CN1207687A - 含有维生素d-类似物的药物制剂 - Google Patents
含有维生素d-类似物的药物制剂 Download PDFInfo
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- CN1207687A CN1207687A CN96199734A CN96199734A CN1207687A CN 1207687 A CN1207687 A CN 1207687A CN 96199734 A CN96199734 A CN 96199734A CN 96199734 A CN96199734 A CN 96199734A CN 1207687 A CN1207687 A CN 1207687A
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- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 1
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- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
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- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Nanotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Medical Informatics (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
优选局部用药的药物制剂,其特征为含有环糊精笼形物和维生素D-类似物。它们适合于治疗银屑病。
Description
本发明涉及含有环糊精笼形物和非天然维生素D-类似物的药物制剂。
本发明尤其涉及可局部用药的这类药物制剂。这类制剂优选适合于治疗银屑病。
含有维生素D-类似物治疗银屑病的局部用制剂已为所知,例如含有卡西利奥的Psorcutan(罗特目录1994,BDI药物索引(Rote Liste 1994Arzneimittelverzeichnis des BDI),Editio Cantor,DE Aulendorf,第31271号)。这些制剂不仅有引起皮肤刺激症状如发红、瘙痒或烧灼感的缺点,还有严重全身性副作用如大面积用药时出现高钙血症而必需中断治疗。其它缺点是,维生素D-类似物与维生素D系列化合物一样,本身易于因氧和/或受光而分解,因此含有这些化合物的药物制剂只有很低的稳定性。
曾有人尝试通过用环糊精制备这些化合物的笼形物,以改善维生素D系列化合物本身和一些它的代谢产物(例如骨化醇=维生素D2、胆钙化醇=维生素D3和25-羟基维生素D3骨化二醇)的稳定性和溶解度(药剂学(Pharmazie)35期,1993年,779-787页;北方药学学报(Acta Pharm.Nord),2期,1990年,303-312页,药物进展和工业制药学(Drug Dev.and Ind.Pharm.),19期,1993年,875-885页和GB-A2,037,773)。根据我们所知,迄今为止尚无研究以制备含有环糊精笼形物和非天然人工合成维生素D-类似物的局部用制剂以及检测其作用。
现已发现,这样一些局部用药物对治疗寻常性银屑病和这类疾病的其它症状具有极佳的作用,它们与上述具相同作用的药物相比较,似乎不会导致严重的不希望的全身性副作用。
适合于制备本发明药物的维生素D-类似物例如有钙三醇(Calcitriol)(1α,25-二氢维生素D3)、骨化二醇(25-羟基维生素D3)、卡西波曲(CAS-1128-00-9)、胆钙化醇(维生素D3)和Tacalcitol(CAS-57333-96-7)。此外例如还有US-专利说明书5,098,899中提及的维生素D-类似物也适合于制备本发明药物。
合适的维生素D-类似物尤其还有WO 94/07853中说明的化合物,其中有通式I的维生素D-系列中的25-羧酸-衍生物其中R1,R2和R3相互独立地分别为一个氢原子、一个带有1或3至9个碳原子的直链或支链的饱和链烷酰基、或者一个芳酰基,并且-OH-意为一个α-或β-位的羟基,R4和R4a同时各为一个氢原子、一个氯原子或氟原子、一个三氟甲基、一个带有至多4个碳原子的直链或支链的饱和或不饱和的烃基,或者R4和R4a与碳原子25共同为一个3-至7-元的环烷基以及Y为以下残基之一
其中m=0或1和
n=2,3,4,5或6
如果m=1则n=1。
例如(5Z,7E,22E)-(1S,3R,24R)-1,3,24-三羟基-9,10-断胆甾-5,7,10(19),22-四烯-25-羧酸-异丙酯。
这种维生素D-类似物的笼形物以前不为所知,与以前已知的维生素D-系列的笼形物相比较,其特征为具有优越的特性,它也属于本发明的主题。通过用环糊精包含提高了活性物质的生物利用率,尤其是在浅表皮肤层局部用药时,并且因此可减小活性物质的剂量(缓释)。
这些环糊精衍生物不仅适合于制备局部用药物,还可以有利地应用于制备全身用药的剂型,并且同样地具有缓释活性物质的本发明优点。这样可以降低活性物质的严重全身性副作用同时又使该物质稳定。
在制备口服和全身用药的这样小剂量的含钙三醇-类似物药物剂型时,几乎不可避免地出现剂量单位中活性物质浓度的明显波动(含量均一性不足),并且活性物质剂量越小,则这种波动现象越明显。
在这种制剂的贮存中还可见因为活性物质的氧化分解反应而使活性物质的浓度降低。
此外,这样小剂量的这些钙三醇-类似物的生物利用率具有明显的首过效应,并且具有很大的个体之间和个体内的波动变化。
对于口服用药现已发现:如果制备的药物剂型含有这些活性物质的粉末状环糊精-包含化合物,则至少可以基本上避免尤其在含有小剂量钙三醇-类似物的药物剂型贮存时观察到的优点。
适用于制备这种笼形物的环糊精例如如通式II所示其中R′为一个氢原子、甲基、2-羟乙基或2-羟基丙基R″为一个氢原子或者,当R1为一个甲基时,也为一个甲基和r为数字4至7。
这种环糊精优选为α-环糊精、γ-环糊精、二甲基-β-环糊精、2-羟基乙基-β-环糊精、2-羟基丙基-β-环糊精和尤其是β-环糊精(药物进展和工业制药学(Drug Dev.and Ind.Pharm.),
17期,1991年,1503-1549页、包封现象杂志(J.Incl.Phenom.),1期,1983年,135-150页和WO93/13138)。在制备笼形物时,可以将维生素D-类似物与环糊精任选在添加其它的制药学佐剂的情况下充分地混合(例如通过搅拌、揉捏),或者将各组分溶于水中和/或合适的溶剂(例如C1-C4-醇类如甲醇、乙醇或异丙醇,或者C2-C4-酮类如丙酮、甲基乙基酮)中,然后例如通过真空蒸馏、冻干或喷雾干燥去除溶剂。另外还可以将溶解于合适溶剂(例如上述醇类或酮类之一)中的维生素D-类似物加入一种环糊***溶液中,将沉淀的笼形物过滤和干燥。
对于专业人员显而易见的是,通常需要预先试验以了解哪些环糊精能最佳适合于包含所希望的维生素D-类似物。对于很小分子的维生素D-类似物以应用α-环糊精为最佳,包含相当大分子的维生素D-类似物时,可能需要应用γ-环糊精甚或δ-环糊精作为宿主分子。一般情况下选择环糊精对维生素D-类似物的比例以形成1∶1摩尔:摩尔复合物,但是不排除在个别情况下较为合适的是选择摩尔比以例如形成2∶1、3∶1、3∶2或1∶2复合物。
制备局部用药物的方法本身是已知的。但是另一方面也可以制备新的适合皮肤特殊需要的制剂。
这种局部用药制剂的制备按照通常的方式进行,其中将活性物质与合适的添加剂制成所希望的药物剂型,例如溶剂、乳剂、洗剂、乳霜、软膏、油软膏或膏剂。在这样配制的制剂中,活性物质的浓度与药物剂型有关。优选活性物质浓度为5-30重量%。
乳剂、洗剂或乳霜(油/水-乳液)和软膏(水/油-乳液)可以通常的方式应用常规的乳化剂制备(Kirk Othmer:化学技术百科全书(Enzyclopedia ofChemical Technology),第3版,1979年,John Wiley & Sons,纽约,第8卷,900-930页,和Otto-Albrecht Neumueller博士:吕姆普斯化学辞典(Roempps Chemie Lexikon),第7版,1973年,Frankh′sche出版社,斯图加特,1009-1013页)。应用于这些乳剂的蜡、乳化剂和常用的添加剂与常规方法中所应用的相同(Otto-Albrecht Neumueller博士:吕姆普斯化学辞典,第7版,1973年,Frankh′sche出版社,斯图加特,1427-1428页)。
本发明局部用制剂可由一种或二种活性物质、亲水性和/或亲脂性添加剂、脂相、油/水乳化剂、水相和保存剂所组成。
作为亲水性和/或亲脂性添加剂可以应用保湿因子(水配合物)、例如丙二醇、丙三醇、聚乙二醇、尿素、活体复合物(例如胎盘提取物)、酶类、草药提取物(例如胶原)。作为油/水-乳剂中的油相或作为脂相合适的有碳水化合物、例如鱼鲨烯、凡士林、石蜡、甘油三酯或硬脂精,或者蜡,例如蜂蜡或动物或植物油,如橄榄油、花生油、细骨油、杏仁油、西蒙得油、羊毛脂或葵花籽油。合适的油/水-乳化剂例如有十八烷醇、聚氧乙烯硬脂酸酯(例如MYRJ)、复合乳化剂(例如Amphoterin)和脱水山梨醇脂肪酸酯(例如tween80)、羧基乙烯基聚合物(例如Carbopol)、脂肪醇例如鲸蜡醇、肉豆蔻醇或混合酯(例如Dehymuls)。水相可以附加含有缓冲剂,例如乙二胺-N,N,N′,N′-四乙酸的二钠盐和保存剂如苯甲酸、Chlorquinaldol、Parabee或Benzalkoniumchlorid。
此外还将乳液与一种或二种活性物质和任选还与香料,例如Crematest系列的香料相混合,并且搅拌直至均匀分布。
在这样配制的药剂中活性物质的浓度与用药剂型有关。在洗剂和软膏中活性物质浓度优选为0.0001%至3%。
以下实施例进一步说明本发明。实施例1
将200mg二甲基-β-环糊精(0.15mmol)溶于1.00ml水中,在剧烈搅拌下滴加进50mg(5Z,7E,22E)-(1S,3R,24R)-1,3,24-三羟基-9,10-断胆甾-5,7,10(19),22-四烯-羧酸-异丙酯(0.10mmol)于0.5ml二噁烷中的溶液中。继续搅拌15分钟和添加1.2ml二噁烷后,将清亮的溶液在干冰-甲醇-浴池中冷冻,并接着冻干36小时。
为了制备溶液,称量复合物使活性物质的浓度为50μg/g,并且用水补充至100g。实施例2
用超声照射至少5分钟,使3.93g二甲基-β-环糊精和0.209g(5Z,7E,22E)-(1S,3R,24R)-1,3-三羟基-9,10-断胆甾-5,7,10(19),22-四烯-25-羧酸-异丙酯悬浮于100ml水中。将悬浮液搅拌48小时并接着过滤。将滤液在丙酮-干冰-浴池中冷冻和冻干24小时。
为了制备水凝胶,将产生80μg/g活性物质浓度的复合物溶解于99.0g水中,并且用凝胶形成剂(例如Carbopol-B.F.Goodrich Chem.)处理成可以涂抹的剂型。实施例3
在38℃的温度下借助于超声将680mg(0.6mmol)天然β-环糊精溶解于40ml 60%含水乙醇中。接着在稳定搅拌下和充氮气情况下于3分钟内将100mg(5Z,7E,22E)-(1S,3R,24R)-1,3,24-三羟基-9,10-断胆甾-5,7,10(19),22-四烯-25-羧酸-异丙酯于10ml 60%乙醇水溶液中的溶液滴加入。在38℃温度下搅拌15分钟和在1小时内冷却至13℃。
将所形成的沉淀物过滤、用母液洗涤和在真空中干燥。
为了制备脂凝胶,称量复合物使活性成份浓度为40μg/g和研磨进20g凡士林中。接着分批加进凡士林直至100g。
Claims (7)
1.药物制剂,其特征为含有环糊精笼形物和维生素D-类似物。
2.按照权利要求1的局部用药物制剂。
3.按照权利要求2的局部用药物制剂,用以治疗银屑病。
4.按照权利要求1至3的药物制剂,含有钙三醇作为维生素D-类似物。
5.含有通式I维生素D-类似物的环糊精的笼形物其中R1,R2和R3相互独立地分别为一个氢原子、一个带有1或3至9个碳原子的直链或支链的饱和链烷酰基、或者一个芳酰基,OH意为一个α-或β-位的羟基,R4和R4a同时分别为一个氢原子、一个氯原子或氟原子、一个三氟甲基、一个带有至多4个碳原子的直链或支链的饱和或不饱和的烃基,或者R4和R4a与碳原子25共同为一个3-至7-元的环烷基以及Y为以下基团之一
其中m=0或1和
n=2,3,4,5或6且
如果m=1则另外n=1。
6.按照权利要求5的环糊精笼形物,它含有(5Z,7E,22E)-(1S,3R,24R)-1,3,24-三羟基-9,10-断胆甾-5,7,10(19),22-四烯-25-羧酸-异丙酯。
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US6538037B2 (en) | 1991-01-08 | 2003-03-25 | Bone Care International, Inc. | Methods for preparation and use of 1α,24(S)-dihydroxyvitamin D2 |
US6566353B2 (en) | 1996-12-30 | 2003-05-20 | Bone Care International, Inc. | Method of treating malignancy associated hypercalcemia using active vitamin D analogues |
US6503893B2 (en) | 1996-12-30 | 2003-01-07 | Bone Care International, Inc. | Method of treating hyperproliferative diseases using active vitamin D analogues |
US6573256B2 (en) | 1996-12-30 | 2003-06-03 | Bone Care International, Inc. | Method of inhibiting angiogenesis using active vitamin D analogues |
GB9826656D0 (en) | 1998-12-03 | 1999-01-27 | Novartis Ag | Organic compounds |
DE102005017775A1 (de) * | 2005-04-13 | 2006-10-19 | Schering Ag | Komplexe aus Vitamin D-Verbindungen oder deren Analoga mit einem 5Z,7E,10(19)-Trien-System und methlierten Derivaten des ß-Cyclodextrins |
US8426391B2 (en) | 2006-02-03 | 2013-04-23 | Proventiv Therapeutics, Llc | Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 |
SI2679228T1 (en) | 2006-06-21 | 2018-06-29 | Opko Ireland Global Holdings, Ltd. | THERAPY WITH THE USE OF VITAMIN D ADDITIONAL FIBER AND HORMON RESISTANCE OF VITAMIN D |
KR100822133B1 (ko) * | 2006-11-06 | 2008-04-15 | 한미약품 주식회사 | 비타민 d 또는 이의 유도체의 고체분산체 및비스포스포네이트를 포함하는, 골다공증 예방 또는 치료용복합제제 |
DK3342405T3 (da) | 2007-04-25 | 2019-11-11 | Opko Ireland Global Holdings Ltd | Kontrolleret frigivelse af 25-hydroxyvitamin d |
EP2148685A4 (en) | 2007-04-25 | 2010-07-28 | Cytochroma Inc | METHODS AND COMPOUNDS FOR THERAPY BASED ON VITAMIN D |
ES2403107T3 (es) | 2007-04-25 | 2013-05-14 | Cytochroma Inc. | Método de tratamiento de insuficiencia y deficiencia de vitamina D |
WO2008134523A1 (en) | 2007-04-25 | 2008-11-06 | Proventiv Therapeutics, Llc | Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease |
KR101852042B1 (ko) | 2008-04-02 | 2018-04-25 | 사이토크로마 인코포레이티드 | 비타민 d 결핍 및 관련 장애에 유용한 방법, 조성물, 용도 및 키트 |
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SG10201911274TA (en) | 2014-08-07 | 2020-02-27 | Opko Ireland Global Holdings Ltd | Adjunctive therapy with 25-hydroxyvitamin d |
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JPS5910562A (ja) * | 1982-07-07 | 1984-01-20 | Teijin Ltd | プレ−1α−ヒドロキシコレカルシフエロ−ル類の製造法 |
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1996
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