CN1086579C - 一种抗真菌口服制剂 - Google Patents
一种抗真菌口服制剂 Download PDFInfo
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Abstract
本发明涉及一种口服制剂的制备,它含有:一种抗真菌剂,一个足够量的环糊精及其衍生物,一个作为混合液体载体的水性酸性介质和一种醇性共溶剂。附加一种或多种药用甜度剂和一种或多种药用调味剂能得到适口性较好的口服制剂。本发明还涉及所述制剂及含所述制剂的药物剂型的制备方法。
Description
本发明涉及在水性介质中具有低溶解度的抗真菌剂的新组合物,制备所述组合物的方法及含有所述新组合物的适于口服的药物剂型。
吡咯类抗真菌剂如伊曲康唑和沙泊那唑的水溶性相当小,因此极大地阻碍了其有效药物组合物的发展。但是如果根据WO85/02767、US-4,764,604所描述的方法将上面所述化合物与环糊精及其衍生物配合则可提高所述化合物的溶解度和生物利用度。另外,伊曲康唑和沙泊那唑的强酸性制剂(pH≤1.5)可以在活性成分部分溶解的情况下形成。显然,这种强酸性制剂无法用于口服。在pH2.3-2.5的条件下,含有一种共溶剂如PEG 400的水性制剂能够完全溶解伊曲康唑。然而,在考虑到制备的便利与否、适用性、适口性、特别是生物利用度时,这些酸性制剂存在问题,例如:使用时在胃中所述制剂会产生不可逆沉淀。含有环糊精及其衍生物的酸性制剂有可能会带来一种明显的转折。但事实证明,简单的组合仍然存在一系列类似的问题,尤为突出的是制备困难、稳定性不好(货架寿命短)、适口性问题以及不可靠的吸收作用。简言之,易于制备的、具有好的生物利用度和可接受的感官性质的抗真菌剂的口服制剂的需求仍然存在,而且这种需求相当重要。
本发明涉及口服制剂。该制剂含有:一种作为活性成分的抗真菌剂如伊曲康唑或沙泊那唑、足够量的一种作为增溶剂的环糊精或其衍生物、作为混合液体载体(bulk liquid carrier)的一种水性酸性介质和一种能够极大的简化组合物制备的醇性共溶剂。而通过加入一种或多种药用的甜度剂和一种或多种药用调味剂可以得到适口性更好的优选配方。
根据本发明,低剂量制剂适用于治疗真菌感染的患者,尤其适合于治疗口腔念珠菌感染的AIDS患者。由于在念珠菌株上发展起来的对氟康唑的耐药性,在该适应症上对伊曲康唑(和沙泊那唑)的可靠制剂的需求尤其高。一般来说得到有意义的血浆水平的最低剂量为400mg/天。适用的口服制剂典型地含有大约0.5%到约1.5%(W/V)、优选约1%(W/V)的活性成分。
根据本发明,高剂量制剂适用于治疗全身真菌感染的患者。治疗全身真菌感染的适用口服制剂典型地含有大约3%到约5%、优选约4%(W/V)的活性成分。
本发明的制剂也适用于治疗动物的真菌感染,尤为适用于皮肤真菌感染的治疗。
伊曲康唑即(±)-顺式-4[4-[4-[4-[[2-(2,4-二氯苯基)-2-(1H-1,2,4-三唑-1-基-甲基)-1,3-二氧杂环戊烷-4-基]甲氧基]苯基]-1-哌嗪基]苯基]-2,4-二氢-2-(1-甲基丙基)-3H-1,2,4-三唑-3-酮是一种口服、非肠道及局部用药的广谱抗真菌化合物,在US-4,267,179中公开。它的二氟类似物沙泊那唑即(±)(顺式-4-[4-[4-[4-[[2-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基-甲基)-1,3-二氧杂环戊烷-4-基]甲氧基]苯基]-1-哌嗪基]苯基]-2,4-二氢-2-(1-甲氧基丙基)-3H-1,2,4-三唑-3-酮具有改善了的抗曲霉素属(Aspergillus spp.)活性并在US-4,916,134中公开。
适当的环糊精衍生物是α-,β-,γ-环糊精或它们的醚和混合醚,其中环糊精上葡糖酐单元的一个或多个羟基被取代,所述取代基是C1-6的烷基,尤其是甲基、乙基或异丙基;羟基C1-6烷基,尤其是羟乙基、羟丙基或羟丁基;羧基C1-6烷基,尤其是羧甲基或羧乙基;C1-6烷基羰基,尤其是乙酰基;C1-6烷氧羰基C1-6烷基或羧基C1-6烷氧基C1-6烷基,尤其是羧甲氧基丙基或羧乙氧基丙基;C1-6烷基羰基氧基C1-6烷基,尤其是2-乙酰氧基丙基。特别值得注意的作为配位剂和/或增溶剂的是β-环糊精,2,6-二甲基-β-环糊精,2-羟乙基-β-环糊精,2-羟乙基-γ-环糊精,2-羟丙基-γ-环糊精,(2-羧甲氧基)丙基-β-环糊精,尤其是2-羟丙基-β-环糊精。
术语混合醚代表的环糊精衍生物中至少有2个环糊精羟基被用不同的基团如羟丙基和羟乙基醚化。
以平均摩尔取代(M.S.)衡量每摩尔葡糖酐中烷氧基单元的平均摩尔数。根据本发明,用于组合物的环糊精衍生物中的M.S.在0.125到10的范围内,尤其是0.3到3,或0.3到1.5。M.S.的优选范围是大约0.3到大约0.8,尤其是大约0.35到大约0.5,而以大约0.4为更好。通过NMR或IR所确定的M.S.的优选范围是0.3到1,尤其是0.55到0.75。
平均取代度(D.S.)表示每个葡糖酐单元中被取代了的羟基的平均值根据本发明,用于组合物的环糊精衍生物中的D.S.在0.125到3的范围内,尤其是0.2到2或0.2到1.5。优选的D.S.范围是大约0.2到大约0.7,尤其是大约0.35到大约0.5,而以大约0.4为更好。通过NMR或IR所确定的D.S.值的优选范围在0.3到1,尤其是0.55到0.75。
根据本发明,在组合物中使用的较为具体的β-和γ-环糊精羟烷基衍生物是部分被取代的环糊精衍生物,其中,葡糖酐单元上不同位置的羟基被烷基化的平均程度为,在3位是大约0%到20%在2位是2%~70%,及在6位大约是5%到90%。未被取代的β-或γ-环糊精的优选的量低于总环糊精含量的5%,尤其是低于1.5%。另一个特别有兴趣的环糊精衍生物是随机甲基化的β-环糊精。
本发明中最优选的环糊精衍生物是那些部分取代了的β-环糊精醚或混合醚。它们含有羟丙基、羟乙基、尤其是2-羟丙基和或2-(1-羟丙基)取代基。
本发明的组合物中所使用的最优选的环糊精衍生物是羟丙基-β-环糊精,其M.S.在0.35到0.50的范围中,含有少于1.5%的未取代的β-环糊精。由NMR或IR所确定的M.S.值优选范围为0.55到0.75。
取代环糊精可根据US-3,459,731,EP-A-0,149,197,EP-A-0,197,571,US-4,535,152,WO-90/12035和GB-2,189,245中所述方法制备。其它阐述可用于本发明组合物中的环糊精并提供环糊精的制备、纯化和分析指导的文献如下:″Cyclodextrin Technology″JozsefSzejtli,KluwerAcademic Publishers(1988)在药学中的环糊精一章中;″CyclodextrinChemistry″M.L.Bender等,Springer-Verdag,Berlin(1978);″Advancesin Carbohydrate Chemistry″,Vol.12 Ed.M.L.Wolform,Academic Press,New York(157)在Dexter French写的α-糊精一章中p.189-260;″Cyclodextrins and their Inclusions Complexes″J.Szejtli,Akademiai Kiado,Budapest,匈牙利(1982);I.Tabushi,Acc.Chem.Research,1982,15,p.66-72;W.Sanger,Angewandte Chemie,92,p.343-361(1981);A.P.Croft和R.A.Bartsch,Tetrahedron,39,p.1417-1474(1983);Irie等PharmaceuticalResearch,5,p.713-716,(1988);Pitha等Int.J.Pharm.29,73,(1986);DE3,118,,218;DE-3,317,064;EP-A-94,157;US-4,659,696;和US-4,383,992。据本发明,低剂量口服制剂一般含有大约20%到60%(W/V),优选大约40%(W/V)的环糊精,高剂量口服制剂一般含有大约50%到80%(W/V),优选大约60%(W/V)环糊精衍生物。
据本发明,为了在生产过程中提高难溶抗真菌剂的溶解速度,在制剂中加入了一种醇性共溶剂。为达此目的,应选择那些对伊曲康唑和/或沙泊那唑有好的溶解能力的醇性共溶剂,尤其是乙醇,丙二醇和丙三醇,而以丙二醇为更好。若无醇性共溶剂存在,则伊曲康唑或沙泊那唑在水性酸性环糊精介质中的溶解非常缓慢,需要搅拌一粘稠悬浮液极长极长的一段时间才能达到完全溶解。加入醇性共溶剂在大约1%(V/V)到20%(V/V)范围中,尤其是大约10%(V/V)时,能将抗真菌剂在水性酸性环糊精介质中的溶解速度增加至少5倍(当为10%(V/V)时),因此极大地缩短和简化了制备过程。
作为混合液体载体,使用了一种酸性水性介质,而所述载体的酸性最好来源于一个强的药用酸,如盐酸。酸性对抗真菌剂的生物利用度及其口服制剂的感官性质的影响是相反的,最佳效果在pH2.0±0.1得到,即在该pH值时,能得到一种有足够稳定性和生物利用度的抗真菌制剂,并且其感官性质也适用。
毫不奇怪,当迄今为止所述的成份相互混合时将导致一服味道较重的药,除了由于低pH所导致的酸味外,还会有来自活性成分及可能来自共溶剂(例:丙二醇)的苦味。有两类佐药是最佳的味道掩饰剂,即:药用甜度剂和调味剂。在低剂量制剂中,甜度剂是更为重要的添加剂,而调味剂则在高剂量制剂中更为重要。
药用甜度剂优选的含有至少一种强甜度剂,如:糖精、糖精钠或糖精钙、天冬酰苯丙氨酸甲酯、双氧 噻嗪钾、环己氨磺酸钠、alitame;一种二氢查尔酮甜度剂,如:莫尼林、斯替维甙或sucralose(4,1′,6′-三氯-4,1′,6′-三脱氧半乳糖基蔗糖);其中糖精、糖精钠和糖精钙是优选的,和任选的普通甜度剂,如:山梨糖醇、甘露糖醇、果糖、蔗糖、麦芽糖、异麦芽糖、葡萄糖、氢化葡萄糖浆、木糖醇、焦糖和蜂蜜。
强甜度剂在低浓度应用时很方便,以糖精钠为例,浓度范围在0.04%到0.1%(W/V),以最终制剂的总体积为分母。在低剂量制剂中,约0.06%为优选值,而在高剂量制剂中,大约0.08%为优选值。普通甜度剂可以大量地有效地应用,用量范围在大约10%到35%,而大约10%到15%(W/V)为优选。在高剂量制剂中,环糊精衍生物还同时兼作普通甜度剂,所以,无需再加前面提及的普通甜度剂。
在低剂量制剂中,可以用来掩盖苦味成分的药用调味剂最好是果味调味剂,如:樱桃、木莓、黑加仑或草莓口味。无论是考虑其物化稳定性还是考虑感官可接受性,在一种伊曲康唑制剂中将两种樱桃味调味剂结合使用得到了一个非常好的结果。在高剂量制剂中,需使用强的调味剂,如:焦糖巧克力味、凉薄荷口味、迷幻口味以及类似的药用强调味剂。每种调味剂均可以0.05%到1%(W/V)的浓度存在于最终组
合物中。上述强调味剂的组合使用是有利的。最好使用在制剂的酸性条件不会改变或丧失口味和颜色的调味剂。
据本发明,一个优选的高剂量制剂含如下成分:(单位:重量/体积或体积/体积,以制剂总体积为分母)
(a).4%(W/V)伊曲康唑;
(b).60%(W/V)羟丙基-β-环糊精;
(c).10%(V/V)丙二醇;
(d).调节组合物的pH在2.0±0.1范围中的酸和碱;
(e).0.08%(W/V)糖精钠;
(f).最大为1%(W/V)的一种或多种强调味剂;和
(g).水。
根据本发明,此后的制剂制备将以优选的低剂量制剂为准进行描述,它含有如下成分:(单位:重量/体积或体积/体积百分比,以制剂的总体积为分母)
(a).1%(W/V)伊曲康唑;
(b).40%(W/V)羟丙基-β-环糊精;
(c).10%(V/V)丙二醇;
(d).调节组合物的pH在2.0±0.1范围中的酸和碱;
(e).0.06%(W/V)糖精钠;
(f).19%(V/V)山梨糖醇(70%)非结晶溶液;
(g).最大为1%(W/V)的一种或多种强调味剂;和;
(h).水。
任选的上述低剂量制剂可进一步含有最大到0.1%,尤其是0.02%或0.02%(W/V)焦糖甜度剂。
沙泊那唑可以以相似的手段制备相似的制剂,但最好加入其他调味剂。
上述制备过程包括下述步骤:
(a). 活性成分溶于醇性共溶剂及酸中;
(b).溶环糊精于水中,并在搅拌下加入(a)步制备的液至均相;
(c).加入甜度剂和调味剂;
(d).调酸度至pH 2.0±0.1及
(e).稀释制剂至所需的终体积。
具体地,若制备1升上述优选制剂,需在100ml丙二醇中加入3.76ml浓盐酸,搅拌并微热,加入10g伊曲康唑并搅拌至均相。在另一容器是,溶400g羟丙基-β-环糊精于400ml蒸馏水中,活性成分的溶液在搅拌下缓慢加入到环糊精溶液中,再加入190ml山梨糖醇溶液并搅拌至均相。糖精钠(0.6g)溶于50ml蒸馏水中,然后再加入混合物。加入调味剂并用10N氢氧化钠溶液调混合物的pH(约1.7)至2.0±0.1。得到的溶液用蒸馏水稀释至终体积1升。过滤上述溶液,并将滤液装入适当的容器例如:一个100ml的带螺口盖的玻璃瓶中,便得到了一个药物剂型最有利的药物剂型需在液面上有少量体积的气体存在,最好是惰性气体,如:氮气。除了无空气(氧气)存在外,25℃下保存也将有利地影响口服制剂的货架寿命。
万一要制备一个无调味剂和或甜度剂的简化制剂,步骤(c)需从制备过程中部分或完全地省略。
Claims (7)
1.一种适于口服给药的制剂,所述制剂含有:
(a)伊曲康唑或沙泊那唑;
(b)一种足够量的作为伊曲康唑或沙泊那唑的增溶剂的羟丙基-β-环糊精,该羟丙基-β-环糊精的M.S.在0.3到3的范围内,且含有少于5%的未取代的β-环糊精;
(c)一种水性酸性介质作为混合液体载体
(d)1%(V/V)到20%(V/V)的醇性共溶剂,该醇性共溶剂选自乙醇、丙二醇和丙三醇;
(e)一到多种药用强甜度剂和一种普通甜度剂;
(f)一到多种药用调味剂。
2.权利要求1所述的制剂,其中抗真菌剂是伊曲康唑或沙泊那唑,环糊精是羟丙基-β-环糊精,该环糊精的M.S.在0.35到0.50的范围内,且含有少于1.5%的未取代的β-环糊精。
3.权利要求2所述的制剂,其中醇性共溶剂是丙二醇。
4.权利要求3所述的制剂,其pH为2.0±0.1。
5.权利要求4所述的制剂,其中强甜度剂选自糖精、糖精钠或糖精钙,而普通甜度剂选自山梨糖醇、甘露糖醇、果糖、蔗糖、麦芽糖、葡萄糖、焦糖和蜂蜜。
6.权利要求1所述的制剂,以重量/体积或体积/体积百分比计(以制剂的总体积为分母),所述制剂含有:
(a)4%(W/V)伊曲康唑;
(b)60%(W/V)羟丙基-β-环糊精;
(c)10%(V/V)丙二醇;
(d)调节组合物的pH在2.0±0.1范围内的酸和碱;
(e)0.08%(W/V)糖精钠;
(f)最大为1%(W/V)的一种或多种调味剂;和
(g)水。
7.权利要求1所述的制剂,以重量/体积或体积/体积百分比计,(以制剂的总体积为分母),所述制剂含有:
(a)1%(W/V)伊曲康唑或沙泊那唑;
(b)40%(W/V)羟丙基-β-环糊精;
(c)10%(V/V)丙二醇;
(d)调节组合物的pH在2.0±0.1范围内的酸和碱;
(e)0.06%(W/V)糖精钠;
(f)19%(V/V)山梨糖醇(70%)非结晶溶液;
(g)最大为1%(W/V)的一种或多种调味剂;
(h)0.02%(W/V)的焦糖甜度剂;和
(i)水。
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US12950493A | 1993-09-30 | 1993-09-30 | |
US08/129504 | 1993-09-30 | ||
US08/129,504 | 1993-09-30 |
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CN1136776A CN1136776A (zh) | 1996-11-27 |
CN1086579C true CN1086579C (zh) | 2002-06-26 |
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Families Citing this family (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69733664T3 (de) | 1996-04-19 | 2011-04-14 | Grifols Inc. (n.d. Ges.d.Staates Delaware), Los Angeles | Verfahren zur INaktivierung von Viren und Lyophilisierung von Blutproteinen |
KR100883149B1 (ko) * | 1997-10-22 | 2009-02-10 | 젠스 포니카우 | 진균류에 의한 점막염을 국소 치료하기 위한 항진균제의용도 |
US6683100B2 (en) | 1999-01-19 | 2004-01-27 | Novartis Ag | Organic compounds |
US6194181B1 (en) | 1998-02-19 | 2001-02-27 | Novartis Ag | Fermentative preparation process for and crystal forms of cytostatics |
JP2003531099A (ja) | 1999-03-24 | 2003-10-21 | エフ エム シー コーポレーション | 改良された水溶解度をもつ医薬製剤 |
IL145661A0 (en) | 1999-03-31 | 2002-06-30 | Janssen Pharmaceutica Nv | Pregelatinized starch in a controlled release formulation |
WO2001001955A1 (en) * | 1999-07-02 | 2001-01-11 | Janssen Pharmaceutica N.V. | Nasal formulation of an antifungal |
CA2291346A1 (en) | 1999-11-26 | 2001-05-26 | Bernard Charles Sherman | Antifungal solutions |
US6673373B2 (en) | 2001-02-01 | 2004-01-06 | Carlsbad Technology Inc. | Antifungal formulation and the methods for manufacturing and using the same |
BR0207930A (pt) * | 2001-03-05 | 2004-03-02 | Ortho Mcneil Pharm Inc | Composições farmacêuticas lìquidas com sabor mascarado |
CA2363376A1 (en) * | 2001-11-16 | 2003-05-16 | Bernard Charles Sherman | Solid pharmaceutical compositions for oral administration comprising itraconazole |
US20100311701A1 (en) * | 2002-02-15 | 2010-12-09 | Transform Pharmaceuticals, Inc | Pharmaceutical Co-Crystal Compositions |
US7927613B2 (en) | 2002-02-15 | 2011-04-19 | University Of South Florida | Pharmaceutical co-crystal compositions |
US7790905B2 (en) * | 2002-02-15 | 2010-09-07 | Mcneil-Ppc, Inc. | Pharmaceutical propylene glycol solvate compositions |
US7446107B2 (en) * | 2002-02-15 | 2008-11-04 | Transform Pharmaceuticals, Inc. | Crystalline forms of conazoles and methods of making and using the same |
US7078526B2 (en) * | 2002-05-31 | 2006-07-18 | Transform Pharmaceuticals, Inc. | CIS-itraconazole crystalline forms and related processes, pharmaceutical compositions and methods |
AU2003213719A1 (en) * | 2002-03-01 | 2003-09-16 | Regents Of The University Of Michigan | Multiple-component solid phases containing at least one active pharmaceutical ingredient |
US20070059356A1 (en) * | 2002-05-31 | 2007-03-15 | Almarsson Oern | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
AU2003243699B2 (en) * | 2002-06-21 | 2009-01-15 | Transform Pharmaceuticals, Inc. | Pharmaceutical compositions with improved dissolution |
CN1255105C (zh) * | 2002-12-17 | 2006-05-10 | 上海医药工业研究院 | 齐拉西酮及其盐的水溶性包合物及其制备方法 |
US8183290B2 (en) * | 2002-12-30 | 2012-05-22 | Mcneil-Ppc, Inc. | Pharmaceutically acceptable propylene glycol solvate of naproxen |
CA2440172C (en) * | 2003-09-05 | 2011-01-11 | Bernard Charles Sherman | Itraconazole solution |
US20050074494A1 (en) * | 2003-10-06 | 2005-04-07 | Xiu-Xiu Cheng | Itraconazole immediate release formulation |
US20050118265A1 (en) * | 2003-11-28 | 2005-06-02 | Anandi Krishnan | Antifungal oral dosage forms and the methods for preparation |
WO2005055952A2 (en) * | 2003-12-08 | 2005-06-23 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Synergistic anti-cancer compositions |
GR1005154B (el) * | 2005-02-09 | 2006-03-13 | Verisfield (Uk) Ltd. | Σταθερες φαρμακευτικες συνθεσεις ιτρακοναζολης σευδατικο περιβαλλον |
JP2009502258A (ja) * | 2005-07-21 | 2009-01-29 | ノミール・メディカル・テクノロジーズ・インコーポレーテッド | 標的部位の生物学的汚染物質のレベルを下げる方法 |
WO2007047253A2 (en) * | 2005-10-11 | 2007-04-26 | Eastman Chemical Company | Pharmaceutical formulations of cyclodextrins and antifungal azole compounds |
TWI448285B (zh) * | 2006-07-13 | 2014-08-11 | Los Angeles Biomed Res Inst | 用以治療白黴菌症(mucormycosis)及其他真菌類疾病之組合物及方法 |
CN102114002B (zh) | 2006-12-04 | 2016-05-11 | 苏佩努斯制药公司 | 托吡酯的增强的立即释放制剂 |
CA2716348C (en) | 2008-02-21 | 2017-04-04 | Sequoia Pharmaceuticals, Inc. | Diamide inhibitors of cytochrome p450 |
US20100009009A1 (en) | 2008-07-10 | 2010-01-14 | Micropure, Inc. | Method and composition for prevention and treatment of oral fungal infections |
US20100233101A1 (en) | 2009-02-13 | 2010-09-16 | Micropure, Inc. | Composition and method for the oxidative consumption of salivary biomolecules |
KR20110139743A (ko) | 2009-03-19 | 2011-12-29 | 로스 엔젤레스 바이오메디칼 리서치 인스티튜트 엣 하버-유씨엘에이 메디칼 센터 | 모균증 및 다른 진균 질환의 치료를 위한 백신 조성물 및 방법 |
HUE028667T2 (en) * | 2010-12-16 | 2016-12-28 | Borje S Andersson | Parenteral administration of azole pharmaceutical compositions for use in treating diseases susceptible to azole compounds and methods for their preparation. |
CN102670490A (zh) * | 2012-05-10 | 2012-09-19 | 南京特丰药业股份有限公司 | 一种伊曲康唑口服溶液及其制备方法 |
CN103230363A (zh) * | 2013-03-29 | 2013-08-07 | 湖北凤凰白云山药业有限公司 | 一种抗真菌的口服溶液 |
CA3020197A1 (en) | 2017-09-01 | 2019-03-01 | Micropure, Inc. | Aliphatic anionic compounds and oxidative compounds with improved stability and efficacy for use in pharmaceutical compositions |
RU2707286C1 (ru) * | 2019-07-02 | 2019-11-26 | Федеральное государственное бюджетное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | Фармацевтическая противогрибковая композиция на основе производного хлорфенилбутандиона и способ её получения |
CN114191386B (zh) * | 2021-12-26 | 2024-03-12 | 苏州海景医药科技有限公司 | 一种波生坦口服溶液的制备方法 |
CN114191387A (zh) * | 2021-12-26 | 2022-03-18 | 苏州海景医药科技有限公司 | 一种伏立康唑口服液的制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4916134A (en) * | 1987-03-25 | 1990-04-10 | Janssen Pharmacuetica N.V. | 4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]me]phenyl]-1-piperazinyl]phenyl]triazolones |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3459731A (en) * | 1966-12-16 | 1969-08-05 | Corn Products Co | Cyclodextrin polyethers and their production |
US4267179A (en) * | 1978-06-23 | 1981-05-12 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
US4383992A (en) * | 1982-02-08 | 1983-05-17 | Lipari John M | Water-soluble steroid compounds |
US4659696A (en) * | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
DE3346123A1 (de) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | Pharmazeutische praeparate von in wasser schwerloeslichen oder instabilen arzneistoffen und verfahren zu ihrer herstellung |
US4863737A (en) * | 1985-05-01 | 1989-09-05 | University Of Utah | Compositions and methods of manufacture of compressed powder medicaments |
US4883785A (en) * | 1984-07-27 | 1989-11-28 | Chow Wing Sun | Complex of anti-fungal agent and cyclodextrin and method |
US4870060A (en) * | 1985-03-15 | 1989-09-26 | Janssen Pharmaceutica | Derivatives of γ-cylodextrin |
GB8506792D0 (en) * | 1985-03-15 | 1985-04-17 | Janssen Pharmaceutica Nv | Derivatives of y-cyclodextrin |
US5002935A (en) * | 1987-12-30 | 1991-03-26 | University Of Florida | Improvements in redox systems for brain-targeted drug delivery |
ES2033086T3 (es) * | 1988-01-29 | 1993-03-01 | Sankyo Company Limited | Un procedimiento para la preparacion de una composicion farmaceutica. |
ATE201408T1 (de) * | 1992-03-18 | 2001-06-15 | Janssen Pharmaceutica Nv | Itraconazol- und saperconazolstereoisomere |
-
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4916134A (en) * | 1987-03-25 | 1990-04-10 | Janssen Pharmacuetica N.V. | 4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-azolylmethyl)-1,3-dioxolan-4-yl]me]phenyl]-1-piperazinyl]phenyl]triazolones |
Non-Patent Citations (2)
Title |
---|
ANTIMICROB.AGENTS CHEMOTHER.,VOL.36,NO.2 1992.2.1 J.S.HOSTELER等,"Efffect of eyclodextrin on the pharmacology of antifungalazoles" * |
ANTIMICROB.AGENTS CHEMOTHER.,VOL.36,NO.2 1992.2.1 J.S.HOSTELER等,"Efffect of eyclodextrin on the pharmacology of antifungaloral * |
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