WO2011140858A1 - 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 PDF

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WO2011140858A1
WO2011140858A1 PCT/CN2011/071725 CN2011071725W WO2011140858A1 WO 2011140858 A1 WO2011140858 A1 WO 2011140858A1 CN 2011071725 W CN2011071725 W CN 2011071725W WO 2011140858 A1 WO2011140858 A1 WO 2011140858A1
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citrate
amorphous
crystal form
amorphous form
tetrahydrofuran
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PCT/CN2011/071725
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English (en)
French (fr)
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刘桂坤
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Liu Guikun
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Priority to AU2011252630A priority Critical patent/AU2011252630A1/en
Priority to EP11780080.5A priority patent/EP2604609A4/en
Priority to MX2012010952A priority patent/MX2012010952A/es
Priority to JP2013509430A priority patent/JP2013526491A/ja
Priority to KR1020147023651A priority patent/KR20140111044A/ko
Priority to KR1020127026152A priority patent/KR20120137403A/ko
Priority to SG2012068573A priority patent/SG184090A1/en
Priority to US13/583,511 priority patent/US9663439B2/en
Publication of WO2011140858A1 publication Critical patent/WO2011140858A1/zh
Priority to ZA2012/06740A priority patent/ZA201206740B/en
Priority to AU2015201141A priority patent/AU2015201141A1/en

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    • 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
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    • 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

Definitions

  • the present invention relates to 1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)- Form 0 of 4-ethoxybenzenesulfonyl]-cis-3,5-dimethylpiperazinium citrate (Aildenafil citrate) and its preparation method, containing the present invention
  • ED male erectile dysfunction
  • the present application is based on the Chinese Patent Application No. 201010172926.0, filed on May 10, 2010, the content of which is hereby incorporated by reference.
  • ED Male erectile dysfunctioi
  • ED Male erectile dysfunctioi
  • ED Male erectile dysfunctioi
  • the penis can not be erect, can not ejaculate or both, according to statistics, the incidence of men over the age of 40 accounted for 1.9%, 65 years of age or older Men reach 65%.
  • About 125 million men worldwide have varying degrees of erectile dysfunction and are expected to reach 322 million by 2025 (Moreland RB, et al, J Pharmacol Exp Ther, 2001, 296(2): 225-234.) o Therefore, research and development have important clinical and social benefits for ED safe, effective new drugs or new drug delivery systems.
  • Aildenafil citrate chemical name: 1-[3- ( 6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazole[4] , 3-d]pyrimidin-5-yl)-4-ethoxybenzenesulfonyl]-cis-3,5-dimethylpiperazinium citrate, Molecular formula: C 23 H 32 N 6 0 4 S ⁇ C 6 H 8 0 7 , Molecular Weight: 680.73, Chemical Structural Formula:
  • Cidandre citrate and its preparation method discloses edandre citrate and its preparation method, etc., but does not relate to the amorphous form of citrate and its preparation method.
  • the present invention finds that polymorphism exists in the adenafil citrate.
  • the crystal form of the present invention has high biological activity, high purity and good stability, and is industrially produced. It is superior in formulation process and long-term storage. Summary of the invention:
  • the object of the present invention is to study a method for preparing amorphous type 0 of citrate and amorphous form 0 of eric acid, and another object of the present invention is to study the inclusion of bismuth.
  • the pharmaceutical composition of the acid Adina non- amorphous type 0 and the amorphous form of eric acid Adinagen are used in the manufacture of a medicament for treating male erectile dysfunction (male erectile dysfunctioi ⁇ ED).
  • the present invention provides an amorphous form of decanoic acid, wherein the X-ray powder has a diffraction characteristic absorption peak (2 ⁇ ), a D value and a relative intensity as follows, and the error of the diffraction angle of 2 ⁇ is
  • Powder X-ray diffraction is commonly used in structural confirmation, thermodynamic stability and other qualitative and quantitative studies of polymorphs. It is one of the most commonly used methods for studying drug polymorphism.
  • the measurement of the 2 ⁇ value uses a light source with an accuracy of ⁇ 0.2°, so that the above-mentioned values allow a certain reasonable error range, and the error range is ⁇ 0.2°; the strongest characteristic absorption peak of the crystal form 0 ( 2 ⁇ ) is 7.600.
  • the infrared spectrum is 3423 ⁇ 5cm- 1 ; SS lOiScm" 1 ; S ⁇ SiScm” 1 ; 2980 ⁇ 5cm; 2470 ⁇ 5cm; 1693 ⁇ 2cm; 1167 ⁇ 2cm; 1023 ⁇ 2cm; 603 ⁇ 2cm -1
  • Another object of the present invention is to provide a method for preparing amorphous form of citric acid, which is characterized in that: an amount of edurnic acid citrate is added to a reaction bottle containing edenafil citrate. 25-26 times (mass-volume ratio, g/ml) of a mixture of distilled water and tetrahydrofuran, and tetrahydrofuran accounts for 5-15% by volume of the mixture. Start stirring, warm to reflux temperature, 15-20 minutes, filter while hot, stir the filtrate to cool to room temperature, stir for 24-26 hours, precipitate crystals, filter, place for 1 hour, then move to vacuum oven, vacuum After drying for 3 hours, the amorphous form of decanoic acid is obtained.
  • the alfrapa citrate used was prepared according to the following synthetic route:
  • compounds 2, 3, 7 can be purchased. If they are not available in the market, they can be prepared from readily available raw materials according to the literature's precedents according to conventional synthesis methods. For example, compound 2 can be classified according to the literature.
  • compound 4, 5, 6, 8, edurinic acid can be based on the literature (US4666908; Chinese Journal of Pharmaceutical Industry, 2000, 31 (4): 145-147; Chemical Research and Applications, 2002, 14 ( 5): 605-607; Journal of Shenyang Pharmaceutical University, 2002, 19 (3), 174-175. etc.)
  • N-methylpiperazine With the substitution of formula-2,6-dimethylpiperazine, it is convenient to synthesize alidea (8).
  • adenafil (8) can be recrystallized once with methanol.
  • Still another object of the present invention is to provide a pharmaceutical composition comprising a combination of ruthenium citrate amorphous form 0 and a usual excipient of a drug, which are then prepared into various oral preparations according to a conventional method.
  • any conventionally known and widely used excipients such as carriers, fillers, bulking agents, binders, moisturizers, disintegrants, surfactants, lubricants or the like may be used in the pharmaceutical compositions.
  • carriers include, but are not limited to, lactose, white sugar, sodium chloride, dextrose, starch, calcium carbonate, crystalline cellulose, and silicic acid.
  • Binders include, but are not limited to, water, ethanol, propanol, dextrose solution, starch solution, gelatin solution, carboxymethylcellulose, methylcellulose, potassium phosphate, and polyvinylpyrrolidone.
  • Disintegrating agents include, but are not limited to, dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium didecyl sulfate, stearic acid monoglyceride, starch or lactose.
  • Moisturizing agents include, but are not limited to, glycerin or starch.
  • Lubricants include, but are not limited to, purified talc, stearate, boric acid powder, and polyethylene glycol.
  • a preferred route of administration for the pharmaceutical compositions of the invention is oral.
  • Dosage forms include tablets, granules, capsules, sustained release tablets, sustained release pellets and the like. Preference is given to tablets, granules and capsules.
  • compositions containing the crystalline form of the citrate love to that amount of the non-press unit dosage forms containing the 50-70 mg 0
  • the present invention also provides the use of Adinadina citrate in the manufacture of a medicament for treating male erectile dysfunction.
  • mice 60 female mice in 18 ⁇ 22 g in the same period
  • mice 60 female mice in 18 ⁇ 22 g in the same period
  • testes were removed. Potential treatment, the remaining group was only surgically separated, and the testes were not removed, as a sham control group.
  • Each group of animals was returned to the cage and tested after 3 days.
  • the sham-operated control group and the model control group were given 0.5% CMC, and the test drugs were given to Adidia amorphous C ⁇ mg.kg- 1 , 6 mg.kg 1 , 20 mg.kg 1 , and the positive control group was given to the West.
  • the dosage volume is 10ml.kg-60min after administration
  • the male mice are placed in a single cage, and one female mouse is added to each cage, recorded from Female mice were placed in cages for the first time in which males were captured (ie, capture latency:), and the number of male mice crawling back within 30 min.
  • the results showed that, 15 mg / kg- 1 ovariectomized mice can capture latency decreased by 201%, an increase of 4.4 times the number of capture. Influencing factors test:
  • Figure 1 is an X-ray powder diffraction pattern of amorphous form of ruthenium citrate
  • Figure 2 is an infrared spectrum of amorphous form 0 of eric acid
  • Figure 3 is a nuclear magnetic resonance spectrum (H-NMR) of adinafil citrate
  • Figure 4 is a nuclear magnetic resonance carbon spectrum ( 13 C-NMR) of adinafil citrate.
  • adenafil citrate used in the present invention has been described above, and its chemical structure is characterized by elemental analysis, nuclear magnetic resonance spectroscopy, H-NMR nuclear magnetic resonance ( 13 C-NMR, DEPT), and high resolution. Mass spectrometry (HRMs) confirmed that the chemical structure was correct, and nuclear magnetic resonance (-NMR) and nuclear magnetic resonance ( 13C -NMR) were shown in Fig. 3 and Fig. 4.
  • PEG-4000 is co-pulverized with decidyl citrate amorphous type 0, passed through 80 mesh sieve, mixed with other materials, and then made into soft materials by distillery water, granulated, dried at low temperature and then packaged as granules.
  • PEG-4000 is co-pulverized with decidyl acid Aidina 0, passed through 80 mesh sieve, mixed with other materials, made of soft water with distilled water, 16 mesh sieved granules, placed in a drying oven at 40-45 Dry at °C, sieve through 16 mesh, add magnesium stearate to dry granules, and compress.
  • the present invention relates to 1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)- 4-ethoxybenzenesulfonyl]-cis-3,5-dimethylpiperazinium hydride or albendafil citrate crystal form 0 and its preparation method, the invention also relates to The invention relates to a pharmaceutical composition containing Adinadina citrate amorphous form 0 and its use in the manufacture of a medicament for treating male erectile dysfunction (ED); the invention is insoluble in distilled water and tetrahydrofuran by using the raw material acitretin In the mixed solution, stirring, heating, filtration, filtrate stirring, cooling, heat preservation, crystallization filtration and other steps to prepare acridine acid Adipine amorphous type 0, which is prepared into a drug with a pharmaceutical excipient, and is used for treating males. In sexual dysfunction diseases.

Description

说 明 书 枸橼酸爱地那非晶型 0， 其制备方法和用途 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 0及 其制备方法、含有本发明所得晶型 0的药物组合物及该晶型 0用于 制造治疗男性勃起功能障碍 (male erectile dysfunction,ED)的药物中 的应用。 本申请是基于申请日 2010 年 5 月 10 日的、 申请号为 201010172926.0 的中国发明专利申请， 上述专利申请的内容作为参 考引入本文。
背景技术：
男性勃起功能障碍 (male erectile dysfunctioi^ED)是常见疾病， 可 定义为阴茎不能勃起、 不能射精或二者兼具， 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勃起功能障碍，预计到 2025年可 达 到 3.22 亿 (Moreland RB,et al, J Pharmacol Exp Ther,2001,296(2):225-234.) o 因此， 研究开发对 ED安全、 有效的新 型药物或新的给药系统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： C23H32N604S · C6H807， 分子量： 680.73， 化学结构式：
Figure imgf000003_0001
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 0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 0和枸橼酸爱 地那非晶型 0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 0的药物组合物及枸橼酸爱地那非晶型 0在制造治 疗男性勃起功能障碍 (male erectile dysfunctioi^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 0， 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。
Figure imgf000004_0001
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 0 的最强特征吸收峰 （2Θ) 为 7.600。
其红外光谱图在 3423±5cm-1 ; SS lOiScm"1 ; S ^SiScm"1 ; 2980士 5cm ; 2470士 5cm ; 1693士 2cm ; 1167士 2cm ; 1023士 2cm ; 603士 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 0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， 然后移至真空干燥箱中， 真空干燥 3小时， 即得到枸橼酸爱地那非晶型 0。
所用的枸橼酸爱地那非， 根据下列合成路线制得：
Figure imgf000006_0001
化合物 8: 爱地那非
化合物 h 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 ^H-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 0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垸酮。 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 二垸基硫酸钠、 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 50-70 mg 0
本发明还提供了枸橼酸爱地那非晶型 0在制造治疗男性勃起功 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 18〜22 g雌性小鼠 60只：)， 按体重 随机分为 6组， 每组 10只， 其中 5组在乙醚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 C^mg.kg—1, 6 mg.kg1 , 20 mg.kg1, 阳性对照组给西地那非 6 mg.kg , 均为 ig给药， 给药体积均 为 10ml.kg- 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， 15 mg/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
Figure imgf000009_0001
对含量 （HPLC面积归一化法） 的影响
Figure imgf000009_0002
对红外吸收光谱的影响
Figure imgf000010_0001
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 0 在强光 ( 45001χ±5001χ)、高温 ( 60±2°C )、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 0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 0的 X射线粉末衍射图；
图 2为枸橼酸爱地那非晶型 0的红外光谱图；
图 3为枸橼酸爱地那非的核磁共振氢谱 ^H-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 ^H-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 （ -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 018.8g， 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 0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 037.6g， 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 0的颗粒剂
处方： 枸橼酸爱地那非晶型 0 50克， 乳糖 650克， 交联聚维 100克， PEG-4000 90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 0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 0的胶囊
处方： 枸橼酸爱地那非晶型 0 60克， 淀粉 50克， 乳糖 40克， 蔗糖 10克， 微晶纤维素 35克， 10%聚乙烯吡咯垸酮乙醇溶液适量， 硬脂酸镁 1克， 制成 1000粒。
工艺： 枸橼酸爱地那非晶型 0及辅料过 80目筛， 按处方量称 取， 以 10%聚乙烯吡咯垸酮乙醇溶液为粘合剂， 用 16目筛制成适宜 的颗粒， 65 °C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 0的片剂
处方： 枸橼酸爱地那非晶型 0 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 0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°C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。
工业应用性
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 0及其制备方法， 本发 明还涉及含有枸橼酸爱地那非晶型 0的药物组合物及其在制造治疗 男性勃起功能障碍 (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 0， 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。 本发明创造可以批量生产， 具有良好的市场前景。

Claims

权 利 要 求 书
1、 一种枸橼酸爱地那非晶型 0， 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 0， 其特征在 于： 该晶型 0在 X射线粉末衍射测定中的最强特征吸收峰 （2Θ) 为 7.600ο
3、 根据权利要求 1所述的一种枸橼酸爱地那非晶型 0， 其特征在于： 红外光谱图中，在 3423士 5cm-1 ; 3310士 5cm-1 ; 3193士 5cm-1 ; 2980士 5cm-1 ; 2470士 5cm ; 1693士 2cm ; 1167士 2cm ; 1023士 2cm ; 603士 2cm 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 0， 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所述的枸橼酸爱地那非晶型 0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（质量-体积比，克 /毫升) 蒸馏水与四氢呋喃混合液中， 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 0。
6、 根据权利要求 5所述的枸橼酸爱地那非晶型 0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的枸橼酸爱地那非晶型 0与一种或多种 药学上可接受的载体、 赋形剂或稀释剂组成组合物。
8、 根据权利要求 7所述的枸橼酸爱地那非晶型 0的药物组合物， 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 0的药物组合物， 其特征 在于： 在制造治疗男性勃起功能障碍药物中的应用。
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WANG, JIANG ET AL.: "Liquid chromatography tandem mass spectrometry assay to determine the pharmacokinetics of aildenafil in human plasma", JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, vol. 44, 17 January 2007 (2007-01-17), pages 231 - 235, XP022026233 *

Cited By (2)

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CN115054585A (zh) * 2022-07-11 2022-09-16 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
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

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MX2012010952A (es) 2012-11-12
SG10201503635WA (en) 2015-06-29
KR20140111044A (ko) 2014-09-17
CN101830903A (zh) 2010-09-15
US9663439B2 (en) 2017-05-30
AU2015201141A1 (en) 2017-03-30
KR20120137403A (ko) 2012-12-20
SG184090A1 (en) 2012-10-30
ZA201206740B (en) 2013-06-26
MY176891A (en) 2020-08-25
CN101830903B (zh) 2012-07-04
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