WO2017114413A1 - 三乙酰基-3-羟基苯基腺苷在制备预防或者治疗非酒精性脂肪肝药物中的应用 - Google Patents

三乙酰基-3-羟基苯基腺苷在制备预防或者治疗非酒精性脂肪肝药物中的应用 Download PDF

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WO2017114413A1
WO2017114413A1 PCT/CN2016/112623 CN2016112623W WO2017114413A1 WO 2017114413 A1 WO2017114413 A1 WO 2017114413A1 CN 2016112623 W CN2016112623 W CN 2016112623W WO 2017114413 A1 WO2017114413 A1 WO 2017114413A1
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liver
fatty liver
triacetyl
preventing
hydroxyphenyladenosine
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PCT/CN2016/112623
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English (en)
French (fr)
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朱海波
史会杰
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江苏天士力帝益药业有限公司
中国医学科学院药物研究所
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Priority to US16/067,228 priority Critical patent/US11058703B2/en
Priority to AU2016383376A priority patent/AU2016383376B2/en
Priority to JP2018533743A priority patent/JP7382716B2/ja
Priority to EP16881202.2A priority patent/EP3398604A4/en
Priority to CA3010097A priority patent/CA3010097C/en
Priority to RU2018126158A priority patent/RU2759916C2/ru
Priority to KR1020187021547A priority patent/KR20180100152A/ko
Publication of WO2017114413A1 publication Critical patent/WO2017114413A1/zh
Priority to ZA201805080A priority patent/ZA201805080B/en
Priority to HK18114837.8A priority patent/HK1255689A1/zh

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

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  • the invention relates to the application of triacetyl-3-hydroxyphenyladenosine and a pharmaceutical composition containing the same for preparing a medicament for preventing or treating non-alcoholic fatty liver, and belongs to the technical field of medicine.
  • Non-alcoholic fatty liver disease refers to a group of clinical pathological syndromes characterized by hepatic parenchymal cell damage and fat accumulation, excluding excessive drinking and other well-defined causes of liver damage.
  • a metabolic stress liver injury closely related to insulin resistance (IR) and genetic susceptibility.
  • the pathological changes are similar to alcoholic liver disease, but the patient has no history of excessive drinking.
  • the composition includes nonalcoholic simple fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver fibrosis, nonalcoholic fatty liver cirrhosis and related liver cancer (HCC).
  • the exact pathogenesis of NAFLD is still unclear. It is generally recognized as the "second strike” doctrine.
  • the first strike in the two stages of the theory is due to the excessive intake of high-fat diet and the decrease in the amount of decomposition, resulting in lipid deposition. Form a simple fatty liver.
  • IR can weaken and destroy the regulation of insulin metabolism, increase lipid dissolution, increase the concentration of nonesterified free fatty acid (FFA), and promote the uptake of FFA in the liver by the liver.
  • Oxidative stress and lipid peroxidation damage play an important role in the formation and development of fatty liver, which is an important factor for the further development of fatty liver.
  • Mitochondria are the respiratory organs of cells, and the production of reactive oxygen species (ROS) increases damage to mitochondria, further aggravating lipid accumulation in the liver.
  • ROS reactive oxygen species
  • LPO lipid peroxidation
  • MDA malondialdehyde
  • colleagues destroy the structure of biofilm Function, so that cell membrane permeability increases, cytochrome C efflux, initiate apoptosis program, and finally lead to liver fibrosis, cirrhosis, and even progress to liver cancer.
  • LPO lipid peroxidation
  • MDA malondialdehyde
  • Triacetyl-3-hydroxyphenyladenosine (Patent No. ZL200980101131.6, Bulletin No. CN101874036B, Announcement Day 2012.01.25) is a new screening of cordycepin derivatives with significant lipid-lowering activity in the Institute of Materia Medica, Chinese Academy of Medical Sciences. It is a pre-clinical research stage characterized by structural type compounds with small toxic and side effects and good pharmacokinetics. There are no reports of the use of this compound in the prevention or treatment of nonalcoholic fatty liver disease.
  • the technical problem to be solved by the present invention is to provide a compound triacetyl-3-hydroxyphenyl adenosine and a pharmaceutical composition thereof for use in the preparation of a medicament for preventing or treating nonalcoholic fatty liver.
  • a first aspect of the present invention provides a triacetyl-3-hydroxyphenyl adenosine represented by the formula (I) and a pharmaceutically acceptable salt thereof for the preparation of a medicament for preventing or treating nonalcoholic fatty liver disease Applications
  • the non-alcoholic fatty liver is a fatty liver caused by a high-energy diet.
  • the triacetyl-3-hydroxyphenyladenosine of the present invention is capable of significantly reducing serum AST, ALT and TG levels, and significantly improving the liver function of the fatty liver golden hamster and reducing the degree of fatty liver. Thereby preventing or treating non-alcoholic fatty liver.
  • a second aspect of the present invention provides a pharmaceutical composition for the preparation of a medicament for preventing or treating non-alcoholic fatty liver, characterized in that the pharmaceutical composition comprises triacetyl of the formula (I) 3-hydroxy-phenyl adenosine and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
  • the pharmaceutical composition includes tablets, capsules, pills and injections, sustained release preparations, controlled release preparations or various microparticle delivery systems.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the content of the compound of the present invention in its pharmaceutical composition is usually from 0.1 to 95% by weight.
  • the compound of the present invention or a pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be intestinal or non-intestinal.
  • the administration route can be intestinal or non-intestinal.
  • the dosage form can be in a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • a preferred pharmaceutical composition is selected from the group consisting of a tablet, a capsule, a pill, and an injection
  • the compounds of the present invention can be formulated into common preparations, as sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low substitute
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient of the present compound may be first mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • a variety of diluents, binders, wetting agents, disintegrants, glidants useful in the preparation of tablets of the compounds of the invention are also useful in the preparation of capsules of the compounds of the invention.
  • a suitable amount of a solubilizing agent, a solubilizing agent, a pH adjusting agent, and an osmotic pressure adjusting agent which are commonly used in the art may be added as a solvent with water, ethanol, isopropanol, propylene glycol or a mixture thereof.
  • the solubilizing agent or the glidant may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.; the pH adjusting agent may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure adjusting agent It may be sodium chloride, mannitol, glucose, phosphate, acetate or the like. For preparing a lyophilized powder injection, mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the pharmaceutical composition of the present invention can be administered in a wide range of dosages depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, and the like.
  • a suitable daily dose of the compound of the invention will range from 0.001 to 150 mg/kg body weight, preferably from 0.1 to 100 mg/kg body weight, more preferably from 1 to 60 mg/kg body weight, and most preferably from 2 to 30 mg/kg body weight.
  • the above dosages may be administered in one dosage unit or in divided dose units depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • the invention uses the pharmacodynamic research method to confirm the significant effect of triacetyl-3-hydroxyphenyladenosine in preventing or treating non-alcoholic fatty liver disease, and provides a chronic disease with complicated pathogenesis and poor therapeutic effect.
  • a new preventive or therapeutic drug, triacetyl-3-hydroxyphenyladenosine has remarkable curative effect, small toxic and side effects, and is safe to use. It provides scientific research for its clinical application in preventing or treating nonalcoholic fatty liver disease. in accordance with.
  • Figure 1 is a comparison of body weight and liver coefficient of each group of golden hamsters in the experimental example of the present invention
  • Figure 4 is a comparison of the results of determination of lipid content in liver tissues of golden hamsters in the experimental examples of the present invention.
  • Figure 5 is a diagram showing the nuclear magnetic imaging of the liver of golden hamster in the experimental example of the present invention.
  • Figure 6 is a comparison of HE pathological staining results of liver hamsters in each group of the experimental examples of the present invention.
  • Fig. 7 is a comparison of the results of oil red O staining of liver hamsters of each group of golden hamsters in the experimental example of the present invention.
  • Example 1 Application of triacetyl-3-hydroxyphenyladenosine (IMM-H007) in the treatment of nonalcoholic fatty liver disease
  • OCT frozen slice embedding agent American cherry; sodium pentobarbital, sigma company; PEG6000, sigma company; glycine, sigma company; paraformaldehyde, Sinopharm reagents; oil red O, sigma company; HE staining solution, Taiwan Besso Company; Total Cholesterol (TC) Test Kit, Japan Sekisui Medical Technology (China) Co., Ltd.; Total Triglyceride Test Kit, Zhongsheng Beikong Biotechnology Co., Ltd.; Free Fatty Acid Test Kit, Japan Product Water Medical Technology (China) Co., Ltd. Alanine aminotransferase (AST/ALT) test kit, Nanjing Institute of Bioengineering; Aspartate Transaminase (AST/GOT) test kit, Nanjing Institute of Bioengineering;
  • Multi-purpose low temperature high speed centrifuge Eppendorff, Germany; paraffin slicer, Lycra, Germany; frozen slicer, Lycra, Germany; En Vision multi-function microplate reader, PerkinElmer, USA; small animal anesthesia machine, American Matrx product; small animal magnetic Resonance Imager, Bruker PharmaScan 70T/16US, Germany.
  • the animals were raised in the Animal Experimental Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences.
  • the feeding conditions were SPF, temperature 21 ⁇ 2°C, relative humidity 50 ⁇ 5%, photoperiod 12/112, and 5 per cage.
  • the normal group was given normal basal diet, and the high fat diet group was given high fat diet (79.8% basal diet plus 20% lard and 0.2% cholesterol).
  • the animals were free to eat and drink.
  • the feed was commissioned by Beijing Huakang Biotechnology Co., Ltd. Body weight was recorded every 2 weeks in the experiment.
  • liver tissue 100 mg was accurately weighed, triglyceride was added to detect the lysate, and the homogenizer was used to homogenize the tissue in an ice bath to no obvious tissue block. Place on ice for 5 min, transfer to a 1.5 ml centrifuge tube, centrifuge at 14000 g for 10 min at 4 ° C, transfer the supernatant, take a portion of the supernatant for protein quantification, and measure the lipid content according to the instructions of the TC and TG test kits.
  • the liver fixed with paraformaldehyde fixative was rinsed with tap water, dehydrated according to the following steps, 70% ethanol overnight, 80% ethanol overnight, 90% ethanol I30min, 90% ethanol II 30 min, 95% ethanol I60 min, 95% ethanol II 60 min, 100% ethanol I60min, 100% ethanol II 60min, normal tissue can prolong the dehydration time. After the tissue was dehydrated, it was super-transparent, ultra-safe I60min, super-anal II60min, and super-analthic III60min. The normal control group liver can prolong the transparent time. Immersion wax at 65 °C, paraffin wax I50min, paraffin wax 5050min, paraffin wax for 5050min, embedded, slice thickness 7um, 45 °C exhibit, 50 °C baked overnight.
  • the temperature of the slicer freezer was set to -19 ° C, and the sample head was set to -21 ° C.
  • the liver stored in liquid nitrogen or -80 °C is equilibrated with the temperature at -20 ° C, and the tissue is placed on the sampler of the microtome for temperature equilibration. After the tissue block was repaired, it was serially sliced, and the slice thickness was 7 ⁇ m, which was attached to a clean poly-lysine coated glass slide.
  • Frozen sections were fixed in 4% paraformaldehyde physiological solution for 10 min, rinsed with tap water for 2 min, washed with 60% isopropanol for several seconds, and stained with 0.5% oil red O in a dark-proof staining box for 10-15 min, 60% isopropyl The alcohol is separated by a few seconds, and the tap water is gently rinsed. Hematoxylin counterstaining for 3-5min, tap water gently rinse, 1% hydrochloric acid water, rinse with tap water for 2min, return to blue, glycerin gelatin seal, observed under the microscope.
  • paraffin section was dehydrated by the following steps: super-A5 min, super-ampere II 5 min, super-ampere III 5 min, 100% ethanol I3 min, 100% ethanol II 3 min, 95% ethanol I3 min, 95% ethanol II 3 min, 80% ethanol 3 min, tap water rinse for 1 min.
  • the serum TC, TG, LDL-C, HDL-C and FFA of the model group were significantly increased; compared with the model group, after IMM-H007, TC, TG, LDL- C, HDL-C and FFA were significantly reduced (Table 2 and Figure 2).
  • the HE staining results shown in Fig. 6 showed that the normal animal liver cells were arranged radially around the central vein, and the collagen fibers were regularly distributed in the central vein and other vessel walls.
  • the hepatocytes in the model group were vacuolated, and between the hepatocytes. Collagen fibers appeared, and the distribution was irregular. There were vacuoles in the liver cells of the simvastatin group, collagen fibers appeared between the liver cells, and showed irregular distribution.
  • Hepatocytes in each dose group of IMM-H007 were arranged radially around the central vein, and collagen fibers were regularly distributed in the central vein and hepatic lobule border areas.
  • IMM-H007 triacetyl-3-hydroxyphenyladenosine
  • IMM-H007 can significantly reduce the blood lipid levels of non-alcoholic fatty liver golden hamsters, significantly reduce AST, ALT levels, and significantly improve liver function. It is suggested that IMM-H007 can be used to prepare drugs for preventing or treating non-alcoholic fatty liver.

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Abstract

式（I）所示的三乙酰基-3-羟基苯基腺苷在预防或者治疗非酒精性脂肪肝中的应用，所述三乙酰基-3-羟基苯基腺苷能够明显降低血清AST, ALT及TG水平，显著改善肝功能，减轻脂肪肝程度，在预防或者治疗非酒精性脂肪肝方面具有显著疗效、毒副作用小。

Description

三乙酰基-3-羟基苯基腺苷在制备预防或者治疗非酒精性脂肪肝药物中的应用 技术领域
本发明涉及三乙酰基-3-羟基苯基腺苷及含有其的药物组合物在制备预防或者治疗非酒精性脂肪肝药物中的应用，属于医药技术领域。
背景技术
非酒精性脂肪肝(non-alcoholic fatty liver disease,NAFLD)是指除外过量饮酒和其他明确的损伤肝的病因所致的以肝实质细胞损伤和脂肪蓄积为特征的一组临床病理综合征，是一种与胰岛素抵抗(insulin resistance,IR)和遗传易感密切相关的代谢应激性肝损伤，其病理学改变与酒精性肝病相似，但患者无过量饮酒史。其组成包括非酒精性单纯性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝纤维化、非酒精性脂肪性肝硬化及其相关的肝癌(HCC)等。随着我国经济发展，人们饮食的内容和时间有较大的改变，非酒精性脂肪肝发病率不断提高，并呈低龄化趋势，成为严重威胁人类身心健康的常见疾病。
NAFLD的确切发病机制目前尚不清楚，较为公认的是“二次打击”学说，在该学说的两个阶段中首次打击是由于高脂饮食摄入过多而分解量下降，造成脂质沉积，形成单纯性脂肪肝。在二次打击中IR可减弱和破坏胰岛素对脂肪代谢的调节作用，增加脂质溶解，提高游离脂肪酸(nonesterified free fatty acid,FFA)浓度，促进肝脏对血中FFA的摄取。氧化应激与脂质过氧化损伤在脂肪肝的形成和发展过程中起重要作用，是脂肪肝受到第二次打击进一步发展的重要因素。线粒体是细胞的呼吸器官，活性氧(reactive oxygen species,ROS)生成增多损伤线粒体，进一步加重肝脏的脂质蓄积。并且氧应激产生的自由基导致脂质过氧化(lipid peroxidation,LPO)的损害反应，形成一系列脂质自由基及降解产物-丙二醛(malondialdehyde,MDA)，同事破坏生物膜的结构与功能，使细胞膜通透性增加，细胞色素C流出，启动细胞凋亡程序，最后导致肝纤维化、肝硬化，甚至进展为肝癌。目前仍缺乏特效药物，常用的他汀类、贝特类等降血脂药物，疗效欠佳，毒副作用较大。
三乙酰基-3-羟基苯基腺苷(专利号ZL200980101131.6，公告号CN101874036B，公告日2012.01.25)是中国医学科学院药物研究所在虫草素衍生物中筛选出具有显著调血脂活性的新结构类型化合物，并且毒副作用小、药代动力学良好等特征，目前处于临床前研究阶段。目前尚无该化合物在预防或者治疗非酒精性脂肪肝中应用的报道。
发明内容
本发明解决的技术问题是提供化合物三乙酰基-3-羟基苯基腺苷及其药物组合物在制备预防或治疗非酒精性脂肪肝药物中的应用。
为解决本发明的技术问题，提供如下技术方案：
本发明技术方案的第一方面是提供了式(I)所示的三乙酰基-3-羟基苯基腺苷及其药学上可接受的盐在制备预防或者治疗非酒精性脂肪肝的药物中的应用
Figure PCTCN2016112623-appb-000001
所述的非酒精性脂肪肝为高能量饮食引起的脂肪肝，
本发明所述的三乙酰基-3-羟基苯基腺苷治疗非酒精性脂肪肝是其能够明显降低血清AST、ALT及TG水平，显著改善脂肪肝金黄地鼠肝功能，减轻脂肪肝程度，从而预防或者治疗非酒精性脂肪肝。本发明技术方案的第二方面是提供一种药物组合物在制备预防或治疗非酒精性脂肪肝药物中的应用，其特征在于，所述的药物组合物包含式(Ⅰ)所述的三乙酰基-3-羟基-苯基腺苷及其药学上可接受的盐和药学上可接受的载体，
Figure PCTCN2016112623-appb-000002
所述的药物组合物包括片剂、胶囊、丸剂和注射剂、缓释制剂、控释制剂或各种微粒给药系统。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠 道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔黏膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以使液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。优选的药物组合物的剂型选自片剂、胶囊、丸剂、注射剂。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂、可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物先与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各种稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物做溶剂加入适量本领域常用的增溶剂、助溶剂、PH调剂剂、渗透压调节剂。增溶剂或助流剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；PH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可以加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或者药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/kg体重，优选为0.1-100mg/kg体重，更优选为1-60mg/kg体重，最优选为2-30mg/kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其它治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
有益的技术效果
本发明采用药效学研究方法证实了三乙酰基-3-羟基苯基腺苷在预防或者治疗非酒精性脂肪肝的显著作用，为这一病机复杂、治疗效果欠佳的慢性疾病提供了一种新的预防或者治疗药物--三乙酰基-3-羟基苯基腺苷，其疗效显著，毒副作用小，使用安全，为其在预防或者治疗非酒精性脂肪肝方面的临床应用提供科学依据。
附图说明
为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施例并结合附图，对本发明作进一步详细的说明，其中，
图1为本发明所述实验例中金黄地鼠各组体重和肝脏系数比较；
图2为本发明所述实验例中金黄地鼠血清中胆固醇、甘油三酯、高密度脂蛋白、低密度脂蛋白和游离脂肪酸含量测定结果比较；
图3为本发明所述实验例中金黄地鼠ALT及AST酶活力比较；
图4为本发明所述实验例中各组金黄地鼠肝组织脂质含量测定结果比较；
图5为本发明所述实验例中金黄地鼠肝脏核磁成像图；
图6为本发明所述实验例中各组金黄地鼠肝组织HE病理染色结果比较；
图7为本发明所述实验例中各组金黄地鼠肝组织油红O染色情况结果比较。
具体实施方式
下面的实施例用来进一步说明本发明，但这并不意味着对本发明的任何限制。
实施例1：三乙酰基-3-羟基苯基腺苷(IMM-H007)在治疗非酒精性脂肪肝中的应用
一、实验材料
1.试剂
OCT冰冻切片包埋剂，美国樱花；戊巴比妥钠，sigma公司；PEG6000，sigma公司；甘氨酸，sigma公司；多聚甲醛，国药试剂有限公司；油红O，sigma公司；HE染色液，台湾贝索公司；总胆固醇(TC)检测试剂盒，日本积水医疗科技(中国)有限公司；总甘油三酯检测试剂盒，中生北控生物科技股份有限公司；游离脂肪酸检测试剂盒，日本积水医疗科技(中国)有限公司。谷丙转氨酶(AST/ALT)测试盒，南京建成生物工程研究所；谷草转氨酶(AST/GOT)测试盒，南京建成生物工程研究所；
2.仪器
多用途低温高速离心机，德国Eppendorff；石蜡切片机，德国莱卡；冰冻切片机，德国莱卡；En Vision多功能酶标仪，美国PerkinElmer股份有限公司；小动物麻醉机，美国Matrx产品；小动物磁共振成像仪，德国Bruker PharmaScan 70T/16US。
3.实验动物
6-8周龄叙利亚金黄地鼠(LVG hamster，源引进于Charles River Laboratories)20只，体重90-120g，雄性，SPF级，购自北京维通利华实验动物技术有限公司，许可证编号：SCXK(京)2012-0001。
二、实验方法
1.动物分组及饲养
动物适应性喂养5天后按体重随机分为正常对照组(n＝15)、高脂饲料组(n＝15)、IMMH007低剂量组(25mg/kg，n＝15)、IMMH007中剂量组(50mg/kg，n＝15)、IMMH007高剂量组(100mg/kg，n＝15)，每天灌胃给药2次。动物饲养于中国医学科学院药物研究所动物实验中心二部，饲养条件为SPF级，温度21±2℃，相对湿度50±5％，光照周期为12/112，5只每笼。正常组给予正常基础饲料，高脂饲料组给予高脂饲料(79.8％基础饲料加20％猪油和0.2％胆固醇)，动物自由摄食、饮水。饲料委托北京华阜康生物科技有限公司生产。实验中每2周记录体重一次。
2.观察指标及测定方法
2.1血清生化指标
动物禁食12小时，内眦静脉取血0.5ml，静置60min，6000g离心10min，尽可能多的吸取上清，然后6000g离心10min，按照TC、TG、AST和ALT试剂盒说明书测定吸光度值， 计算各指标浓度。取50ul血清与50ul PEG60001:1混合，涡旋均匀，静置10min，1900g常温离心20min，小心吸取上清，4℃保存，按照TC试剂盒说明书测定HDL-C。血浆LDL水平是通过将血浆总胆固醇TC减去HDL-C和0.2倍TG水平，即LDL＝TC-HLD-0.2TG。
实验终点前隔夜禁食，3％戊巴比妥钠腹腔注射麻醉，暴露腹腔，腹主动脉取血后迅速分离肝脏。留取肝一叶，于固定部位切取两块1×1cm3小块后，一块用OCT包埋，投入液氮速冻，液氮中或-80℃保存；另一块投入4％多聚甲醛固定液中，4℃保存。
2.2磁共振成像
动物禁食12小时后，异氟烷麻醉，固定头部，仰卧固定于大鼠线圈上，头先进，定位于腹部中心。
快速自旋回波序列的T2加权像(T2-weighted imaging,T2WI)：TR/TE＝200/3ms，FA＝30°。视野(FOV)＝3.6×3.6，矩阵＝256×256，激励次数＝2次。
2.2肝组织脂质含量分析
准确称取100mg肝脏组织，加入甘油三酯检测裂解液，匀浆器将组织在冰浴中匀浆至无明显组织块。冰上放置5min，转移至1.5ml离心管中，14000g 4℃离心10min，转移上清，取部分上清进行蛋白定量，按照TC、TG检测试剂盒说明书检测脂质含量。
2.3肝组织病理染色
2.3.1石蜡切片的制备
将多聚甲醛固定液固定好的肝脏用自来水冲洗干净，按一下步骤脱水，70％乙醇过夜，80％乙醇过夜，90％乙醇Ⅰ30min,90％乙醇Ⅱ30min，95％乙醇Ⅰ60min,95％乙醇Ⅱ60min，100％乙醇Ⅰ60min，100％乙醇Ⅱ60min，正常组织可适当延长脱水时间。组织脱水后用超安透明，超安Ⅰ60min，超安Ⅱ60min，超安Ⅲ60min，正常对照组肝脏可适当延长透明时间。65℃浸蜡，石蜡Ⅰ50min，石蜡Ⅱ50min，石蜡Ⅲ50min，包埋，切片厚度为7um，45℃展片，50℃烤片过夜。
2.3.2冰冻切片的制备
肝脏组织切片前将切片机冷冻箱温度设为-19℃，样品头设为-21℃。存于液氮或-80℃的肝脏先于-20℃环境平衡温度，再将组织放入切片机样品台上进行温度平衡。组织块修快后连续切片，切片厚度为7um，贴于干净的多聚赖氨酸包被载玻片上。
2.3.3油红O染色
冰冻切片于4％多聚甲醛生理溶液固定10min，自来水冲洗2min，60％异丙醇润洗数秒，于避光染色盒内用0.5％油红O工作液滴染10-15min，60％异丙醇分色数秒，自来水轻柔冲洗， 苏木素复染3-5min，自来水轻柔冲洗，1％盐酸水分化，自来水冲洗2min返蓝，甘油明胶封片，镜下观察。
2.3.4HE染色
石蜡切片按以下步骤脱水，超安Ⅰ5min，超安Ⅱ5min，超安Ⅲ5min，100％乙醇Ⅰ3min，100％乙醇Ⅱ3min，95％乙醇Ⅰ3min,95％乙醇Ⅱ3min，80％乙醇3min，自来水冲洗1min。苏木素染色5min，自来水冲洗1min，1％盐酸乙醇分化数秒，自来水冲洗返蓝，放入80％乙醇润洗数秒，伊红染色10秒，80％乙醇和95％乙醇调色，脱水，即95％乙醇、100％乙醇Ⅰ、100％乙醇Ⅱ、超安Ⅰ、超安Ⅱ、超安Ⅲ60各2min，超净高级封片胶封片，镜下观察。
3.数据分析
数据以平均值±标准误来表示，所有数据采用Graphpad Prism5.0软件进行ONEWAY-ANOVA统计分析；对图像进行对比分析。
三、实验结果
3.1IMM-H007对高脂饮食诱导的非酒精性脂肪肝金黄地鼠的体重和肝脏系数的影响
由表1和图1可见，与正常组金黄地鼠比较，模型组金黄地鼠体重明显增加，肝脏系数增加；与模型组比较，给予IMM-H007治疗后，体重和肝脏系数均有下降。但是给予辛伐他汀治疗后，金黄地鼠肝脏系数未见下降，反而显著升高。
表1.IMM-H007对慢性脂肪肝金黄地鼠体重及肝脏系数的影响
Figure PCTCN2016112623-appb-000003
***P<0.001，与正常组比较；###P<0.001,##P<0.01,#P<0.05与模型组比较
3.2IMM-H007对高脂饮食诱导的非酒精性脂肪肝金黄地鼠血清中血脂指标的影响
与正常组金黄地鼠相比，模型组金黄地鼠血清TC、TG、LDL-C、HDL-C及FFA均显著升高；与模型组比较，给予IMM-H007后，TC、TG、LDL-C、HDL-C及FFA均显著降低(表2和图2)。
表2.IMM-H007对高脂饮食诱导的非酒精性脂肪肝金黄地鼠血清中血脂指标的影响
Figure PCTCN2016112623-appb-000004
Figure PCTCN2016112623-appb-000005
***P<0.001，与正常组比较；###P<0.001,##P<0.01,#P<0.05与模型组比较
3.3IMM-H007对高脂饮食诱导的非酒精性脂肪肝金黄地鼠肝功能的影响
由表3可知，模型组金黄地鼠血清谷丙转氨酶、谷草转氨酶水平显著升高，经IMM-H007治疗后，血清ALT和AST均显著下降。但是给予辛伐他汀治疗后谷丙转氨酶未见降低，反而显著升高(表3和图3)；而谷草转氨酶水平与模型组无显著性差异，提示IMM-H007具有良好的肝保护作用，而辛伐他汀显示出肝损伤作用。
表3.IMM-H007对高脂饮食诱导的非酒精性脂肪肝金黄地鼠血清中ALT、AST水平的影响
Figure PCTCN2016112623-appb-000006
***P<0.001，与正常组比较；###P<0.001,##P<0.01,#P<0.05与模型组比较
3.4IMM-H007对高脂饮食诱导的非酒精性脂肪肝金黄地鼠肝脏脂质变化的影响
由表4和图4可见，与正常组金黄地鼠相比，模型组金黄地鼠肝脏中TC、TG显著升高；与模型组比较，给予辛伐他汀和IMM-H007后，TC、TG均显著降低。
表4.IMM-H007对高脂饮食诱导的非酒精性脂肪肝金黄地鼠肝脏脂质变化的影响
Figure PCTCN2016112623-appb-000007
Figure PCTCN2016112623-appb-000008
***P<0.001，与正常组比较；###P<0.001,##P<0.01,#P<0.05与模型组比较
3.5肝脏MRI分析
MR检查结果显示，与正常组比较，模型组金黄地鼠皮下及腹腔脂肪显著增加，给予辛伐他汀和IMM-H007后可减少皮下及腹腔脂肪(图5)。
3.6肝脏组织病理学观察
图6所示HE染色结果发现，正常动物肝细胞以中央静脉为中心向周围呈放射状排列，胶原纤维规律性分布在中央静脉和其他血管壁；模型组动物肝细胞出现空泡化，肝细胞间出现胶原纤维，且分布无规律性；辛伐他汀组动物肝细胞内有空泡出现，肝细胞间出现胶原纤维，且呈现不规律性分布。IMM-H007各剂量组肝细胞以中央静脉为中心向周围呈放射性排列，胶原纤维呈规律性分布在中央静脉和肝小叶边界区。
油红O染色结果发现(图7)，正常组动物肝细胞以中央静脉为中心向周围呈放射性状排列，胞内中性脂肪含量较少；高脂膳食组动物肝细胞内有大量脂肪沉积，出现空泡化；辛伐他汀组动物肝细胞内有脂肪沉积，大片坏死灶。IMM-H007各剂量组动物肝细胞内也可见脂肪沉积，但是与模型组比较，明显减少。
综上所述，三乙酰基-3-羟基苯基腺苷(IMM-H007)可显著降低非酒精性脂肪肝金黄地鼠的血脂水平，明显降低AST、ALT水平，显著改善肝功能。提示IMM-H007可用于制备预防或者治疗非酒精性脂肪肝的药物。

Claims (5)

  1. 如式(Ⅰ)所示的三乙酰基-3-羟基苯基腺苷及其药学上可接受的盐在制备预防或者治疗非酒精性脂肪肝的药物中的应用，
    Figure PCTCN2016112623-appb-100001
  2. 根据权利要求1的应用，其特征在于，所述的非酒精性脂肪肝为高能量饮食引起的脂肪肝。
  3. 一种药物组合物在制备预防或治疗非酒精性脂肪肝药物中的应用，其特征在于，所述的药物组合物包含式(Ⅰ)所述的三乙酰基-3-羟基-苯基腺苷及其药学上可接受的盐和药学上可接受的载体，
    Figure PCTCN2016112623-appb-100002
  4. 根据权利要求3的应用，其特征在于，所述的药物组合物为片剂、胶囊、丸剂或注射剂。
  5. 根据权利要求3的应用，其特征在于，所述的药物组合物为缓释制剂、控释制剂或各种微粒给药系统。
PCT/CN2016/112623 2015-12-31 2016-12-28 三乙酰基-3-羟基苯基腺苷在制备预防或者治疗非酒精性脂肪肝药物中的应用 WO2017114413A1 (zh)

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