WO2006034624A1

WO2006034624A1 - Process for preparing oil preparation of tetrodotoxin

Info

Publication number: WO2006034624A1
Application number: PCT/CN2005/001365
Authority: WO
Inventors: Zhiqiang Huang; Haiyan Huang; Haifeng Huang
Original assignee: Zhiqiang Huang
Priority date: 2004-09-28
Filing date: 2005-08-31
Publication date: 2006-04-06
Also published as: CN100367966C; CN1754539A

Abstract

A process for preparing oil preparation of tetrodotoxin, characterized in that tetrodotoxin is dissolved with water or alcohol of acidity, and is prepared to the oil preparation with one (or more) surfactant (S) (or amphiphilicity lipid), oil and antioxidant. The oil preparation can be prepared to capsule, emulsion, nutritional supplement or suppository et al.

Description

河飩毒素油相制剂的制备方法技术领域 Method for preparing scorpion toxin oil phase preparation

本发明涉及一种河飩毒素油相制剂的制备方法。背景技术 The invention relates to a preparation method of a river scorpion toxin oil phase preparation. Background technique

河飩毒素 (Tetrodotoxin, TTX)是从河飩鱼的内脏中提取出的一种活性物质，其毒性比氰化纳高 1250倍。现代医学研究表明，河飩毒素还广泛存在于虾虎鱼、蝾螈、章鱼、贝类、螺类、海星、蟹类等海洋生物体内。河飩毒素的结晶是一种氨基氢化喹唑啉类型化合物，分子式为： C„H₁₇N₃O_s ，分子量为: 319.27。这种令人生畏的毒素只需 0.3mg - 0.5mg就可致人亍死地，因为它能专一地阻断神经细胞膜 Na⁺通道，所以，河飩毒素成为神经生物学和生理学研究无可替代的工具药 (S丄. Hu,C.Y.Kao.Toxicon,1985，23:723 -724)。 Tetrodotoxin (TTX) is an active substance extracted from the viscera of river trout, and its toxicity is 1250 times higher than that of cyanide. Modern medical research has shown that scorpion toxin is also widely found in marine organisms such as goby, carp, octopus, shellfish, snails, starfish, and crabs. The crystallization of scorpion toxin is a kind of aminohydroquinazoline type compound with the formula: C„H ₁₇ N ₃ O _s , molecular weight: 319.27. This daunting toxin can only be 0.3mg - 0.5mg. People die, because it can specifically block the Na ⁺ channel of nerve cell membranes, so the scorpion toxin becomes an irreplaceable tool for neurobiology and physiology research (S丄. Hu, CYKao. Toxicon, 1985, 23: 723 - 724).

日本对河飩毒素药用研究已有七十多年历史，据报道，河鲍毒素具有镇痛、镇痉、镇痒、局麻等医药功效 (潘心富等.1984，药学通报， 4 - 40-43)。但是，因河飩毒素毒性极强，而且河飩毒素的治疗剂量与中毒量接近，故河飩毒素制剂至今尚未列入药典。 Japan has been studying the medicinal properties of scorpion toxin for more than 70 years. According to reports, abalone toxin has the effects of analgesia, Zhenqi, Zhenqi, local anesthesia, etc. (Pan Xinfu et al. 1984, Pharmacopoeia, 4-40- 43). However, because the scorpion toxin is extremely toxic, and the therapeutic dose of scorpion toxin is close to the amount of poisoning, the scorpion toxin preparation has not yet been included in the pharmacopoeia.

我国从上世纪八十年代初，开始对河飩毒素的药用价值进行研究，研究表明：河飩毒素除了具有很好的镇痛和局麻作用外，还发现河飩毒素具有非常好的戒毒效果，且本身无药物依赖性 (CN1227102A ; CN1145225A ; CN1353990A; CN1356104A)。 In the early 1980s, China began to study the medicinal value of scorpion toxin. The research shows that: in addition to its good analgesic and local anesthetic effects, scorpion toxin has a very good detoxification. The effect is itself drug-independent (CN1227102A; CN1145225A; CN1353990A; CN1356104A).

现有的河飩毒素制剂，一般是河飩毒素用酸性水溶解后，再」成注射剂，在医学上主要用于镇痛或戒毒，但是有一定的毒副作用，在临床 4吏用中，发现部分患者出现不同程度的口、舌、唇、四肢麻木等轻度中毒反应（满洲医学杂志， 1993 , 130： 639；陈冀胜 .1986，海洋药物， 2： 31； EP750909)。现有的河飩毒素制剂，仅有水溶液制剂，在治疗使用方法上，只是: ¾行皮下、肌肉、静脉注射或呼吸道给药。这种水溶液制剂，在胃酸的作用下，毒素很容易被分解，使河豚毒素的活性显著降低，按目前现有技术制备、河豚毒素口服制剂，不但疗效差，而且成本很高。发明的公开 The existing scorpion toxin preparation is generally dissolved in acidic water after the scorpion toxin is dissolved into an injection, which is mainly used for analgesia or detoxification in medicine, but has certain toxic and side effects, and is found in clinical use. Some patients have varying degrees of mild poisoning reactions such as mouth, tongue, lips, and limb numbness (Manchuria Medical Journal, 1993, 130: 639; Chen Yusheng. 1986, Marine Medicine, 2: 31; EP750909). The existing scorpion toxin preparations, which are only in the form of an aqueous solution, are only used in the treatment of 3⁄4 lines of subcutaneous, intramuscular, intravenous or respiratory administration. In the aqueous preparation, under the action of gastric acid, the toxin is easily decomposed, and the activity of tetrodotoxin is significantly lowered. The oral preparation of tetrodotoxin prepared according to the prior art is not only poor in efficacy but also high in cost. Disclosure of invention

本发明的目的是为了提供一种可以口服使用的河飩毒素油相制剂的制备方法。该制备方法工艺简单，原料来源方便，生产成本低，容易实施。用该制备方法和工艺制成的河飩毒素油相制剂，除具有镇痛、戒毒的作用外，还具有使用方便、安全、高效、非成瘾性的特点。 SUMMARY OF THE INVENTION The object of the present invention is to provide a process for the preparation of a hydroquinone oil phase preparation which can be used orally. The preparation method has the advantages of simple process, convenient source of raw materials, low production cost and easy implementation. The scorpion toxin oil phase preparation prepared by the preparation method and the process has the characteristics of convenient use, safety, high efficiency and non-addictability in addition to the effects of analgesic and detoxification.

为了达到上述目的，本发明主要是通过以下技术手段完成的： In order to achieve the above object, the present invention is mainly accomplished by the following technical means:

( 1 )、将河飩毒素溶解于酸性水或酸性醇或其它酸的缓冲溶液中，混合搅拌均匀，制成 "A"溶液（"A"溶液的 pH值范围为 4 - 7); (1) Dissolving the scorpion toxin in a buffer solution of acidic water or acidic alcohol or other acid, mixing and stirring uniformly to prepare an "A" solution (the pH range of the "A" solution is 4 - 7);

(2)、将 "A"溶液加入到亲水非离子表面活性剂（或双亲性油酯，或亲水亲油非离子表面活性剂）的混合液中，其比例为 1 : 1至 1 : 40之间；两种溶液经充分搅拌均匀，混合成为 "B"溶液； (2) Adding the "A" solution to a mixture of a hydrophilic nonionic surfactant (or an amphiphilic oil ester or a hydrophilic lipophilic nonionic surfactant) in a ratio of 1:1 to 1: Between 40; the two solutions are thoroughly stirred and mixed to form a "B" solution;

(3 )、将 "B "溶液加入到亲油非离子表面活性剂中（或亲油性乳化剂中，或医用油中），溶液 " B"与表面活性剂的比例为 1 : 5至 1 : 50，经充分搅拌均匀后，混合成为 "C"溶液。这样，即制成了本发明所述的河飩毒素油相制剂。 (3), adding the "B" solution to the lipophilic nonionic surfactant (or lipophilic emulsifier, or medical oil), the ratio of the solution "B" to the surfactant is 1: 5 to 1: 50, After fully stirring, mix to form a "C" solution. Thus, the scorpion toxin oil phase preparation of the present invention was prepared.

(注：上述溶液在制备过程中，可加入适量的抗氧化剂，若抗氧化剂为水溶性的，可在上述 "A"溶液中加入；若抗氧化剂为脂溶性的，可在上述 "C"溶液中加入。） (Note: The above solution may be added with an appropriate amount of antioxidant during the preparation process. If the antioxidant is water-soluble, it may be added in the above "A" solution; if the antioxidant is fat-soluble, it may be in the above "C" solution. Joined.)

上述制备方法制成的河飩毒素油相制剂，其河飩毒素的有效含量为： 0.01 g /ml— 20 g/ml。 The scorpion toxin oil phase preparation prepared by the above preparation method has an effective content of scorpion toxin: 0.01 g / ml - 20 g / ml.

上述溶液所涉及的医用油，为中国药典规定的注射油或口服油，包括：花生油、麻油、豆油、棉子油、杏仁油、茶油和鱼油； The medical oil involved in the above solution is an injection oil or an oral oil prescribed by the Chinese Pharmacopoeia, including: peanut oil, sesame oil, soybean oil, cottonseed oil, almond oil, tea oil and fish oil;

上述溶液所涉及到的缓冲液（酸溶液），包括：醋酸、苯甲酸、石炭酸、柠檬酸及其医学上可接受的酸的缓冲液； The buffer (acid solution) involved in the above solution includes: a buffer solution of acetic acid, benzoic acid, carbolic acid, citric acid and a medically acceptable acid thereof;

上述溶液所涉及的表面活性剂，主要为：苯甲酸苄酯、油酸乙酯、聚乙二醇（PEG)、甘油油酸酯、十甘油单油酸酯、十甘油单辛酸酯、聚乙二醇 - 8 -甘油辛酸酯 /癸酸酯、聚甘油 -3-油酸酯、六甘油单月桂酸酯、油酸乙脂、吐温、司盘等。上述溶液涉及的抗氧化剂，包括：没食子酸丙酯、特丁基苯二酚、叔丁基对羟基茴香醚、 VC VE (其含量为 0.001% 0.2% )。 The surfactants involved in the above solutions are mainly: benzyl benzoate, ethyl oleate, polyethylene glycol (PEG), glyceryl oleate, decaglycerol monooleate, decaglycerin monocaprylate, poly Ethylene glycol-8-glyceryl octoate/caprate, polyglycerol-3-oleate, hexaglycerol monolaurate, oleate, Tween, Span, etc. The antioxidants involved in the above solution include: propyl gallate, tert-butyl benzene, tert-butyl-p-hydroxyanisole, VC VE (content 0.001% 0.2%).

依照本发明制备方法制成的河飩毒素油相制剂，可以直接用来口服，也可以制成液体胶囊、乳剂、营养补剂或栓剂。 The scorpion toxin oil phase preparation prepared according to the preparation method of the present invention can be directly used for oral administration, or can be formulated into a liquid capsule, an emulsion, a nutritional supplement or a suppository.

动物试验 Animal test

一、小鼠热板法镇痛试验： First, the mouse hot plate method analgesia test:

取体重 15g-19g雌性小鼠 30只，分为三组: 河飩毒素（0.1 g /ml)油剂 1组；河飩毒素（0.5 _g /ml) 油剂 2组及花生油对照组。按 "热板法"测定，水温恒定在 55 ±0.5°C，以小白鼠舐后足为痛阀指标。各组小鼠分别腹腔注射 TTX油剂和花生油 0.2ml /只，注药后 0.5 1.5 2 3 5 10小时分别测定各剂量组及对照组小鼠痛阀值。结果表明： TTX油剂有镇痛作用，约在药后 2小时左右起效，高峰在 3 - 5小时，与花生油组比较有非常显著差异（P< 0.01 )，见表 1。其特点是出现药效时间较慢，但药效持续时间较长。表 1 TTX油剂对小鼠热板痛阀的影响（S ¾±S) 组别药前药^帽 ^h) Thirty female mice weighing 15g-19g were divided into three groups: scorpion toxin (0.1 g / ml) oil group 1; scorpion toxin (0.5 _g / ml) oil group 2 and peanut oil control group. According to the "hot plate method", the water temperature is constant at 55 ± 0.5 °C, and the hind paws of the white rats are the pain valve indicators. Each group of mice was intraperitoneally injected with TTX oil and peanut oil 0.2ml / only, 0.5 1.5 2 3 5 10 hours after injection, the pain threshold of each dose group and control group were measured. The results showed that: TTX oil had analgesic effect, about 2 hours after the drug started, the peak was 3 - 5 hours, and there was a significant difference compared with the peanut oil group (P < 0.01), see Table 1. It is characterized by a slower onset of efficacy, but a longer duration of efficacy. Table 1 Effect of TTX oil on mouse hot plate pain valve (S 3⁄4±S) Group drug prodrug ^ Cap ^h)

0.5 1.5 2 3 5 10 花生油 13.1±1.4 13.0±1.6 13.2±0.5 13·5±2.4 14.1±2.6 13.3±2.4 13.6±0.6 18.3±1.9 17.7±2.6^¾!¾ 14.2±1.2

IL¾ 17.7±1.6 20.0士 2.1 18.6±3.3 15.0±1.6 0.5 1.5 2 3 5 10 Peanut oil 13.1±1.4 13.0±1.6 13.2±0.5 13·5±2.4 14.1±2.6 13.3±2.4 13.6±0.6 18.3±1.9 17.7±2.6 ^3⁄4!3⁄4 14.2±1.2

IL3⁄4 17.7±1.6 20.0士2.1 18.6±3.3 15.0±1.6

1³·^0±1 · ¹⁴·⁴士 ^{29 16}·^{3± 1} ·⁶ 1 ³ · ^0±1 · ¹⁴ · ⁴ ± ^{29 16} · ^{3± 1} · ⁶

η=10, 与花生油对照：？<0.05 , ^ ΡΟ.ΟΙ η=10, compared with peanut oil: ? <0.05 , ^ ΡΟ.ΟΙ

. 二、小鼠醋酸扭体法的镇痛试验： Second, the analgesic test of mouse acetic acid writhing method:

小鼠体重 15g - 19g左右，随机分为二组，每组 10只，给小鼠腹腔注射 TTX ( 0 .5 g /mi)油剂 0.2 ml/只和同法同量的花生油作对照，一天注射二次，共用三次药。药后 3小时和第二天用药后 10小时，分别腹腔注射 0.6%醋酸液 0.2 ml/只，记录 20分钟内小鼠扭体数。扭体指标：小鼠腹部内凹，躯干与后腿伸长，臀部抬起。结果表明：河飩毒素油剂可使小鼠扭体抑制率升高，连续给药后，镇痛持续时间延长在 10小时以上，与花生油对照组比较差异有显著性 (P<0.01 ), 见表 2。 The mice weighed 15g - 19g, were randomly divided into two groups, 10 mice in each group. The mice were intraperitoneally injected with TTX (0.5 g / mi) oil 0.2 ml / only with the same amount of peanut oil for one day. Inject twice and share three times. Three hours after the drug and 10 hours after the second day of administration, 0.2 ml of 0.6% acetic acid solution was intraperitoneally injected, and the number of writhing in the mouse was recorded within 20 minutes. Twisting index: mouse abdomen concave, torso With the hind legs extended, the hips lifted. The results showed that: scorpion toxin oil can increase the inhibition rate of writhing in mice. After continuous administration, the duration of analgesia was prolonged for more than 10 hours. Compared with the peanut oil control group, the difference was significant (P<0.01). Table 2.

TTX油剂对小鼠扭体镇痛的作用 Effect of TTX oil on writhing analgesia in mice

用药后 3小时三次用药后 10小时 3 hours after medication, 10 hours after medication

鼠数 Number of rats

组别 Group

(只）扭休数 /20'扭体反应扭休数 /20' 扭体反应 (only) twisting number /20' writhing reaction twisting number /20' writhing reaction

i ±s 抑制率 P值土 S 抑制率 " ¹里花生油 10 22.7±6.8 23.5士 6.0 i ±s inhibition rate P value soil S inhibition rate " ¹ peanut oil 10 22.7 ± 6.8 23.5 ± 6.0

74% <0.01 47% <0.05 74% <0.01 47% <0.05

ΤΤΧ(0.5 μ g/ml) ΤΤΧ (0.5 μg/ml)

10 5.9±4.1 12.4±3.0 10 5.9 ± 4.1 12.4 ± 3.0

油剂 Oil agent

临床试验镇痛效果 Clinical trial analgesic effect

收治住院或非住院癌痛患者 42例，其中男性 25例，女性 17例，年齢最小的 22岁，最大的 76岁。这些自愿受试者，分别患有食道贲门癌症 12例、肺癌 7例、胃癌 8例、肝癌 5例、淋巴肉瘤 4例、肠癌 2例、鼻咽癌 3例、口腔癌 1例，均为中、晚期癌症患者，疼痛剧烈。其中 33例已使用过***、 ***进行缓解疼痛， 24例使用过镇痛药，并产生了耐药性。经使用本发明制成的软胶囊（每粒油剂 lml)、口服油剂 lml，每日服用 3 - 4次，每次 1 - 2粒或 1 - 2ml油剂，用药 7 - 50天，最长 8个月。产生显著效果 17例，缓解 23例，无效 2例，有效率达到 95%。临床试验戒毒效果 There were 42 patients with hospitalized or non-hospital cancer pain, including 25 males and 17 females. The youngest was 22 years old and the oldest was 76 years old. These volunteers had 12 cases of esophageal and cardiac cancer, 7 cases of lung cancer, 8 cases of gastric cancer, 5 cases of liver cancer, 4 cases of lymphosarcoma, 2 cases of intestinal cancer, 3 cases of nasopharyngeal carcinoma, and 1 case of oral cancer. In patients with advanced and advanced cancer, the pain is severe. Of these, 33 had used morphine and dulantin to relieve pain, 24 had used analgesics, and developed resistance. Soft capsules (1 ml per oil) and 1 ml oral oils can be taken 3 to 4 times a day, 1-2 capsules or 1 - 2 ml oil each time, for 7 to 50 days, most It is 8 months long. Significant effect was achieved in 17 cases, 23 cases were relieved, 2 cases were ineffective, and the effective rate was 95%. Clinical trial detoxification effect

自愿戒毒者 28例，均为***吸毒者，其中男性 23例，女性 5例，年龄最小的 17岁，最大的 33岁。吸毒史 3个月到 4年不等，瘾量多在 0.5g-1.0g 间。用药方法是根据吸毒者瘾量的大小、吸毒时间的长短及戒断反应的轻重，采取不同方法治疗，对戒毒患者每天早、中、晚各口服河飩毒素油相制剂胶囊 1-2粒（1 - 2ml油剂），一般 6 - 7天为一个疗程。戒毒患者在第一次口服本发明胶囊时，可辅助使用镇静剂（肌肉注射安定、冬眠灵等），经用药治疗 6天以后，戒毒患者的情况明显好转，停药后不再出现严重的戒断反应。用纳洛酮做催瘾试验呈阴性，尿***检测为阴性，有效率可达到 96%。 There were 28 cases of voluntary drug abusers, all of which were heroin addicts, including 23 males and 5 females, the youngest 17 years old and the largest 33 years old. The history of drug abuse ranges from 3 months to 4 years, and the amount of addiction is between 0.5g and 1.0g. The method of administration is based on the size of the drug addict's addiction, the length of the drug use, and the severity of the withdrawal response. Different methods are used to treat the detoxification patients, and the oral administration of the scorpion toxin oil phase capsules is 1-2 capsules per day (in the morning, middle and evening). 1 - 2ml oil), usually 6 - 7 days for a course of treatment. Detoxification patients can assist the use of sedatives (intramuscular injection, hibernation, etc.) when the capsules of the present invention are administered for the first time. After 6 days of treatment, the situation of detoxification patients is obviously improved, and no serious withdrawals occur after stopping the drug. reaction. use Naloxone was negative for addiction test and negative for urinary morphine test, with an effective rate of 96%.

试验证明，依照本发明制备方法制成的河飩毒素油相制剂，具有以下几大特点- Tests have shown that the scorpion toxin oil phase preparation prepared according to the preparation method of the present invention has the following characteristics -

1、可以阻止河飩毒素与细胞直接接触，能较好地抵抗胃酸或酶的降解作用，在使用过程中，用微量的河飩毒素制剂，即可发挥很好的镇痛、戒毒作用，由于给药剂量远离中毒剂量，具有相当可靠的安全程度； 1. It can prevent the direct contact between the scorpion toxin and the cells, and can better resist the degradation of gastric acid or enzyme. During the use, a small amount of scorpion toxin preparation can exert good analgesic and detoxification effects. The dose is kept away from the toxic dose and has a fairly reliable degree of safety;

2、本发明使用油溶液作为药物载体，其选择性高，靶向性强，可减少药物剂量，降低毒性，使药物的吸收缓慢而药效持久，其药效作用的持续时间可达 10— 20小时。 2. The invention uses an oil solution as a drug carrier, which has high selectivity and strong targeting, can reduce the dosage of the drug, reduce toxicity, slow absorption of the drug and lasting effect, and the duration of the pharmacodynamic effect can reach 10— 20 hours.

3、本发明方法制备成的口服制剂，可为患者用药带来极大的方便，并可减轻患者的痛苦。即使患者使用***或***产生耐药成瘾后，用本发明制剂，仍能起到很好的疗效，而且不会产生耐药性和成瘾性，实现了低毒、高效、无成瘾性、无副作用的安全用药要求。实现本发明的最佳方式 3. The oral preparation prepared by the method of the invention can bring great convenience to the patient, and can alleviate the suffering of the patient. Even if the patient uses morphine or dulantin to develop drug-resistant addiction, the preparation of the present invention can still achieve a good effect, and does not produce drug resistance and addiction, achieving low toxicity, high efficiency, and no addiction. Sexual, no side effects of safe medication requirements. The best way to implement the invention

下面通过实施例对本发明的实施过程做进一步的详细描述：实施例一 The implementation process of the present invention will be further described in detail below by way of examples: Embodiment 1

1、取河飩毒素 lmg，加入 0.1%醋酸溶液 5ml，使其混合溶解成 "A" 溶液； 1. Take l-toxin 1 mg, add 5 ml of 0.1% acetic acid solution, and mix and dissolve into "A" solution;

2、取无水乙醇 24ml，将 " A"溶液 lml加入混合其中，搅拌制成 25ml 的 "B"溶液； 2, take 24ml of absolute ethanol, add 1ml of "A" solution to it, stir to make 25ml of "B" solution;

3、取苯甲酸苄脂 75ml，将 "B"溶液加入混合其中，搅拌制成 100ml 的 "C"溶液； 3. Take 75 ml of benzyl benzoate, add the "B" solution to the mixture, and stir to make a 100 ml "C" solution;

4、在 "C"溶液中加入没食子酸丙酯 2 ml，再加入花生油至 1000 ml, 混合搅拌均匀后，即制成本发明所述的河飩毒素油相制剂。实施例二 4. Add 2 ml of propyl gallate to the "C" solution, add peanut oil to 1000 ml, and mix and stir evenly to prepare the scorpion toxin oil phase preparation of the present invention. Embodiment 2

1、取河飩毒素 lmg，加入 0.05%醋酸溶液 10ml，使其混合溶解成 " A" 溶液； 1. Take 1 mg of scorpion toxin, add 10 ml of 0.05% acetic acid solution, and mix and dissolve it into "A". Solution

2、取聚乙二醇 - 8 -甘油辛酸 /癸酸酯 44ml，将 "A"溶液 4ml加入混合其中，搅拌制成 48ml的 " B"溶液； 2. Take 44ml of polyethylene glycol-8-glycerol octoate/caprate, add 4ml of "A" solution to it, stir and make 48ml "B" solution;

3、取聚甘油― 3 -油酸酯 152ml，将 "B"溶液加入混合其中，搅拌均匀后，制成 200ml的 "C"溶液； 3. Take 152 ml of polyglycerol-3-oleate, add the "B" solution to the mixture, stir well, and make 200 ml of "C" solution;

4、在 " C"溶液中加入维生素 E 200mg，搅拌混合均匀后，即制成本发明所述的河飩毒素油相制剂。实施例三 4. Add 200 mg of vitamin E to the "C" solution, and mix and mix well to prepare the scorpion toxin oil phase preparation of the present invention. Embodiment 3

1、取河鰊毒素 lmg，加入 0.02%醋酸溶液 20ml，使其混合溶解成 " A" 溶液； 1. Take 1 mg of scorpion toxin, add 20 ml of 0.02% acetic acid solution, and mix and dissolve it into "A" solution;

2、取聚乙二醇 - 8 -甘油辛酸 /癸酸酯 20ml，将 " A"溶液 4ml加入混合其中，搅拌均匀后制成 24ml的 "B"溶液； 2. Take 20ml of polyethylene glycol-8-glycerol octoate/caprate, add 4ml of "A" solution to it, mix well and make 24ml "B" solution;

3、取甘油 - 3 -油酸酯 76ml，将 " B "溶液加入其中，混合搅拌均匀，制成 100ml的 "C"溶液； 3, take glycerol - 3 - oleate 76ml, add "B" solution, mix and mix evenly, make 100ml "C" solution;

4、在 "C"溶液中加入维生素 E lg，再加花生油至 1000ml, 混合搅拌均匀，即制成本发明所述的河飩毒素油相制剂。实施例四 4. Add vitamin E lg to the "C" solution, add peanut oil to 1000 ml, and mix and stir evenly to prepare the scorpion toxin oil phase preparation of the present invention. Embodiment 4

1、取河飩毒素（含柠檬酸盐） lmg，加入 98%乙醇 10ml和维生素 C 2g，使其混合溶解成 "A"溶液； 1, take scorpion toxin (including citrate) lmg, add 98% ethanol 10ml and vitamin C 2g, mix and dissolve into "A" solution;

2、取油酸乙脂 40mi，将" A"溶液加入其中，混合搅拌均匀，制成 50ml "B"溶液； 2, take oleic acid ethyl ester 40mi, add "A" solution, mix and mix evenly, make 50ml "B" solution;

3、在 " B"溶液中加入 lg的维生素 E，再加入鱼油至 500ml, 混合搅拌均匀，即制成本发明所述的河飩毒素油相制剂。实施例五 3. Add lg of vitamin E to the "B" solution, add fish oil to 500 ml, and mix and mix evenly to prepare the scorpion toxin oil phase preparation of the present invention. Embodiment 5

1、取河飩毒素 lmg, 加入 0.01%醋酸溶液 lml，使其混合溶解成 " A" 2、取吐温 - 40 6ml, 将 " A"溶液 lml加入其中，混合搅拌均匀，制成 "B"溶液； 1. Take 1 mg of scorpion toxin, add 1 ml of 0.01% acetic acid solution, and mix and dissolve it into "A". 2, take Tween - 40 6ml, add 1 ml of "A" solution, mix and mix evenly, make "B"solution;

3、取司盘 - 80 13ml，将 " B"溶液加入其中，混合搅拌均匀，制成 20ml "C"溶液； 3, take the disc - 80 13ml, add the "B" solution, mix and mix evenly, make 20ml "C" solution;

4、在 "C"溶液中加入 lg的维生素 E，再加入花生油至 100 ml, 混合搅拌均勾，即制成本发明所述的河飩毒素油相制剂。实施例六 4. Add lg of vitamin E to the "C" solution, add peanut oil to 100 ml, and mix and stir to form the scorpion toxin oil phase preparation of the present invention. Embodiment 6

1、取河飩毒素 lmg，加入 1%醋酸溶液 4ml，使其混合溶解成 "A"溶液； 1. Take l-toxin 1 mg, add 4 ml of 1% acetic acid solution, and mix and dissolve it into "A" solution;

2、取六甘油单月桂酸酯 26 ml, 将 " A"溶液 4 ml加入其中，混合搅拌均匀，制成 30ml "B"溶液； 2. Take 26 ml of hexaglycerol monolaurate, add 4 ml of "A" solution, mix well and mix to make 30ml "B" solution;

3、取甘油油酸酯 70 ml, 将上述 "B"溶液加入其中，混合搅拌均勾，制成 100ml "C"溶液； 3. Take 70 ml of glycerol oleate, add the above "B" solution, mix and stir, and make 100ml "C" solution;

4、在 "C"溶液中加入 lg的维生素 E，再加入鱼油至 500 ml, 混合搅拌均匀，即制成本发明所述的河飩毒素油相制剂。 4. Add lg of vitamin E to the "C" solution, add fish oil to 500 ml, and mix and stir evenly to prepare the scorpion toxin oil phase preparation of the present invention.

通过试验证明，使用本发明制备方法制成的河飩毒素油相制剂，不但可明显减轻和缓解癌症、类风湿性关节炎以及其他慢性疾病给患者带来的痛苦，并且可以戒除人体对***、阿片、 ***、 ***等毒品的依赖性。工业应用性本发明能够在工业上应用，具有工业实用性。 It has been proved by experiments that the scorpion toxin oil phase preparation prepared by the preparation method of the invention not only can obviously alleviate and alleviate the pain caused by cancer, rheumatoid arthritis and other chronic diseases, and can quit the human body for heroin, Dependence of drugs such as opioids, morphine, and dulantin. Industrial Applicability The present invention can be industrially applied and has industrial applicability.

Claims

权利要求 Rights request

1、河飩毒素油相制剂的制备方法，其特征在于：将河飩毒素溶解于酸性水或酸性醇，或酸的缓冲液中，再与一种或多种表面活性剂或双亲性油酯、医用油进行溶合后，制成油相制剂，该制剂主要用于镇痛或戒除药物依赖。 1. A method for preparing a scorpion toxin oil phase preparation, characterized in that: the scorpion toxin is dissolved in an acidic water or an acidic alcohol, or an acid buffer, and then combined with one or more surfactants or amphiphilic oil esters. After the medical oil is dissolved, it is prepared into an oil phase preparation, which is mainly used for analgesic or drug withdrawal.

2、根据权利要求 1所述的油相制剂，其特征在于：每毫升油相制剂的河飩毒素有效含量为： O.Ol g /ml— 20 g/ml。 The oil phase preparation according to claim 1, wherein the effective content of the scorpion toxin per ml of the oil phase preparation is: O.Ol g /ml - 20 g / ml.

3、根据权利要求 1所述的表面活性剂，其特征在于主要包括：苯甲酸苄酯、油酸乙酯、聚乙二醇（PEG)、甘油油酸酯、十甘油单油酸酯、十甘油单辛酸酯、聚乙二醇 -8-甘油辛酸酯 /癸酸酯、聚甘油 -3- 油酸酯、吐温、司盘。 3. The surfactant according to claim 1, which mainly comprises: benzyl benzoate, ethyl oleate, polyethylene glycol (PEG), glycerol oleate, decaglycerol monooleate, ten Glycerol monocaprylate, polyethylene glycol-8-glyceryl caprylate/caprate, polyglycerol-3-oleate, Tween, Span.

4、根据权利要求 1所述的制剂，其特征在于：河飩毒素酸溶液 pH值的范围为 3 - 7; 河飩毒素酸溶液与表面活性剂（或双亲性油酯）的比例为 1 : 1至 1 : 40。 4. The preparation according to claim 1, wherein the pH of the scorpion toxin solution is in the range of 3 - 7; the ratio of the scorpion toxin solution to the surfactant (or amphiphilic oil ester) is 1: 1 to 1: 40.

5、根据权利要求 1所述的制剂，其特征在于：将河飩毒素酸溶液加入到亲水亲油平衡值为 9.6<HLB< 17的亲水非离子表面活性剂中，搅拌均匀，再与亲水亲油平衡值为 1 <HLB< 10的亲油非离子表面活性剂进行混合，加入抗氧化剂后，充分摇拌均匀，制成透明的油相制剂。 5. The preparation according to claim 1, wherein: the scorpion toxin acid solution is added to a hydrophilic nonionic surfactant having a hydrophilic-lipophilic balance of 9.6 < HLB<17, stirred uniformly, and then The oleophilic nonionic surfactant having a hydrophilic-lipophilic balance value of 1 <HLB<10 is mixed, and after adding an antioxidant, the mixture is thoroughly shaken to prepare a transparent oil phase preparation.

6、根据权利要求 1所述的制剂，其特征在于：河飩毒素酸溶液，用浓度为 90%以上的乙醇进行稀释后，与苯甲酸苄酯混合搅拌均匀，再用医用油进行稀释、混合、搅拌均匀。 6. The preparation according to claim 1, wherein the scorpion toxin acid solution is diluted with ethanol having a concentration of 90% or more, mixed with benzyl benzoate, and uniformly diluted with a medical oil. Stir well.

7、根据权利要求 6所述的制剂，其特征在于：河飩毒素乙醇溶液与苯甲酸苄酯溶液的比例为 1 : 1至 1 ·· 30。 The preparation according to claim 6, wherein the ratio of the scorpion toxin ethanol solution to the benzyl benzoate solution is from 1:1 to 1··30.

8、根据权利要求 1所述的制剂，其特征在于：可将河飩毒素油相制剂制成胶囊、乳剂、营养补剂、栓剂。 8. The preparation according to claim 1, wherein the scorpion toxin oil phase preparation is formulated into a capsule, an emulsion, a nutritional supplement, and a suppository.