CN101830903B - 枸橼酸爱地那非晶型o及其制备方法和应用 - Google Patents
枸橼酸爱地那非晶型o及其制备方法和应用 Download PDFInfo
- Publication number
- CN101830903B CN101830903B CN2010101729260A CN201010172926A CN101830903B CN 101830903 B CN101830903 B CN 101830903B CN 2010101729260 A CN2010101729260 A CN 2010101729260A CN 201010172926 A CN201010172926 A CN 201010172926A CN 101830903 B CN101830903 B CN 101830903B
- Authority
- CN
- China
- Prior art keywords
- crystal form
- citrate crystal
- aildenafil citrate
- aildenafil
- 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.)
- Expired - Fee Related
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Gynecology & Obstetrics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明涉及1-[3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧基苯磺酰基]-顺式-3,5-二甲基哌嗪枸橼酸盐或枸橼酸爱地那非(Aildenafil citrate)晶型O及其制备方法,本发明还涉及含有枸橼酸爱地那非晶型O的药物组合物及其在制造治疗男性***功能障碍(ED)的药物中的应用;本发明通过将原料枸橼酸爱地那非溶于蒸馏水与四氢呋喃混合液中,搅拌,升温,过滤,滤液搅拌,降温,保温,结晶过滤等步骤制备得到枸橼酸爱地那非晶型O,将其与医药赋型剂制备成药物,并运用于治疗男性性功能障碍疾病中。
Description
技术领域:
本发明涉及1-[3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧基苯磺酰基]-顺式-3,5-二甲基哌嗪枸橼酸盐(枸橼酸爱地那非,Aildenafil citrate)的晶型O及其制备方法、含有本发明所得晶型O的药物组合物及该晶型O用于制造治疗男性***功能障碍(male erectile dysfunction,ED)的药物中的应用。
背景技术:
男性***功能障碍(male erectile dysfunction,ED)是常见疾病,可定义为***不能***、不能***或二者兼具,据统计,其发病率在40岁以上的男性中占1.9%,65岁以上的男性则达到65%。全世界现约有1.25亿男性患有不同程度的***功能障碍,预计到2025年可达到3.22亿(Moreland RB,et al,J Pharmacol ExpTher,2001,296(2):225-234.)。因此,研究开发对ED安全、有效的新型药物或新的给药***具有重要的临床价值和社会效益。为此,一些结构新颖、作用机制独特的新药被推向市场或正在进行临床、临床前研究。
枸橼酸爱地那非(Aildenafil citrate),化学名:1-[3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧基苯磺酰基]-顺式-3,5-二甲基哌嗪枸橼酸盐,分子式:C23H32N6O4S·C6H8O7,分子量:680.73,化学结构式:
是一种处于临床研究中的新药,对ED有效。中国专利(申请号02100198.7)公开了枸橼酸爱地那非及其制备方法等,但没有涉及枸橼酸爱地那非晶型及制备方法。
本发明在研究制备枸橼酸爱地那非的过程中,发现枸橼酸爱地那非存在多晶型现象,本发明晶型O生物活性高,纯度高,稳定性好,在工业生产上具有优越性,适合制剂工艺过程和长期储存。
发明内容:
本发明的目的在于研究一种枸橼酸爱地那非晶型O和枸橼酸爱地那非晶型O的制备方法,本发明的另一个目的在于研究含有枸橼酸爱地那非晶型O的药物组合物及枸橼酸爱地那非晶型O在制造治疗男性***功能障碍(male erectile dysfunction,ED)药物中的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明提供了一种枸橼酸爱地那非晶型O,该晶型的X射线粉末衍射特征吸收峰(2θ)、D值和相对强度如下,2θ衍射角的误差为±0.2。
衍射角(2θ) | D值 | 相对强度(%) |
7.600 | 11.6227 | 100 |
10.160 | 8.6992 | 42 |
13.780 | 6.4210 | 18 |
14.220 | 6.2233 | 32 |
14.980 | 5.9092 | 48 |
16.900 | 5.2419 | 19 |
18.580 | 4.7716 | 20 |
18.960 | 4.6768 | 32 |
19.300 | 4.5952 | 24 |
20.980 | 4.2308 | 15 |
22.700 | 3.9140 | 27 |
23.740 | 3.7448 | 27 |
24.700 | 3.6014 | 16 |
25.520 | 3.4875 | 16 |
粉末X-射线分析(powder x--ray diffraction,PXRD)常用于多晶型的结构确认、热力学稳定性以及其他定性定量研究,是研究药物多晶型最常用的方法之一。
本发明中2θ值的测定使用光源,精度为±0.2°,因此代表上述所取的值允许有一定合理的误差范围,其误差范围为±0.2°;该晶型O的最强特征吸收峰(2θ)为7.600。
其红外光谱图在3423±5cm-1;3310±5cm-1;3193±5cm-1;2980±5cm-1;2470±5cm-1;1693±2cm-1;1167±2cm-1;1023±2cm-1;603±2cm-1
具有可将其与其它晶型区别开来的特征吸收峰,测定时用KBr压片,误差范围根据中国药典确定。
该结晶性粉末的热分析结果表明:样品不含结晶溶剂。
本发明的另外一个目的,公开了枸橼酸爱地那非晶型O的制备方法,其特征在于:给盛有枸橼酸爱地那非的反应瓶中加入枸橼酸爱地那非量25-26倍(质量-体积比,克/毫升)蒸馏水与四氢呋喃混合液,四氢呋喃占混合液体积的5-15%。开动搅拌,升温至回流温度,15-20分钟后趁热过滤,滤液搅拌下降温至室温,保温搅拌24-26小时,析出结晶,过滤,室内放置1小时,然后移至真空于燥箱中,真空干燥3小时,即得到枸橼酸爱地那非晶型O。
所用的枸橼酸爱地那非,根据下列合成路线制得:
反应式中:
化合物2:4-氨基-1-甲基-3-正丙基吡唑-5-甲酰胺
化合物3:2-乙氧基苯甲酰氯
化合物4:4-(2-乙氧基苯酰胺)-1-甲基-3-正丙基吡唑-5-酰胺
化合物5:1-甲基-3-丙基-5-[(2-乙氧基)苯基]-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮
化合物6:1-甲基-3-丙基-5-[(2-乙氧基-5-磺酰基)苯基]-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮
化合物7:顺式-2,6-二甲基哌嗪
化合物8:爱地那非
化合物1:枸橼酸爱地那非
其中,化合物2,3,7可购买,如果在市场买不到,可以根据文献的先例按常规合成法由易得的原料制得,如化合物2可按文献(Chem.Pharm.Bull.1984,32(4):1568-1577;精细化工,2001,18(7):396-397等)制备;化合物3可按文献(化学研究与应用,2002,14(5):605-607等)制备;化合物7也可按已有的文献方法方便的制得。
其中,化合物4,5,6,8,枸橼酸爱地那非,可以根据文献(US4666908;中国医药工业杂志,2000,31(4):145-147;化学研究与应用,2002,14(5):605-607;沈阳药科大学学报,2002,19(3),174-175.等)提供的方法,由化合物6制备化合物8,只需将其中的N-甲基哌嗪用顺式-2,6-二甲基哌嗪替换,便可方便地合成爱地那非(8)。为了得到高纯度的枸橼酸爱地那非,爱地那非(8)可用甲醇重结晶一次。然后,爱地那非在23-28倍的甲醇或乙醇(质量-体积比,g/ml)中,回流温度下,与等摩尔枸橼酸反应0.5-1小时,生成枸橼酸爱地那非粗品,甲醇重结晶后,用于晶型研究。它的化学结构经核磁共振氢谱(1H-NMR)、核磁共振碳谱(13C-NMR)等确证,证明化学结构是正确的,见图3和图4。
上述制备枸橼酸爱地那非的反应是常规反应,只要参考普通教科书和相关文献,便可容易地确定进行这些反应的适当试剂和条件,这对本领域技术人员来说是显而易见的。
本发明的又一个目的,提供了包含枸橼酸爱地那非晶型O和药物常用赋形剂结合制备成药物组合物,再按照常规方法制备成各种口服制剂。
在药物组合物中可以使用任何常规已知的和在本领域广泛使用的赋形剂,例如载体、填料、膨胀剂、粘合剂、增湿剂、崩解剂、表面活性剂、润滑剂或稀释剂。例如载体包括但不限于乳糖、白糖、氯化钠、葡萄糖、淀粉、碳酸钙、结晶纤维素和硅酸。粘合剂包括但不限于水、乙醇、丙醇、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、甲基纤维素、磷酸钾和聚乙烯吡咯烷酮。崩解剂包括但不限于干燥淀粉、海藻酸钠、琼脂粉末、碳酸氢钠、碳酸钙、十二烷基硫酸钠、硬脂酸单甘油酯、淀粉或乳糖。增湿剂包括但不限于甘油或淀粉。润滑剂包括但不限于纯化的滑石粉、硬脂酸酯、硼酸粉末和聚乙二醇。
本发明药物组合物优选的给药途径是口服。剂型包括片剂、颗粒剂、胶囊、缓释片、缓释微丸等等。优选片剂、颗粒剂、胶囊。
药物组合物中含有的该晶型的枸橼酸爱地那非的量按单元剂型含50-70mg。
本发明还提供了枸橼酸爱地那非晶型O在制造治疗男性***功能障碍药物中的应用。
药效学试验:对去势小鼠性功能的测定
昆明种雄小鼠60只,(同期饲养18~22g雌性小鼠60只),按体重随机分为6组,每组10只,其中5组在***麻醉下摘除双侧睾丸,作去势处理,剩余一组仅进行手术分离,不摘除睾丸,作为假手术对照组。各组动物回笼饲养,3d后进行试验。假手术对照组、模型对照组均给予0.5%CMC,受试药给爱地那非晶型O 2mg.kg-1,6mg.kg-1,20mg.kg-1,阳性对照组给西地那非6mg.kg-1,均为ig给药,给药体积均为10ml.kg-1。给药后60min,将雄性小鼠单只置于笼中,每笼中加入雌性小鼠1只,记录自雌性小鼠投于笼中雄鼠第1次捕捉雌鼠的时间(即捕捉潜伏期),以及30min内雄性小鼠爬背的次数。结果显示,15mg/kg-1可使去势小鼠捕捉潜伏期缩短201%,捕捉次数增加4.4倍。影响因素试验:
对外观的影响
样品 | 项目 | 0月 | 0.5月 | 1月 |
枸橼酸爱地那非晶型O | 高温试验高湿试验光照试验 | 白色结晶性粉末白色结晶性粉末白色结晶性粉末 | 白色结晶性粉末白色结晶性粉末白色结晶性粉末 | 白色结晶性粉末白色结晶性粉末白色结晶性粉末 |
对含量(HPLC面积归一化法)的影响
样品 | 项目 | 0月(%) | 0.5月(%) | 1月(%) |
枸橼酸爱地那非晶型O | 高温试验高湿试验光照试验 | 99.9699.9699.96 | 99.9699.9599.96 | 99.9599.9699.96 |
对有关物质的影响
样品 | 项目 | 0月(%) | 0.5月(%) | 1月(%) |
枸橼酸爱地那非化合物晶型O | 高温试验高湿试验光照试验 | 0.040.040.04 | 0.040.040.04 | 0.040.050.04 |
对红外吸收光谱的影响
样品 | 项目 | 0月 | 0.5月 | 1月 |
枸橼酸爱地那非化合物晶型O | 高温试验高湿试验光照试验 | 见图2见图2见图2 | 未改变未改变未改变 | 未改变未改变未改变 |
对X粉末衍射的影响
样品 | 项目 | 0月 | 0.5月 | 1月 |
枸橼酸爱地那非化合物晶型O | 高温试验高湿试验光照试验 | 见图1见图1见图1 | 未改变未改变未改变 | 未改变未改变未改变 |
本发明的有益效果为:
从以上五表中可以看出:枸橼酸爱地那非晶型O在强光(4500lx±500lx)、高温(60±2℃)、高湿(RH92.5%)条件下从0-1个月,外观、X粉末衍射、红外吸收光谱均未发生变化,说明晶型稳定,无转晶发生,仍保持原来的晶型;另外有关物质、含量没有改变,说明晶型O化学稳定性良好,适合药物制剂的制造及长期储存。
附图说明:
图1为枸橼酸爱地那非晶型O的X射线粉末衍射图;
图2为枸橼酸爱地那非晶型O的红外光谱图;
图3为枸橼酸爱地那非的核磁共振氢谱(1H-NMR);
图4为枸橼酸爱地那非的核磁共振碳谱(13C-NMR)。
具体实施方式:
下面结合实施例和附图对本发明做进一步的说明,使本领域专业技术人员更好的理解本发明。实施例仅为解释性的,决不意味着它以任何方式限制本发明的范围。
本发明中所用的枸橼酸爱地那非,前面已做了叙述,它的化学结构经元素分析、核磁共振氢谱(1H-NMR)、核磁共振碳谱(13C-NMR,DEPT)、高分辩质谱(HRMs)确证,证明化学结构是正确的,其中核磁共振氢谱(1H-NMR)、核磁共振碳谱(13C-NMR,)见图3和图4。
实施例1
在1000ml反应瓶中,加入20克枸橼酸爱地那非、450ml蒸馏水、50ml四氢呋喃,开动搅拌,加热升温至回流,15分钟后趁热过滤,滤液搅拌下降温至室温,保温搅拌25小时,析出结晶,过滤,室内放置1小时,然后移至真空干燥箱中,真空干燥3小时,即得到枸橼酸爱地那非晶型O18.8g,精制率94%,采用HPLC面积归一法测得含量99.96%。经X射线衍射仪、红外光谱仪检测(见图1,图2),显示枸橼酸爱地那非晶型O的特征。
实施例2
在2000ml反应瓶中,加入40克枸橼酸爱地那非、900ml蒸馏水、95ml四氢呋喃,开动搅拌,加热升温至回流,20分钟后趁热过滤,滤液搅拌下降温至室温,保温搅拌25小时,析出结晶,过滤,室内放置1小时,然后移至真空干燥箱中,真空干燥4小时,即得到枸橼酸爱地那非晶型O37.6g,精制率94%,采用HPLC面积归一法测得含量99.96%。经X射线衍射仪、红外光谱仪检测(见图1,图2),显示枸橼酸爱地那非晶型O的特征。
实施例3
含有枸橼酸爱地那非晶型O的颗粒剂
处方:枸橼酸爱地那非晶型O 50克,乳糖650克,交联聚维100克,PEG-400090克,羟丙基甲基纤维素135克,蒸馏水适量,制成1000袋。
工艺:PEG-4000与枸橼酸爱地那非晶型O共同粉碎,过80目筛,与其它物料混匀后用蒸馏水制软材、制粒、低温干燥后分装为颗粒剂。
实施例4
含有枸橼酸爱地那非晶型O的胶囊
处方:枸橼酸爱地那非晶型O 60克,淀粉50克,乳糖40克,蔗糖10克,微晶纤维素35克,10%聚乙烯吡咯烷酮乙醇溶液适量,硬脂酸镁1克,制成1000粒。
工艺:枸橼酸爱地那非晶型O及辅料过80目筛,按处方量称取,以10%聚乙烯吡咯烷酮乙醇溶液为粘合剂,用16目筛制成适宜的颗粒,65℃干燥,14目筛整粒,加入硬脂酸镁混合均匀,测颗粒含量,计算装量,装入胶囊即可。
实施例5
含有枸橼酸爱地那非晶型O的片剂
处方:枸橼酸爱地那非晶型O 70克,微晶纤维素5克,乳糖140克,10克PEG-4000,硬脂酸镁1克,14克聚维酮K30,交联羧甲基纤维素钠10克,蒸馏水适量,制成1000片。
工艺:PEG-4000与枸橼酸爱地那非晶型O共同粉碎,过80目筛,与其它物料混匀后用蒸馏水制软材,16目筛制颗粒,置干燥箱中于40-45℃干燥,16目筛整粒,硬脂酸镁加入干颗粒中混匀,压片。
以上内容仅为本发明的较佳实施例,对于本领域的普通技术人员,依据本发明的思想,在具体实施方式及应用范围上均会有改变之处,本说明书内容不应理解为对本发明的限制。
Claims (9)
1.一种枸橼酸爱地那非晶型O,其特征在于:用CuKa射线作为特征X射线粉末衍射测定中,其图谱具有下列2θ衍射角、D值和相对强度,2θ衍射角的误差为±0.2;
。
2. 根据权利要求1所述的一种枸橼酸爱地那非晶型O,其特征在于:该晶型O在X射线粉末衍射测定中的最强特征吸收峰(2θ)为7.600。
3.根据权利要求1所述的一种枸橼酸爱地那非晶型O,其特征在于:红外光谱图中,在3423±5cm-1;3310±5cm-1; 3193±5cm-1;2980±5cm-1;2470±5cm-1;1693±2cm-1;1167±2cm-1;1023±2cm-1;603±2cm-1处具有可将其与其他晶型区分开来的特征吸收峰。
4.根据权利要求1所述的一种枸橼酸爱地那非晶型O,其特征在于:在热分析仪测定结果表明:样品不含结晶溶剂。
5.权利要求1至4任意一项所述的枸橼酸爱地那非晶型O的制备方法,其特征在于:通过将枸橼酸爱地那非溶于25-26倍的蒸馏水与四氢呋喃混合液中,其质量-体积比以克/毫升计,开始搅拌,升温至回流温度,15-20分钟后趁热过滤,滤液在搅拌下降温至室温,保温搅拌24-26小时,析出结晶,过滤,干燥,即得到枸橼酸爱地那非晶型O。
6.根据权利要求5所述的枸橼酸爱地那非晶型O的制备方法,其特征在于:所述的蒸馏水与四氢呋喃混合液,其中四氢呋喃占混合液体积的5-15%。
7.一种含有权利要求1至4任意一项所述的枸橼酸爱地那非晶型O组合物,其特征在于:由枸橼酸爱地那非晶型O与一种或多种药学上可接受的载体、赋形剂组成组合物。
8.权利要求7所述的枸橼酸爱地那非晶型O的药物组合物的用途,其特征在于:该组合物用于制备口服制剂。
9.权利要求8所述的枸橼酸爱地那非晶型O的药物组合物制备的口服制剂的应用,其特征在于:在制造治疗男性***功能障碍药物中的应用。
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010101729260A CN101830903B (zh) | 2010-05-10 | 2010-05-10 | 枸橼酸爱地那非晶型o及其制备方法和应用 |
SG2012068573A SG184090A1 (en) | 2010-05-10 | 2011-03-11 | Aildenafil citrate crystal form o, preparation method and use thereof |
SG10201503635WA SG10201503635WA (en) | 2010-05-10 | 2011-03-11 | Aildenafil citrate crystal form o, preparation method and use thereof |
AU2011252630A AU2011252630A1 (en) | 2010-05-10 | 2011-03-11 | Aildenafil citrate crystal form O, preparation method and use thereof |
JP2013509430A JP2013526491A (ja) | 2010-05-10 | 2011-03-11 | メチソシルデナフィル・クエン酸塩結晶型o及びその調製方法並びに応用 |
US13/583,511 US9663439B2 (en) | 2010-05-10 | 2011-03-11 | Aildenafil citrate crystal form O, preparation method and use thereof |
KR1020147023651A KR20140111044A (ko) | 2010-05-10 | 2011-03-11 | 구연산아일데나필 결정 형태 o 및 그의 제조방법과 용도 |
MYPI2012004059A MY176891A (en) | 2010-05-10 | 2011-03-11 | Aildenafil citrate crystal form o, preparation method and use thereof |
PCT/CN2011/071725 WO2011140858A1 (zh) | 2010-05-10 | 2011-03-11 | 枸橼酸爱地那非晶型o及其制备方法和应用 |
EP11780080.5A EP2604609A4 (en) | 2010-05-10 | 2011-03-11 | CRYSTALLINE O-FORM OF SILDENAFIL CITRATE, PROCESS FOR PREPARATION AND USE THEREOF |
KR1020127026152A KR20120137403A (ko) | 2010-05-10 | 2011-03-11 | 구연산아일데나필 결정 형태 o 및 그의 제조방법과 용도 |
MX2012010952A MX2012010952A (es) | 2010-05-10 | 2011-03-11 | Forma cristalina de citrato de aldefanil, metodo de preparacion y uso del mismo. |
ZA2012/06740A ZA201206740B (en) | 2010-05-10 | 2012-09-10 | Aildenafil citrate crystal form o,preparation method and use thereof |
AU2015201141A AU2015201141A1 (en) | 2010-05-10 | 2015-03-04 | Aildenafil citrate crystal form O, preparation method and use thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2010101729260A CN101830903B (zh) | 2010-05-10 | 2010-05-10 | 枸橼酸爱地那非晶型o及其制备方法和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101830903A CN101830903A (zh) | 2010-09-15 |
CN101830903B true CN101830903B (zh) | 2012-07-04 |
Family
ID=42715138
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2010101729260A Expired - Fee Related CN101830903B (zh) | 2010-05-10 | 2010-05-10 | 枸橼酸爱地那非晶型o及其制备方法和应用 |
Country Status (11)
Country | Link |
---|---|
US (1) | US9663439B2 (zh) |
EP (1) | EP2604609A4 (zh) |
JP (1) | JP2013526491A (zh) |
KR (2) | KR20140111044A (zh) |
CN (1) | CN101830903B (zh) |
AU (2) | AU2011252630A1 (zh) |
MX (1) | MX2012010952A (zh) |
MY (1) | MY176891A (zh) |
SG (2) | SG184090A1 (zh) |
WO (1) | WO2011140858A1 (zh) |
ZA (1) | ZA201206740B (zh) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101830903B (zh) * | 2010-05-10 | 2012-07-04 | 刘桂坤 | 枸橼酸爱地那非晶型o及其制备方法和应用 |
CN104725469B (zh) * | 2013-12-18 | 2019-07-12 | 重庆莱美药业股份有限公司 | 一种制备他替瑞林α晶型的方法 |
CN107602571A (zh) * | 2017-11-07 | 2018-01-19 | 中国医药集团总公司四川抗菌素工业研究所 | 枸橼酸艾地那非晶体及其制备方法和药物组合物 |
CN110432924B (zh) * | 2019-08-06 | 2021-10-22 | 杭州智团信息技术有限公司 | 肠鸣音检测装置、方法和电子设备 |
CN112745323B (zh) * | 2020-12-30 | 2021-10-29 | 北京悦康科创医药科技股份有限公司 | 枸橼酸爱地那非晶型h及其制备方法和用途 |
CN115054585B (zh) * | 2022-07-11 | 2022-11-18 | 北京悦康科创医药科技股份有限公司 | 含有枸橼酸爱地那非的片剂及其制备方法和用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1977846A (zh) * | 2005-12-06 | 2007-06-13 | 刘宝顺 | 治疗阳痿的药物组合物 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4666908A (en) | 1985-04-05 | 1987-05-19 | Warner-Lambert Company | 5-Substituted pyrazolo[4,3-d]pyrimidine-7-ones and methods of use |
CN101671338B (zh) * | 2009-09-27 | 2012-07-25 | 刘桂坤 | 枸橼酸爱地那非晶型d及其制备方法和用途 |
CN101691372B (zh) * | 2009-09-27 | 2011-11-23 | 刘桂坤 | 枸橼酸爱地那非晶型c及其制备方法和用途 |
CN101671337B (zh) * | 2009-09-27 | 2011-08-10 | 刘桂坤 | 枸橼酸爱地那非晶型a及其制备方法和用途 |
CN101671339B (zh) * | 2009-09-27 | 2012-06-27 | 刘桂坤 | 枸橼酸爱地那非晶型b及其制备方法和用途 |
CN101698668B (zh) * | 2009-11-10 | 2012-07-25 | 刘桂坤 | 枸橼酸爱地那非晶型v及其制备方法和用途 |
CN101830903B (zh) * | 2010-05-10 | 2012-07-04 | 刘桂坤 | 枸橼酸爱地那非晶型o及其制备方法和应用 |
-
2010
- 2010-05-10 CN CN2010101729260A patent/CN101830903B/zh not_active Expired - Fee Related
-
2011
- 2011-03-11 SG SG2012068573A patent/SG184090A1/en unknown
- 2011-03-11 SG SG10201503635WA patent/SG10201503635WA/en unknown
- 2011-03-11 WO PCT/CN2011/071725 patent/WO2011140858A1/zh active Application Filing
- 2011-03-11 EP EP11780080.5A patent/EP2604609A4/en not_active Withdrawn
- 2011-03-11 US US13/583,511 patent/US9663439B2/en active Active
- 2011-03-11 JP JP2013509430A patent/JP2013526491A/ja active Pending
- 2011-03-11 MX MX2012010952A patent/MX2012010952A/es unknown
- 2011-03-11 KR KR1020147023651A patent/KR20140111044A/ko not_active Application Discontinuation
- 2011-03-11 MY MYPI2012004059A patent/MY176891A/en unknown
- 2011-03-11 AU AU2011252630A patent/AU2011252630A1/en not_active Abandoned
- 2011-03-11 KR KR1020127026152A patent/KR20120137403A/ko active Application Filing
-
2012
- 2012-09-10 ZA ZA2012/06740A patent/ZA201206740B/en unknown
-
2015
- 2015-03-04 AU AU2015201141A patent/AU2015201141A1/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1977846A (zh) * | 2005-12-06 | 2007-06-13 | 刘宝顺 | 治疗阳痿的药物组合物 |
Also Published As
Publication number | Publication date |
---|---|
SG184090A1 (en) | 2012-10-30 |
SG10201503635WA (en) | 2015-06-29 |
EP2604609A1 (en) | 2013-06-19 |
KR20140111044A (ko) | 2014-09-17 |
MX2012010952A (es) | 2012-11-12 |
US9663439B2 (en) | 2017-05-30 |
JP2013526491A (ja) | 2013-06-24 |
CN101830903A (zh) | 2010-09-15 |
US20130165448A1 (en) | 2013-06-27 |
ZA201206740B (en) | 2013-06-26 |
MY176891A (en) | 2020-08-25 |
KR20120137403A (ko) | 2012-12-20 |
AU2015201141A1 (en) | 2017-03-30 |
EP2604609A4 (en) | 2014-01-15 |
AU2011252630A1 (en) | 2012-10-11 |
WO2011140858A1 (zh) | 2011-11-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101671337B (zh) | 枸橼酸爱地那非晶型a及其制备方法和用途 | |
CN101691372B (zh) | 枸橼酸爱地那非晶型c及其制备方法和用途 | |
CN101830903B (zh) | 枸橼酸爱地那非晶型o及其制备方法和应用 | |
EP3383372B1 (en) | Solid dispersions comprising a sgc stimulator | |
CN102351857A (zh) | 盐酸托烷司琼化合物 | |
CN101671338B (zh) | 枸橼酸爱地那非晶型d及其制备方法和用途 | |
CN112745323B (zh) | 枸橼酸爱地那非晶型h及其制备方法和用途 | |
CN102367252A (zh) | 一种盐酸托烷司琼化合物 | |
CN101698668B (zh) | 枸橼酸爱地那非晶型v及其制备方法和用途 | |
CN101671339B (zh) | 枸橼酸爱地那非晶型b及其制备方法和用途 | |
CN101684108B (zh) | 2-(3-氰基-4-异丁氧基苯基)-4-甲基-5-噻唑甲酸及其组合物 | |
CN108640910A (zh) | 阿瑞吡坦l-脯氨酸溶剂化物-组合物和共晶体 | |
CN104447683A (zh) | 一种稳定的比拉斯汀化合物 | |
EP3575300A1 (en) | Novel crystalline forms of ibrutinib | |
CN101619039A (zh) | 2-(4-乙基-1-哌嗪基)-4-(4-氟苯基)-5,6,7,8,9,10-六氢芳辛并[b]吡啶及其组合物 | |
CN105399725A (zh) | 曲格列汀化合物其盐、晶体、药物组合物和用途 | |
CN110950835A (zh) | 稳定的鲁格列净化合物 | |
CN110950857A (zh) | 一种稳定的盐酸鲁拉西酮水合物化合物 | |
CN110950855A (zh) | 一种稳定的伊潘立酮化合物 | |
CN105622728A (zh) | 一种稳定的奥利万星化合物 | |
CN102120746B (zh) | 一种盐酸氯吡格雷晶型ⅱ及其制备方法和用途 | |
CN104370810B (zh) | 孟鲁司特钠化合物 | |
CN101607960B (zh) | 醋茶溴索及其组合物 | |
WO2009152684A1 (zh) | 一种右佐匹克隆结晶及其组合物、其制备方法和应用 | |
CN101735039A (zh) | 索法酮的晶型ⅱ及其制备方法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20190404 Address after: 518029 L09, 7th Building, 4th Floor, Bagua 4th Road Workshop, Shanglin Community, Yuanling Street, Futian District, Shenzhen City, Guangdong Province Patentee after: Gordon Smart Technology (Shenzhen) Co.,Ltd. Address before: 523123 Qifeng Road, Dongguan City, Guangdong Province, New Century Haoyuan Yalanju 4E Patentee before: Liu Guikun |
|
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120704 |