尔(Timolol)和安慰剂处理右眼。
使用无接触眼压计(NCT)间隔30分钟,直至210分钟的时间测量IOP读数。
结果:
时间(分钟) | IOP读数*(mmHg) | ||
安慰剂 | 噻吗洛尔 | 福司可林 | |
右眼(经处理的) | |||
0306090120150180210 | 14131211.51110.5109 | 1387543.54.56 | 1476.54.55677.5 |
*6次测定的平均值
左眼(对照)IOP值范围是12-13mmHg。
对照组IOP值范围是4-4.5mmHg。
统计分析:安慰剂、福司可林和噻吗洛尔的IOP读数经过ANOVA分析(单向)。p值为0.0022,这是非常显著的,表明该组数值的偏差不是偶然的。
安慰剂和福司可林的IOP读数进行“t”检验,确定福司可林和安慰剂的中值是否有显著差异。p值为0.0177,有显著差异。类似地,安慰剂和噻吗洛尔的IOP读数的“p”值为0.0087,也具有显著差异。
福司可林和噻吗洛尔的IOP读数也要进行“t”检验。p值为0.3999,不具有显著差异,显示福司可林制剂的活性与噻吗洛尔相比没有显著区别。
结论:福司可林组合物具有与噻吗洛尔相当的抗青光眼活性。
Claims (14)
1.一种增溶二萜溶于水的方法,所述二萜诸如为天然或合成的福司可林、异福司可林、7-脱乙酰福司可林、它们的同类物、类似物和衍生物中的一种或各种混合物。
2.权利要求1的二萜可以来源于一种植物例如但不限于毛喉鞘蕊花。
3.权利要求1的方法,其中所使用的增溶剂为α-、β-、γ-环糊精,或它们的衍生物如任意甲基化的β-环糊精(RAMEBCD)、2-羟基-丙基-β-环糊精(HPBCD)、羟丙基γ-环糊精(HPGCD),优选使用任意甲基化的β-环糊精(RAMEBCD)作为络合剂。
4.一种制备含有0.09%至6%二萜的澄清溶液的方法,所述二萜诸如为福司可林、异福司可林、它们的类似物或衍生物,该方法为通过将上述化合物与5%至70%环糊精或环糊精衍生物相混合。
5.一种方法,其中所述活性化合物在选自乙醇、丙酮、乙酸乙酯、二氯甲烷或其它溶剂中的一种有机溶剂中重结晶,随后与环糊精或环糊精衍生物混合并在水中形成悬浮液,之后在室温下搅拌40-160小时,然后过滤。
6.一种制备眼用、局部用和全身用的溶液或固体澄清水制剂的方法,其包含0.09%-6%二萜,所述二萜诸如为福司可林、其同类物、类似物或衍生物。
7.权利要求6的制剂可被配制成胶囊剂、片剂、食品、注射剂、贴剂、软膏剂、凝胶剂、乳剂、霜剂、洗剂、洁牙剂、喷剂、滴剂或包括持续释放剂型的其它剂型用于人类或动物。
8.单独使用或与抗氧化剂和/或抗青光眼制剂联合使用权利要求6的制剂用于降低眼压高或青光眼的动物或人的眼压的方法。
9.在患有干眼病的动物或人中单独使用或与聚乙烯吡咯烷酮、透明质酸和它们的衍生物联合使用权利要求6的制剂的方法。
10.使用权利要求6的制剂制备研究和商业用的水溶性分子和受体探针的方法。
11.使用权利要求6的制剂显示二萜诸如福司可林、其同类物、类似物和衍生物对健康有益的方法,其中给药方式为局部、经皮、静脉内、舌下或口服。
12.权利要求1的物质在福司可林和相关二萜制剂如作为饮品中的应用以用于福司可林已知应用中的控制肥胖、控制体重、为瘦人增重、控制高血压、过敏。
13.权利要求1的物质在福司可林和相关二萜水溶性制剂如作为乳剂、喷剂、溶液或气雾剂或药用化妆品中的应用以用于如促进胶原蛋白活性、抗皱性、控制脂肪、黑素细胞调节剂。
14.权利要求1的物质可与抗氧化剂、脂酶抑制剂、其它抗肥胖产品包括羟基柠檬酸、garcinol和它们的盐、vasoirri gators以及其它已知的胶原蛋白增效剂、消炎药、磷酸二酯酶抑制剂联合使用。
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Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060122261A1 (en) * | 2003-11-20 | 2006-06-08 | Muhammed Majeed | [method of preparing labdane diterpene composition, preferably isoforskolin and deacetylforskolin from forskolin extract and their use for promoting lean body mass and other applications] |
US20110077292A1 (en) * | 2004-07-01 | 2011-03-31 | Biotest Laboratories, Llc. | Forskolin carbonates and uses thereof |
JP2007210988A (ja) * | 2006-02-07 | 2007-08-23 | Sabinsa Corp | ジテルペンフォルスコリン及びその誘導体で男性ホルモン及び女性ホルモンを生理学的に増大するための組成物 |
WO2007108727A1 (en) * | 2006-03-22 | 2007-09-27 | Leangene Ab | Method for monitoring the effect of compounds on foxc2 expression |
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US20110003816A1 (en) * | 2008-03-07 | 2011-01-06 | Sun Pharma Advanced Research Company Limited | Ophthalmic composition |
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WO2020186235A1 (en) | 2019-03-14 | 2020-09-17 | The Broad Institute, Inc. | Compositions and methods for modulating cgrp signaling to regulate intestinal innate lymphoid cells |
SI4093374T1 (sl) | 2020-01-23 | 2024-03-29 | Scipharm S.A.R.L. | Kompleks 7-deacetilforskolina in (pvp) |
KR20220149987A (ko) * | 2021-05-03 | 2022-11-10 | 연세대학교 산학협력단 | 안구건조증 또는 안구건조증 연관 안과 질환의 예방, 개선 또는 치료용 조성물 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU181703B (en) * | 1980-05-09 | 1983-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing aqueus solutuins of water insoluble or hardly soluble vitamines, steroides, localanesthetics, prostanoides and non-steroid and antiphlogistic agents |
US4476140A (en) * | 1983-05-16 | 1984-10-09 | Yale University | Composition and method for treatment of glaucoma |
US6407079B1 (en) * | 1985-07-03 | 2002-06-18 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions containing drugs which are instable or sparingly soluble in water and methods for their preparation |
HU199444B (en) * | 1985-09-10 | 1990-02-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing 7-isopropoxy-isoflavone-cyclodextrene inclusion complex and pharmaceutical compositions therefrom |
US5070209A (en) * | 1986-11-20 | 1991-12-03 | Hoechst Roussel Pharmaceuticals Inc. | 12-halogenated forskolin derivatives |
US5302730A (en) * | 1987-06-29 | 1994-04-12 | Nippon Kayaku Kk | Process for the preparation of 6,7-diacyl-7-deacetylforskolin derivatives |
US5846992A (en) * | 1987-10-08 | 1998-12-08 | Hoechst Marion Roussel, Inc. | Synergistic intraocular pressure lowering combinations |
ATE74003T1 (de) * | 1988-01-14 | 1992-04-15 | Akzo Nv | Waessriges pharmazeutisches praeparat. |
IL89530A0 (en) * | 1989-03-08 | 1989-09-10 | Jeffrey J Feigenbaum | Compositions containing forskolin |
US5376645A (en) * | 1990-01-23 | 1994-12-27 | University Of Kansas | Derivatives of cyclodextrins exhibiting enhanced aqueous solubility and the use thereof |
JP3040015B2 (ja) * | 1991-08-21 | 2000-05-08 | 日研化学株式会社 | フォルスコリンの包接化合物 |
TW422696B (en) * | 1995-03-20 | 2001-02-21 | Katsuhiko Mukai | Ophthalmic composition containing active vitamin D |
US6471972B1 (en) * | 1996-11-07 | 2002-10-29 | Lvmh Recherche | Cosmetic treatment method for fighting against skin ageing effects |
US5804596A (en) * | 1997-02-27 | 1998-09-08 | Sabinsa Corporation | Method of preparing a forskohlin composition from forskohlin extract and use of forskohlin for promoting lean body mass and treating mood disorders |
GB9711643D0 (en) * | 1997-06-05 | 1997-07-30 | Janssen Pharmaceutica Nv | Glass thermoplastic systems |
IT1294205B1 (it) * | 1997-07-23 | 1999-03-24 | Farmigea Spa | Procedimento per la solubilizzazione in acqua e in veicoli acquosi di sostanze farmacologicamente attive |
US6540895B1 (en) * | 1997-09-23 | 2003-04-01 | California Institute Of Technology | Microfabricated cell sorter for chemical and biological materials |
US6699849B1 (en) * | 1998-02-23 | 2004-03-02 | Cyclops, Ehf. | Cyclodextrin complexes of benzodiazepines |
US6645994B1 (en) * | 2001-06-01 | 2003-11-11 | Alcon, Inc. | Method of treating dry eye disorders |
CA2463687A1 (en) * | 2001-10-18 | 2003-04-24 | Decode Genetics Ehf | Cyclodextrin complexes |
PT1534340E (pt) * | 2002-09-06 | 2012-03-13 | Cerulean Pharma Inc | Polímeros à base de ciclodextrina para a administração de medicamentos ligados por ligação covalente |
-
2003
- 2003-09-08 US US10/605,086 patent/US6960300B2/en not_active Expired - Lifetime
-
2004
- 2004-09-02 CA CA2537820A patent/CA2537820C/en not_active Expired - Fee Related
- 2004-09-02 BR BRPI0413957-7A patent/BRPI0413957A/pt not_active IP Right Cessation
- 2004-09-02 RS YUP-2006/0169A patent/RS20060169A/sr unknown
- 2004-09-02 JP JP2006525448A patent/JP5021305B2/ja not_active Expired - Fee Related
- 2004-09-02 EA EA200600528A patent/EA012836B1/ru unknown
- 2004-09-02 EP EP04783024A patent/EP1718568B1/en not_active Not-in-force
- 2004-09-02 AU AU2004272005A patent/AU2004272005B2/en not_active Ceased
- 2004-09-02 CN CN2004800288047A patent/CN1882508B/zh not_active Expired - Fee Related
- 2004-09-02 NZ NZ545765A patent/NZ545765A/en not_active IP Right Cessation
- 2004-09-02 WO PCT/US2004/028644 patent/WO2005025500A2/en active Search and Examination
- 2004-09-02 MX MXPA06002684A patent/MXPA06002684A/es active IP Right Grant
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2005
- 2005-08-31 US US11/215,040 patent/US20050284812A1/en not_active Abandoned
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2006
- 2006-03-06 ZA ZA200601898A patent/ZA200601898B/xx unknown
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Cited By (11)
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CN103459362A (zh) * | 2010-12-09 | 2013-12-18 | 英德斯生物科技私人有限公司 | 山竹醇与环糊精络合物及其方法 |
CN103459362B (zh) * | 2010-12-09 | 2015-11-25 | 英德斯生物科技私人有限公司 | 山竹醇与环糊精络合物及其方法 |
CN103588745A (zh) * | 2013-11-26 | 2014-02-19 | 陕西嘉禾植物化工有限责任公司 | 一种从毛喉鞘蕊花中提取和分离弗斯可林的方法 |
CN103588745B (zh) * | 2013-11-26 | 2015-10-28 | 陕西嘉禾植物化工有限责任公司 | 一种从毛喉鞘蕊花中提取和分离弗斯可林的方法 |
CN110325217A (zh) * | 2017-01-09 | 2019-10-11 | 塞法姆公司 | 制备水溶性毛喉萜的新工艺 |
CN110325217B (zh) * | 2017-01-09 | 2023-08-08 | 塞法姆公司 | 制备水溶性毛喉萜的新工艺 |
CN109619542A (zh) * | 2017-10-06 | 2019-04-16 | 青叶化成株式会社 | 食用缓释性功能材料的制备方法及食用缓释性功能材料 |
CN109619542B (zh) * | 2017-10-06 | 2022-07-15 | 青叶化成株式会社 | 食用缓释性功能材料的制备方法及食用缓释性功能材料 |
CN108651819A (zh) * | 2018-05-18 | 2018-10-16 | 南昌大学 | 一种稳定态全谷物超微粉速食粉的制备方法 |
CN117586217A (zh) * | 2024-01-17 | 2024-02-23 | 云南省药物研究所 | 一种基于国产毛喉鞘蕊花的佛司可林高效制备方法 |
CN117586217B (zh) * | 2024-01-17 | 2024-03-19 | 云南省药物研究所 | 一种基于国产毛喉鞘蕊花的佛司可林制备方法 |
Also Published As
Publication number | Publication date |
---|---|
HK1098450A1 (en) | 2007-07-20 |
US20050051483A1 (en) | 2005-03-10 |
WO2005025500A2 (en) | 2005-03-24 |
EP1718568B1 (en) | 2012-12-26 |
BRPI0413957A (pt) | 2006-10-31 |
AU2004272005A1 (en) | 2005-03-24 |
NZ545765A (en) | 2009-11-27 |
CA2537820C (en) | 2013-03-26 |
EA200600528A1 (ru) | 2006-08-25 |
CA2537820A1 (en) | 2005-03-24 |
CN1882508B (zh) | 2010-07-14 |
ZA200601898B (en) | 2008-09-25 |
US6960300B2 (en) | 2005-11-01 |
MXPA06002684A (es) | 2007-03-15 |
JP2007505040A (ja) | 2007-03-08 |
EA012836B1 (ru) | 2009-12-30 |
AU2004272005B2 (en) | 2011-03-10 |
EP1718568A2 (en) | 2006-11-08 |
US20050284812A1 (en) | 2005-12-29 |
WO2005025500A3 (en) | 2005-06-09 |
JP5021305B2 (ja) | 2012-09-05 |
RS20060169A (en) | 2008-08-07 |
EP1718568A4 (en) | 2009-01-07 |
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