WO2024021826A1 - 一种治疗癌性疼痛的药物组合物及其制备方法 - Google Patents

一种治疗癌性疼痛的药物组合物及其制备方法 Download PDF

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WO2024021826A1
WO2024021826A1 PCT/CN2023/096579 CN2023096579W WO2024021826A1 WO 2024021826 A1 WO2024021826 A1 WO 2024021826A1 CN 2023096579 W CN2023096579 W CN 2023096579W WO 2024021826 A1 WO2024021826 A1 WO 2024021826A1
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parts
pharmaceutical composition
weight
filtrate
decoction
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周田明
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周田明
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/56—Loganiaceae (Logania family), e.g. trumpetflower or pinkroot
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/66—Papaveraceae (Poppy family), e.g. bloodroot
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/714—Aconitum (monkshood)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/53—Liquid-solid separation, e.g. centrifugation, sedimentation or crystallization
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a pharmaceutical composition, specifically a pharmaceutical composition for treating cancer pain and a preparation method thereof.
  • Cancer pain is one of the most common and painful symptoms for patients with late-stage malignant tumors. Cancer pain is caused by the cancer itself and the cancer treatment process (including surgery, radiotherapy, chemotherapy, etc.) as well as mental and psychological pain. It is caused by various factors such as , social and economic constraints. It often severely affects the quality of life of patients, and patients even commit suicide due to cancer pain.
  • the World Health Organization and the International Pain Society have developed a "three-step analgesic plan" based on the current situation of cancer pain. Although it makes cancer pain patients suffer to a certain extent. be relieved;
  • the technical problem to be solved by the present invention is to overcome the defects of the above technology and provide a pharmaceutical composition for treating cancer pain and a preparation method thereof.
  • the technical solution provided by the present invention is a pharmaceutical composition for treating cancer pain.
  • the pharmaceutical composition is prepared from the following raw materials in parts by weight: 15-20 parts of raw aconite, 6 parts of celandine -10 parts, Panax notoginseng 5-8 parts, Nux vomica 0.6-1 part, Sangcaowu 6-10 parts, Gouqi 1-2 parts.
  • the pharmaceutical composition is prepared from the following raw materials by weight: 15 parts of raw aconite, 6 parts of celandine, 5 parts of Panax notoginseng, 0.6 parts of Nux vomica, 6 parts of Aconite root, and 1 part of Gelsemium .
  • the pharmaceutical composition was prepared from the following raw materials in parts by weight: 18 parts of Aconite, 8 parts of Chelidonium, 6 parts of Notoginseng, 0.8 parts of Nux vomica, 8 parts of Gelsemium rhizome, and 1 part of Gelsemium rhizome.
  • the pharmaceutical composition is prepared from the following raw materials in parts by weight: 20 parts of raw aconite, 10 parts of celandine, 8 parts of Panax notoginseng, 1 part of Nux vomica, 10 parts of Aconite root, and 2 parts of Gelsemium .
  • the invention also provides a method for preparing a pharmaceutical composition for treating cancer pain, which is characterized by comprising the following steps:
  • Step 1) First, take raw aconite, nux vomica, and raw aconite in parts by weight, wash them, put them into water, and boil them for three hours to get the primary processing liquid;
  • Step 2) Then take celandine and Panax notoginseng according to the weight, hook it up and add it to the preliminary processing liquid obtained in step 1, decoct twice for one hour; for the first decoction, add the amount of water: 8-10 times the total weight of the raw materials, boil for 180 minutes, filter and take the filtrate; for the second decoction, add water 3-4 times the total weight of the raw materials, boil for 60 minutes, filter and take the filtrate; combine the two The obtained filtrate is combined to obtain the decoction extract;
  • Step 3) Add 20% of the 75% edible ethanol to the total amount of the decoction extract obtained in step 2 and let it stand for 24 hours. Evaporate to recover the ethanol, filter it and take the pure liquid; then filter it with a microporous membrane. Filter and take the filtrate; combine the obtained pure liquid with the filtrate and put it into a concentration tank, and obtain it after concentration.
  • the sources of raw materials used in the present invention are as follows:
  • Aconite pungent, sweet, hot, toxic; returns to the heart, kidneys, and spleen meridian; restores yang and relieves adverse effects, replenishes fire and assists yang, and drives away wind, cold, and damp evils.
  • raw aconitine contains aconitine, hypoaconitine, mesoconitine and racemic aconitine, which have analgesic and sedative effects.
  • Chelidonium bitter, pungent, lukewarm, toxic; returns to the lung, spleen and stomach meridians; analgesic, cough-relieving and expectorant, diuretic and detoxification; used for analgesia, cough-relieving, diuresis, detoxification, stomachache, abdominal pain, enteritis, dysentery, Chronic bronchitis, whooping cough, cough, jaundice, edema, ascites, scabies sores, snake and insect bites.
  • chelidonium contains a variety of alkaloids, including chelidonine and ⁇ -proopioid.
  • the roots and flowers also contain other alkaloids, which have antispasmodic and analgesic effects.
  • Panax notoginseng sweet, slightly bitter, warm, slightly toxic; returns to the liver, stomach, and large intestine meridians; stops bleeding, disperses blood stasis, reduces swelling, and relieves pain; is mainly used to stop bleeding, remove blood stasis, relieve pain, activate blood circulation, reduce swelling, and treat gastric cancer and lung cancer ,, pain and bleeding caused by osteosarcoma, rectal cancer, sigmoid colon cancer, etc.
  • Nux vomica bitter, cold, slightly toxic; enters the liver and spleen meridian; dissipates blood heat, reduces swelling, and relieves pain; treats esophageal cancer, stomach cancer, intestinal cancer, lung cancer, skin cancer, leukemia, etc.; externally used to treat skin cancer, Deflated phlegm core, laryngeal numbness, rheumatic arthralgia, bruises.
  • Radix Aconitum pungent, bitter, hot, and toxic (Acne Radix Radix Sinensis is highly toxic); returns to the heart, liver, spleen, and kidney meridians; expels wind and removes dampness, warms the meridians and relieves pain. Treat wind-cold-dampness.
  • the roots of Radix Aconiflora contain aconitine, hypoconitine, and aconitine, which have analgesic effects.
  • Gelsemium Also known as elegans, gallbladder, and great tea medicine. Pachet, bitter, warm; highly toxic.
  • Functions include dispelling wind and dissipating blood stasis, reducing swelling and relieving pain, attacking poison and killing insects. , rheumatic arthralgia, neuralgia, scrofula, bruises, fractures, hemorrhoids.
  • the roots and whole plant contain indole alkaloids.
  • the ingredients that have been extracted so far include: Gelsmine, N-methoxy-gelscmine, Sempervirine, Koumicine, Koumidine, Koumine, Kouminine, Kouminidine, Kounidine, Gelsenicine, Gelsemin.
  • Gelsemin B can inhibit and stop the rhythmic contraction of the isolated diaphragm connected to the nerve, and has the same effect as the existing diaphragm. Direct stimulation of the phrenic nerve can still cause diaphragm contraction after respiratory arrest. It has no direct paralyzing effect on peripheral neuromuscular devices.
  • Gelsemin A has analgesic effect on mice, and its effective dose is similar to the toxic dose. There are also reports that the analgesic effect is enhanced when combined with aspirin.
  • Gelsemium has the effects of dispelling wind and blood stasis, reducing swelling and relieving pain, and attacking poison and killing insects. It is an external medicine used to treat bruises and injuries. It also has analgesic effect on fractures, rheumatic arthralgia and neuralgia. Gelsemium is very poisonous and should be strictly prohibited for internal use and caution for external use.
  • the pharmaceutical composition for treating cancer pain provided by the present invention has a reasonable overall structure, precise compatibility, no obvious toxic and side effects, and can prevent the spread, metastasis and thrombosis of cancer cells. It can inhibit the damage caused by chemical harmful factors such as 5-hydroxytryptophan and other inflammatory and pain-causing factors released by cancer cells to normal cells and nerves; it also has the effect of promoting blood circulation and removing blood stasis, thereby achieving the therapeutic purpose of preventing pain if there is blockage and no pain if there is blockage.
  • a pharmaceutical composition for treating cancer pain of the present invention and its preparation method will be further described in detail below with reference to the examples.
  • a pharmaceutical composition for treating cancer pain which is prepared from the following raw materials by weight: 15 parts of raw aconite, 6 parts of celandine, 5 parts of Panax notoginseng, 0.6 parts of Nux vomica, and raw grass 6 parts of blackberry, 1 part of Gelsemium.
  • Step 1) First, take raw aconite, nux vomica, and raw aconite in parts by weight, wash them, put them into water, and boil them for one hour to get the primary processing liquid;
  • Step 2) Then take asparagus, celandine, and Panax notoginseng in parts by weight, and add them to the preliminary processing liquid obtained in step 1, and perform two decoctions; for the first decoction, the amount of water added is 3% of the total weight of the raw materials. -5 times, decoct for 60 minutes, filter and take the filtrate; for the second decoction, add water 3-4 times the total weight of the raw materials, decoct for 50 minutes, filter and take the filtrate; combine the two filtrates.
  • the extract must be boiled;
  • Step 3 Let the decoction extract obtained in step 2 stand for 24 hours to settle, then filter it and take the pure liquid; then filter it with a microporous membrane filter and take the filtrate; combine the obtained pure liquid with the filtrate and put it in the Put it into the concentration tank and get it after concentration treatment.
  • a pharmaceutical composition for treating cancer pain is prepared from the following raw materials in parts by weight: 18 parts of Aconite, 8 parts of Chelidonium, 6 parts of Notoginseng, 0.8 part of Nux Vomica, and Aconite Radix. 8 parts, 1 part of Gelsemium;
  • Step 1) First, take raw aconite, nux vomica, and raw aconite in parts by weight, wash them, put them into water, and boil them for one hour to get the primary processing liquid;
  • Step 2) Then take asparagus, celandine, and Panax notoginseng in parts by weight, and add them to the preliminary processing liquid obtained in step 1, and perform two decoctions; for the first decoction, the amount of water added is 3% of the total weight of the raw materials. -5 times, decoct for 60 minutes, filter and take the filtrate; for the second decoction, add water 3-4 times the total weight of the raw materials, decoct for 50 minutes, filter and take the filtrate; combine the two filtrates.
  • the extract must be boiled;
  • Step 3 Let the decoction extract obtained in step 2 stand for 24 hours to settle, then filter it and take the pure liquid; then filter it with a microporous membrane filter and take the filtrate; combine the obtained pure liquid with the filtrate and put it in the Put it into the concentration tank and get it after concentration treatment.
  • a pharmaceutical composition for treating cancer pain is prepared from the following raw materials by weight: 20 parts of raw aconite, 10 parts of celandine, 8 parts of Panax notoginseng, 1 part of Nux vomica, and raw grass. 10 parts of blackberry and 2 parts of Gelsemium.
  • Step 1) First, take raw aconite, nux vomica, and raw aconite in parts by weight, wash them, put them into water, and boil them for one hour to get the primary processing liquid;
  • Step 2 Then take Gelsemium, celandine, and Panax notoginseng in parts by weight, and add them to the preliminary processing liquid obtained in Step 1, and perform two decoctions; for the first decoction, add an amount of water equal to the total weight of the raw materials. 3-5 times, decoct for 60 minutes, filter and take the filtrate; for the second decoction, add water 3-4 times the total weight of the raw materials, decoct for 50 minutes, filter and take the filtrate; combine the two filtrates. , the extract must be boiled;
  • Step 3 Let the decoction extract obtained in step 2 stand for 24 hours to settle, then filter it and take the pure liquid; then filter it with a microporous membrane filter and take the filtrate; combine the obtained pure liquid with the filtrate and put it in the Put it into the concentration tank and get it after concentration treatment.
  • the pharmaceutical composition prepared by the present invention is liquid.
  • mice were randomly divided into experimental groups and control groups according to weight and gender, with 22 animals in each group, half male and half female. They were fasted and watered for 12 hours before the experiment.
  • the experimental group was intragastrically administered the pharmaceutical composition liquid prepared according to the present invention, at a standard of 48g/kg, in two doses, with an interval of 4 hours;
  • the control group was given the same amount of normal water, and was observed continuously for 7 days after administration. The appearance, behavioral activities, mental state, and respiratory changes of the two groups of mice were observed and compared daily, and the weight was weighed every other day.
  • mice The weight of the mice increased normally, and no other obvious abnormal reactions were observed.
  • the mice were sacrificed and dissected, and it was found that there were no obvious abnormalities in their main organs, so the drug was classified as non-toxic.
  • mice 2.2 90 experimental mice were divided equally into the control group, the commercially available analgesic drug group (67mg/kg), and the large, medium and small dose groups of pharmaceutical compositions (8.4g/kg, 4.2g, 2.1g/kg respectively. Relative to 20 times, 10 times and 5 times the clinical human dosage), 18 animals in each group were given equal volumes of vehicle, commercially available analgesics and different doses of oral liquid pharmaceutical compositions;
  • each experimental group was intraperitoneally injected with 0.6% HAc physiological saline solution 0.2m/mouse, and the number of writhing reactions (abdomen indentation, hind limb extension, buttock elevation) and writhing reaction rate of the mice within 30 minutes were observed and compared. Record the results and calculate the analgesic percentage of each group according to the following formula.
  • the administration group includes the commercially available analgesic drug group and the large, medium and small dose groups of the pharmaceutical composition;
  • This group of 40 patients with cancer pain included 28 males and 12 females.
  • the minimum age was 28 years old, the maximum age was 72 years old, and the average age was 50 years old.
  • Instructions for use Take 20 ml three times a day, orally on a semi-empty stomach.
  • Level I (mild pain) the pain is bearable but does not affect daily production and sleep;
  • Level II (moderate pain), the pain is obvious and unbearable, daily life and sleep are affected, and analgesics are required;
  • Grade III (severe pain) The pain is intense, unbearable, requires analgesics, and sleep is seriously disturbed.
  • the degree of relief after treatment is generally divided into 4 levels:
  • the fastest time to achieve results is 8 hours, the slowest is 24 hours, and the average is 16 hours.
  • the age of onset, pain type and degree were comparable between the two groups (P>0.05).

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Abstract

本发明公开了一种治疗癌性疼痛的药物组合物及其制备方法，所述药物组合物由下述重量份的原料制备得到：生附子15-20份、白屈菜6-10份、三七5-8份、马钱子0.6-1份、生草乌6–10份，勾吻1-2份；所述药物组合物的制备方法，包括以下步骤：1）首先按重量份取用生附子、马钱子、生草乌，清洗后放入水中，煎煮三小时，得初加工液体；2）然后按重量份取用白屈菜、三七，勾吻，并加入到所得初加工液体中，进行两次煎煮，每次煎煮后过滤取其滤液；将两次所得滤液合并，得煎煮提取液；3）将所得煎煮提取液静置沉淀24h后，经过滤后取其纯清液体；然后再用微孔滤膜过滤器过滤，取滤液；将所得纯清液体与滤液合并后放入浓缩罐，经浓缩处理后即得。

Description

一种治疗癌性疼痛的药物组合物及其制备方法 技术领域
本发明涉及一种药物组合物，具体是指一种治疗癌性疼痛的药物组合物及其制备方法。
 背景技术
癌症发病率在我国逐年增高，癌痛作为恶性肿瘤后期患者最常见、最痛苦的症状之一，癌痛是由癌症本身和癌症治疗过程（包括手术、放疗、化疗等）有关的以及精神、心理、社会和经济等多种原限所致。它常使患者的生活质量受到严重影响，患者甚至因癌痛而自杀，世界卫生组织和国际疼痛学会根据癌痛现状制定出“三阶梯止痛方案”，虽然在一定程度上使癌痛患者的痛苦得到减轻；
但因杜冷丁和吗啡的临床使用受政策法规、社会人文等多种因素的制约，由于杜冷丁、吗啡耐药和副作用，致使癌性疼痛症状的控制仍不令人满意，癌痛口服液即没有杜冷丁和吗啡的成瘾和耐药等副作用，又有良好的镇痛效果。疼痛复发再次治疗效果依然非常理想；
因此，寻找一种能有效缓解癌性疼痛，又无明显毒副作用的药物，虽然可能只是一种理想化的追求目标，但中医认为癌性疼痛与痰浊内停，阻碍气血运行有关的理论，则为发掘中医中药治疗癌性疼痛提供了一条治疗途径，因此充分发挥祖国医学的优势，结合现代研究成果，开发中医中药作为一种协同方法治疗癌性疼痛，并寻找更为有效，更为安全，以及毒副作用更小的药物，是本发明的意义所在。
 发明内容
本发明要解决的技术问题是克服上述技术的缺陷，提供一种治疗癌性疼痛的药物组合物及其制备方法。
为解决上述技术问题，本发明提供的技术方案为一种治疗癌性疼痛的药物组合物，所述药物组合物由下述重量份的原料制备得到：生附子15-20份、白屈菜6-10份、三七5-8份、马钱子0.6-1份、生草乌6–10份，勾吻1-2份。
进一步地，所述药物组合物由下述重量份的原料制备得到：生附子15份、白屈菜6份、三七5份、马钱子0.6份、生草乌6份，钩吻1份。
进一步地，所述药物组合物由下述重量份的原料制备得到：附子18份、白屈菜8份、三七6份、马钱子0.8份、生草乌8份，钩吻1份。
进一步地，所述药物组合物由下述重量份的原料制备得到：生附子20份、白屈菜10份、三七8份、马钱子1份、生草乌10份，钩吻2份。
本发明还提供了一种治疗癌性疼痛的药物组合物的制备方法，其特征在于，包括以下步骤：
步骤1）首先按重量份取用生附子、马钱子、生草乌，清洗后放入水中，煎煮三小时，得初加工液体； 
步骤2）然后按重量份取用白屈菜、三七，勾吻并加入到步骤1所得初加工液体中，进行两次煎煮，煎煮一小时；第一次煎煮时，加水量为原料总重量的8-10倍，煎煮180min，过滤后取其滤液；第二次煎煮时，加水量为原料总重量的3-4倍，煎煮60min，过滤后取其滤液；将两次所得滤液合并，得煎煮提取液；
步骤3）将步骤2所得煎煮提取液的总量，加20%的75%食用乙醇静置沉淀24h后，经蒸溜回收乙醇，过滤后取其纯清液体；然后再用微孔滤膜过滤器过滤，取滤液；将所得纯清液体与滤液合并后放入浓缩罐，经浓缩处理后即得。
本发明所用原料来源如下：
生附子：辛、甘，大热，有毒；归心、肾，脾经；回阳救逆，补火助阳，逐风寒湿 邪。治亡阳虚脱，肢冷脉微，阳萎，宫冷，心腹冷 痛，虚寒吐泻，阴寒水肿，阳虚外感，寒湿痹痛。此外生附子含乌头碱、次乌头碱、中乌头碱及消旋去甲乌药碱，具有镇痛、镇静的功效。
白屈菜：苦、辛，微温，有毒；归肺、脾、胃经；镇痛，止咳祛痰，利尿解毒；用于镇痛、止咳、利尿、解毒、主胃痛、腹痛、肠炎、痢疾、慢性支气管炎、百日咳、咳嗽、黄疸、水肿、腹水、疥癣疮肿、蛇虫咬伤。此外白屈菜含多种生物碱，其中有白屈菜碱(Chelidonine)、a"原阿片碱，另外根和花还含有其它生物碱，具有解痉、止痛功效。
三七：甘、微苦，温，有小毒；归肝、胃、大肠经；止血，散瘀，消肿，定痛；主治止血，散瘀，止痛，活血，消肿，疗治胃癌，肺癌,，骨肉瘤，直肠癌，乙状结肠癌所致之疼痛岀血等。
马钱子：苦、寒、有小毒；入肝、脾经；散血热，消肿，止痛；治食管癌、胃癌、肠，癌、肺癌、皮肤癌、白血病等；外用治皮肤癌、瘪病痰核、喉痹、风湿痹痛、跌打损伤。
生草乌：辛、苦，热，有毒(生草乌有大毒)；归心、肝、脾、肾经；祛风除湿，温经止痛。治风寒湿痹。此外生草乌的块根含乌头碱、次乌头碱、新乌头戚，具有镇痛的功效。
钩吻 ： 别名 胡蔓草，断肠草，大茶药。辛、苦，温；有大毒。
功能主治 祛风散瘀，消肿止痛，攻毒杀虫。，风湿痹痛，神经痛，瘰疠，跌打损伤，骨折，痔疮。
化学成分： 根及全草含有吲哚类生物碱。目前已提取出的成分有；钩吻素甲(Gelsmine)、N-甲氧基钩吻素甲(N-methoxy-gelscmine)、钩吻素丙(Sempervirine)、钩吻素丁(Koumicine)、钩吻素戊(Koumidine)、钩吻素子(Koumine)、钩吻素寅(Kouminicine)、钩吻素卯(Kouminidine)、钩吻素辰(Kounidine)、钩吻素己(Gelsenicine)、钩吻素。
药理研究： 1.对呼吸系统的作用 钩吻素乙可抑制呼吸，但并非中枢性，去大脑或切断迷走神经均不影响其对呼吸的抑制。麻黄碱、印防已素对此无显著拮抗作用。
2.对末梢神经的作用 钩吻素乙对连神经之离体膈肌，能抑制并停其节律收缩，与在位膈肌之作用相同。呼吸停止后直接刺激膈神经仍能引起膈肌收缩。其对末稍的神经肌肉装置，并无直接麻痹作用。
3.对运动神经原的作用 动物中毒后，皆表现眼睑下垂，垂头，脚软，全身肌肉虚弱，故推测其作用在脊髓。可使运动神经原麻痹。
4.镇痛作用 钩吻素甲对小鼠有镇痛作用，其有效剂量与中毒剂量相近。也有报告，与阿斯匹林合用则镇痛作用增强。
按语： 钩吻有祛风散瘀，消肿止痛，攻毒杀虫之效。是治疗跌打损伤的外用药。对骨折及风湿痹痛、神经痛亦有止痛作用。钩吻之毒甚大，应严禁内服，外用亦需慎之又慎。
【钩吻的用量】：是发明人自己经过多次服用后获得的。
本发明与现有技术相比的优点在于：本发明所提供的治疗癌性疼痛的药物组合物，其全方结构合理，配伍精当，无明显毒副作用，具有防止癌细胞扩散转移和血栓形成，可抑制癌细胞释放5-羟色氨等致炎致痛等化学有害因子对正常细胞与神经的损害；同时还具有活血化瘀作用，从而达到不通则痛，通则不痛的治疗目的。
 具体实施方式
下面结合实施例对本发明一种治疗癌性疼痛的药物组合物及其制备方法做进一步的详细说明。
实施例1
一种治疗癌性疼痛的药物组合物，所述药物组合物由下述重量份的原料制备得到：生附子15份、白屈菜6份、三七5份、马钱子0.6份、生草乌6份，钩吻1份。
所述药物组合物的制备方法，其特征在于，包括以下步骤：
步骤1）首先按重量份取用生附子、马钱子、生草乌，清洗后放入水中，煎煮一小时，得初加工液体； 
步骤2）然后按重量份取用芦笋、白屈菜、三七，并加入到步骤1所得初加工液体中，进行两次煎煮；第一次煎煮时，加水量为原料总重量的3-5倍，煎煮60min，过滤后取其滤液；第二次煎煮时，加水量为原料总重量的3-4倍，煎煮50min，过滤后取其滤液；将两次所得滤液合并，得煎煮提取液；
步骤3）将步骤2所得煎煮提取液静置沉淀24h后，经过滤后取其纯清液体；然后再用微孔滤膜过滤器过滤，取滤液；将所得纯清液体与滤液合并后放入浓缩罐，经浓缩处理后即得。
实施例2
一种治疗癌性疼痛的药物组合物，所述药物组合物由下述重量份的原料制备得到：附子18份、白屈菜8份、三七6份、马钱子0.8份、生草乌8份，钩吻1份；
所述药物组合物的制备方法，其特征在于，包括以下步骤：
步骤1）首先按重量份取用生附子、马钱子、生草乌，清洗后放入水中，煎煮一小时，得初加工液体； 
步骤2）然后按重量份取用芦笋、白屈菜、三七，并加入到步骤1所得初加工液体中，进行两次煎煮；第一次煎煮时，加水量为原料总重量的3-5倍，煎煮60min，过滤后取其滤液；第二次煎煮时，加水量为原料总重量的3-4倍，煎煮50min，过滤后取其滤液；将两次所得滤液合并，得煎煮提取液；
步骤3）将步骤2所得煎煮提取液静置沉淀24h后，经过滤后取其纯清液体；然后再用微孔滤膜过滤器过滤，取滤液；将所得纯清液体与滤液合并后放入浓缩罐，经浓缩处理后即得。
实施例3
一种治疗癌性疼痛的药物组合物，所述药物组合物由下述重量份的原料制备得到：生附子20份、白屈菜10份、三七8份、马钱子1份、生草乌10份，钩吻2份。
所述药物组合物的制备方法，其特征在于，包括以下步骤：
步骤1）首先按重量份取用生附子、马钱子、生草乌，清洗后放入水中，煎煮一小时，得初加工液体； 
步骤2）然后按重量份取用钩吻、白屈菜、三七，并加入到步骤1所得初加工液体中，进行两次煎煮；第一次煎煮时，加水量为原料总重量的3-5倍，煎煮60min，过滤后取其滤液；第二次煎煮时，加水量为原料总重量的3-4倍，煎煮50min，过滤后取其滤液；将两次所得滤液合并，得煎煮提取液；
步骤3）将步骤2所得煎煮提取液静置沉淀24h后，经过滤后取其纯清液体；然后再用微孔滤膜过滤器过滤，取滤液；将所得纯清液体与滤液合并后放入浓缩罐，经浓缩处理后即得。
实施例4  药物毒性实验
1、实验材料
1.1  实验动物：ICR小鼠44只，雌雄各半，购于北京海淀兴旺实验动物养殖场，许可证编号SCXK-(军) 2007-004。
1.2  药品试剂
1）本发明所制备药物组合物，本品为液体。
将44只按体重与性别随机分成实验组和对照组，每组22只，雌雄各半，实验前禁食不禁水12h。
实验组灌胃给予本发明所制备药物组合物液体，按48g/kg标准，分两次给药，其中间隔4h；
对照组给等量的常水，给药后连续观察7日，每日观察比较两组小鼠的外观、行为活动、精神状态、呼吸变化，隔日称一次体重。
结果显示：给药后7日内，动物未见死亡，一般状况良好，毛色正常，无立毛，饮食正常、小便正常，大便为干燥成行，无腹泻溏泄，呼吸正常，活动自如，无异常行为表现；
小鼠体重增长正常，未见其它明显异常反应，且其处死解剖，发现其主要脏器未见明显异常，故该药物属于无毒级。
实施例5   动物止痛实验
1、实验材料
1.1  实验动物：ICR小鼠90只，雌雄兼用，购于北京海淀兴旺实验动物养殖场，许可证编号SCXK-(军) 2007-004。
1.2  药品试剂
1）本发明所制备药物组合物；
2）阳性对照药：市售止痛药物；
3）冰乙酸（HAc），分析纯。
2、实验方法
2.1 试剂配制
将0.6%冰乙酸用生理盐水溶液配制，具体方法为：准确吸取100%的冰醋酸0.3ml，溶于pH 7-7.2的生理盐水溶液50ml中。
2.2  实验小鼠90只，平均分为对照组，市售止痛药物组（67mg/kg），药物组合物大、中、小剂量组(分别为8.4g/kg、4.2g、2.1g/kg，相对于临床人用量的20倍、10倍和5倍)，每组18只，分别给予等体积溶媒、市售止痛药物和不同剂量的药物组合物口服液；
各实验组给药后1h，随即腹腔注射0.6%HAc生理盐水溶液0.2m/只，观察30分钟内小鼠扭体反应次数(腹部内凹，伸展后肢，臀部抬高)和扭体反应率并记录结果，按下式计算各组镇痛百分率，其中给药组包括市售止痛药物组、药物组合物大、中、小剂量组；
统计学处理采用SPSS软件进行组间t检验。结果表明：市售止痛药物及药物组合物大、中、小三个剂量均能显著减少冰醋酸引起的小鼠扭体反应的次数(p<0.05, p<0.01)，且随着镇痛效果随药物的剂量增加而增加。
实施例6  临床实验
1.1  实验内容
本组40例癌性疼痛患者男28例，女12例，最小年龄28岁，最大年龄72岁，平均50岁。其中肺癌10例、肝癌16例、胃癌8例、胰腺癌6例，中度疼痛22例，重度疼痛18例，全部病例均经影像学、胃镜、CT及病理组织检查，诊断明确，有中重度疼痛，无明显肝肾功能障碍者，患者神志清楚，能够配合观察治疗。
用药方法：每日三次，每次20毫升，半空腹口服。
1.2  疼痛分级标准
根据文献资料，将疼痛分为4级：
0级：无疼痛；
I级：（轻度疼痛）疼痛可忍受，但不影响日常生产及睡眠；
II级：（中度疼痛），疼痛明显，不能忍受，日常生活及睡眠受至影响，要求服用镇痛药；
III级：（重度疼痛）疼痛激烈，不能忍受，需要镇痛药，睡眠严重受到干扰。
1.3  疗效标准
治疗后缓解程度一般分为4级：
1）完全缓解（CR）无疼痛；
2）部分缓解：（PR）疼痛较给药前明显减轻，睡眠基本不受干扰，能正常生活；
3）轻微疗效：（MR）疼痛较给药前减轻，但有明显疼痛，睡眠受到干扰；
4）无效：（NR）与给药前比较无减轻疼痛。
1.4  实验结果
患者服用癌痛定口服液后，有22例在8-12小时，疼痛开始减轻，直到疼痛消失，CR率为55例；部分缓解例，PR率为22.5%；轻微疗效5例，MR率为12.5%，无效4例；NR率为10%，总有效率为90%；
取得效果时间最快8小时，最慢24小时，平均16小时。两组发病年龄、疼痛类型及程度均有可比性（P>0.05）。
以上对本发明及其实施方式进行了描述，这种描述没有限制性。总而言之如果本领域的普通技术人员受其启示，在不脱离本发明创造宗旨的情况下，不经创造性的设计出与该技术方案相似的结构方式及实施例，均应属于本发明的保护范围。

Claims (5)

  1. 一种治疗癌性疼痛的药物组合物，其特征在于，所述药物组合物由下述重量份的原料制备得到：生附子15-20份、白屈菜6-10份、三七5-8份、马钱子0.6-1份、生草乌6–10份，勾吻1-2份。
  2. 根据权利要求1所述的一种治疗性疼痛的药物组合物，其特征在于，所述药物组合物由下述重量份的原料制备得到：生附子15份、白屈菜6份、三七5份、马钱子0.6份、生草乌6份，钩吻1份。
  3. 根据权利要求1所述的一种治疗癌性疼痛的药物组合物，其特征在于，所述药物组合物由下述重量份的原料制备得到：附子18份、白屈菜8份、三七6份、马钱子0.8份、生草乌8份，钩吻1份。
  4. 根据权利要求1所述的一种治疗癌性疼痛的药物组合物，其特征在于，所述药物组合物由下述重量份的原料制备得到：附子20份、白屈菜10份、三七8份、马钱子1份、生草乌10份，钩吻2份。
  5. 根据权利要求1-4任意一项所述的药物组合物的制备方法，其特征在于，包括以下步骤：
    步骤1）首先按重量份取用生附子、马钱子、生草乌，清洗后放入水中，煎煮三小时，得初加工液体； 
    步骤2）然后按重量份取用白屈菜、三七，勾吻并加入到步骤1所得初加工液体中，进行两次煎煮，煎煮一小时；第一次煎煮时，加水量为原料总重量的8-10倍，煎煮180min，过滤后取其滤液；第二次煎煮时，加水量为原料总重量的3-4倍，煎煮60min，过滤后取其滤液；将两次所得滤液合并，得煎煮提取液；
    步骤3）将步骤2所得煎煮提取液的总量，加20%的75%食用乙醇静置沉淀24h后，经蒸溜回收乙醇，过滤后取其纯清液体；然后再用微孔滤膜过滤器过滤，取滤液；将所得纯清液体与滤液合并后放入浓缩罐，经浓缩处理后即得。
PCT/CN2023/096579 2022-07-25 2023-05-26 一种治疗癌性疼痛的药物组合物及其制备方法 WO2024021826A1 (zh)

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CN115054664A (zh) * 2022-07-25 2022-09-16 北京康恩泰生物医药有限公司 一种治疗癌性疼痛的药物组合物及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1312099A (zh) * 2001-02-21 2001-09-12 陈祖沛 一种治疗肿瘤的药物
CN102008563A (zh) * 2010-12-09 2011-04-13 湖南景民制药有限公司 一种抗癌中药及其配制方法
CN102432618A (zh) * 2011-12-08 2012-05-02 南京海昌中药集团有限公司 一种从马钱子总碱中分离纯化马钱子碱的制备工艺
CN103239635A (zh) * 2012-02-13 2013-08-14 周田明 抗癌痛口服液
CN115054664A (zh) * 2022-07-25 2022-09-16 北京康恩泰生物医药有限公司 一种治疗癌性疼痛的药物组合物及其制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1141137C (zh) * 2002-03-13 2004-03-10 张平 一种用于癌性疼痛镇痛的中药注射液
CN107837380A (zh) * 2017-12-12 2018-03-27 汤阴县瑞星生物有限公司 一种治疗癌性疼痛的中药组合物及其制备方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1312099A (zh) * 2001-02-21 2001-09-12 陈祖沛 一种治疗肿瘤的药物
CN102008563A (zh) * 2010-12-09 2011-04-13 湖南景民制药有限公司 一种抗癌中药及其配制方法
CN102432618A (zh) * 2011-12-08 2012-05-02 南京海昌中药集团有限公司 一种从马钱子总碱中分离纯化马钱子碱的制备工艺
CN103239635A (zh) * 2012-02-13 2013-08-14 周田明 抗癌痛口服液
CN115054664A (zh) * 2022-07-25 2022-09-16 北京康恩泰生物医药有限公司 一种治疗癌性疼痛的药物组合物及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QIXIN YE, LI ZHUANGWEI, ZHONG MEIXIANG: "Explore on Treatment of the Malignant Tumor with Tcm Cream for Exterior Use", JIANGXI JOURNAL OF TRADITIONAL CHINESE MEDICINE, vol. 36, no. 6, 26 June 2005 (2005-06-26), pages 12 - 13, XP093134341 *
YARU WANG, ZHANG LAN; TIAN PENGNA; SONG LEI; NAN YAN: "Observation on Integrated Traditional Chinese and Western Medicine in Treating 25 Cases of Medium and Severe Cancer Induced Pain", WORLD CHINESE MEDICINE, vol. 9, no. 7, 17 July 2014 (2014-07-17), pages 878 - 879, 882, XP093134344, ISSN: 1673-7202, DOI: 10.3969/j.issn.1673-7202.2014.07.013 *

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