CN113577229A

CN113577229A - Compound globefish liver oil composition and preparation method and application thereof

Info

Publication number: CN113577229A
Application number: CN202110894544.7A
Authority: CN
Inventors: 赵继红; 赵琦; 赵越洋; 汤波澜
Original assignee: Taizhou Kangte Biological Engineering Co ltd
Current assignee: Taizhou Kangte Biological Engineering Co ltd
Priority date: 2018-08-03
Filing date: 2018-08-03
Publication date: 2021-11-02
Also published as: CN113694165A; CN109331042A

Abstract

The invention provides a compound globefish liver oil composition and a preparation method and application thereof. The compound globefish liver oil composition of the invention consists of active ingredients and/or pharmaceutically acceptable carriers, wherein the active ingredients comprise globefish liver oil and vegetable oil, the globefish liver oil is globefish liver oil extracted from globefish liver containing tetrodotoxin in vivo, and the vegetable oil is volatile oil and/or squeezed oil extracted from natural plants. The composition of the invention is used for treating various cancers or leukemia, can kill or invert cancer cells, can inhibit the growth and the diffusion of the cancer cells, and can relieve or eliminate the pain of late cancer. Meanwhile, the curative effects of analgesics, chemotherapeutics and targeted drugs can be improved, and the dependence, tolerance and side effects of the analgesics, the chemotherapeutics and the targeted drugs can be reduced or eliminated. Belongs to a broad-spectrum anticancer drug with safety, high efficiency, quick effect, low price and no side effect. Can also be used for non-cancer analgesia and drug withdrawal.

Description

Compound globefish liver oil composition and preparation method and application thereof

The application is a divisional application with application date of 2018, 8 and 3, application number of 201810877348.7 and invented name of 'a compound globefish liver oil composition and a preparation method and application thereof'.

Technical Field

The invention relates to a compound globefish liver oil composition, which is a compound Chinese patent medicine prepared by taking globefish liver oil and vegetable oil as raw materials on the basis of traditional Chinese medicine and folk prescription, and belongs to the field of traditional Chinese medicine.

Background

Chinese medicine is the largest medical treasury in the world. The inventor has long studied tetrodotoxin and its lipidated compound, and finds that the tetrodotoxin lipidated compound has no toxicity, not only has the functions of resisting cancer, easing pain and removing addiction, but also can amplify the curative effect of the common medicine and inhibit the dependence, tolerance and side effect of the common medicine. The application of the invention shows that the Chinese patent medicine developed by using the tetrodotoxin lipidate as the basic raw material can treat both symptoms and root causes of the cancer.

The ancient folk prescription uses globefish or globefish liver oil to treat cancer. The Ming dynasty Li Shizhen (compendium of materia Medica) (Vol forty-four times) records: globefish liver and son have big toxicity, can be mainly used for treating scabies, tinea and insect sores, has sweet, warm and nontoxic smell, and can be used for mainly tonifying deficiency, removing dampness, treating waist and feet and removing hemorrhoid diseases. The records of "Dingcao Mong Jian" and "Kai Bao Ben Cao" of Fugu puffer, such as "removing infantile malnutrition and relieving swelling" are also recorded. According to the record of Chinese medicine dictionary, globefish liver oil is mainly used for treating tuberculous lymphadenitis and chronic skin ulcer. The Chinese herbal record shows that the Fugu ocellatus liver oil has the following functions and main indications: detumescence and detoxification, resolving hard mass and easing pain, killing parasites, mainly scrofula, sore and furuncle, innominate toxic swelling, chronic skin ulcer, premature ejaculation, impotence and irregular menstruation. Abroad, babylon also states: globefish is a globefish, toxic and can cure diseases. The river and the front being along the river area have the globefish to treat the gastric ulcer, the experience of treating the septal disease and the saying that people who eat much more globefish can not have cancer.

The prior art uses swellfish liver oil for the treatment of cancer and cancer pain. In the early seventies, people in China prepared globefish liver oil into 'new pills' for clinical experiments on treating tumors. (Wuhanlin: "toxic fish and medicinal fish in China, Shanghai science and technology Press, P274, 1978) in 1980-1984, Shanwen et al, Kyoto research institute for tumor prevention and treatment in Beijing, used globefish liver oil for analgesia in 90 cases of advanced cancer patients, and the results show that the effective rate of analgesia is 93.3%, the significant efficiency is 85.5%, and the ineffective rate is 6.7%. (Zhang Shanwen, Huanghong, et al, globefish liver oil analgesia effect observation, Beijing medicine, 1986, volume 8, 6) in 1995, Liuchangqing, et al, showed that globefish liver oil can increase the number of T cells, especially T helper cells, in peripheral blood of tumor patients by improving specific immune function and non-specific immune function, so that the tumor growth is slowed down and the tumor body weight is reduced. Meanwhile, the globefish liver oil also thinks that the blood circulation promoting and blood stasis removing functions of the globefish liver oil can prevent tumor cells from being implanted in blood vessels, so that cancer metastasis is difficult to form. (Liuchangqing, et al, Experimental research on antitumor and anti-metastatic effects of liver oil of detoxified globefish, Chinese and Western medicine J.1995, volume 15, phase 9).

The prior art utilizes the discussion of globefish liver oil to improve the immune function and the mechanism thereof. The papers of Suronghua of Nanjing railway medical college, etc. show that globefish liver oil can enhance the immune function of mice, has obvious enhancement effect on the red blood cell immune system of mice, and has enhancement effect on the immunity of animals of different species. (Shuronghua, Wei-Dai Ying, etc. ' Observation of the effect of liver oil of detoxified puffer on the immune system of mouse's red blood cells ', Observation of the effect of liver oil of detoxified puffer on the immune system of different animals ' and ' mouse model immune enhancement effect of liver oil of detoxified puffer on the serum of anti-lymphocyte ' are reported in Nanjing railway medical college) ' however, what matters in liver oil of puffer play the role of immunity is not described. As a result of gas chromatography analysis by Cimex et al, puffer fish liver oil was found to contain 19.3% docosapentaenoic acid (DPA). (Sedum and Zhoudsen, etc.' separation and identification of fatty acids in liver oil of Chongwengu dolphin (liver oil of Chongwendu Fugu ocellatus); journal of Marine drugs, No. 3 in 1983) according to the relevant data, DPA is a rare substance, which is not found in fish oil, cod liver oil and other animals, but is present in large amount in liver of virulent globefish. The control showed that the globefish liver oil is not substantially different from deep sea fish oil except for being rich in DPA. Therefore, the invention considers that the effective substance of the globefish liver oil for enhancing the animal immune function is mainly docosapentaenoic acid (DPA). (see the following Table)

Table for comparing components of liver oil of puffer fish with deep sea fish oil

The ancient folk prescription records that Chinese herbal medicines are used for treating tumors and pains. In the Chinese medicine treasury, a plurality of Chinese herbal medicines are used for removing stasis and resolving masses and eliminating hardness and relieving scrofula. Such as: the ancient literature suggests that the curcuma zedoary has the effects of removing accumulation and hardness, removing accumulation and lump, removing accumulation and resolving stagnation, removing symptoms and accumulation and the like. Turmeric is considered to have the functions of treating heart and abdomen masses, chronic infectious disease convulsive … … carbuncle and swelling, treating abdominal mass and blood clots, treating carbuncle and swelling, removing heart and abdomen qi stagnation and flatulence, treating distension and fullness syndrome, swelling, asthma and dysphagia and the like. In addition, in a large number of ancient medical works, several folk prescriptions or prescriptions for treating cancer using Chinese herbal medicines can be found.

Modern technology finds that the anticancer active ingredients of Chinese herbal medicines are mainly volatile oil. Several papers show that volatile oil in Chinese herbal medicine is the most significant effective component for treating cancer. Essential oils are the essences of plants and have the ability to penetrate cells rapidly. Gas chromatographic analysis shows that the zedoary volatile oil contains a large amount of beta-elemene, curzerene, curcumenol and other components; the Curcuma rhizome volatile oil contains curcumol, curcumene, curcumin, etc. At present, several anticancer components similar to the above components have been found in Chinese herbal medicines, and these components have the effects of directly killing cancer cells and inhibiting the growth and spread of cancer cells. (Jianjianpi, zedoary turmeric rhizome antitumor research general, Jilin traditional Chinese medicine, second stage of 2000; Fanghong king et al, chemical components and antitumor effect of pelargonium graveolens volatile oil, pharmaceutical science report, 24-5 of 1989; Hai des and et al, HPLC method for simultaneously determining the content of 5 antitumor components in the bighead atractylodes rhizome volatile oil, journal of pharmaceutical analysis, elegant 2011.31-6, Sunyan Yan et al, turmeric volatile oil anticancer active component research, Chinese herbal medicine, 7 th stage of 2006, 7 th stage of zanthoxylum bungeanum volatile oil antitumor physical effect research, snake log, 18 rd stage of 2006).

In the prior art, the following technical problems mainly exist:

one, the prior art treatments for cancer present several problematic issues. For example, cancer metastasis or multiple complications after surgery, many intolerable side effects during chemotherapy, tolerance to targeted therapy, expensive replacement of imported targeted drugs, morphine for severe pain, morphine dependence, and the like. If the problems are not solved well, the disasters which are difficult to overcome are brought to cancer patients. The inventor considers that the problems are difficult to solve only by relying on western medicines and can be well solved only by adopting traditional Chinese medicines. The inventor finds that tetrodotoxin lipidate (globefish liver oil) is a safe, efficient and widely practical medicine raw material, and can completely develop a special Chinese patent medicine by utilizing the specific function of the tetrodotoxin lipidate.

Secondly, the prior art has entered a miszone for partial research on tetrodotoxin. Human pharmacological studies on tetrodotoxin have been in progress for 105 years. Some documents believe that tetrodotoxin can relieve pain by blocking sodium ion channels to inhibit the transmission of pain information by nerve centers. (Xuying, et al, influence of tetrodotoxin on sodium channel and possible analgesic mechanism thereof, China pharmacological report, 2003-19-3, Dupu, Hades, et al, influence of tetrodotoxin on sodium channel and pharmacological action thereof, China marine medicine, No. 1-2 1988) the inventor has carried out a plurality of animal experiments, and the experimental results show that a single tetrodotoxin aqueous solution has no obvious analgesic effect on mice. Meanwhile, the inventor also prepares the buccal tablet by using single tetrodotoxin, and finds that the buccal tablet has no analgesic effect on human bodies after being tried for many times. Therefore, it is worth to review whether the above theory of achieving analgesia by blocking sodium channels is correct.

Thirdly, the prior art misbelieves that the effective component of the globefish liver oil is trace tetrodotoxin. The fenkaying and the like prove the analgesic effect of the globefish liver oil on the mice from various aspects through a large number of animal experiments. Since they used crude tetrodotoxin, it was mistaken that the analgesic active ingredient of tetrodotoxin is residual tetrodotoxin. (Wei Ying, Jiangyu't toxin Fugu liver oil analgesia experiment observation of removing toxin Fugu liver oil, Nanjing railway medical college academic journal, No. 1 of 1983) Huang so strong etc. in the patent related to Fugu liver oil, the effective anticancer and analgesic components are also localized in Fugu liver oil by dissolving trace Fugu toxin into Fugu liver oil or its emulsion. However, they are not aware that tetrodotoxin has evolved into tetrodotoxin lipidate, the original tetrodotoxin monomer structure has disappeared, and the presence of tetrodotoxin cannot be detected either by mouse testing or by HPLC. (Huangqiang et al "a fugu oil preparation and its preparation method" (2008/1/9 CN100360133C) and "a TTX fish liver oil emulsion" (2017/5/22 CN 201710364807.7).

Fourth, the prior art has no clear expression on the anti-cancer mechanism of the globefish liver oil. Liu Chang Qing and so on think that the globefish liver oil kills cancer cells by improving the phagocytic power of immune cells and inhibits cancer metastasis by reducing the blood viscosity and reducing the adhesion of the cancer cells on blood vessels. (Liu Chang Qing, et al, Experimental research on antitumor and anti-metastatic effects of liver oil of Fugu ocellatus, Dedu Fugu ocellatus, J.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.Med.J.1995 Vol.15, No. 9) these discussions have certain practical significance for the application of liver oil of Fugu ocellatus, but there is no more sufficient theoretical basis for the application of liver oil of Fugu ocellatus as an anticancer drug.

Fifth, the prior art only shows that the plant essential oil composition is used for treating soft tissue cancer. The Steve M Besset et al patents use plant essential oil compositions for the treatment of soft tissue cancer (breast cancer), and there is no description of their use in the treatment of various cancers, nor in the combination of their use in anti-cancer, analgesic or withdrawal treatments. (Steve. M Besset et al, Natural plant essential oil compositions and methods for cancer therapy, application No. 99814148.8, publication No. CN 1329498A) in addition, there is a discussion of the use of beta-elemene or some other component for the treatment of cancer, but only in the research stage. (Wanjuan et al, Experimental research on the inhibition of growth of human hepatoma cell line SMMC-7721 by volatile oil of zedoary turmeric, Tianjin Chinese medicine, Vol.20, No. 1 in 2003, research progress on anti-tumor mechanism by beta-elemene, Hou hongfeng et al, proceedings of the institute of traditional Chinese medicine in Hunan, Vol.12, Vol.22, No. 4 in 2002).

Sixthly, the prior art does not report that the globefish liver oil and various vegetable oils are combined for application. In the literature, no discussion is found about the use of vegetable oil in combination with the liver oil of puffer fish. The invention utilizes the principle of amplifying the curative effect of the common medicament of globefish liver oil, combines the globefish liver oil with a plurality of vegetable oils, not only can exert respective curative effect, but also can form complementary and mutually promoted amplifying effect, and simultaneously can avoid the side effect possibly caused by excessive use of volatile oil.

Seventhly, the prior art cannot carry out deep processing suitable for food or medicines on the globefish liver oil. In the prior documents and patents, the expression that crude puffer fish liver oil is saponified by sodium hydroxide or other alkaline substances is not found, and the unsaponifiable puffer fish liver oil cannot meet the requirements of detoxification, deacidification, deodorization, degumming, decolorization and deodorization, does not meet the food sanitation standard, and cannot be used for food or medicines. (Wangweiguo et al, application of globefish liver oil in preparing food for treating drug dependence (2003/8/6 CN 1116880C), Huangqiang et al, globefish oil preparation and its preparation method (2008/1/9 CN 100360133C)).

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a compound globefish liver oil composition and a preparation method and application thereof.

The technical scheme of the invention is as follows:

a compound globefish liver oil composition comprises active components and/or pharmaceutically acceptable carriers, wherein the active components comprise globefish liver oil and plant oil, the globefish liver oil is globefish liver oil extracted from globefish liver containing tetrodotoxin, the plant oil is volatile oil and/or pressed oil extracted from natural plants, and the plant oil is plant oil with one or more functions of resisting cancer, relieving pain and removing addiction.

The globefish liver oil is refined globefish liver oil obtained by detoxification, deacidification, deodorization, degumming, decoloration and deodorization.

In the composition, the weight of the globefish liver oil accounts for 40-80% of the total weight of the composition, and the weight of the vegetable oil accounts for 10-50% of the total weight of the composition.

The vegetable oil is volatile oil and pressed oil, wherein the weight of the volatile oil accounts for 5% -25% of the total weight of the composition; the weight of the pressed oil accounts for 5-25% of the total weight of the composition.

The globefish liver oil accounts for 80% of the total weight of the composition, and the vegetable oil is volatile oil and pressed oil, wherein the weight of the volatile oil accounts for 10% of the total weight of the composition; the weight of the expressed oil was 10% of the total weight of the composition.

The globefish liver oil accounts for 70% of the total weight of the composition, and the vegetable oil is volatile oil and pressed oil, wherein the volatile oil accounts for 21% of the total weight of the composition; the weight of the expressed oil was 9% of the total weight of the composition.

The globefish liver oil accounts for 70% of the total weight of the composition, and the vegetable oil is volatile oil and pressed oil, wherein the weight of the volatile oil accounts for 15% of the total weight of the composition; the weight of the expressed oil was 15% of the total weight of the composition.

The globefish liver oil accounts for 80% of the total weight of the composition, and the vegetable oil is volatile oil, wherein the volatile oil accounts for 20% of the total weight of the composition.

Said vegetable oil is selected from the group consisting of allium macrostemon oil (Allium albus oil), Citrus oil (Citrus aurantium oil), white Atractylodes rhizome oil (Atractylodes macrocephala oil), turmeric oil (turmeric), zanthoxylum oil (pepper oil), Magnolia flower oil (Magnolia grandiflora oil), Asarum oil (Asarum oil), zedoary oil (Curcumaria oil), Angelica dahurica oil (Angelica oil), ginger oil (gingerol oil), Ferulium oil (Ferulic oil), Lithospermum oil (Sesamum oil), valerian oil (Valeriana oil), Corydalis oil (Corydalis oil), Hypericum oil (Sandalia corymbosa oil), Hypericum oil (Sandalia grandiflora oil), safflower oil (safflower oil), Peppermint oil (Morinda officinalis oil), Morinda officinalis oil (Morinda officinalis oil), Garcinia officinalis oil (clove oil), Garcinia oil (clover oil), Magnolia officinalis oil (clove oil (clover oil), Magnolia grandiflora oil (clover oil), Magnolia officinalis oil (Lilium oil (Olive oil), Magnolia grandiflora oil (Citrus oil), Magnolia grandis oil (Citrus oil), Garcinia grandis oil (Citrus oil), Citrus oil (Citrus oil), Citrus oil (Citrus grandis oil (Citrus oil), Citrus grandis oil), Citrus oil (Citrus grandis oil), Citrus grandis oil), Citrus oil (Citrus grandis oil), Citrus grandis oil (Citrus grandis oil), Citrus grandis oil (E grandis oil), Citrus oil (E grandis oil), Citrus grandis oil (E) and/s grandis oil), sage Oil (sapiens Oleum), perilla leaf Oil (olive ocimum relinquis), Oleum fructus bruceae (java Oleum), tagetes Oil (Oleum pingium vaccinia caltha), bone fat-supplementing Oil (psoralen Oleum), Vitex leaf Oil (Vitex folium Oleum), Epimedium Oil (epidium Oleum), Centella asiatica Oil (Centella asiatica Oleum), poppy Oil (Oleum paver), leek seed Oil (porrum semens Oil), radish seed Oil (radiatum Oil), carrot seed Oil (CAROTA olmedium), anise Oil (faniciculi Oleum), Patchouli (Patchouli olum), Geranium Oil (gerium junceum), chinese yew Oil (xuelium yew), chinese yew Oil (xylophilus Oil), chinese yew Oil (xylocarpa leaf Oil), chinese yew Oil (carolywood Oil), chinese violet Oil (carolym Oil), chinese arborvita Oil (caraway Oil), chinese magnolium Oil (caraway Oil), chinese yew Oil (caraway Oil), chinese yew Oil (caraway Oil), chinese yew Oil (chinese Oil), chinese Oil (chinese yew Oil (chinese yew Oil), chinese yew Oil (chinese tam (chinese Oil (chinese tam Oil), chinese tam Oil (chinese tam Oil), chinese tam Oil (chinese tam Oil), chinese tam Oil (chinese tam Oil), chinese tam Oil (chinese tam Oil), chinese tam Oil (chinese tam Oil), chinese tamari (chinese tamari Oil), chinese tam Oil (chinese tamari Oil (chinese tam Oil), chinese tam Oil (chinese tam Oil), chinese tamari Oil (chinese tam Oil), chinese tam Oil (chinese tam Oil), chinese tam Oil (chinese tamari Oil (chinese tam Oil (.

The globefish liver oil is purchased from Kangte bioengineering Co., Ltd, Taizhou, Jiangsu province.

The vegetable oil is purchased from Hecheng Natural perfume oil of Jiangxi Co.

The preparation method of the compound globefish liver oil composition comprises the following steps:

1) preparing globefish liver oil: extracting crude puffer liver oil from puffer liver by heating over water, saponifying with sodium hydroxide or other alkaline substances, centrifuging, washing with saline water, adsorbing with active carbon, fine filtering, detoxicating, deacidifying, deodorizing, degumming, decolorizing, and deodorizing to obtain refined puffer liver oil.

2) Mixing refined globefish liver oil and vegetable oil to obtain the composition.

A pharmaceutical preparation containing the compound globefish liver oil composition is a soft capsule, a dropping pill, an emulsion or a suppository.

The compound globefish liver oil composition is applied to the preparation of the medicine for treating cancer. The cancer refers to various cancers or leukemia, and various cancers causing pain or drug dependence.

The compound globefish liver oil composition is applied to the preparation of medicines for treating cancer pain or non-cancer pain.

The compound globefish liver oil composition is applied to the preparation of medicines for treating cancer drug dependence or non-cancer drug dependence.

In the present invention, the inventors have made a great technical contribution by making the following unexpected findings through creative efforts:

first, tetrodotoxin aqueous solution has no significant analgesic effect on mice, but has significant analgesic effect in oil phase preparations. Secondly, tetrodotoxin is mainly distributed in the liver of puffer fish, but not in the ovary. Thirdly, the tetrodotoxin is dissolved with the tetrodotoxin liver oil for a long time in the puffer fish liver to form rich tetrodotoxin lipidosome. And fourthly, the tetrodotoxin lipidation is very stable, has no toxicity of tetrodotoxin, cannot be destroyed by alkaline substances, and cannot cause harm to human bodies. The tetrodotoxin lipidate has similar efficacy to tetrodotoxin, can amplify the curative effect of the common medicament, and can inhibit the dependence and tolerance of the common medicament. Sixthly, the globefish liver oil can meet the food or medicine standard only through saponification treatment. And seventhly, the globefish liver oil is compatible with the vegetable oil phase containing effective components for resisting cancer, easing pain, removing addiction and the like, so that advantage complementation can be realized, and a more remarkable treatment effect can be generated.

The above findings, the present invention is confirmed by the following experiments and effect examples of the specific embodiments:

experiment I, comparison experiment of analgesic effect of tetrodotoxin in aqueous solution and in oil phase preparation

1. Experiment of analgesic effect of tetrodotoxin in aqueous solution on mice

A mouse hot plate method: mice were divided into 3 groups of 10 mice each, and injected with 0.3. mu.g/kg, 1.0. mu.g/kg, 3.0. mu.g/kg of tetrodotoxin aqueous solution (ip), respectively, and showed no significant difference (P > 0.05) compared to the administration before administration. ② mouse writhing method: the mice were divided into 3 groups of 10 mice each, and the abdominal cavity was injected with an aqueous acetic acid solution (0.4%/0.1 ml/10g), and then injected with an aqueous tetrodotoxin solution (ip) at 0.3. mu.g/kg, 1.0. mu.g/kg, and 3.0. mu.g/kg, respectively, which showed no significant difference (P > 0.05) from the administration level before the administration.

2. Experiment of analgesic effect of tetrodotoxin in oil phase preparation on mice

Four groups of 32 mice were divided in equal parts: low dose group, medium dose group, high dose group and blank group. Dissolving tetrodotoxin 1mg in soybean oil 1000ml, with tetrodotoxin content of 1 μ g/ml. The first three groups of mice were gavaged with 0.2ml, 0.3ml and 0.4ml of soybean oil, respectively, and the blank group was gavaged with soybean oil. The mouse licking test was performed with the following combined data:

note: x denotes the average number; SD index standard deviation; p refers to the determination of whether there is a significant difference.

The result shows that the tetrodotoxin oil phase preparation has very obvious analgesic effect (P is less than 0.001) on mice, and has no obvious dose-effect relationship. The tetrodotoxin has obvious analgesic effect in the oil phase preparation.

Experiment II, experiment that tetrodotoxin evolves into tetrodotoxin lipidation in grease

1. Dissolving tetrodotoxin 10mg in 1000ml soybean oil, with theoretical content of tetrodotoxin 10 μ g/ml. Within 48 hours, 40ml of the preparation is taken, 40ml of pure water is added, and the preparation is stirred, washed by water and finely filtered to obtain 40ml of water washing liquid. Mice (ip) were first injected with 0.1ml of aqueous wash solution and died, indicating that the aqueous wash solution contained monomeric tetrodotoxin. Then, the content of the tetrodotoxin in the water washing liquid is determined by a High Performance Liquid Chromatography (HPLC), and the result shows that the content of the tetrodotoxin is close to 10 mu g/ml.

2. Storing the oil phase preparation of tetrodotoxin for 40 days or more. Adding 40ml of pure water into 40ml of oil solution, stirring, washing, and finely filtering to obtain 40ml of water washing liquid. The water washing solution is first 0.1ml and injected into mouse (ip) without death, and this shows that the water washing solution contains no monomer tetrodotoxin. And then, measuring the content of the tetrodotoxin in the water washing liquid by using a High Performance Liquid Chromatography (HPLC), wherein the result shows that the content of the tetrodotoxin is 0.

The significance of this experiment is that tetrodotoxin, which has just begun to dissolve in soybean oil, still exists in a short time, and after 30 days or more, tetrodotoxin evolves into a new substance, which is called tetrodotoxin lipidate. The structure of this tetrodotoxin lipidate has not been clarified yet due to the limitations of the inventors' conditions.

Experiment III, experiment that tetrodotoxin is mainly distributed in liver of puffer fish but not ovary

Selecting one highly toxic maternal globefish, taking 100g of ovary and liver respectively, cutting up, soaking in 4 times of pure water respectively, stirring, standing for 4 hours, taking 10ml of supernatant respectively for later use. The liver soaking solution is diluted by 10 times of pure water, 0.1ml of injection mouse (ip) is taken, and the mouse dies within 15 min. The toxicity of the ovarian soak solution was tested in the same manner as above, and the mice did not die. Then, the experiment was continued by gradually decreasing the dilution ratio of the ovarian soak solution, and it was found that the mice died by diluting the ovarian soak solution with 5 times of pure water. The tetrodotoxin content in the liver is 2 times of the content of the ovarian tetrodotoxin. It can be seen that tetrodotoxin is mainly distributed in the liver, not in the ovary.

The significance of the experiment lies in that because tetrodotoxin is mainly accumulated in the liver of the puffer fish, a large amount of tetrodotoxin can be promoted to be dissolved with the puffer fish liver oil in the liver for a long time to form saturated tetrodotoxin lipidization. Tetrodotoxin extracted from globefish liver is just non-lipidated tetrodotoxin, but the lipidated tetrodotoxin cannot be separated.

Experiment four, the safety and the stability of the globefish liver oil (globefish toxin lipidation) are tested

1. And (3) safety test: taking 100ml unsaponified crude puffer liver oil, adding 50ml pure water, heating to 60 deg.C, and magnetically stirring for 1 hr to obtain 50ml water washing solution of crude puffer liver oil. The same method is used to prepare 50ml of saponified Fugu ocellatus liver oil water washing solution for use. Two groups of mice (ip) are injected with the two water washes, the first dose is 0.2ml, and the mice injected with crude oil water wash die in 5-15min, and the mice injected with saponified oil water wash do not die. The second injection of 0.4ml of non-dead mice resulted in no death. The crude puffer fish liver oil contains monomer tetrodotoxin, which can kill mouse, and the saponified puffer fish liver oil does not contain the toxicity of tetrodotoxin, and has reliable safety.

2. And (4) performing a stability test: the 24 mice were divided into 3 groups: crude puffer liver oil, saponified puffer liver oil, and blank group. The crude puffer fish liver oil and 0.3ml of saponified puffer fish liver oil are respectively taken to irrigate the stomachs of the first 2 groups of mice and irrigate the soybean oil in the blank group to carry out the licking test. The results show that both have substantially the same analgesic effect. The method shows that the saponified tetrodotoxin liver oil (tetrodotoxin lipidate) does not change the original characteristics and has good stability.

Fifth, the globefish liver oil after saponification can meet the food or drug standard

In the process of refining globefish liver oil, the invention adopts sodium hydroxide or other alkaline substances to saponify the crude globefish liver oil. Because the tetrodotoxin can disappear rapidly in sodium hydroxide or other alkaline substances, the invention not only can completely eliminate the tetrodotoxin in the puffer fish liver oil, but also can ensure that the acid value and other indexes of the puffer fish liver oil meet the relevant national regulations, and overcomes the defect that the puffer fish liver oil prepared by the prior art can not be used for food or medicines.

The invention overcomes the defects of the prior art by the following technologies:

the invention utilizes the characteristics of the globefish liver oil (globefish toxin lipidation) to carry out compatibility with trace plant essential oil containing various anti-cancer substances, analgesic substances and/or addiction-removing substances, thereby not only amplifying the treatment effect of the plant essential oil, but also inhibiting the possible side effect of the plant essential oil.

The composition of the invention has the technical advantages compared with tetrodotoxin: the composition of the invention has no toxicity of tetrodotoxin and no harm to human body; but can also amplify the curative effect of the common medicine and inhibit the dependence and tolerance of the common medicine.

The composition of the invention has technical advantages over individual puffer liver oil or individual vegetable oil: the composition of the invention amplifies the anticancer, analgesic and addiction-removing effects of the volatile oil and inhibits the possible side effects of the volatile oil.

The invention has the following technical effects:

first, the present invention utilizes globefish liver oil to solve the common problems of cancer cell division, proliferation, metastasis and implantation. The cancers produced by the human body are various, but all cancer cells have its commonness. The common property refers to that cancer cells have the characteristics of loose structure, easy fragmentation, easy movement and easy formation of new lesions. The globefish liver oil can directly kill cancer cells by enhancing the phagocytic power of immune cells, inhibit the growth and diffusion of the cancer cells, and inhibit the aggregation of platelets by promoting blood circulation to remove blood stasis, thereby preventing the cancer cells from aggregating, proliferating, nidating and forming a metastasis in blood vessels.

Secondly, the invention solves the individual problem of cancer cells by applying the plant volatile oil with various varieties and low content. All cancer cells have their individuality, which refers to the diversity of cancer cells and the variability that appears after the formation of new lesions. The invention aims at different cancer cells and selects volatile oil containing a plurality of different anti-cancer substances. The volatile oil has strong penetrability and can reach tumor parts in a short time, so that different anticancer substances can be brought into cancer cells to kill different cancer cells at multiple targets. The combination of the commonness and the individuality is realized, the formation of new tumors can be effectively prevented or responded, and the aim of treating both principal and secondary aspects of diseases is fulfilled.

Thirdly, for cancer patients who have become dependent after long-term use of morphine analgesics, the addiction-removing component in the volatile oil can control the dependence and tolerance of morphine to a certain extent under the coordination of the globefish liver oil.

Fourthly, the invention can relieve the complication formed by the operation of the cancer patients who have been operated or treated with chemotherapy, and reduce or eliminate the unstable leucocyte or other side effects caused by the chemotherapeutic drug.

Fifth, the present invention can reduce the tolerance of targeted drugs to cancer patients being treated with the targeted drugs. When a cancer patient uses the targeting drug and takes the anti-cancer drug, tolerance generally cannot be formed, the phenomenon of frequent replacement of the targeting drug cannot occur, and the targeting drug can be gradually reduced or stopped according to the using effect.

Sixthly, for the later-stage cancer patients which are considered as being incapable of being treated, if the product is insist on taking the product, five treatments of cardiac therapy, medication, food therapy, physical therapy and physical therapy are combined, and the traditional Chinese medicine is properly used for conditioning, the life quality can be generally improved, the pain and the pain are relieved, the life period is prolonged, and even the patients can be reversed or enter a phase-sustaining stage. Even near the end of life, intolerable severe pain generally does not occur.

Detailed Description

Example 1 preparation of refined Fugu liver oil

Taking 20kg of cleaned globefish liver (or liver residue left after extracting globefish toxin), heating in a water bath kettle, keeping the temperature at 98 ℃, preserving the temperature for 15 hours, and taking upper clear oil to obtain 10kg of crude globefish liver oil for later use.

② preparing 30% w/v sodium hydroxide aqueous solution, taking 3000ml, adding into the above 10kg crude puffer liver oil, controlling temperature at 60-80 deg.C, stirring for 25 min, keeping constant temperature, naturally precipitating, and taking supernatant for use.

And thirdly, separating the chaotic oil residue by using a centrifugal machine, removing saponified substances, and mixing the retained clear oil with the supernatant for later use.

Fourthly, preparing 10kg of 8% w/v salt solution, controlling the temperature to be 60-80 ℃, dissolving the puffer liver oil clear liquid into the salt solution, stirring, washing, keeping the temperature constant, naturally precipitating, and removing the washing water to obtain the puffer liver oil clear liquid for later use.

Fifthly, adding 1.5kg of active carbon into the puffer liver oil clear liquid, controlling the temperature to be 60-80 ℃, stirring and adsorbing for 60 minutes, pouring into a fine filter paper bag, and performing fine filtration twice to obtain about 10kg of refined puffer liver oil for later use.

Example 2 preparation of Compound Fugu liver oil composition for treating cancer

Taking 8kg of refined globefish liver oil, adding 1kg of pressed oil of magnolia sieboldii seeds, and uniformly stirring for later use.

② taking 100g of allium macrostemon oil, citrus oil, curcuma oil, zedoary turmeric oil, ginger oil, geranium oil, garlic oil, blumea oil, vitex oil and perilla leaf oil respectively, adding 1000g (volatile oil) in total, mixing with the above-mentioned first step, uniformly stirring so as to obtain 10kg of swellfish liver oil and vegetable oil composition. (the vegetable oil is selected from Heng Cheng Natural perfume oil Co., Ltd. of Jiangxi)

③ preparing 2 million capsules from 10kg of the composition, wherein each capsule contains 0.5g of the composition by net weight, 1 percent of volatile oil, 10 percent of dracaena odorata seed pressed oil and 80 percent of refined globefish liver oil.

Fourthly, the tentative name of the combined preparation is as follows: the pill is suitable for treating cancers in the early, middle and late stages. The using method comprises the following steps: it is administered orally 2-3 times a day, 3 granules each time.

Example 3 preparation of Compound Fugu liver oil composition for treating advanced cancer and cancer pain

Taking 7kg of refined globefish liver oil, adding 0.9kg of brucea javanica squeezed oil, and uniformly stirring for later use.

② taking allium macrostemon oil, citrus oil, largehead atractylodes rhizome oil, geranium oil, turmeric oil, asarum oil, zedoary turmeric oil, angelica dahurica oil, asafetida oil, common burreed rhizome oil, perilla leaf oil, lithospermum oil, perilla leaf oil and vitex negundo leaf oil, 150g respectively, mixing the total amount of 2100g (volatile oil) with the above-mentioned first step, uniformly stirring so as to obtain 10kg of swellfish liver oil and vegetable oil composition. (the vegetable oil is selected from Heng Cheng Natural perfume oil Co., Ltd. of Jiangxi)

③ preparing 2 ten thousand soft capsules from 10kg of the composition, wherein each capsule has a net weight of 0.5g, wherein each volatile oil content is 1.5 percent, the total content is 21 percent, the content of oleum fructus brucease is 9 percent, and the content of refined puffer liver oil is 70 percent.

The combined preparation is tentatively named as 'pain-relieving and stasis-removing pill', and is suitable for various late-stage cancers with spread of cancer cells and pain or addiction of analgesics. The using method comprises the following steps: it is administered orally 2-3 times a day, 3 granules each time.

Example 4 preparation of Compound Fugu liver oil composition for treating non-cancer pain

Taking 8kg of refined globefish liver oil for later use.

Secondly, mixing lily magnolia oil, asarum oil, angelica dahurica oil, garlic oil and safflower oil which are 200g respectively, peppermint oil, clove oil, sage oil, common burreed rhizome oil, pepper oil, ginger oil, lithospermum oil and perilla leaf oil which are 125g respectively with the first step for total of 2000g (volatile oil), and uniformly stirring to obtain 10kg of the globefish liver oil and vegetable oil composition. (the vegetable oil is selected from Heng Cheng Natural perfume oil Co., Ltd. of Jiangxi)

③ preparing 2 thousands of soft capsules from 10kg of the composition, wherein each capsule contains 0.5g of composition net weight, and each capsule contains 5 volatile oils, 2% of each volatile oil, such as magnolia flower oil, asarum oil, angelica dahurica oil, garlic oil and safflower oil, and 10% of the total volatile oil; peppermint oil, clove oil, sage oil, burreed tuber oil, zanthoxylum oil, ginger oil, lithospermum oil, perilla leaf oil and other 8 volatile oils, each content being 1.25%, and the total content being 10%; the content of refined globefish liver oil is 80%.

Fourthly, the combined preparation is tentatively named as the dolphin oil pain-easing pill and is applicable to arthritis, rheumatoid arthritis and various chronic pains. The using method comprises the following steps: it is administered orally 2-3 times a day, 3 granules each time.

Example 5 preparation of Compound Fugu liver oil composition for treating non-cancer drug dependence

Taking 7kg of refined globefish liver oil, adding 1.5kg of squeezed oil of leek seeds, and uniformly stirring for later use.

② mixing 150g of each of magnolia flower oil, asarum oil, angelica dahurica oil, asafetida oil, valerian oil, corydalis tuber oil, morinda officinalis oil, peppermint oil, burreed tuber oil and centella oil with 1500g (volatile oil), and stirring uniformly to obtain 10kg of the swellfish liver oil and vegetable oil composition. (the vegetable oil is selected from Heng Cheng Natural perfume oil Co., Ltd. of Jiangxi)

③ preparing 2 ten thousand soft capsules from 10kg of the composition, wherein each capsule contains 0.5g of the composition by net weight, 1.5 percent of each volatile oil, 15 percent of tuber onion seed oil, and 70 percent of refined puffer liver oil.

Fourthly, the combined preparation is tentatively named as the dolphin oil addiction-removing pill and is used for abstaining the dependence of heroin, opium and various novel drugs. The using method comprises the following steps: it is administered orally 2-3 times a day, 3 granules each time.

Example 6 comparison of the tumor-inhibiting effect of the dolphin oil stasis-removing pill prepared in example 2 with that of brucea oil, it was verified that the tumor-inhibiting effect of the dolphin oil stasis-removing pill on mice exceeds that of brucea oil (which is used as an anticancer drug).

60 mice with the weight of 18-22g are all inoculated with lung adenocarcinoma (LA795) tumor strains, and the strains are divided into 3 groups and matched with males and females. The tumor culture period is 7 days, and the administration treatment period is 45 days. The first 2 groups are separately filled with oleum fructus Bruceae and oleum Tortoise stasis removing pill, and the blank group is filled with soybean oil. Tumor body weight and mouse body weight were weighed on day 46. The results are shown in the following table:

the experimental results are as follows:

the tumor weight of the brucea javanica oil is reduced by 2.48 g/mouse compared with that of a control group, and the tumor inhibition rate is 38.5% (P is less than 0.05); the tumor weight of the pig oil stasis removing pill group is reduced by 4.29 g/mouse compared with that of a control group, and the tumor inhibition rate is 66.6% (P is less than 0.01).

Experiments show that the dolphin oil stasis-removing pill has better tumor inhibition effect on lung adenocarcinoma (LA795) than single brucea javanica oil.

Example 7 comparison experiments of tumor inhibition effects of the globefish oil stasis removing pill prepared in example 2 and the composition of globefish liver oil and plant essential oil prove that the tumor inhibition effect of the globefish oil stasis removing pill on mice is superior to that of the composition of globefish liver oil and plant essential oil. (the variety and content of the plant essential oil in the plant essential oil composition are the same as those of the volatile oil in the dolphin oil stasis-removing pill in the example 2)

96 mice with the weight of 18-22g are inoculated with tumor strains, wherein: 48 sarcomas (S180) and 48 adenocarcinoma of the lung (LA795), which were equally divided into 8 groups and matched male and female. The tumor culture period is 7 days, and the administration treatment period is 45 days. The first 3 groups are separately filled with globefish liver oil, plant essential oil composition, and globefish oil stasis removing pill liquid, and the blank group is filled with soybean oil. Tumor body weight and mouse body weight were weighed on day 46. The results are shown in the following table:

the experimental results are as follows:

sarcoma (S180) trial showed: the tumor weight of the globefish liver oil is reduced by 1.96 g/mouse compared with that of a control group, and the tumor inhibition rate is 32% (P is less than 0.05); the tumor weight of the vegetable essential oil is reduced by 2.01 g/control group, the tumor inhibition rate is 32.8 percent (P is less than 0.05), the tumor weight of the pig oil stasis removing pill is reduced by 3.44 g/control group, and the tumor inhibition rate is 56.2 percent (P is less than 0.01).

② the test of lung adenocarcinoma (LA795) shows: the tumor weight of the globefish liver oil is reduced by 2.24 g/mouse compared with that of a control group, and the tumor inhibition rate is 35.1% (P is less than 0.05); the tumor weight of the vegetable essential oil is reduced by 2.16 g/control group, the tumor inhibition rate is 33.8 percent (P is less than 0.05), the tumor weight of the pig oil stasis removing pill is reduced by 4.32 g/control group, and the tumor inhibition rate is 67.7 percent (P is less than 0.01).

Experiments show that the pig oil stasis removing pill has better tumor inhibition effect than the combination of the pig liver oil and the plant essential oil, especially on lung adenocarcinoma (LA795), and the pig oil stasis removing pill is 2 times of the combination of the plant essential oil.

Example 8 the effect of the pig oil stasis removing pills prepared in example 2 on the inhibition of the side effects of chemotherapeutic drugs was verified using the combination of pig oil stasis removing pills and chemotherapeutic drugs.

Xinghua Tangliuzhu, a certain number of women, 63 years old, in 2017, found out breast cancer in 4 months, advanced stage. Chemotherapy is performed four times before operation, chemotherapy is performed once after operation, and the hair is completely exposed after the first chemotherapy. After the operation, the pig oil stasis-removing pills are taken, and other medicines are not taken until the pig oil stasis-removing pills are taken, so that the pig oil is basically recovered at present, and the head of the pig is full of black hair again.

Shenyang city, Liu Yi, female, 40 years old. In 2017, colon cancer in the late stage is detected in 3 months. After operation, chemotherapy is carried out for 16 courses, liver metastasis is found, and then the chemotherapy is continued until 2018 for 5 months. After chemotherapy, the body is weak, the appetite is not good, the face is swollen, and the face and the whole body are raised with many lumps which are unparalleled and bitter. The pill is administered 3 times a day, 3 pills each time, and after two weeks, the condition of the patient is obviously improved, edema disappears, and pimples full of face and body are controlled, and the physical strength is basically recovered to the preoperative state. The former 'radio frequency dissolving' operation to be done in 7 months is not done as the condition of the patient is improved.

In Xuezhizi city, women, 45 years old, and 2017 spring, lung adenocarcinoma, advanced stage, were detected. The pill is administered 3 times a day, 3 granules each time, beginning in 5 months of 2017. After 6 months of examination, the tumors were found to have collapsed into small lumps. Later, she stopped taking the pills for eliminating stasis with pig oil and changed to chemotherapy with the Tian price import medicine. The inventor persuade her to use both of them, she did not accept it, and he died of the spring festival in 2018.

Example 9 the effect of inhibiting the tolerance of the dolphin oil stasis-removing pill prepared in example 2 to a targeted drug was verified by using the dolphin oil stasis-removing pill in combination with the targeted drug.

The result of the follow-up observation shows that the dolphin oil stasis removing pill can produce reversion or treatment effect on the lung cancer, and simultaneously discovers that the dolphin oil stasis removing pill can effectively inhibit the tolerance and side effect of the targeted medicine.

The following are the cases therein:

one of Sichuan Liu in Taixing city, male, aged 67 years and 2016, has lung cancer, and at advanced stage, there are many bone metastases. The pill for removing blood stasis is administered 3 times a day, 3 pills each time, beginning in 2016 and 9 months. After taking the medicine, the disease condition is improved, the cancer index stops rising, and the focus is not increased by reexamination (CT). Later, the target drugs are used simultaneously, and the tolerance and the side effect of the target drugs do not appear. At present, the survival quality is still good, and the state of illness enters into a compatible state.

One in Taixing city Liu, male, 69 years old, 8 months in 2017 suffered from lung cancer, late stage. After surgery, the tumor index is increased, and lymphatic metastasis occurs soon because the body constitution is poor and chemotherapy cannot be performed. 3 times a day, 3 pills each time, 3 pills are taken after 10 months in 2017. And meanwhile, when the targeted drug is taken, the current cancer index is normal, and the tolerance of the targeted drug does not appear.

In Taixing city, a certain woman in age 73 years suffers from esophageal cancer in 6 months in 2017, and the disease is advanced. Lymph metastasis after surgery, go to Shanghai for chemotherapy. The chemotherapy has no effect, and the pill is administered 3 times a day, 3 pills each time. The neck lymphoma was found to shrink after 1 month of administration, and the neck lymphoma was substantially disappeared after 2 months of administration. Later on, the body recovers at present in order to enhance the treatment effect and take the targeted drug at the same time, and the tolerance of the targeted drug does not appear.

Example 10 the "pig oil stasis removing pill" prepared in example 2 was used to treat advanced cancer, and the therapeutic effect of pig oil stasis removing pills on advanced cancer was observed.

Some women in the Xinghua city, 82 years old and 2014, suffer from lymph cancer, have large neck swelling, have pus and blood flowing in some places, cannot be operated because the tumor surrounds the aorta, and can only survive for three months according to the judgment of a hospital. After discharge, the pill is taken until 42 days, and the place with detumescence of neck and suppuration and bleeding is healed. After eating the dolphin oil stasis-removing pill for two years, the lymph cancer disappears.

In 2016, gastric adenocarcinoma was detected in the advanced stage of certain Shandong clothing, female and 33 years old. She had difficulty in family, had not lived in a hospital for one day, had not taken other medicines bought from money, and had the pig oil stasis-removing pill from the beginning, 2-3 times a day, 3 pills each time. After one year, the hospital examination shows that the gastric adenocarcinoma completely disappears, and only little inflammation is left in the lesser curvature of the stomach. At present, she does not eat the dolphin oil stasis-removing pills any more, and the body is completely recovered.

Nantong, in the city of Nantong, is bent to a certain degree, female, aged 56 years, and in the advanced stage of lung cancer, and spreads to bones, brains, livers, and other parts. Individuals spend over 100 million for treatment and the results are not well controlled. The pill for removing blood stasis is taken 3 times a day, 3 pills each time, and is still taken at present in 2016 month 6. Before the pill is taken, the targeted drug tolerance is formed, the targeted drug is replaced once and continues to generate the tolerance, and after the pill is taken, the targeted drug tolerance does not appear. At present, the metastasis of a plurality of cancers begins to reverse, and the survival quality is gradually good.

The Xinghua plum is a female aged 82 years old with breast cancer two years ago and has no operation. In 2018, at the end of 4 months, the tumor grows to be large and hard like wood, the appearance is broken and bloody, and the pain is great. The pill for removing blood stasis is taken twice a day in 5 months in 2018, 3 pills in the morning and at night. The swelling subsides after 10 days, the external ulcer converges and the pain is relieved. After the medicine is taken for two months, the tumor is reduced to 3 centimeters, the tumor body is soft, and the pain basically disappears.

Lung cancer was detected in 2016, late stage, in the case of male, 79 years old in Xinghua City. After the operation, the pig is not treated by chemotherapy, and the pig oil stasis removing pills are taken for 3 times a day, 3 pills are taken each time, so that the cancer disappears at present and the pig can live to be healthy.

Dananzhen in Xinghua, women, 80 years old, suffer from late rectal cancer in 2015. The pill is administered 3 times a day, 3 granules each time. When the focus is ulcerated, the pill is stuffed from anus with TUYOUXIAYU pill. The cancer disappears completely after two years, and the body is very healthy as before.

Example 11. Using the "analgesic and blood stasis removing pill" prepared in example 3, a mouse experiment with morphine was conducted to verify that the analgesic and blood stasis removing pill amplifies the analgesic effect of morphine, and compared with swellfish liver oil alone.

4 groups of mice, each group containing 12 mice, were divided into a normal saline group, a morphine single group, 1 group using globefish liver oil for combined administration, and 2 groups using analgesic and blood stasis-removing pills for combined administration. Saline group is injected with saline 0.3 ml/one, morphine group is injected with morphine 50 mug/one, 1 group is co-administered with morphine 50 mug/one, meanwhile, globefish liver oil is used for intragastric administration (0.3 ml/one), 2 groups is co-administered with morphine 50 mug/one, meanwhile, antalgic and stasis-eliminating pill liquid is used for intragastric administration (0.3 ml/one), and acetic acid writhing test is carried out. The results are shown in the following table:

	physiological saline group	Morphine single prescription group	Combination administration of 1 group	Combination of 2 groups
					Latency time	135.51±30.2	288.21±25.31	299.15±33.86	456.55±23.56
Number of times of body twisting	45.04±3.44	22.56±8.08	20.68±7.11	15.48±6.55

The experimental results are as follows:

the two groups of combined administration groups have significant difference (P is less than 0.01) compared with the normal saline group and the morphine single-side group

Experiments show that the analgesic effect of morphine can be amplified after the two groups of combined administration groups are combined with morphine, wherein the analgesic and blood stasis-removing pill is superior to globefish liver oil.

Example 12A mouse experiment with morphine was conducted using the "analgesic blood stasis removing pill" prepared in example 3 to verify the effect of the analgesic blood stasis removing pill in inhibiting morphine tolerance, and compared with swellfish liver oil alone.

Purpose of the experiment: the analgesic and stasis-removing pill and the swellfish liver oil of the invention have the effect of inhibiting the tolerance of the morphine.

4 groups of mice, each group comprises 20 mice, and the mice are divided into a normal saline group and a morphine single-prescription group, wherein 1 group is subjected to combined administration by using globefish liver oil, and 2 groups is subjected to combined administration by using pain-relieving and stasis-removing pills. Saline group is injected with saline 0.3 ml/one, morphine group is injected with morphine 50 mug/one, 1 group is co-administered with morphine 50 mug/one, meanwhile, globefish liver oil is used for intragastric administration (0.3 ml/one), 2 groups is co-administered with morphine 50 mug/one, meanwhile, analgesia and blood stasis removing pill liquid is used for intragastric administration (0.3 ml/one), and hot plate test is carried out. The results are shown in the following table:

	physiological saline group	Morphine single prescription group	Combination administration of 1 group	Combination of 2 groups
					Threshold of pain at the base	12.87±_S4.26	13.96±_S3.72	12.80±_S3.46	13.12±_S4.06
Pain threshold after administration	46.73±_S10.32	15.51±_S4.89	28.63±_S7.88	34.26±_S6.38

The experimental results are as follows:

Experiments show that the two groups of combined administration groups can inhibit the tolerance of morphine after being combined with morphine, wherein the analgesic and stasis-removing pill is superior to globefish liver oil.

Example 13 the "analgesic and blood stasis removing pill" prepared in example 3 was used to treat advanced cancer and cancer pain, and the therapeutic effect of the analgesic and blood stasis removing pill on patients with advanced cancer was observed.

80 patients with advanced cancer had more spread in 24, 1 in 35, and no other spread. 23 morphine patients were taken daily, 35 general analgesics were taken, and 22 general analgesics were taken intermittently. The pill is administered 3 times a day, 3 granules each time. It can be used for treating severe pain with the assistance of thermal therapy for relieving pain. After 2 months, most people have pain relieved and cancer spread is controlled. The following are observations before and after dosing:

description of the drawings: the obvious effect means that pain is eliminated, pain is relieved after taking the analgesic, the tumor is reduced and softened, the diffusion is controlled, the cancer index is obviously reduced, the life quality is high, and the external recuperation is performed frequently. The effective rate is slightly worse, the pain is controlled, and the analgesic is not taken generally. Ineffectiveness means that pain continues, being analgesic with morphine daily, but dependence is suppressed.

The results show that: the effective rate of the treatment is 95%, wherein the significant efficiency is 66%, and the ineffective rate is 5%. The dose of morphine was reduced in 23 patients who took morphine, except 5, indicating that morphine dependence was controlled.

Example 14. Using the non-anticancer drug "Dolphin oil analgesic pill" prepared in example 4 to treat rheumatoid arthritis, the therapeutic effect of the Dolphin oil analgesic pill on the typical cases of rheumatoid arthritis was observed.

In Zhang, women, age 65, severe rheumatoid arthritis, bending deformation of both hands and legs, walking supported by the double crutches, arthralgia of the whole body, inability to sleep at night and life self-care. The pain is relieved after the pill is taken from 2014, the column crutch does not need to be laboured before, and the night sleep is improved compared with the past. After taking the medicine for three months, the joint bending is controlled, and the life can be basically self-care. For three years, she keeps taking the dolphin oil pain-relieving pill every day, and can cook, wash clothes and busy housework although the original condition cannot be completely changed.

In Taixing city, a woman is 73 years old and has severe rheumatoid arthritis, and the patient is asked for medical questions for more than ten years everywhere, but the patient does not have a good treatment and costs nearly millions of yuan, which is still more and more serious. The pain is relieved after the pill is taken for a month from 2016, the bending deformation of both hands and legs is controlled, and the life quality is obviously improved.

Example 15 the non-anticancer drug "fuyou de-addiction pill" prepared in example 5 was used to treat drug dependence and the effect of fugu oil de-addiction pills on the typical cases of drug dependence was observed.

Hainan Aming, male, 40 years old, heroin addiction 22 years old, nose sucking in the first 15 years old, intravenous injection in the middle 3 years old, intramuscular injection later for 5 years, 5g daily dose, divided into 4 injections. During this period, Bingdu should be taken occasionally. In 2015, hospitalization was performed. In the first three days, a small amount of methadone is taken every day, and the pill for removing addiction of dolphin oil is taken 3 times every day, 3 pills every time, and is matched with drug-dropping traditional Chinese medicines. Stopping methadone on the fourth day, taking a hypnotic in the evening, and keeping the rest as old. The drug rehabilitation is completely successful on the 13 th day.

Hainan floret, female, 25 years old, after 2014, the patient starts to take the ice toxin, and phenomena such as dysphoria, hallucination, and splenic qi violence appear. 2016 is used for abstinence of drugs in hospital, and comprises 3 times daily and 3 pills each time, and can be administered together with Chinese medicinal composition for abstinence of drugs after two months.

Claims

1. The preparation method of the compound globefish liver oil composition for treating cancer is characterized by comprising the following steps:

taking 8kg of refined globefish liver oil, adding 1kg of pressed oil of magnolia sieboldii seeds, and uniformly stirring for later use;

collecting 100g of allium macrostemon oil, citrus oil, curcuma oil, zedoary turmeric oil, ginger oil, geranium oil, garlic oil, blumea oil, vitex oil and perilla leaf oil respectively, adding 1000g (volatile oil) in total, mixing with the above-mentioned first step, and uniformly stirring so as to obtain 10kg of swellfish liver oil and vegetable oil composition;

③ preparing 2 million capsules from 10kg of the composition, wherein each capsule contains 0.5g of the composition by net weight, 1 percent of volatile oil, 10 percent of dracaena odorata seed pressed oil and 80 percent of refined globefish liver oil;

wherein, the preparation method of the refined globefish liver oil comprises the following steps:

taking 20kg of cleaned globefish liver (or liver residue left after extracting globefish toxin), heating in a water bath kettle, keeping the temperature at 98 ℃, preserving the heat for 15 hours, and taking upper clear oil to obtain 10kg of crude globefish liver oil for later use;

preparing 30% w/v sodium hydroxide aqueous solution, adding 3000ml sodium hydroxide aqueous solution into the crude globefish liver oil 10kg, controlling the temperature at 60-80 deg.C, stirring for 25 min, keeping the temperature constant, naturally precipitating, and collecting supernatant for use;

separating the chaotic oil residue by a centrifugal machine, removing saponified substances, and mixing the retained clear oil with the supernatant for later use;

fourthly, preparing 10kg of 8% w/v salt solution, controlling the temperature to be 60-80 ℃, dissolving the puffer liver oil clear liquid into the salt solution, stirring, washing, keeping the temperature constant, naturally precipitating, and removing the washing water to obtain the puffer liver oil clear liquid for later use;

2. The preparation method of the compound globefish liver oil composition for treating advanced cancer and cancer pain is characterized by comprising the following steps:

taking 7kg of refined globefish liver oil, adding 0.9kg of brucea javanica squeezed oil, and uniformly stirring for later use;

② taking allium macrostemon oil, citrus oil, largehead atractylodes rhizome oil, geranium oil, turmeric oil, asarum oil, zedoary turmeric oil, angelica dahurica oil, asafetida oil, common burreed rhizome oil, perilla leaf oil, lithospermum oil, perilla leaf oil and vitex negundo leaf oil, 150g respectively, mixing the total amount of 2100g (volatile oil) with the above-mentioned first step, uniformly stirring to obtain 10kg of the composition of the globefish liver oil and the vegetable oil;

③ preparing 2 million capsules from 10kg of the composition, wherein the net weight of the composition in each capsule is 0.5g, the content of each volatile oil is 1.5 percent, the total content is 21 percent, the content of the oleum fructus brucease is 9 percent, and the content of the refined globefish liver oil is 70 percent;

3. The preparation method of the compound globefish liver oil composition for treating non-cancer pain is characterized by comprising the following steps:

firstly, taking 8kg of refined globefish liver oil for later use;

secondly, mixing lily magnolia oil, asarum oil, angelica dahurica oil, garlic oil and safflower oil which are 200g respectively, peppermint oil, clove oil, sage oil, common burreed rhizome oil, pepper oil, ginger oil, lithospermum oil and perilla leaf oil which are 125g respectively with the first step for total of 2000g (volatile oil), and uniformly stirring to obtain 10kg of the globefish liver oil and vegetable oil composition;

③ preparing 2 thousands of soft capsules from 10kg of the composition, wherein each capsule contains 0.5g of composition net weight, and each capsule contains 5 volatile oils, 2% of each volatile oil, such as magnolia flower oil, asarum oil, angelica dahurica oil, garlic oil and safflower oil, and 10% of the total volatile oil; peppermint oil, clove oil, sage oil, burreed tuber oil, zanthoxylum oil, ginger oil, lithospermum oil, perilla leaf oil and other 8 volatile oils, each content being 1.25%, and the total content being 10%; refined globefish liver oil content is 80%;

4. The preparation method of the compound globefish liver oil composition for treating non-cancer drug dependence is characterized by comprising the following steps:

taking 7kg of refined globefish liver oil, adding 1.5kg of squeezed oil of tuber onion seeds, and uniformly stirring for later use;

secondly, 150g of each of magnolia flower oil, asarum oil, angelica dahurica oil, asafetida oil, valerian oil, corydalis tuber oil, morinda officinalis oil, mint oil, trigone oil and centella asiatica oil are taken to be mixed with the first step, and the mixture is stirred uniformly to obtain 10kg of the globefish liver oil and vegetable oil composition;

③ preparing 2 ten thousand soft capsules from 10kg of the composition, wherein each capsule contains 0.5g of the composition by net weight, 1.5 percent of each volatile oil, 15 percent of tuber onion seed oil, and 70 percent of refined puffer liver oil;

5. The use of the compound tetrodotoxin liver oil composition of claim 1 in the preparation of a medicament for the treatment of cancer.

6. The use of the compound tetrodotoxin liver oil composition of claim 2 in the preparation of a medicament for treating advanced cancer and cancer pain.

7. The use of a compound tetrodotoxin liver oil composition as defined in claim 3 for the preparation of a medicament for the treatment of non-cancer pain.

8. The use of the compound tetrodotoxin liver oil composition of claim 4 in the preparation of a medicament for treating non-cancer drug dependence.