WO2020143746A1 - 绿原酸在制备预防或治疗疼痛的药物或药物组合物中的用途 - Google Patents

绿原酸在制备预防或治疗疼痛的药物或药物组合物中的用途 Download PDF

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WO2020143746A1
WO2020143746A1 PCT/CN2020/071345 CN2020071345W WO2020143746A1 WO 2020143746 A1 WO2020143746 A1 WO 2020143746A1 CN 2020071345 W CN2020071345 W CN 2020071345W WO 2020143746 A1 WO2020143746 A1 WO 2020143746A1
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pain
preparation
pharmaceutical composition
chlorogenic acid
cancer
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French (fr)
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张洁
张亚卓
姬勋
黄望
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四川九章生物科技有限公司
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Priority to AU2020206399A priority Critical patent/AU2020206399A1/en
Priority to EP20738511.3A priority patent/EP3909576B1/en
Priority to US17/422,429 priority patent/US20220117926A1/en
Publication of WO2020143746A1 publication Critical patent/WO2020143746A1/zh

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention relates to the field of pain-related medicines, and in particular to the use of chlorogenic acid in the preparation of drugs or pharmaceutical compositions for preventing or treating pain.
  • Pain is a complex clinical common symptom and disease that reflects subjective feelings.
  • IASP International Association for Pain
  • pain was updated as: pain is a painful experience caused by actual or potential tissue damage at the sensory, emotional, cognitive, and social levels.
  • the American Pain Society proposed that pain is the fifth vital sign after heart rate, blood pressure, pulse and breathing.
  • the classification of pain is relatively complicated.
  • IASP was classified according to the specific characteristics of pain, such as the location, duration, intensity, cause of the disease, and pain caused by system disturbances. Clifford Woolf believes that the systematic classification of IASP is insufficient to guide research and treatment, and the pain is divided into nociceptive pain, neuropathic pain and inflammatory pain. If classified according to duration, pain is divided into acute pain and chronic pain, and clinically refers to chronic pain.
  • the new ICD classification method divides chronic pain into the following seven categories: 1 chronic primary pain; 2 chronic cancer pain; 3 chronic postoperative pain and post-traumatic pain; 4 neuropathic pain; 5 chronic head and maxillofacial Department of pain; 6 chronic visceral pain; 7 chronic skeletal muscle pain.
  • cancer pain is a syndrome caused by a series of different pathophysiological changes, including early inflammatory pain, neuropathic pain caused by sensory nerve and sympathetic nerve damage, visceral pain, bone damage, cell death, Bone destruction and bone pain, and at the same time lead to changes in pain emotions cause anxiety, fear, cognitive impairment, etc.
  • tumor-related pain tumors directly invade local tissues and tumor metastases Caused by bone tissue involvement.
  • Pain related to tumor treatment common after surgery, traumatic examination operation, radiotherapy and cytotoxic chemotherapy drugs.
  • Non-tumor-related pain including pain caused by non-tumor factors such as other complications and complications.
  • Cancer pain is a complex pathological process. At present, it is speculated that cancer pain is caused by cancer cells in the tumor microenvironment and secretes pain-causing media. At the same time, chemokines or mediators released by tumor cells can also recruit other cells such as nerve cells and lymph. Cells, endothelial cells and fibroblasts further secrete mediators such as tumor necrosis factor alpha (TNF- ⁇ ), prostaglandin E (PGE), endothelin (ET), interleukin 1 (IL-1), interleukin 6 (IL-6), epithelial growth factor, transforming growth factor B and platelet-derived growth factor, adenosine triphosphate (ATP), nerve growth factor (NGF), etc. These mediators sensitize or activate specific receptors on primary afferent sensory neurons To play a role in the body, leading to the generation and maintenance of cancer pain.
  • TNF- ⁇ tumor necrosis factor alpha
  • PGE prostaglandin E
  • ET endothelin
  • IL-1 interleuk
  • cancer pain assessment is a reasonable and effective prerequisite for analgesic treatment, and its assessment should follow the "conventional, quantitative, comprehensive and dynamic" assessment principle.
  • the treatment of cancer pain should also adopt the principle of comprehensive treatment.
  • effective application of analgesic treatment methods can be used to continuously and effectively eliminate pain, prevent and control adverse drug reactions, and reduce the psychological burden of pain and treatment. To maximize the patient's quality of life.
  • Chronic skeletal muscle pain refers to persistent or recurrent pain caused by bone, joint, muscle or other related soft tissue diseases, which is nociceptive pain.
  • Bone and joint pain includes and is not limited to the bone and joint pain includes and is not limited to knee joint pain, ankle joint pain, wrist joint pain, elbow joint pain, shoulder joint pain, patellar joint pain, hip joint pain, femoral joint pain, cervical spine And lumbar pain.
  • the pain included in this section has the following characteristics: contains persistent inflammation caused by infection, autoimmunity, or metabolic causes, such as rheumatoid arthritis, gouty inflammation; and structural structures that affect bones, joints, tendons, or muscles Changes, such as osteoarthrosis, soft tissue injury, strain, etc.
  • cancer pain is a complication caused by cancer itself.
  • Anti-cancer treatment for cancer patients such as surgery, radiotherapy or chemotherapy, may relieve or relieve cancer pain.
  • Drug analgesic therapy is a three-step analgesic treatment plan developed by WHO based on cancer pain. According to the patient's pain level, analgesic drugs of different intensities are targeted. For mild pain, non-steroidal anti-inflammatory drugs (NSAIDs) can be used; for moderate pain, weak opioids can be used, and NSAIDs can be combined; for severe pain, strong opioids can be used, and NSAIDs can be combined.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • NSAIDs are the basic drugs for the treatment of mild cancer pain, including ibuprofen, diclofenac, indomethacin, celecoxib and acetaminophen.
  • the common adverse reactions are peptic ulcer, gastrointestinal bleeding, platelet dysfunction, renal damage and liver damage.
  • opioids are the first choice for the treatment of moderate and severe pain.
  • the short-acting drugs currently used clinically for moderate to severe cancer pain are morphine immediate-release tablets, and the long-acting drugs are morphine sustained-release tablets, oxycodone sustained-release tablets, and fentanyl transdermal patches.
  • Adverse reactions include constipation, nausea, vomiting, drowsiness, itching, urinary retention, delirium, cognitive impairment, and respiratory depression.
  • Cancer pain is mostly chronic pain. Although WHO three-step analgesic therapy is used clinically to treat cancer pain, the pain control effect is not very satisfactory. 36-50% of cancer patients still suffer from different degrees of pain. Moreover, three-step analgesic drugs (opioids and NSAIDs) also have serious adverse reactions. Due to the mental dependence of opioid analgesics, that is, addiction, countries around the world have also issued corresponding drug management programs to strengthen the management and use of opioids.
  • the drugs used to treat bone and joint pain are similar to the drugs used to treat cancer pain. They are acetaminophen, COX-2 inhibitors, NSAIDs and opioids.
  • the treatment strategy is still WHO's three-step analgesic therapy. Obviously, while receiving treatment, patients also suffer from the toxic side effects of these drugs. Therefore, it is urgent to develop a safe and effective medicine for treating pain with little toxic and side effects.
  • the present invention first provides the use of chlorogenic acid in the preparation of a medicament or pharmaceutical composition for preventing or treating pain.
  • the pain is cancer pain.
  • the pain is skeletal muscle pain.
  • the pain is inflammatory pain.
  • the pain is neuropathic pain.
  • the pain is immune pain.
  • cancer pain is neuropathic pain.
  • cancer pain is nociceptive pain.
  • cancer pain is chronic pain.
  • the skeletal muscle pain is bone and joint pain
  • the bone joint pain is knee joint pain, ankle joint pain, wrist joint pain, elbow joint pain, shoulder joint pain, patella joint pain, hip joint pain, femoral joint pain, cervical spine and/or lumbar spine pain.
  • the prevention or treatment of pain is to reduce mechanical hyperalgesia or radiant heat hyperalgesia caused by cancer.
  • the drug or pharmaceutical composition is a drug or pharmaceutical composition that inhibits the expression of tumor necrosis factor alpha (TNF- ⁇ ), interleukin 1 ⁇ (IL-1 ⁇ ) and interleukin 6 (IL-6).
  • TNF- ⁇ tumor necrosis factor alpha
  • IL-1 ⁇ interleukin 1 ⁇
  • IL-6 interleukin 6
  • the medicine or pharmaceutical composition is a medicine or pharmaceutical composition that regulates/increases the expression of serotonin (5-HT) and dopamine (DA) caused by pain.
  • the invention also provides a medicine for preventing or treating pain, which is a pharmaceutical preparation prepared by using chlorogenic acid as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
  • the prevention or treatment of pain is to reduce mechanical hyperalgesia or radiant heat hyperalgesia caused by cancer.
  • each preparation unit in the preparation contains 1-3000 mg of chlorogenic acid; each preparation unit in the preparation contains 1-3000 mg of chlorogenic acid; the preparation unit is: each capsule, tablet, bag, pill, Stick or bottle.
  • the human dosage of chlorogenic acid in the pharmaceutical preparation is 1-10 mg/kg.
  • the pharmaceutical preparation is an oral preparation or an injection preparation.
  • the invention also provides a pharmaceutical composition for preventing or treating pain, which is characterized in that it is a pharmaceutical composition including the aforementioned pharmaceutical preparation.
  • chlorogenic acid can effectively prevent and treat pain, especially cancer pain and bone and joint pain. Therefore, the use of chlorogenic acid provided by the present invention in the preparation of a medicament for preventing or treating pain has good industrial value.
  • the medicine of the present invention can effectively relieve cancer pain and bone and joint pain without toxic side effects; it can replace analgesic drugs such as opioids and nonsteroidal anti-inflammatory drugs to avoid long-term use of opioids
  • analgesic drugs such as opioids and nonsteroidal anti-inflammatory drugs to avoid long-term use of opioids
  • the toxic and side effects produced by the drugs improve the quality of life of patients, and have good clinical application prospects.
  • FIG. 1 is a graph showing the threshold of mechanical pain hypersensitivity of rats in each experimental group in experimental example 3.
  • FIG. 1 is a graph showing the threshold of mechanical pain hypersensitivity of rats in each experimental group in experimental example 3.
  • FIG. 2 is a graph of the threshold of radiation heat pain of rats in each experimental group in Experimental Example 3.
  • FIG. 2 is a graph of the threshold of radiation heat pain of rats in each experimental group in Experimental Example 3.
  • FIG. 3 is a bar graph of TNF- ⁇ expression in the serum of rats in each experimental group in Experimental Example 3.
  • FIG. 3 is a bar graph of TNF- ⁇ expression in the serum of rats in each experimental group in Experimental Example 3.
  • Fig. 4 is a bar graph of the expression of IL-1 ⁇ in the serum of rats in each experimental group in Experimental Example 3.
  • Fig. 5 is a bar graph of IL-6 expression in the serum of rats in each experimental group in Experimental Example 3.
  • Fig. 6 is a bar graph of NE content in the brain tissue of rats in each experimental group in Experimental Example 3.
  • Fig. 7 is a bar graph of DA content in the brain tissue of rats in each experimental group in Experimental Example 3.
  • Fig. 8 is a bar graph of 5-HT content in the brain tissue of rats in each experimental group in Experimental Example 3.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products, obtained by purchasing commercially available products.
  • Example 1 The prescription of the oral pharmaceutical preparation of the present invention
  • Preparation method Aseptically weigh chlorogenic acid and aseptically divide into powders.
  • Preparation method Weigh chlorogenic acid, filler and binder according to the prescription, granulate, whole granulate and divide into granules.
  • Preparation method Weigh chlorogenic acid, filler, binder according to prescription, granulate, adjust granule, add lubricant, and press to obtain tablet.
  • the above filler is one or more of mannitol, lactose, starch, microcrystalline cellulose, dextrin; binder is sodium carboxymethyl cellulose, PVP; lubricant is magnesium stearate, talc, Micronized silica gel.
  • Example 2 The injection formulation of the present invention
  • Preparation method (1) Aseptically weigh chlorogenic acid according to prescription and aseptically divide into powder injections.
  • Preparation method (2) Weigh chlorogenic acid according to the prescription, dissolve it in water for injection, filter and sterilize, freeze-dry, and fill to obtain a freeze-dried powder injection.
  • Preparation method Weigh chlorogenic acid, scaffold, and antioxidant according to the prescription, dissolve it in water for injection, filter sterilize, fill, freeze-dry, and obtain freeze-dried powder injection.
  • the above scaffolds are mannitol, lactose, glucose; antioxidants are sodium bisulfite, vitamins, glutathione, folic acid.
  • Chlorogenic acid batch number: 171101, content 99.83%, prepared by Sichuan Jiuzhang Biological Technology Co., Ltd.
  • the model group with mechanical pain hypersensitivity and radiant heat pain response was selected based on pain behavior as the criterion.
  • Mechanical hyperalgesia reaction continuous pain measurement starting from the 10th day after surgery, contacting the fine fiber of the contact stimulator to the middle of the plantar side of the affected side of the rat, and the maximum force can be increased to 80g within 5 seconds to observe the paw contraction reaction of the rat And record the paw withdrawal threshold. Each animal was tested 5 times, and the interval between the two tests was 5 minutes. The paw withdrawal threshold in the model group was significantly different from that in the sham operation group, indicating a mechanical hyperalgesia.
  • Radiation heat pain reaction Place the rat on the glass plate and irradiate the affected plantar with a heat radiation instrument. Each rat is tested three times on the plantar foot, each time 5 minutes apart, recording the response from irradiation to paw withdrawal Time, paw withdrawal time is its pain threshold. The pain threshold of the model group was significantly different from that of the sham-operated group, indicating a radiation-heat pain response.
  • each group has 8 rats, which are the high-dose chlorogenic acid group (80mg/kg), the middle-dose group (40mg/kg), the low-dose group (20mg/kg), the model Negative group (NS normal saline) and sham operation group 8 (NS normal saline).
  • the administration volume was 0.2mL/10g, once a day, continuous administration for 15 days; the model negative group and sham operation group were given the same volume of normal saline.
  • hypothalamus was quickly separated, added with perchloric acid ice bath homogenate, centrifuged, and the supernatant was taken and determined by HPLC-EC method (Hou Yanning, Wang Na et al. Progesterone on the morphine position of rats Preference effect and the influence of central monoamine transmitter levels. China Pharmacological Journal, 2006, 22(8), 980-983) NE, DA, 5-HT content.
  • the model group selected after the operation had a significant difference in mechanical paw withdrawal threshold (p ⁇ 0.05), indicating successful tibial implant modeling.
  • Chlorogenic acid administration in the 40mg/kg and 20mg/kg dose groups was significantly different from the model group on the 7th day after administration (p ⁇ 0.05), and the 40mg/kg dose group was the most Significantly, it is basically equivalent to the sham operation group. It shows that the dose of chlorogenic acid 20-40mg/kg can significantly improve and treat bone cancer-induced radiation hyperalgesia hypersensitivity, and shows a dose-effect relationship. In the 80 mg/kg dose group, the mechanical paw withdrawal threshold was different from the model group, but it was not statistically significant (p>0.05). See Table 2 and Figure 2 for details.
  • the content of NE, DA, 5-HT in the brain tissue of 40mg/kg and 20mg/kg rats in the chlorogenic acid dose group was basically the same as that in the sham operation group, with no significant difference (p>0.05), compared with the model negative group Significant difference (p ⁇ 0.05); the 80 mg/kg dose group had no significant difference with the model negative group (p>0.05), and had a significant difference with the sham operation group (p ⁇ 0.05). See Table 4 and Figure 6, Figure 7 and Figure 8 for details.
  • the chlorogenic acid 20-40mg/kg dose group had a significant difference compared with the model negative group, of which the 40mg/kg dose group and the sham operation group Equivalently, it shows that chlorogenic acid can effectively improve and relieve cancer pain, and shows a dose-effect relationship within a certain dose range.
  • the cytokines TNF- ⁇ , IL-1 ⁇ , IL-6 play an important regulatory role, and are important regulatory mediators in the neuro-endocrine-immune function system. External noxious stimuli will increase their expression. The content is directly related to the degree of cancer pain.
  • NE, DA, and 5-HT in brain tissue are important participants in cell biology pathways related to pain perception.
  • the content of NE, DA, 5-HT in the brain tissue of rats in the chlorogenic acid 20-40mg/kg dose group was basically the same as that in the sham operation group, and there was no significant difference.
  • chlorogen Acid can induce the expression of DA and 5-HT caused by pain and reduce the expression of NE; indicating that chlorogenic acid can improve and relieve pain, which is consistent with the experimental results of pain behavior.
  • chlorogenic acid can effectively improve and relieve pain, and can be used to prepare the medicine or pharmaceutical composition for preventing or treating pain of the present invention.
  • the medicine of the invention can effectively reduce the mechanical hyperalgesia and radiant heat hyperalgesia caused by cancer, and has no toxic and side effects; it can replace analgesic drugs such as opioids and non-steroidal anti-inflammatory drugs to avoid long-term use of opioids
  • analgesic drugs such as opioids and non-steroidal anti-inflammatory drugs to avoid long-term use of opioids
  • the toxic and addictive effects of drugs can improve the quality of life of patients and have good clinical application prospects.

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Abstract

一种绿原酸在制备预防或治疗疼痛的药物中的用途，所述疼痛包括癌痛、骨骼肌疼痛等。一种预防或治疗疼痛的药物，所述药物是以绿原酸为活性成分、加上药学上可接受的辅料制备而成的药物制剂。绿原酸能够有效缓解癌痛和骨关节疼痛，可以替代镇痛药物如阿片类药物和非甾体类抗炎药物治疗。

Description

绿原酸在制备预防或治疗疼痛的药物或药物组合物中的用途 技术领域
本发明涉及疼痛相关药物领域，具体涉及绿原酸在制备预防或治疗疼痛的药物或药物组合物中的用途。
背景技术
疼痛，是一种复杂的，体现主观情感感受的临床常见症状和疾病。1979年国际疼痛研究学会(The International Association for the Study of Pain，IASP)将疼痛定义为一种与组织损伤或潜在组织损伤相关的不愉快的主观感觉和情绪体验。2016年将疼痛定义更新为：疼痛是具有感觉、情绪、认知和社会层面的实际或潜在组织损伤所引起的痛苦体验。1985年美国疼痛学会提出疼痛是继心率、血压、脉搏和呼吸之后的第5大生命体征。
疼痛的分类比较复杂，1994年IASP根据疼痛的具体特征如疼痛发生部位、持续时间、持续强度、发病原因及系统紊乱所引起的疼痛等方面进行分类。Clifford Woolf认为IASP的系统性分类不足以进行指导研究和治疗，将疼痛又分为伤害感受性疼痛、神经病理性疼痛和炎性疼痛。如果按照持续时间分类，疼痛分为急性疼痛和慢性疼痛，而临床上一般指慢性疼痛。新的ICD分类方法将慢性疼痛划分为以下7大类：①慢性原发性疼痛；②慢性癌性疼痛；③慢性术后痛和创伤后疼痛；④神经病理性疼痛；⑤慢性头部和颌面部疼痛；⑥慢性内脏疼痛；⑦慢性骨骼肌疼痛。
其中，癌性疼痛是一系列不同病理生理改变所引起的综合征，包括早期炎性疼痛，随着病程进展出现感觉神经与交感神经损伤引起的神经病理性疼痛、内脏痛、骨损伤、细胞死亡、骨破坏和骨痛，并同时导致疼痛情绪改变引起焦虑、恐惧、认知障碍等。关于癌性疼痛的治疗，美国NCCN《成人癌痛临床指南》(2018版)强调疼痛管理应到达5A目标，即优化疼痛(Analgesia，optimize analgesia)、优化日常生活活动(Activities，optimize activities of daily living)、减小不良反应(Adverse effects，minimize adverse effects)、避免异常药物摄入(Aberrant drug taking，avoid aberrant drug taking)和疼痛与情绪的关系(Affect，relationship between pain and mood)。
2011年我国卫生部制定并发布了《癌症疼痛诊疗规范》(2011版)，指出癌性疼痛原因多样，大致可分为三类：①肿瘤相关性疼痛：因肿瘤直接侵犯压迫局部组织，肿瘤转移累及骨组织等所致。②肿瘤治疗相关性疼痛：常见于手术、创伤性检查操作、放射治疗以及细胞毒化疗药物治疗后产生。③非肿瘤相关性疼痛：包括其他合并症、并发症等非肿瘤因素所致的疼痛。
癌性疼痛是一个复杂的病理过程，目前推测癌症疼痛产生是由于肿瘤微环境中癌细胞产生和分泌致痛介质，同时肿瘤细胞释放的趋化因子或介质还能募集其他细胞如神经细 胞、淋巴细胞、内皮细胞和成纤维细胞进一步分泌介质，如肿瘤坏死因子α(TNF-α)、前列腺素E(PGE)、内皮素(ET)、白细胞介素1(IL-1)、白细胞介素6(IL-6)、上皮生长因子、转化生长因子B及血小板源性生长因子、三磷酸腺苷(ATP)、神经生长因子(NGF)等，这些介质致敏或激活初级传入感觉神经元上的特异受体而发挥作用，导致癌性疼痛的产生和维持。
因此，癌性疼痛评估是合理有效的止痛治疗前提，其评估应遵守“常规、量化、全面和动态”的评估原则。而癌性疼痛治疗也应该采用综合治疗的原则，根据患者的病情和身体状况，有效应用止痛治疗手段，持续有效地消除疼痛，预防和控制药物的不良反应，降低疼痛及治疗带来的心理负担，最大限度地提高患者生活质量。
而慢性骨骼肌疼痛是指源于骨骼、关节、肌肉或其他相关软组织疾病所产生的持续性或复发性疼痛是属于伤害性疼痛。骨关节疼痛包含且不限于所述骨关节疼痛包含且不限于膝关节疼痛、踝关节疼痛、腕关节疼痛、肘关节疼痛、肩关节疼痛、髌骨关节疼痛、髋骨关节疼痛、股骨关节疼痛、颈椎和腰椎疼痛等。其病因很多，如压迫性神经病理痛或者躯体牵涉性疼痛。这一部分所包含的疼痛具有以下特征：含有由传染、自身免疫或代谢病因所引起的持续性炎症，如类风湿性关节炎，痛风性炎症；还有影响骨骼、关节、肌腱或肌肉的结构性改变，如骨关节病，软组织损伤，劳损等。
目前，癌性疼痛的治疗方法包括病因治疗、药物止痛疗法和非药物疗法(癌症疼痛诊疗规范2011版)。癌性疼痛是癌症本身引起的一种并发症，针对癌症患者给予抗癌治疗，如手术、放疗或化疗等，可能会解除或者缓解癌性疼痛。药物止痛疗法是WHO根据癌痛制订的三阶梯止痛治疗方案。根据患者疼痛程度，有针对性地选用不同强度的镇痛药物。对于轻度疼痛，可选用非甾体类抗炎药物(NSAIDs)；中度疼痛，可选用弱阿片类药物，并可合用NSAIDs；重度疼痛，可选用强阿片类药物，并可合用NSAIDs。NSAIDs是治疗轻度癌性疼痛的基本药物，包括布洛芬、双氯芬酸、吲哚美辛、塞来昔布和对乙酰氨基酚。其常见的不良反应为消化性溃疡、消化道出血、血小板功能障碍、肾功能损伤和肝功能损伤等。而阿片类药物是治疗中度和重度疼痛的首选药物。目前临床上用于中重度癌痛的短效药物是吗啡即释片，长效药为吗啡缓释片、羟考酮缓释片和芬太尼透皮贴剂等。其不良反应主要包括便秘、恶心、呕吐、嗜睡、瘙痒、尿潴留、谵妄、认知障碍和呼吸抑制等。
癌痛多为慢性疼痛，虽然临床上采用WHO三阶梯止痛疗法治疗癌性疼痛，但疼痛控制效果并不是很理想，仍有36-50％的癌症患者忍受不同程度的疼痛。况且，三阶梯止痛药物(阿片类药物和NSAIDs)也存在着严重的不良反应。由于阿片类止痛药物的精神依赖性即成瘾性，世界各国也出台了相应的药物管理方案，加强对阿片类药物的管理与使用。
治疗骨关节疼痛的药物和治疗癌性疼痛的药物相似，均为对乙酰氨基酚、COX-2抑制剂及NSAIDs和阿片类药物。治疗策略依然为WHO的三阶梯止痛疗法。显而易见，患者在得到治疗的同时，也会承受这些药物带来的毒副作用。因此，开发一种毒副作用小， 安全有效的治疗疼痛的药物是迫在眉睫。
发明内容
为了解决上述问题，本发明首先提供了绿原酸在制备用于预防或治疗疼痛的药物或药物组合物中的用途。
如前述的用途，所述疼痛为癌性疼痛。
如前述的用途，所述疼痛为骨骼肌疼痛。
如前述的用途，所述疼痛为炎性疼痛。
如前述的用途，所述疼痛为神经性疼痛。
如前述的用途，所述疼痛为免疫性疼痛。
进一步地，所述癌性疼痛为神经病理性疼痛。
进一步地，所述癌性疼痛为伤害感受性疼痛。
进一步地，所述癌性疼痛为慢性疼痛。
进一步地，所述骨骼肌疼痛为骨关节疼痛
更进一步地，所述骨关节疼痛为膝关节疼痛、踝关节疼痛、腕关节疼痛、肘关节疼痛、肩关节疼痛、髌骨关节疼痛、髋骨关节疼痛、股骨关节疼痛、颈椎和/或腰椎疼痛。
如前述的用途，优选地，所述预防或治疗疼痛，为降低癌症导致的机械性痛觉超敏或辐射热痛觉超敏。
如前述的用途，所述药物或药物组合物是抑制肿瘤坏死因子α(TNF-α)、白介素1β(IL-1β)和白介素6(IL-6)的表达的药物或药物组合物。
如前述的用途，所述药物或药物组合物是调节/提高疼痛引起的5-羟色胺(5-HT)和多巴胺(DA)的表达的药物或药物组合物。
本发明还提供了一种预防或治疗疼痛的药物，所述药物是以绿原酸为活性成分、加上药学上可接受的辅料制备而成的药物制剂。
优选地，所述预防或治疗疼痛，为降低癌症导致的机械性痛觉超敏或辐射热痛觉超敏。
如前述的药物，所述制剂中每制剂单位含绿原酸1-3000mg；所述制剂中每制剂单位含绿原酸1-3000mg；所述制剂单位为：每粒、片、包、丸、支或者瓶。
如前述的药物，所述药物制剂中绿原酸的人体使用剂量为1-10mg/kg。
如前述的药物，所述的药物制剂是口服制剂或者注射制剂。
本发明还提供了一种预防或治疗疼痛的药物组合物，其特征在于，它是包括前述药物制剂的药物组合物。
发明人偶然发现，绿原酸可以有效预防和治疗疼痛，尤其是癌性疼痛和骨关节疼痛。因此，本发明提供的绿原酸在制备预防或治疗疼痛的药物的用途，具有很好的产业化价值。
在持续用药情况下，本发明的药物能够有效缓解癌痛和骨关节疼痛，且无毒副作用；可以替代镇痛药物如阿片类药物和非甾体类抗炎药物治疗，避免因长期使用阿片类药物产 生的毒副作用，提高患者的生存质量，具有良好的临床应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1实验例3中各试验组大鼠机械性痛觉超敏缩爪阈值曲线图。
图2实验例3中各试验组大鼠辐射热痛阈值曲线图。
图3实验例3中各试验组大鼠血清中TNF-α表达量柱形图。
图4实验例3中各试验组大鼠血清中IL-1β表达量柱形图。
图5实验例3中各试验组大鼠血清中IL-6表达量柱形图。
图6实验例3中各试验组大鼠脑组织中NE含量柱形图。
图7实验例3中各试验组大鼠脑组织中DA含量柱形图。
图8实验例3中各试验组大鼠脑组织中5-HT含量柱形图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1本发明口服药物制剂处方
1、处方一
绿原酸1000g。
制备方法：无菌称取绿原酸，无菌分装成散剂。
2、处方二
绿原酸1000g、填充剂500g、粘合剂5g。
制备方法：按照处方称取绿原酸、填充剂、粘合剂，制粒，整粒、分装成颗粒剂。
3、处方三
绿原酸1000g、填充剂500g、粘合剂5g、润滑剂3g。
制备方法：按照处方称取绿原酸、填充剂、粘合剂，制粒，整粒，加润滑剂，压片，得片剂。
上述填充剂为甘露醇、乳糖、淀粉、微晶纤维素、糊精当中的一种或几种；粘合剂为羧甲基纤维素钠、PVP；润滑剂为硬脂酸镁、滑石粉、微粉硅胶。
实施例2本发明注射制剂处方
1、处方一
绿原酸1000g。
制备方法(1)：按处方无菌称取绿原酸，无菌分装成粉针剂。
制备方法(2)：按照处方称取绿原酸，溶解于注射用水，过滤除菌，冷冻干燥，灌装，得冻干粉针剂。
2、处方二
绿原酸1000g、支架剂2667g、抗氧化剂67g。
制备方法：按照处方称取绿原酸、支架剂、抗氧化剂，溶解于注射用水，过滤除菌，灌装，冷冻干燥，得冻干粉针剂。
上述支架剂为甘露醇、乳糖、葡萄糖；抗氧化剂为亚硫酸氢钠、维生素、谷胱甘肽、叶酸。
实施例3绿原酸预防或治疗大鼠骨癌痛动物试验
1.试验材料
1.1动物
SD大鼠，雌性，体重180-200g，购于成都达硕实验动物有限公司。
1.2细胞株
Walker鼠患乳腺癌细胞株，购于中国科学院上海生命科学研究院。
1.3药物
绿原酸，批号：171101，含量为99.83％，由四川九章生物科技有限公司制备。
2.试验方法
2.1细胞悬液制备
取SD雌性大鼠2只，腹腔注射癌细胞0.5mL(4×10 4个细胞/μL)后，第7d时收集腹水，以无菌0.01mol/L PBS漂洗细胞3次，调整至4×10 3个细胞/μL的浓度备用。
2.2模型建立
随机取60只SD大鼠，麻醉后在胫骨上段皮肤切开1cm小口，先用10mL注射器针头穿刺打孔，然后换上10μL注射器进入骨髓腔，缓慢注入3μL含3×10 3个Walker鼠患乳腺癌细胞，骨蜡封住针孔，皮肤缝合置，术后置于37℃热板上复温，待其复苏后送回笼中继续饲养，得模型组。另随机取8只SD大鼠，于左侧胫骨上段骨髓腔注入等体积PBS溶液，其余操作同模型组，得假手术组。
术后第10天起，以疼痛行为学为评判标准，筛选出具有机械性痛觉超敏反应和辐射热痛反应的模型组大鼠。
机械性痛觉超敏反应：从术后第10天开始连续测痛，将接触刺激仪细纤维接触大鼠患侧足底中部，在5秒内最大可追加至80g力量，观察大鼠缩爪反应并记录缩爪阈值。每只动物测试5次，两次测试间隔5min。模型组缩爪阈值与假手术组缩爪阈相比差异显著，说明具有机械性痛觉超敏反应。
辐射热痛反应：将大鼠置于玻璃板上，使用热辐射仪照射其患侧足底，每只大鼠术足 底各测试3次，每次间隔5min，记录从照射到缩爪反应的时间，缩爪时间即为其痛阈值。模型组痛阈值与假手术组痛阈值相比差异显著，说明具有辐射热痛反应。
2.3动物给药
将筛选出建模成功的大鼠随机分组，每组8只，分别为绿原酸高剂量组(80mg/kg)、中剂量组(40mg/kg)、低剂量组(20mg/kg)、模型阴性组(N.S生理盐水)以及假手术组8只(N.S生理盐水)。腹腔注射给药，给药体积为0.2mL/10g，一天一次，连续给药15天；模型阴性组和假手术组给同等体积生理盐水。
2.4指标检测
2.4.1疼痛行为学
自给药后第二天起，每次给药前均进行机械性痛觉超敏和辐射热痛考察，记录缩爪阈值和痛阈值。
2.4.2细胞因子
末次给药结束后，从大鼠眼球取血，脱颈处死各组动物。血液标本室温静置20min后用离心，取上清液，用ELISA法测定小鼠外周血血清中TNF-α、IL-1β、IL-6的含量。
大鼠处死后，迅速分离出下丘脑，加高氯酸冰浴匀浆，离心，取上清液，采用HPLC-EC法依法测定(候艳宁，王娜等.孕酮对大鼠吗啡位置偏爱效应及中枢单胺递质水平的影响.中国药理学报，2006，22(8)，980-983)NE、DA、5-HT的含量。
3.统计学处理
所有数据均以
Figure PCTCN2020071345-appb-000001
表示。采用SPSS 11.0软件进行统计处理，t检验分析，P＜0.05认为差异有显著性。
4.试验结果
4.1疼痛行为学
4.1.1机械性痛觉超敏反应
术后所筛选出的模型组，在给药期间与假手术组相比，机械性缩爪阈值具有显著性差异(p＜0.05)，说明胫骨种植造模成功。
绿原酸给药40mg/kg和20mg/kg剂量组在给药后第5-7天起，与模型组相比缩爪阈值有显著性差异(p＜0.05)，尤其40mg/kg剂量组，与假手术组基本一致；说明绿原酸20-40mg/kg的给药剂量，能够显著改善和缓解骨癌产生的机械性痛觉超敏，并呈量效关系。80mg/kg剂量组，机械性缩爪阈值与模型组相比有差异，但无统计学意义(p＞0.05)。具体见表1和图1。
表1.各试验组大鼠机械性痛觉超敏反应缩爪阈值
Figure PCTCN2020071345-appb-000002
Figure PCTCN2020071345-appb-000003
Figure PCTCN2020071345-appb-000004
注：N.S，无添加。
4.1.2辐射热痛反应
绿原酸给药40mg/kg和20mg/kg剂量组在给药后第7天起，与模型组相比辐射热痛阀值有显著性差异(p＜0.05)，以40mg/kg剂量组最为显著，与假手术组基本相当；说明绿原酸20-40mg/kg的给药剂量，能够显著改善和治疗骨癌诱导的辐射热痛觉超敏，并呈量效关系。80mg/kg剂量组，机械性缩爪阈值与模型组相比有差异，但无统计学意义(p＞0.05)。具体见表2和图2。
表2.各试验组大鼠辐射热痛反应痛阈值
Figure PCTCN2020071345-appb-000005
Figure PCTCN2020071345-appb-000006
注：N.S，无添加。
4.2细胞因子
各试验组在给药15天后，绿原酸40mg/kg和20mg/kg剂量组血清中的TNF-α、IL-1β和IL-6表达量均低于模型阴性组，与其相比具有显著性差异(p＜0.05)，80mg/kg剂量组无显著性差异。具体见表3和图3、图4、图5。
表3.各试验组大鼠血清中细胞因子含量
Figure PCTCN2020071345-appb-000007
注：*为与模型阴性组比较p＜0.05，#与假手术组比较p＜0.05。
绿原酸剂量组40mg/kg和20mg/kg大鼠脑组织中NE、DA、5-HT含量，与与假手术组基本一致，无显著差异(p＞0.05)，与模型阴性组相比具有显著性差异(p＜0.05)；80mg/kg剂量组与模型阴性组无显著性差异(p＞0.05)，与假手术组有显著性差异(p＜0.05)。具体见表4和图6、图7、图8。
表4.各试验组大鼠脑组织中NE、DA、5-HT含量
Figure PCTCN2020071345-appb-000008
Figure PCTCN2020071345-appb-000009
注：*为与模型阴性组比较p＜0.05，#与假手术组比较p＜0.05。
5.小结
胫骨种植模型各试验组，在机械性痛觉超敏和辐射热痛指标中，绿原酸20-40mg/kg剂量组与模型阴性组相比具有显著性差异，其中40mg/kg剂量组与假手术组相当，说明了绿原酸能够有效改善和缓解癌性疼痛，并在一定的剂量范围内呈量效关系。
在癌痛发生过程中，细胞因子TNF-α、IL-1β、IL-6起着重要的调控作用，是神经-内分泌-免疫功能系统中重要的调控介质，外界伤害性刺激会增加其表达，含量高低与癌痛程度直接相关。
各试验组中，绿原酸20-40mg/kg剂量组大鼠血清中检测出的TNF-α、IL-1β、IL-6表达量与模型阴性组具有显著性差异，且与假手术组无显著性差异，说明绿原酸能够有效调节TNF-α、IL-1β、IL-6各因子在血清中含量，维持正常水平，预示着绿原酸能够改善 和缓解癌性疼痛，与疼痛行为学的试验结果一致。
脑组织中NE、DA、5-HT是疼痛感受相关细胞生物学途径的重要参与者。绿原酸20-40mg/kg剂量组大鼠脑组织中NE、DA、5-HT含量与与假手术组基本一致，无显著差异，与模型阴性组相比具有显著性差异，说明了绿原酸能够诱导疼痛引起的DA、5-HT表达，降低NE表达；表明绿原酸能够改善和缓解疼痛，与疼痛行为学的试验结果一致。
综上，绿原酸能够有效改善和缓解疼痛，能够用于制备本发明的预防或治疗疼痛的药物或药物组合物。本发明的药物能够有效降低癌症导致的机械痛觉超敏和辐射热痛觉超敏，且无毒副作用；可以替代镇痛药物如阿片类药物和非甾体类抗炎药物治疗，避免因长期使用阿片类药物产生的毒副成瘾作用，提高患者的生存质量，具有良好的临床应用前景。

Claims (10)

  1. 绿原酸在制备用于预防或治疗疼痛的药物或药物组合物中的用途。
  2. 根据权利要求1所述的用途，其特征在于，所述疼痛为癌性疼痛、骨骼肌疼痛、炎性疼痛、神经性疼痛或免疫性疼痛；
    优选地，所述癌性疼痛为神经病理性疼痛、伤害感受性疼痛或慢性疼痛；
    优选地，所述骨骼肌疼痛为骨关节疼痛；进一步优选地，所述骨关节疼痛为膝关节疼痛、踝关节疼痛、腕关节疼痛、肘关节疼痛、肩关节疼痛、髌骨关节疼痛、髋骨关节疼痛、股骨关节疼痛、颈椎和/或腰椎疼痛。
  3. 根据权利要求1所述的用途，其特征在于：所述预防或治疗疼痛，为降低癌症导致的机械性痛觉超敏或辐射热痛觉超敏。
  4. 根据权利要求1所述的用途，其特征在于：所述药物或药物组合物是抑制肿瘤坏死因子α、白介素1β和白介素6的表达的药物或药物组合物。
  5. 根据权利要求1所述的用途，其特征在于，所述药物或药物组合物是调节/提高疼痛引起的5-羟色胺和多巴胺的表达的药物或药物组合物；
    和/或，所述药物或药物组合物是调节/降低疼痛引起的去甲肾上腺素的表达的药物或药物组合物。
  6. 一种预防或治疗疼痛的药物制剂，其特征在于，所述药物是以绿原酸为活性成分、加上药学上可接受的辅料制备而成的药物制剂；
    优选地，所述预防或治疗疼痛，为降低癌症导致的机械性痛觉超敏或辐射热痛觉超敏。
  7. 根据权利要求6所述的药物制剂，其特征在于，所述制剂中每制剂单位含绿原酸1-3000mg；所述制剂单位为：每粒、片、包、丸、支或者瓶。
  8. 根据权利要求7所述的药物制剂，其特征在于，所述药物制剂中绿原酸的人体使用剂量为1-10mg/kg。
  9. 根据权利要求7所述的药物制剂，其特征在于，所述的药物制剂是口服制剂或者注射制剂。
  10. 一种预防或治疗疼痛的药物组合物，其特征在于，它是包括如权利要求6-9任一所述药物制剂的药物组合物。
PCT/CN2020/071345 2019-01-11 2020-01-10 绿原酸在制备预防或治疗疼痛的药物或药物组合物中的用途 WO2020143746A1 (zh)

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