WO2022042541A1 - 眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用 - Google Patents

眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用 Download PDF

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WO2022042541A1
WO2022042541A1 PCT/CN2021/114291 CN2021114291W WO2022042541A1 WO 2022042541 A1 WO2022042541 A1 WO 2022042541A1 CN 2021114291 W CN2021114291 W CN 2021114291W WO 2022042541 A1 WO2022042541 A1 WO 2022042541A1
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extract
uric acid
cobra venom
cobra
venom
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PCT/CN2021/114291
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French (fr)
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秦正红
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苏州人本药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/58—Reptiles
    • A61K35/583—Snakes; Lizards, e.g. chameleons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

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  • the invention relates to the field of medicine, in particular to the application of a cobra venom or an extract thereof in the preparation of a medicine for lowering uric acid and/or anti-gouty arthritis.
  • Uric acid is the end product of purine metabolism in humans. Due to the lack of uric acid oxidase in the human body, humans are prone to form hyperuricemia.
  • Hyperuricemia is a metabolic disorder caused by purine metabolism disorders that increase uric acid production or decrease excretion. Disease, according to statistics, about 5%-12% of hyperuricemia will eventually develop into gout. If hyperuricemia persists for a long time, uric acid will be deposited in joints, subcutaneous tissues and kidneys in the form of urate, causing a series of clinical diseases such as gouty arthritis, subcutaneous gout stones, kidney stones or gouty nephropathy. kidney failure, life-threatening. Long-term hyperuricemia leads to an increase in the morbidity and mortality of cardiovascular diseases, diabetes and other diseases, and is a chronic metabolic disease that seriously endangers human health.
  • Human uric acid mainly comes from the following two sources:
  • the treatment for hyperuricemia is mainly to reduce the level of uric acid in the blood, one is a drug that inhibits the synthesis of uric acid, and the other is a drug that increases the excretion of uric acid.
  • Drugs that inhibit uric acid synthesis mainly include xanthine oxidase inhibitors, which reduce the production of uric acid by inhibiting xanthine oxidase in the uric acid synthesis pathway.
  • the drugs that inhibit the synthesis of uric acid mainly include allopurinol and febuxostat. The side effects of allopurinol are gastrointestinal reactions, skin rash, and abnormal liver function.
  • Cobra venom is a complex mixture composed of various components secreted by the venom glands of cobras.
  • Traditional Chinese medicine believes that cobras and their toxic components can clear the meridians and collaterals, dispel rheumatism, and have the effect of strengthening the body. chronic pain, joint pain and neuralgia. At present, it is not clear whether cobra venom is suitable for the treatment of hyperuricemia and gouty arthritis.
  • the technical problem to be solved by the present invention is to provide a new application of cobra venom, that is, the application of cobra venom or its extract in the preparation of medicines for lowering uric acid and/or anti-gouty arthritis.
  • the present invention provides the application of cobra venom or its extract in preparing medicines for lowering uric acid and/or anti-gouty arthritis.
  • the present invention also provides the application of cobra venom or its extract in preparing a medicament capable of preventing uric acid deposition, having the effect of removing gout stones, or having the effect of repairing joint damage caused by uric acid deposition.
  • the present invention also provides the application of cobra venom or its extract in preparing medicines for lowering uric acid and simultaneously resisting gouty arthritis.
  • the present invention also provides the application of cobra venom or its extract in preparing a medicine for preventing or treating hyperuricemia, gout, gouty arthritis, subcutaneous gouty stones or gouty nephropathy.
  • the cobra venom is Chinese cobra venom.
  • the Chinese cobra is artificially cultivated, and the snake venom is collected and freeze-dried to make light yellow powder.
  • Cobra venom can be used only when the protein content is over 90%, the ash content is less than 2%, and the neurotoxin content is over 6%.
  • the cobra venom is total cobra venom.
  • the extract is the small-molecule protein extract after cobra venom ammonium chloride precipitation, the small-molecule protein extract after one or more methods of cobra venom molecular sieve filtration, ion exchange, and reverse chromatography, or the above-mentioned extract after purification The obtained cobra neurotoxin.
  • the dosage of the medicine is 0.1-50 mg/kg/day for 1-360 days; preferably, the dosage is 0.1-10 mg/kg/day , lasting 1-120 days; more preferably, the administration dose is 0.1-1 mg/kg/day, lasting 3-10 days.
  • the dosage of the medicine is 2-30 ⁇ g/kg/day for 1-360 days.
  • the drug comprises cobra venom and one or more other uric acid-lowering drugs.
  • the other uric acid lowering drugs are selected from at least one of xanthine oxidase inhibitors, uricosuric agents, urate transporter-1 inhibitors, uricase and statins.
  • the other uric acid lowering drugs are at least one of allopurinol, febuxostat and benzbromarone.
  • the medicament also includes a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable solvents, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic agents Pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integration agents, penetration enhancers, pH regulators, buffers, enhancers At least one of plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, filter aids, release retarders, polymer matrix materials and film-forming materials A sort of.
  • the drug is a tablet, capsule, oral solution, spray, oral fast-dissolving drug film, or injection.
  • the tablet is an effervescent tablet.
  • the cobra venom or its extract of the present invention can effectively reduce the blood uric acid level of hyperuric acid mice, and at the same time, it also has obvious improvement effect on gouty arthritis, can repair joint damage caused by uric acid deposition, reduce joint swelling, and improve joint synovium Tissue thickening, reducing inflammatory cell infiltration and protecting chondrocytes.
  • Clinical experiments show that the purified neurotoxin extracted from cobra venom can quickly eliminate subcutaneous gout stones in gout patients. The inflammatory mass disappears three days after the patient's injection, and the uric acid stones gradually shrink without side effects.
  • cobra venom has the effect of repairing gouty arthritis while reducing uric acid.
  • Fig. 1 is the ankle joint picture of Chinese cobra venom NNAV high-dose group mice, NNAV low-dose group mice and model control group, normal control group mice in Experimental Example 2 of the present invention, wherein A is the normal control group, and B is NNAV High-dose group, C is NNAV low-dose group, D is model control group;
  • Fig. 2 is the HE staining diagram of the ankle joints of the normal control group mice and NNAV low-dose group mice in Experimental Example 2 of the present invention
  • a in Fig. 2 and B in 2 are the HE staining diagrams of the normal control group
  • Fig. 2 C in Figure 2 to E in Figure 2 are HE staining images of the NNAV low-dose group
  • Fig. 3 is the HE staining diagram of the ankle joints of the NNAV high-dose group mice and the model control group in Experimental Example 2 of the present invention;
  • a to 3 in Fig. 3 are the HE staining diagrams of the NNAV high-dose group, Fig. 3 D in Figure 3 to F in Figure 3 are all model control groups;
  • FIG. 4 is a picture of the back of the foot of a gout patient before and after treatment in the clinical experiment of the present invention, the left picture is before treatment, and the right picture is after treatment.
  • Chinese cobra snake venom (NNAV) lyophilized powder was purchased from Ludongshan Snake Farm in Baojing, Hunan.
  • the protein content is more than 90%, the ash content is less than 2%, and the neurotoxin content is 6.2% by HPLC.
  • Uric acid purchased from Anhui Kuer Bioengineering Co., Ltd.
  • Uric acid determination kit purchased from Nanjing Jiancheng Bioengineering Institute, batch number 20171025.
  • MSU microcrystalline sodium urate
  • MSU is added to 0.9% sodium chloride solution to obtain MSU suspension with a concentration of 25 mg/ml.
  • Electronic digital caliper purchased from Shanghai Tool Factory Co., Ltd.; Microplate reader: purchased from Thermo Fisher.
  • mice Male ICR mice, weighing 20-25 g, were provided by Shanghai Shrek Experimental Animal Center.
  • Each dose group of NNAV was given an aqueous solution of the corresponding concentration at a volume of 10 ml/kg, and the normal control group and the model control group were given the same amount of distilled water, once a day, for 8 weeks. .
  • 0.02ml of MSU suspension was injected again.
  • the circumference of the right ankle joint of each rat was measured, and on the 56th day, the ankle joint injury degree of each rat was scored according to Table 1.
  • mice After 60 minutes of administration on the 57th day of the experiment, except the normal control group mice were injected with normal saline, the other groups of mice were injected with 250 mg/kg MSU suspension according to their body weight. Blood was collected, the serum was separated, and the uric acid level in the serum was determined by using a uric acid assay kit according to the method and steps in its instructions.
  • Joint swelling rate (ankle joint circumference after modeling-ankle joint circumference before modeling)/ankle joint circumference before modeling ⁇ 100%, the data of each group is expressed as (X ⁇ SD), using SPSS17.0 statistical software t test and one-way ANOVA were performed, p ⁇ 0.05 indicated a statistically significant difference, and the ankle joint score was statistically processed by the anecdotal sum method.
  • the levels of serum uric acid in each dose group of NNAV decreased, and the high dose group had a significant difference (p ⁇ 0.01), indicating that the cobra venom of the present invention can effectively reduce the level of uric acid, It can be used to prevent or treat hyperuricemia.
  • Uric acid purchased from Anhui Cool Bioengineering Co., Ltd.
  • Microcrystalline sodium urate Take 1g of uric acid, add 194ml of distilled water and 6ml of 1mol/L NaOH, boil to dissolve the uric acid completely, after cooling in a water bath, drop in dilute HCl to pH 7.0, the solution is milky white, and placed in a refrigerator at 4°C overnight , filtered, dried at 50°C, stored, and prepared for immediate use.
  • MSU is added to 0.9% sodium chloride solution to obtain MSU suspension with a concentration of 20 mg/ml.
  • Electronic digital caliper purchased from Shanghai Tool Factory Co., Ltd.; Microplate reader: purchased from Thermo Fisher.
  • mice Male ICR mice, weighing 20-25 g, were provided by Shanghai Shrek Experimental Animal Center.
  • Each NNAV dose group was given an aqueous solution of the corresponding concentration at a volume of 10 ml/kg, and the normal control group and the model control group were given the same amount of distilled water, once/d, for 120 days.
  • the circumference of the right ankle joint of each mouse was measured, and then 0.02ml of MSU suspension (concentration 20mg/ml) was carried out according to the first modeling method.
  • Joint swelling rate (the circumference of the ankle joint after modeling - the circumference of the ankle joint before modeling)/the circumference of the ankle joint before modeling ⁇ 100%, the data of each group is expressed as (X ⁇ SD), and the statistical software SPSS 17.0 was used for the analysis. t-test and one-way ANOVA, p ⁇ 0.05 indicated that the difference was statistically significant, and the ankle joint score was statistically processed by the anecdotal sum method.
  • mice The joint swelling rate of NNAV on MSU-induced gouty arthritis in mice (X ⁇ S,%)
  • the ankle joint score results of each group of mice are shown in Table 6.
  • the ankle joint injury degree of the low-dose group and the high-dose group was significantly better than that of the model control group.
  • a in Figure 1 is the normal control group
  • B in 1 is the NNAV high-dose group
  • C in Figure 1 is the NNAV low-dose group
  • D in Figure 1 is the model control group. It can be seen from Figure 1 that the joints are swollen
  • the degree of repair was as follows: the NNAV high-dose group was better than the NNAV low-dose group, and the NNAV low-dose group was better than the model control group, indicating that the Chinese cobra venom can repair the joint damage caused by MAU, and then can be used to prevent or treat gout caused by MAU deposition. .
  • a in Figure 2 and B in 2 are HE staining images of the normal control group, and no obvious pathological changes were found in A in Figure 2 and B in 2.
  • C in Figure 2 to E in Figure 2 are HE staining images of the NNAV low-dose group, and C in Figure 2 shows: the synovial tissue is slightly thickened (+), with a small amount of inflammatory cell infiltration (+), the joint Chondrocyte focal necrosis (+).
  • D in Figure 2 shows: necrosis of articular chondrocytes (+), mild thickening and fibrosis of synovial tissue (+), with mild inflammatory cell infiltration (++).
  • E in Figure 2 shows: no obvious pathological changes were found.
  • a to 3 in Figure 3 are HE staining images of the NNAV high-dose group, and A in Figure 3 shows: the synovial tissue is slightly thickened (+), and a small amount of inflammatory cell infiltration (++) can be seen. B in Figure 3 shows: no obvious pathological changes were found. C in Figure 3 shows: synovial thickening (+), mild fibrosis (+), scattered traces of inflammatory cell infiltration (+).
  • D in Figure 3 to F in 3 are all model control groups, and D in Figure 3 shows: synovial thickening (++), mild fibrosis (+), and inflammatory cell infiltration (++).
  • E in Figure 3 shows: the synovium was significantly thickened (+++), mild to moderate fibrosis (++), with a small amount of inflammatory cell infiltration (+).
  • F in Figure 3 shows: synovial membrane thickening (+++), mild to moderate fibrosis (++), with inflammatory cell infiltration (+), and necrosis of articular cartilage cells (++).
  • + means mild; ++ means moderate; +++ means severe.
  • Preparation of the tested drug using the method disclosed in Example 1 of the patent document CN104974238A, first extract the small molecule protein in the Chinese cobra venom, and then purify by ion exchange and reverse phase chromatography to obtain a neurotoxin with a purity of more than 97%,
  • the whole sequence sequencing proved to be short-chain neurotoxin cobrotoxin, composed of 62 amino acids, and the molecular weight determined by mass spectrometry was 6948 Daltons.
  • the amino acid sequence and molecular weight are completely consistent with the Chinese cobra venom short-chain neurotoxin cobrotoxin reported by GenBank.
  • Preparation of drug solution The short-chain neurotoxin cobrotoxin prepared above was dissolved in 0.9% physiological saline to obtain a neurotoxin solution with a concentration of 3 ⁇ g/ml, which was filtered through a 20nm filter to sterilize and remove viruses.
  • the injections are produced by the preparation room of Oriental Hospital in Korea, and meet the requirements of GMP regulations of Oriental Medicine.
  • the cobra neurotoxin of the present invention is used for treatment.
  • the swelling and pain can be reduced by continuous injection for 3 days and once a day, and the total effective rate is about 90%.
  • the swelling caused by uric acid deposition can be seen after 3 days, and some patients can see the swelling disappear after 3 months of continuous use. No obvious adverse drug reactions occurred during treatment.
  • the cobra venom neurotoxin of the present invention has significant therapeutic effect on gout patients, the total effective rate can reach about 90% according to preliminary observation, the course of treatment is short, the effect is quick, and there is no toxic and side effect.
  • the purified Chinese cobra short-chain neurotoxin (98% purity, HPLC) was formulated into a sterile injection solution (physiological hydrochloric acid solution), and administered locally to volunteers suffering from gout.
  • the total amount of injection is 0.5-2 ml (normal saline solution containing 3 micrograms of Chinese cobra short-chain neurotoxin), once a day, and drink plenty of water during the injection.
  • the pictures of the back of the foot of the gout patient before treatment and for 3 times of treatment are shown in Figure 4, the left picture is before treatment, and the right picture is after treatment. It can be seen from Figure 4 that after 3 treatments, the mass caused by uric acid deposition in gout patients was significantly reduced, and the effect was remarkable.

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Abstract

提供了眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用。所述眼镜蛇蛇毒或其提取物具有降低高尿酸小鼠的血尿酸水平；修复尿酸钠沉积导致的关节损伤；降低关节肿胀率；改善关节滑膜组织增厚；减少炎症细胞浸润；保护软骨细胞；消除痛风患者皮下痛风结石的作用。

Description

眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用
本申请要求于2020年08月24日提交中国专利局、申请号为202010859311.9、发明名称为“眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药领域，具体涉及一种眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用。
背景技术
尿酸是人类嘌呤代谢的终末产物，由于人体内缺乏尿酸氧化酶，而使人类极易形成高尿酸血症，高尿酸血症是由于嘌呤代谢紊乱使尿酸生成增多或者排泄减少所致的代谢性疾病，据统计约有5％-12％的高尿酸血症最终会发展成痛风。高尿酸血症如长期存在，尿酸将以尿酸盐的形式沉积在关节、皮下组织及肾脏等部位，引起痛风性关节炎、皮下痛风结石、肾脏结石或痛风性肾病等一系列临床疾病，严重的会发生肾功能衰竭，危及生命。长期高尿酸血症导致心血管疾病、糖尿病等疾病的发病率和病死率增加，是严重危害人类健康的一种慢性代谢性疾病。
人体尿酸主要来源于以下两个方面：
(1)人体组织细胞分解代谢产生的核酸和其它嘌呤类化合物，经一些酶的作用而生成内源性尿酸；
(2)食物中所含的嘌呤类化合物、核酸及核蛋白成分，经过消化与吸收后，经一些酶的作用生成外源性尿酸。
目前针对高尿酸血症的治疗主要是降低血液中的尿酸水平，一类是抑制尿酸合成的药物，一类是增加尿酸排泄的药物。抑制尿酸合成的药物主要有黄嘌呤氧化酶抑制剂，通过抑制尿酸合成途径中的黄嘌呤氧化酶，从而导致尿酸生成的减少。抑制尿酸合成的药物主要有别嘌醇和非布司他，别嘌醇副作用是胃肠道反应，皮疹，肝功能异常。在临床上如果要给患者口服别嘌醇要进行多位点的基因检测，防止别嘌醇过敏反应的发生。另外一大类是促进尿酸排泄的药物，主要有排尿酸剂，其能够抑制尿酸盐在肾 小管的重吸收，代表药物有苯溴马隆。此外，还有尿酸盐转运体-1抑制剂、尿酸酶等。
眼镜蛇蛇毒是由眼镜蛇的毒腺分泌的多种组分构成的复杂混合物，祖国传统医学认为眼镜蛇及其毒性成分可通经络，祛风湿，并具有强身健体之功效，可用其他传统中药复配治疗各种慢性疼痛、关节痛和神经痛。目前，尚未明确眼镜蛇蛇毒是否可适用于高尿酸血症和痛风性关节炎的治疗。
发明内容
因此，本发明要解决的技术问题在于提供一种眼镜蛇蛇毒的新应用，即眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用。
本发明提供了眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用。
本发明还提供了眼镜蛇蛇毒或其提取物在制备能够防止尿酸盐沉积、具有去痛风结石作用或者具有修复尿酸沉积引起的关节损伤作用的药物中的应用。
本发明还提供了眼镜蛇蛇毒或其提取物在制备降尿酸同时抗痛风性关节炎的药物中的应用。
本发明还提供了眼镜蛇蛇毒或其提取物在制备预防或者治疗高尿酸血症、痛风、痛风性关节炎、皮下痛风结石或者痛风性肾病的药物中的应用。
优选的，所述眼镜蛇蛇毒为中华眼镜蛇蛇毒。
其中，中华眼镜蛇为人工养殖的，蛇毒采集后经冷冻干燥制成淡黄色粉末。眼镜蛇毒经检测蛋白含量90％以上，灰分少于2％，神经毒素含量6％以上的方可应用。
进一步的，所述眼镜蛇蛇毒是眼镜蛇总毒。提取物为眼镜蛇蛇毒氯化铵沉淀过后的小分子蛋白提取物、眼镜蛇蛇毒分子筛过滤、离子交换、反向层析中一种或多种方法后的小分子蛋白提取物或者上述提取物经纯化后得到的眼镜蛇神经毒素。
进一步的，以中华眼镜蛇蛇毒为药物的活性成分时，所述药物的给药 剂量为0.1～50mg/kg/天，持续1～360天；优选的，给药剂量为0.1～10mg/kg/天，持续1～120天；更优选的，给药剂量为0.1～1mg/kg/天，持续3～10天。
进一步的，以眼镜蛇神经毒素为药物活性成分时，所述药物的给药剂量为2～30μg/kg/天，持续1～360天。
进一步的，所述药物包含眼镜蛇蛇毒和一种或多种其他降尿酸药物。
进一步的，所述其他降尿酸药物选自黄嘌呤氧化酶抑制剂、排尿酸剂、尿酸盐转运体-1抑制剂、尿酸酶和抑制素中的至少一种。所述其他降尿酸药物为别嘌呤醇、非布索坦和苯溴马隆中的至少一种。
进一步的，所述药物中还包括药学可接受的载体。
优选的，所述药学可接受的载体选自药学上可接受的溶剂、增溶剂、助溶剂、乳化剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂、高分子骨架材料和成膜材料中的至少一种。
优选的，所述药物是片剂、胶囊、口服溶液、喷雾剂、口腔速溶药膜、或注射剂。
优选的，所述片剂为泡腾片。
本发明技术方案，具有如下优点：
本发明的眼镜蛇蛇毒或其提取物能够有效降低高尿酸小鼠的血尿酸水平，同时还对痛风性关节炎有明显改善作用，能够修复尿酸沉积导致的关节损伤，减轻关节肿胀，改善关节滑膜组织增厚情况，减少炎症细胞浸润，保护软骨细胞。临床实验表明，从眼镜蛇蛇毒中提取后经纯化得到的神经毒素可以快速消除痛风患者的皮下痛风结石，患者最快注射三天后炎性肿块消失，尿酸结石逐渐缩小，无副作用。综上所述，眼镜蛇蛇毒在降尿酸的同时具有修复痛风性关节炎的作用。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下 面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1是本发明实验例2中中华眼镜蛇毒NNAV高剂量组小鼠、NNAV低剂量组小鼠和模型对照组、正常对照组小鼠的踝关节图片，其中A为正常对照组，B为NNAV高剂量组、C为NNAV低剂量组，D为模型对照组；
图2是本发明实验例2中正常对照组小鼠和NNAV低剂量组小鼠的踝关节的HE染色图；图2中的A和2中的B为正常对照组的HE染色图；图2中的C至图2中的E均为NNAV低剂量组的HE染色图；
图3是本发明实验例2中NNAV高剂量组小鼠和模型对照组的踝关节的HE染色图；图3中的A至3中的C均为NNAV高剂量组的HE染色图，图3中的D至图3中的F均为模型对照组；
图4是本发明临床实验中痛风患者治疗前后的足背部图片，左图为治疗前，右图为治疗后。
具体实施方式
实验例1动物药效学实验
1.实验材料和方法
1.1药物与试剂
中华眼镜蛇蛇毒(NNAV)冻干粉，购自湖南保靖吕洞山蛇场。经HPLC检测蛋白含量90％以上，灰分少于2％，神经毒素含量为6.2％。
尿酸：购自安徽酷尔生物工程有限公司；尿酸测定试剂盒：购自南京建成生物工程研究所，批号20171025。
微晶型尿酸钠(MSU)的制备方法：取1g尿酸加入194ml蒸馏水与1mol/LNaOH6ml，煮沸，使尿酸完全溶解，水浴冷却后，滴入稀HCl至pH7.0，溶液呈乳白色，4℃冰箱放置过夜，过滤，50℃烘干，保存，临用临配。
MSU混悬液的配制方法：将MSU加入0.9％的氯化钠溶液，得到浓度为25mg/ml的MSU混悬液。
1.2实验仪器
电子数显卡尺：购自上海工具厂有限公司；酶标仪：购自赛默飞。
1.3实验动物
雄性ICR小鼠，体重20～25g，由上海史莱克实验动物中心提供。
1.4方法
(1)50只雄性ICR小鼠随机分为5组(n＝10)：正常对照组、模型对照组、NNAV低剂量组(给药剂量：0.1mg/kg)、中剂量组(0.5mg/kg)、高剂量组(1.0mg/kg)，各组每鼠测量基础踝关节周径后造模，固定小鼠后肢右腿，右脚弯曲，于小鼠小腿外侧踝关节上约5mm处进针至踝关节，将0.02ml MSU混悬液(浓度25mg/ml)注入关节腔，正常对照组注射等量生理盐水。第一次造模后开始给药，NNAV各剂量组按10ml/kg体积灌服相应浓度的水溶液，正常对照组与模型对照组均灌服等量蒸馏水，1次/d，连续给药8周。实验于第7、14、21天测定每鼠右踝关节周径后，按第一次造模方法，再次注射0.02ml MSU混悬液。实验第28、35、42、49、56天测定每鼠右踝关节周径，第56天按表1对每鼠踝关节损伤程度进行评分。
表1评分标准
分值 踝关节损伤程度
0 关节未见肿胀、变形、弯曲
1 关节轻度肿胀
2 关节肿胀、稍有弯曲
3 关节肿胀、变形、明显弯曲，牵拉不直
(2)在实验第57天给药60min后，除正常对照组小鼠腹腔注射生理盐水外，其余各组小鼠按照体重腹腔注射250mg/kg MSU混悬液，每鼠腹腔注射60min后，眼眶取血，分离血清，采用尿酸测定试剂盒按照其说明书中的方法步骤，测定血清中尿酸水平。
(3)数据处理与分析
关节肿胀率＝(造模后踝关节周径-造模前踝关节周径)/造模前踝关节周径×100％，各组数据以(X±SD)表示，采用SPSS17.0统计软件进行t检验和单因素方差分析，p<0.05表示差异有统计学意义，踝关节评分采用轶和法两两比较统计处理。
2.实验结果
(1)中华眼镜蛇蛇毒对尿酸钠致高尿酸血症小鼠血清尿酸的影响
从下表可以看出，NNAV各剂量组与模型对照组比较，血清尿酸水平均有降低，其中高剂量组有显著性差异(p<0.01)，说明本发明的眼镜蛇蛇毒能够有效降低尿酸水平，可用于预防或者治疗高尿酸血症。
表2 NNAV对尿酸钠致高尿酸血症小鼠血清尿酸水平影响(X±S,n＝10)
组别 剂量(mg/kg) 血清尿酸水平(μmol/L)
正常对照组 - 131.29±11.27
模型对照组 - 212.582±25.45
NNAV低剂量组 0.1 204.02±16.73
NNAV中剂量组 0.5 193.13±19.09
NNAV高剂量组 1.0 180.30±14.31**
注：**p<0.01。
(2)中华眼镜蛇蛇毒对MAU致小鼠痛风性关节炎的治疗作用
结果见表3，从表3中数据可以看出，各NNAV给药组小鼠关节肿胀度与模型对照组比较均有降低，降低程度呈剂量依赖性，NNAV高剂量组1-8周均有明显降低(p<0.05)，说明中华眼镜蛇蛇毒可以改善小鼠痛风性关节炎的关节肿胀率，具有预防或者治疗痛风小鼠的作用。
表3 NNAV对MSU致痛风小鼠关节肿胀率的影响(X±S,％)
关节肿胀(％) 模型对照组 NNAV 0.1mg/kg NNAV 0.5mg/kg NNAV 1mg/kg
第0周 11.22±0.45 11.22±0.55 11.21±0.48 11.24±0.33
第1周 13.42±5.31 8.76±3.24* 7.58±3.76* 7.94±3.54*
第2周 11.42±3.70 8.19±4.58 6.43±4.46* 5.56±3.23**
第3周 13.28±4.68 11.77±4.09 8.80±4.60* 7.72±4.42*
第4周 15.85±4.04 11.54±4.48* 10.24±5.12* 9.85±5.91*
第5周 12.79±4.28 9.28±4.13 8.44±5.95 6.53±5.45*
第6周 12.83±4.08 8.89±4.80 8.61±5.92 7.36±4.43*
第7周 13.41±5.15 9.21±4.74 8.39±4.47* 8.46±4.12*
第8周 13.72±4.60 9.24±4.57 8.61±4.40* 8.43±4.99*
注：*p<0.05，**p<0.01。
(3)中华眼镜蛇蛇毒对MAU致小鼠痛风性关节损伤的修复作用
结果见表4所示，从表4中可以看出，中剂量组和高剂量组的踝关节损伤程度明显好于模型对照组(p<0.05)，说明中华眼镜蛇蛇毒能够修复MAU导致的关节损伤，进而可用于预防或者治疗MAU沉积导致的痛风性关节炎。
表4 NNAV对MSU致小鼠痛风性关节损伤的影响(X±S,％)
Figure PCTCN2021114291-appb-000001
实验例2动物药效学实验
1.实验材料和方法
1.1药物与试剂
中华眼镜蛇蛇毒(NNAV)：同实验例1。
尿酸：购自安徽酷尔生物工程有限公司。
微晶型尿酸钠(MSU):取1g尿酸加入194ml蒸馏水与1mol/L NaOH 6ml，煮沸，使尿酸完全溶解，水浴冷却后，滴入稀HCl至pH 7.0，溶液呈乳白色，4℃冰箱放置过夜，过滤，50℃烘干，保存，临用临配。
MSU混悬液的配制方法：将MSU加入0.9％的氯化钠溶液，得到浓度为20mg/ml的MSU混悬液。
1.2实验仪器
电子数显卡尺：购自上海工具厂有限公司；酶标仪：购自赛默飞。
1.3实验动物
雄性ICR小鼠，体重20～25g，由上海史莱克实验动物中心提供。
1.4方法
(1)32只雄性ICR小鼠随机分为4组(n＝8)：正常对照组、模型对照组、NNAV低剂量组(0.5mg/kg)、高剂量组(1.0mg/kg)，各组每鼠测量基础踝关节周径后，除正常对照组，其余各组造模，固定小鼠后肢右腿，右脚弯曲，于小鼠小腿外侧踝关节上约5mm处进针至踝关节，将0.02ml MSU混悬液(浓度20mg/ml)注入关节腔。第一次造模后开始给药，NNAV各剂量组按10ml/kg体积灌服相应浓度的水溶液，正常对照组与模型对照组灌服等量蒸馏水，1次/d，连续给药120天。实验于第7、14、21天测定每鼠右踝关节周径后按第一次造模方法，再次0.02ml MSU混悬液(浓度20mg/ml)。实验第28、35、42、49、56、63、70、77、84、91、98、105、112、119天测定每鼠右踝关节周径，第120天按表1对每鼠踝关节损伤程度进行评分，第121天各组小鼠处死，解剖观察主要脏器后取各鼠右踝关节，去除表皮，用4％甲醛固定，HE染色观察组织的病理变化情况，具体步骤包括：1)组织取材，脱水；2)石蜡包埋后切片，厚度3μm；3)烘箱60℃烤片30min～1hr；4)染色：二甲苯Ⅰ 5min，二甲苯Ⅱ 5min，二甲苯Ⅲ 5min，无水乙醇1min，95％酒精1min，75％酒精1min，自来水冲洗数秒，苏木素染色液染2min，自来水冲洗数秒，分化液快速分化后温水冲洗返蓝，伊红染色液染1min，75％酒精30s，95％酒精30s，无水乙醇30s，二甲苯透明1min.；5)封片，晾干；6)镜检。
(2)数据处理与分析
关节肿胀率＝(造模后踝关节周径-造模前踝关节周径)/造模前踝关节周径×100％，各组数据以(X±SD)表示，采用SPSS 17.0统计软件进行t检验和单因素方差分析，p<0.05表示差异有统计学意义，踝关节评分采用轶和法两两比较统计处理。
2.实验结果
(1)中华眼镜蛇蛇毒对MAU致小鼠痛风性关节炎的治疗作用
结果见表5，NNAV各给药组小鼠关节肿胀程度与模型对照组比较， 第1～5周有所降低，但未见明显差异，第6～17周低剂量组与高剂量组均有显著性降低(p<0.05，p<0.01)，说明中华眼镜蛇蛇毒可以改善小鼠痛风性关节炎的关节肿胀，具有预防或者治疗痛风的作用。
表5 NNAV对MSU致小鼠痛风性关节炎的关节肿胀率(X±S,％)
Figure PCTCN2021114291-appb-000002
注：*p<0.05，**p<0.01。
每组小鼠踝关节评分结果见表6，低剂量组和高剂量组的踝关节损伤程度明显好于模型对照组。图1中的A为正常对照组，1中的B为NNAV高剂量组，图1中的C为NNAV低剂量组，图1中的D为模型对照组，由图1可以看出，关节肿胀的修复程度依次为：NNAV高剂量组好于NNAV低剂量组，NNAV低剂量组好于模型对照组，说明中华眼镜蛇蛇毒能够修复MAU导致的关节损伤，进而可用于预防或者治疗MAU沉积导致的痛风。
表6 NNAV对MSU致痛风小鼠踝关节外观评价
Figure PCTCN2021114291-appb-000003
(2)病理分析
NNAV对MSU诱导的痛风性关节炎小鼠用药120天后，解剖肉眼观察未见动物主要脏器有明显的病理改变，踝关节病理镜检结果显示：NNAV小鼠踝关节的滑膜增生、纤维化、炎症细胞浸润、软骨细胞坏死等指标均好于模型对照组，见图2和3。
具体地，图2中的A和2中的B为正常对照组的HE染色图，图2中的A和2中的B中未见明显病理改变。图2中的C至图2中的E均为NNAV低剂量组的HE染色图，图2中的C显示：滑膜组织轻度增厚(+)，伴少量炎症细胞浸润(+)，关节软骨细胞点灶状坏死(+)。图2中的D显示：关节软骨细胞可见坏死(+)，滑膜组织轻度增厚纤维化(+)，伴轻度炎症细胞浸润(++)。图2中的E显示：未见明显病理改变。
图3中的A至3中的C均为NNAV高剂量组的HE染色图，图3中的A显示：滑膜组织轻度增厚(+)，可见少量炎症细胞浸润(++)。图3中的B显示：未见明显病理改变。图3中的C显示：滑膜增厚(+)，轻度纤维化(+)，散在微量炎症细胞浸润(+)。
图3中的D至3中的F均为模型对照组，图3中的D显示：滑膜增 厚(++)，轻度纤维化(+)，可见炎症细胞浸润(++)。图3中的E显示：滑膜明显增厚(+++)，轻中度纤维化(++)，伴少量炎症细胞浸润(+)。图3中的F显示：滑膜明显增厚(+++)，轻中度纤维化(++)，伴炎症细胞浸润(+)，关节面软骨细胞可见坏死(++)。
其中，+表示轻度；++表示中度；+++表示重度。
临床观察
受试药物的制备：采用专利文献CN104974238A实施例1公开的方法，先提取中华眼镜蛇蛇毒中的小分子蛋白，然后经过离子交换和反相层析法纯化，获得纯度为97％以上的神经毒素，经全序列测序证明为短链神经毒素cobrotoxin，有62个氨基酸组成，质谱分子量测定为6948道尔顿。氨基酸序列和分子量与基因库报告的中华眼镜蛇毒短链神经毒素cobrotoxin完全一致。
药物溶液的配制：将上述制得的短链神经毒素cobrotoxin溶解于0.9％生理盐水中，制得浓度为3μg/ml的神经毒素溶液，经过20nm滤膜过滤灭菌并除病毒，即得。注射剂由韩国东方医院制剂室制作，符合东方医药GMP法规要求。
患者：韩国东方医药诊所确诊的通风患者志愿者20例，接受神经毒素治疗，初步观察神经毒素的治疗效果。
治疗方法与疗效：
经过3天到5天治疗，每次注射一次，使用本发明眼镜蛇神经毒素治疗，20例病患中，一般连续注射3天、每天一次就能消肿、止痛，总有效率为90％左右，部分病人在3天以后可见尿酸沉积引起的肿块缩小，部分病人在连续使用3个月后肿块消失。治疗期间未发生明显药物不良反应。本发明所述的眼镜蛇毒神经毒素在痛风病人中有显著的治疗效果，初步观察总有效率可达90％左右，疗程短，见效快，且无毒副作用。
典型病案举例：
吴某，男，53岁，于2019年5月就诊。患者通风急性发作，疼痛难忍，神经毒素注射治疗。
将纯化的中华眼镜蛇短链神经毒素(98％纯度，HPLC)配制成无菌注射液(生理盐酸溶液)，给患有痛风的志愿者局部给药围绕痛风石沉淀部位 多点皮下注射，每次注射总量0.5～2毫升(含3微克中华眼镜蛇短链神经毒素的生理盐水溶液)，每天注射1次，注射期间多喝水。该痛风患者治疗前以及治疗3次的足背部图片如图4所示，左图为治疗前，右图为治疗后。由图4可知，治疗3次后痛风患者的尿酸沉积引起的肿块明显缩小，效果显著。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (14)

  1. 眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用。
  2. 眼镜蛇蛇毒或其提取物在制备能够防止尿酸盐沉积、具有去结石作用或者具有修复关节损伤作用的药物中的应用。
  3. 眼镜蛇蛇毒或其提取物在降尿酸和/或抗痛风性关节炎中的应用。
  4. 眼镜蛇蛇毒或其提取物在制备预防或者治疗高尿酸血症、痛风、痛风性关节炎、皮下痛风结石或者痛风性肾病的药物中的应用。
  5. 根据权利要求1～4中任一所述的应用，其特征在于，所述眼镜蛇蛇毒为中华眼镜蛇蛇毒。
  6. 根据权利要求1～4中任一所述的应用，其特征在于，所述提取物为眼镜蛇蛇毒氯化铵沉淀后的提取物、眼镜蛇蛇毒分子筛去除大分子蛋白的提取物或者上述提取物经纯化后得到的眼镜蛇神经毒素。
  7. 根据权利要求5所述的应用，其特征在于，以中华眼镜蛇蛇毒为药物的活性成分时，所述药物的给药剂量为0.1～50mg/kg/天，持续时间为1～360天。
  8. 根据权利要求6所述的应用，其特征在于，以眼镜蛇神经毒素为药物活性成分时，所述药物的给药剂量为2～30μg/kg/天，持续时间为1～360天。
  9. 根据权利要求1～4、7和8中任意一项所述的应用，其特征在于，所述药物包含眼镜蛇蛇毒和一种或多种其他降尿酸药物。
  10. 根据权利要求9所述的应用，其特征在于，所述其他降尿酸药物选自黄嘌呤氧化酶抑制剂、排尿酸剂、尿酸盐转运体-1抑制剂、尿酸酶中的至少一种。
  11. 根据权利要求1～4、7和8中任意一项所述的应用，其特征在于，所述药物中还包括药学可接受的载体。
  12. 根据权利要求11所述的应用，其特征在于，所述药学可接受的载体选自药学上可接受的溶剂、增溶剂、助溶剂、乳化剂、着色剂、粘合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗粘合剂、整合剂、渗透促 进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、助滤剂、释放阻滞剂、高分子骨架材料和成膜材料中的至少一种。
  13. 根据权利要求11或12所述的应用，其特征在于，所述药物的剂型为片剂、胶囊剂、口腔速溶药膜、口服溶液、喷雾剂或注射剂。
  14. 根据权利要求13所述的应用，其特征在于，所述片剂包括泡腾片。
PCT/CN2021/114291 2020-08-24 2021-08-24 眼镜蛇蛇毒或其提取物在制备降尿酸和/或抗痛风性关节炎的药物中的应用 WO2022042541A1 (zh)

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